Progress in the Chemistry of Tetrahydroquinolines - Chemical Reviews

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Progress in the Chemistry of Tetrahydroquinolines Isravel Muthukrishnan,† Vellaisamy Sridharan,*,†,‡ and J. Carlos Menéndez*,§

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Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India ‡ Department of Chemistry and Chemical Sciences, Central University of Jammu, Rahya-Suchani (Bagla), District-Samba, Jammu 181143, Jammu and Kashmir, India § Unidad de Química Orgańica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain ABSTRACT: Tetrahydroquinoline is one of the most important simple nitrogen heterocycles, being widespread in nature and present in a broad variety of pharmacologically active compounds. This Review summarizes the progress achieved in the chemistry of tetrahydroquinolines, with emphasis on their synthesis, during the period from mid-2010 to early 2018.

5.1. Formation of the N−C2 and C2−C3 Bonds 5.2. Formation of the N−C2 and C3−C4 Bonds 5.3. Formation of the N−C2 and C4−C4a Bonds 5.4. Formation of the N−C2 and N−C8a Bonds 5.5. Formation of the C2−C3 and C3−C4 Bonds 5.6. Formation of the C2−C3 and C4−C4a Bonds 5.7. Formation of the N−C8a and C4−C4a Bonds 6. Synthesis of 1,2,3,4-Tetrahydroquinolines via the Povarov Reaction 6.1. Two-Component Povarov Reactions 6.2. Three-Component Povarov Reactions 6.2.1. Lewis Acid-Catalyzed Povarov Reactions 6.2.2. Brønsted Acid-Catalyzed Povarov Reactions 6.2.3. Enzyme-Catalyzed Povarov Reactions 6.2.4. ABB′ Povarov Reactions 6.2.5. Miscellaneous Three-Component Povarov Reactions 6.3. Four-Component Povarov Reactions 6.4. Intramolecular Povarov Reactions 6.5. Oxidative Povarov Reactions 6.6. Asymmetric Synthesis of Chiral 1,2,3,4Tetrahydroquinolines via the Povarov Reaction 6.6.1. Reactions Catalyzed by Chiral Phosphoric Acids 6.6.2. Reactions Catalyzed by Chiral (Thio)ureas

CONTENTS 1. Introduction 2. Tetrahydroquinolines in Nature 3. Tetrahydroquinoline-Based Bioactive Compounds 3.1. Tetrahydroquinolines Acting at Chemotherapeutic Targets 3.1.1. Antiviral Tetrahydroquinolines 3.1.2. Antibacterial Tetrahydroquinolines 3.1.3. Antifungal Tetrahydroquinolines 3.1.4. Antiparasitic Tetrahydroquinolines 3.1.5. Anticancer Tetrahydroquinolines 3.2. Tetrahydroquinolines Acting at Pharmacodynamic Targets 3.2.1. Ligands of G-Coupled Protein Receptors (GCPRs) 3.2.2. Ligands of Nuclear Receptors 3.3. Tetrahydroquinolines Acting on Neurons 3.4. Miscellaneous Pharmacologically Active Tetrahydroquinolines 3.5. Tetrahydroquinolines as Pesticides 4. Synthesis of 1,2,3,4-Tetrahydroquinolines by Intramolecular Reactions 4.1. Formation of the N−C2 Bond 4.2. Formation of the C2−C3 Bond 4.3. Formation of the C3−C4 Bond 4.4. Formation of the C4−C4a Bond 4.5. Formation of the N−C8a Bond 5. Synthesis of 1,2,3,4-Tetrahydroquinolines Involving the Generation of Two Bonds

© XXXX American Chemical Society

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DOI: 10.1021/acs.chemrev.8b00567 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 6.6.3. Cobalt-Catalyzed Enantioselective Reactions 6.6.4. Enantioselective Domino Reactions 7. Synthesis of 1,2,3,4-Tetrahydroquinolines Involving the Generation of Three or More Bonds: Miscellaneous Approaches 8. Additional Methods for the Asymmetric Synthesis of 1,2,3,4-Tetrahydroquinolines 8.1. One-Bond Formation 8.1.1. Formation of the N−C2 Bond 8.1.2. Formation of the C2−C3 Bond 8.1.3. Formation of the C3−C4 Bond 8.1.4. Formation of the C4−C4a Bond 8.1.5. Formation of the N−C8a Bond 8.2. Two-Bond Formation 8.2.1. Formation of the N−C2 and C3−C4 Bonds 8.2.2. Formation of N−C8a and C2−C3 Bonds 8.2.3. Formation of C2−C3 and C3−C4 Bonds 8.3. Formation of Three Bonds 8.4. Deracemization of Tetrahydroquinolines 9. Synthesis of 1,2,3,4-Tetrahydroquinolines by Rearrangement Reactions 10. Synthesis of 1,2,3,4-Tetrahydroquinolines by Construction of the Aryl Ring or Both Rings 11. Synthesis of 1,2,3,4-Tetrahydroquinolines by Partial Hydrogenation of Quinolines 11.1. Racemic Hydrogenations 11.1.1. Partial Hydrogenation with Fe and Ru Catalysts 11.1.2. Partial Hydrogenation with Co, Rh, and Ir Catalysts 11.1.3. Partial Hydrogenation with Ni, Pd, and Pt Catalysts 11.1.4. Partial Hydrogenation with Au Catalysts 11.1.5. Miscellaneous Hydrogenation Reactions 11.2. Asymmetric Hydrogenations 11.2.1. Brønsted Acid-Catalyzed Asymmetric Hydrogenation 11.2.2. Asymmetric Hydrogenation by Rh and Ir Catalysts 11.2.3. Asymmetric Hydrogenation by Ru Catalysts 11.2.4. Asymmetric Hydrogenation by Other Metal Catalysts 11.2.5. Miscellaneous Approaches for the Synthesis of Chiral Tetrahydroquinolines from Quinolines 12. Synthesis of Tetrahydroquinolines with Other Hydrogenation Patterns 12.1. Synthesis of 5,6,7,8-Tetrahydroquinolines by Generation of the Pyridine Ring 13. Functionalization of Tetrahydroquinolines 13.1. N-Functionalization of Tetrahydroquinolines 13.2. Functionalization of Carbon Atoms at the Tetrahydropyridine Ring 13.3. Functionalization of the Aryl Ring 13.4. Synthesis of Complex Heterocycles from Tetrahydroquinolines 13.5. Dehydrogenation of Tetrahydroquinolines 14. Concluding Remarks

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Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments References

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1. INTRODUCTION Nitrogen heterocycles play a key role in chemistry and biology, and they are also extremely important for the pharmaceutical and agrochemical industries. Tetrahydroquinoline (THQ) is a particularly relevant heterocyclic system that is a key structural feature of many natural and unnatural compounds with interesting biological properties. Due to its importance, much effort has been devoted to the development of synthetic methods that give access to the THQ skeleton. In spite of the widespread interest in this heterocycle, it has not received much attention in the review literature, although some space has been devoted to tetrahydroquinolines in reports dealing with more general topics.1−3 The first review dealing exclusively with THQ chemistry appeared in 1996,4 and a specific survey of the synthesis of tetrahydroquinolines and related systems using domino reactions is also available.5 In 2011, we published a Chemical Reviews paper on the chemistry of tetrahydroquinolines, with emphasis on the 1996 to mid-2010 period,6 and now we have made an effort to comprehensively update the literature on the synthesis, reactivity, and applications of tetrahydroquinoline derivatives from mid-2010 to early 2018. Although we highlight the most common system, i.e., 1,2,3,4-tetrahydroquinoline, we have also covered other less usual hydrogenation patterns such as 5,6,7,8-tetrahydroquinoline (Figure 1). Since the present study was conceived as an update of the 2011 one, for a more complete examination of the topic the interested reader is advised to consult both articles.

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Figure 1. Structures of 1,2,3,4-tetrahydro- and 5,6,7,8-tetrahydroquinoline.

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2. TETRAHYDROQUINOLINES IN NATURE A large amount of 1,2,3,4-tetrahydroquinoline-based natural products are known, many of which have shown interesting pharmacological activities. We will limit the present section to compounds for which a significant addition to chemical knowledge has been made in the 2010−2018 period. Tetrahydroquinoline-derived natural products range from simple alkyl derivatives to more elaborate polycyclic structures. Among the former, we will first mention 2-alkyl- and 2-arylalkyl derivatives such as (−)-angustureine 1, (−)-cuspareine 2, (−)-galipeine 3, and (−)-galipinine 4, which were initially isolated from angostura (Galipea of f icinalis, Angostura trifoliata), a Venezuelan shrub-like tree with a variety of medicinal properties (Figure 2).7−9 The structure originally proposed for galipeine 3a was prepared by total synthesis, but it gave slightly different optical rotation and spectral data than the natural product. This discrepancy led to the reassignment of its

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Scheme 1. Overview of the Biosynthetic Pathway of the Benzastatin Alkaloids

Figure 2. 2-Alkyl- and 2-arylalkyl-1,2,3,4-tetrahydroquinoline alkaloids.

structure as the regioisomeric compound 3b, which was synthesized and found to fully match the experimental data for the natural material.10 The more densely functionalized 2-alkenyl-1,2,3,4-tetrahydroquinoline derivative JBIR-73 (compound 5) was isolated from Streptomyces sp. RI18 together with two previously known members of the benzastatin family, namely virantmycin 6 and benzastatin D 7 (Figure 3).11 The benzastatins are derived

Figure 4. Representative 5-alkyl-1,2,3,4-tetrahydroquinoline alkaloids. Figure 3. Structures of representative members of the benzastatin alkaloids.

have shown interesting biological activities.14 Many of these alkaloids contain a terpenic side chain at C-6, and their biosynthesis has been investigated in recent years.15−19 Some members of this family that have been isolated recently include the aflaquinolones (compounds 15−21, Figure 5). Aflaquinolones A and B (18 and 21) were obtained by Gloer and coworkers from a culture of Aspergillus sp. (section Flavipedes; MYC-2048, NRRL 58570), and the same group reported the related aflaquinolones C−G (15−17, 19, 20) from an isolate of the marine Aspergillus sp. SF-5044.20 Scopuquinolone B (22), a diastereomer of aflaquinolone B, was later isolated from the fungus Scopulariopsis sp. and was evaluated for activity against the settlement of larvae of the barnacle Balanus amphitrite, showing promising antifouling activity.21 Additional members of this family were isolated from Aspergillus nidulans MA-143 and include aniduquinolones A−C (23−25), 6-deoxyaflaquinolone F (26), isoaflaquinolone E (27), and 14-hydroxyaflaquinolone E (28).22 Another group of prenylated quinolinone alkaloids, the aspoquinolones A−D (29−32), was isolated from Aspergillus

biosynthetically from geranylated p-aminobenzoic acid derivatives 8. They arise from an unusual cyclization pathway based on a nitrene-transfer reaction catalyzed by Bez-E, a member of the cytochrome P450 family, and having a fused aziridine 9 as a common precursor to indoline-derived alkaloids 10 and tetrahydroquinoline 11 (Scheme 1).12 Eight 1,2,3,4-tetrahydroquinolines bearing long alkyl chains at C-5, exemplified by compounds 12−14 in Figure 4, were isolated from a combined culture of Streptomyces nigrescens HEK616 and Tsukamurella pulmonis TP-B0596. Their structures, including the absolute configuration of compound 13, were determined by a combination of spectroscopic analysis and total synthesis.13 These compounds inhibited the growth of yeast cells by targeting the membrane lipids (see section 3). A family of 3,4-dioxygenated 3,4-dihydro 4-aryl-1,2,3,4tetrahydroquinolin-2-(1H)-ones have been isolated from a variety of plants and marine fungi, and some of its members C


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Figure 5. 4-Aryl-1,2,3,4-tetrahydroquinolin-2-(1H)-one alkaloids and other natural aryltetrahydroquinolines.

nidulans by Hertweck and co-workers,23 and Wang and coworkers reported the isolation from the mycelia of Aspergillus sp. XS-20090B15 of two additional compounds that represented the first examples of prenylated dihydroquinolone derivatives containing an amino acid residue in their C-6 side chain, namely 22-O-(N-Me-L-valyl)aflaquinolone B (33) and 22-O-(N-Me-Lvalyl)-21-epi-aflaquinolone B (34) from the mycelia of Aspergillus sp. XS-20090B15.24 Still in the area of aryl tetrahydroquinoline alkaloids, we will finally mention (+)-tortuosamine 35, an alkaloid isolated from plants of the South African genus Sceletium25 that contains a 5,6,7,8-tetrahydroquinoline framework.26 Many biologically relevant tricyclic alkaloids contain a tetrahydroquinoline core. Among them, a small family of pyrrolo[3,2-c]quinoline derivatives has a particular biological relevance and has inspired much synthetic work. The main representatives of this family are martinellic acid 36 and martinelline 37, novel nonpeptide antagonists of the bradykinin B1 and B2 receptors (Figure 6). These alkaloids were initially isolated from the roots of the tropical plant Martinella iquitosensis, widely distributed in the Amazon basin,27 and have received much attention from synthetic chemists.28,29 Yaequinolone J1 (38) and its diastereomer yaequinolone J2 (39) are tricyclic prenylated quinolinone alkaloids isolated from a strain of Penicillium sp. FKI-2140, which inhibit the growth of the brine shrimp Artemia salina.30 The absolute configuration of

these compounds could not be determined by physical methods and has been assigned only recently by total synthesis,31 thus achieving the first determination of the absolute stereochemistry of a member of the prenylquinolinone class of alkaloids.

3. TETRAHYDROQUINOLINE-BASED BIOACTIVE COMPOUNDS 3.1. Tetrahydroquinolines Acting at Chemotherapeutic Targets

3.1.1. Antiviral Tetrahydroquinolines. Some 1,4-disubstituted 1,2,3,4-tetrahydroquinoline derivatives 40 and the quinolines arising from their aromatization were evaluated for their antiviral properties against the human immunodeficiency virus (HIV) by Bermejo and co-workers (Figure 7). Although the aromatic compounds were generally superior, some of the tetrahydroquinolines displayed activity in the recombinant virus assay (RVA).32 Several N-substituted tetrahydroquinoline derivatives (compounds 41−45)33−36 have exhibited potent activities as allosteric inhibitors of the HIV-1 reverse transcriptase and also had good anti-HIV-1 activities. These compounds can thus be regarded as non-nucleoside reverse transcriptase inhibitors (NNRTIs), an increasingly important class of antiviral agents. 3.1.2. Antibacterial Tetrahydroquinolines. Several fused tetrahydroquinoline derivatives have been identified as having antibacterial properties. Compounds 46, arising from Povarov D


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Figure 8. Representative antibacterial tetrahydroquinolines.

substituents.39 Compounds 48, which are fluorescent because of the presence of the anthracene unit, were investigated for bacterial fluorescent imaging, although with negative results. On the other hand, the corresponding aromatic quinoline derivatives were useful in the detection of both Gram-positive and Gram-negative bacteria, even at sub-μM concentrations, although their mode of binding was not identified.40 3.1.3. Antifungal Tetrahydroquinolines. As mentioned in section 2, a total of eight 5-alkyl-1,2,3,4-tetrahydroquinolines were isolated from a combined culture of Streptomyces nigrescens HEK616 and Tsukamurella pulmonis TP-B0596 (Figure 9). Figure 6. Representative tricyclic alkaloids contain a tetrahydroquinoline core.

Figure 9. Representative antifungal tetrahydroquinolines.

These compounds inhibited the growth of yeast cells, probably by targeting the membrane lipids exemplified by compound 49.13 The related 1-alkyl-1,2,3,4-tetrahydroquinolines 50 were also studied, but showed no activity as antifungals. In contrast, the (±)-trans-N-alkylperhydroquinolines 51 showed a high antimycotic activity, which was comparable to the one found for the widely used antifungal clotrimazole.41 Other tetrahydroquinolines with interesting antifungal properties include compounds 52, one of which showed a MIC value of 13.75 μg/mL against Cladosporium cladosporoides,42 and 53, with a moderate activity against a panel of clinically important fungi, including yeasts, hialohyphomycetes, and dermatophytes.43 3.1.4. Antiparasitic Tetrahydroquinolines. Some 2,4diaryl-1,2,3,4-tetrahydroquinoline derivatives with general structure 54 showed selective toxicity against Trypanosoma cruzi epimastigotes and amastigotes, including a strain expressing β-galactosidase, and also against Leishmania chagasi promastigotes. The presence of the C-3 methyl substituent was found to be important for the activity of these compounds

Figure 7. Representative antiviral tetrahydroquinolines.

reactions, were separated into their individual diastereomers and enantiomers and studied for antibacterial activity (Figure 8). The conclusion was that the exo isomers were more active than their endo counterparts, although most compounds showed only moderate potency.37 Some related Povarov products showed antimycobacterial activity,38 which was particularly pronounced for compounds 47, bearing carbazolyl or dibenzofuranyl E


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(Figure 10).44,45 Another family of tetrahydroquinoline-derived compounds with structure 55 has been tested against several

cytotoxicity toward a panel of human cancer cell lines and the ability to induce apoptosis on Hep3B human carcinoma cells. A subsequent experiment with a thymic nude mice xenograft confirmed its antitumor activity.48 1-Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines 58 were identified as antitumor agents targeting the colchicine site on tubulin.49 This work was later extended to 1-heteroaryl-6methoxy-1,2,3,4-tetrahydroquinoline derivatives such as compounds 59 and 60, which inhibited the binding of colchicine to tubulin and exhibited GI50 values in the nanomolar range in cellular assays. They also showed activity against a cell line that overexpresses the P-glycoprotein efflux pump, one of the main factors leading to anticancer drug resistance.50 A series of cis-2,4-diaryl-r-3-methyl-1,2,3,4-tetrahydroquinolines showed cytotoxic effects on cellular lines of human breast cancer. Selected compounds, such as 61, were further studied and showed synergistic effects in combination with established anticancer drugs such as paclitaxel and gemcitabine.51 A similar library of compounds bearing a 6,7-methylenedioxy substituent (compounds 62) was later synthesized based on their structural analogy to podophyllotoxin, and they showed cytotoxicity in U937 and HeLa cell lines.52 1-Arylsulfonyl-1,2,3,4-tetrahydroquinolines, most notably compound 63, showed good cytotoxicities on K562 cells.53 Almost simultaneously to this report, another group proved that the inclusion of a N-hydroxyacrylamide side chain in the same framework (e.g., compound 64) led, not unexpectedly, to histone deacetylase inhibitors due to coordination of the hydroxamic acid unit with the Zn2+ cation in the active site of the enzyme. These compounds were shown to suppress the growth of prostate cancer cells.54 Regarding fused tetrahydroquinoline derivatives, furo[3,2c]tetrahydroquinolines 65 were tested for their ability to inhibit cellular proliferation, finding IC50 values in the 2.5−16.7 μM range. The most active compound of the series induced mitochondrial murine apoptosis in C6 glioma cells by upregulating the expression of Bax and caspases 3 and 9, and by

Figure 10. Representative antiparasitic tetrahydroquinolines.

relevant protozoal infections. Two of these compounds showed moderate growth inhibition of Plasmodium falciparum and a good selectivity index. Almost all compounds were moderately active against Trypanosoma cruzi, the etiologic agent of Chagas disease, but not against Trypanosoma brucei rhodesiense, which causes Africal trypanosomiasis (sleeping sickness). Finally, two of the compounds showed moderate growth inhibition toward Leishmania donovani.46 3.1.5. Anticancer Tetrahydroquinolines. 1-Acyl-2-benzamido-1,2,3,4-tetrahydroquinolines 56 were identified as potent inhibitors of the lipopolysaccharide (LPS)-induced transcriptional activity of the NF-κB factor, which is involved in many processes, including the regulation of cellular growth and apoptosis (Figure 11). Some of these compounds showed sub-micromolar activity against a variety of human cancer cell lines.47 A small library of enantiomerically pure 2-alkyl-1,2,3,4tetrahydroquinolines was prepared by asymmetric hydrogenation of the corresponding aromatic quinolines. These compounds were inspired by the structure of angustureine 1 (Figure 2), an alkaloid from the bark of the Venezuelan shrub Galipea off icinalis (angostura), mentioned in section 2, and some of them showed interesting anticancer properties. In particular, 1,2,3,4-tetrahydroquin-8-ol 57 showed a good

Figure 11. Representative anticancer tetrahydroquinolines. F


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Figure 12. Representative tetrahydroquinolines with activity as ligands of G-coupled protein receptors (GCPRs).

σ1/σ2 selectivity. This is a class of receptors that were initially proposed to belong to the opioid family but that are now known to be unrelated and that are relevant to the treatment of a number of diseases, including depression. The best compound was 75, and its activity was shown to reside in only one of its four possible stereoisomers.65 The G protein-coupled estrogen receptor (GPER-1, GPER30) is a transmembrane receptor that specifically binds natural and unnatural estrogens, but not other steroidal hormones, and is able to regulate the physiological events usually associated to estrogen action. Furthermore, GPER-1 expression is associated with the progression of female reproductive cancer.66 In this context, the fused tetrahydroquinolines 76 and 77 were found to activate GPER-1 with an affinity similar to that found for the endogenous ligand 17β-estradiol, but they showed no response on the estrogen receptor α.67 Similarly, a series of iodosubstituted tetrahydro-3H-cyclopenta[c]quinolines, represented by 78 and 79, was synthesized as potential targeted imaging agents for GPER-1. After radiolabeling with 125I, these radiotracer ligands allowed performing in vivo biodistribution experiments in mice that proved that they were transported into tumors, as well as into the adrenal gland and reproductive organs.68 3.2.2. Ligands of Nuclear Receptors. 3.2.2.1. Androgen Receptor Modulators. Nonsteroidal selective androgen receptor modulators (SARMs) are potentially interesting for the treatment of osteoporosis, since they may show osteoanabolic activity without the virilizing effects of steroidal androgens. Some fused tetrahydroquinolines were proposed as SARMs on the basis of a previously proposed four-point pharmacophore model. These studies led to the conclusion that a hydroxyl group in the tetrahydroquinoline C-2 side chain was essential for androgen receptor (AR) binding and a nitro group at C-6 was essential for agonistic activity (compound 80). Interestingly, a simple replacement of the nitro with a cyano led to an antagonist (compound 81).69,70 In an attempt to improve aqueous solubility, the same group identified analogues 82 as interesting

down-regulating Bcl-2.55 The somewhat related, cis-fused tetrahydrochromeno[4,3-b]quinolines 66 exhibited significant antiproliferative activity against MCF-7 breast cancer cell lines.56 Some 5,6,7,8-tetrahydroquinolines and their fused derivatives have also been studied as anticancer agents. Some examples include the 3-cyano derivatives 67,57 the corresponding Nacylthioureas 68,58 and fused systems 69.59,60 3.2. Tetrahydroquinolines Acting at Pharmacodynamic Targets

3.2.1. Ligands of G-Coupled Protein Receptors (GCPRs). Derivatives of the 2-acylaminomethyl-1,2,3,4-tetrahydroquinoline scaffold were designed as MT2 melatonin receptor agonists from previously known N-anilinoethylamide ligands, whose chain was conformationally constrained to mimic the bioactive conformation of melatonin. The best compound of this library (UCM1014, 70), reported in 2015, was the most potent MT2-selective full agonist known at that time, with picomolar MT2 binding affinity and more than 10,000-fold selectivity over the MT1 receptor (Figure 12).61 Later, the same group developed another family of melatonin receptor ligands, derived from a tetrahydroquinoline scaffold bearing an acylated amino substituent at C-3 (e.g., compounds 71 and 72).62 Compounds behaving as μ-opioid receptor (MOR) agonists and δ-opioid receptor (DOR) antagonists are expected to have a good analgesic profile, since they should retain the MORmediated analgesia while simultaneously displaying reduced tolerance and dependence. Compound 73 is a member of a library of peptidomimetic tetrahydroquinoline derivatives designed with this purpose, which was equipotent with morphine as an analgesic and was proposed as a promising lead compound.63 In subsequent studies, the same group explored the introduction of heteroatoms in the C-6 side chain and identified compounds (e.g., 74) that improved the overall MOR agonist/DOR antagonist profile of compound 73.64 Some hexahydro-2H-pyrano[3,2-c]quinoline derivatives were identified as potent antagonists of the σ1 receptor, with a high G


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for the treatment of inflammatory diseases because of its role in the regulation of interleukin (IL)-17 and other pro-inflammatory pathways. Starting from an N-sulfonyl-1,2,3,4-tetrahydroquinoline high-throughput screening hit, structure−activity relationship (SAR) exploration led to the conclusion that the presence of benzamide substituents at C-7 (e.g., compound 87) leads to improved RORc inverse agonist potencies.76,77 Additional work allowed the discovery of biaryl derivatives such as 88 as additional RORc inverse agonists (Figure 14).78

AR agonists, while hetero analogues of 80 bearing oxygen and nitrogen atoms at the five-membered ring showed decreased activity.71 Owing to the potential toxicological risks associated to the nitro group, an effort was made to replace it by other substituents, and these studies revealed that it was possible to switch the cyanotetrahydroquinolines from antagonists into agonists by manipulation of the C-2 side chain, as shown in compounds 83 (Figure 13).72

3.3. Tetrahydroquinolines Acting on Neurons

Some representative THQs acting on neuronal targets and potentially useful for the treatment of neurodegenerative diseases and other neuronal disorders are summarized in Figure 15. In patients with Alzheimer’s disease, cerebral cholinergic pathways are compromised, and the resultant cholinergic deficit contributes to cognitive impairment. On the other hand, acetylcholinesterase is commonly associated with β-amyloid plaques and neurofibrillary tangles. Based on this “cholinergic hypothesis”, many acetylcholinesterase inhibitors have been developed, and three of them are on the market for the symptomatic treatment of early Alzheimer’s disease. Some tetrahydroquinoline derivatives, including representative compounds 89 79 and 90, 80 have been shown to inhibit acetylcholinesterase with weak affinity. The homopentameric α7 subtype of nicotinic acetylcholine receptors is considered a promising target for maladies characterized by cognitive impairments such as Alzheimer’s disease, and also for the treatment of inflammation and neuropathic pain. 4-(4-Bromophenyl)-3a,4,5,9b-tetrahydro3H-cyclopenta[c]quinoline-8-sulfonamide 91 has been identified as an allosteric positive modulator of this receptor,81,82 and electrophysiological characterization showed that its activity was due exclusively to the (+)-(S,R,S) enantiomer (compound 92).83 It has been shown that the very effective channel activation achieved with this and related compounds is due to their ability to interact with two different sites of the receptor.84 Cells of the central nervous system contain the postsynaptic density (PSD) protein. Shank is the central scaffolding protein of this complex, and it has important roles in neuronal morphology and signaling, and also in synaptic plasticity. Shank mutations have been reported in several neuronal disorders, including typical autism and Asperger syndrome. The linking of Shank to the PSD complex is done through its PDZ domain, and some 2-carboxytetrahydroquinolines, such as 92, have been identified as nonpeptide inhibitors of the Shank3 PDZ domain.85 The overproduction of nitric oxide in the central nervous system has been associated with the spinal transmission of pain, migraine, and chronic tension-type headaches and also with neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Consequently, the inhibition of neuronal nitric oxide synthase (nNOS) has potential therapeutic value. Selectivity for nNOS is important because of the presence of other NOS isoforms in many other tissues. In this context, several potent and selective nNOS inhibitors were identified among a library of 1,2,3,4-tetrahydroquinolines bearing a 6substituted 2-thienylamidino group so that they mimic the endogenous substrate, L-arginine.86 Among them, compound (R)-93 showed excellent potency and selectivity for nNOS; it was able to reverse thermal hyperalgesia in the Chung model of neuropathic pain and reduce tactile hyperesthesia in a rat model of dural inflammation related to migraine pain.

Figure 13. Representative tetrahydroquinolines acting as selective androgen receptor modulators (SARMs).

3.2.2.2. Glucocorticoid Receptor Ligands. Glucocorticoids are widely employed in the treatment of inflammatory and autoimmune disorders, but their long-term use may have many serious side effects, including myopathy, osteoporosis, hypertension, and diabetes. For this reason, research into nonsteroidal ligands of the glucocorticoid receptor is important, and some 6aryl-1,2,3,4-tetrahydroquinolines, most notably indolyl derivatives such as compounds 84 and 85, have shown promise in this area (Figure 14).73 Subsequent work allowed establishing

Figure 14. Representative tetrahydroquinolines acting as modulators of the glucocorticoid and retinoid nuclear receptors.

additional structure−activity relationships, including the discovery that the presence of a C-3 hydroxy substituent (compound 86) improves the selectivity for the glucocorticoid receptor with regard to other nuclear hormone receptors,74 some of them being orally available.75 3.2.2.3. Retinoid Receptor Ligands. The nuclear receptor known as retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) has emerged as a promising target H


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Figure 15. Representative tetrahydroquinolines active on neuronal targets.

The BKCa channel, the large-conductance calcium-activated potassium channel, is a regulator of neuronal excitability and synaptic transmission. Cyclopenta[c]quinolines bearing a 6carboxy substituent were shown to be potent BKCa agonists, and one of them (compound 94) was shown to depress the spontaneous neuronal discharges in an electrophysiological model of migraine.87 Neurotrophic factors (NTFs) are peptides or small proteins that stimulate the growth, survival, and differentiation of neurons. In the mature nervous system, these factors promote the survival of neurons, induce synaptic plasticity, and modulate the formation of long-term memories. The pharmacological screening of a library of tetrahydroquinolines led to the identification of some of them (exemplified by compound 95) as neurotrophic agents (Figure 15).88 3.4. Miscellaneous Pharmacologically Active Tetrahydroquinolines

Plasma cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl esters from the atheroprotective highdensity lipoprotein (HDL) to the proatherogenic low- and verylow-density lipoproteins (LDL, VLDL). It is, therefore, an interesting target for reducing the progression of atherosclerosis. Torcetrapib 96 reached phase III trials, but its study was discontinued due to off-target toxicity.89 More recently, a series of tetrazole torcetrapib analogues (compounds 97) have been synthesized, some of which induced a significant and robust HDL increase in a mouse transgenic model and showed good pharmacokinetic properties (Figure 16).90 Sirtuins are a family of NAD-dependent histone deacetylases that are implicated in a large number of metabolic pathways that regulate, among other processes, cellular differentiation, gene silencing, and DNA repair and thus have a significant impact on age-related diseases, including diabetes, cancer, and neurological disorders. The complex fused tetrahydroquinoline derivatives 98 have shown activity as sirtuin-2 inhibitors.91 Factor VIIa is the key enzyme that initiates the coagulation cascade, and therefore its inhibitors are anticoagulants. Optimization of a screening hit derived from 6-amidino1,2,3,4-tetrahydroquinoline led to BMS-593214 (99), a potent inhibitor of Factor VIIa with good selectivity toward other coagulation factors and that showed antithrombotic activity in a rabbit arterial thrombosis model.92 Some tetrahydroquinoline derivatives, such as compound 100, have been proved to afford protection to hepatocytes from toxicity induced by intra-

Figure 16. Miscellaneous pharmacologically active tetrahydroquinolines.

peritoneal injection of CCl4, as found after measuring several hepatic biochemical parameters, namely SGOT, SGPT, SALP, and bilirubin.93 Fused tetrahydroquinoline derivatives 101 behave as oxygen radical scavengers, in some cases showing better activity than commonly used antioxidants such as ascorbic acid and BHT.94 3.5. Tetrahydroquinolines as Pesticides

Aspernigerin 102 is a natural product originally isolated from a Aspergillus niger strain, and it has shown promising insecticidal, herbicidal, and fungicidal activities.95 Based on this lead, a number of analogues have been constructed by replacing one of the 1,2,3,4-tetrahydroquinoline groups with another moiety such as an aromatic amine (compounds 103)96 or a pyrazole ring (compounds 104,97 which are also antifungal) (Figure 17). This strategy afforded some compounds with improved I


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Figure 17. Representative tetrahydroquinolines with activity as pesticides.

amine, SOCl2-mediated conversion of the benzyl alcohol to the corresponding halide, and further treatment with a 3-propenyl Grignard reagent. This starting material underwent oxidative cyclization in the presence of palladium(II) acetate, copper(II) bromide, and potassium carbonate in dimethylformamide or tetrahydrofuran to give 2-substituted 1,2,3,4-tetrahydroquinolines 111 in good yields. This method was compatible with the presence of halide functionality and provides a direct access to 2substituted 1,2,3,4-tetrahydroquinolines 111 in up to 86% yield. This approach was later extended to the synthesis of 2substituted 1,2,3,4- tetrahydroquinolines and 1,2,3,4-tetrahydroquinoxaline derivatives 113 with an acetoxy functionality using palladium(II) acetate and phenyliododiacetate as an oxidant in acetic acid at room temperature starting from compounds 112 (Scheme 3).101 The oxidative cyclization

antifungal and insecticidal properties in comparison with the natural product. The control of mosquito populations is of great importance from the point of view of public health. For instance, the incidence of dengue fever has undergone a dramatic rise in many parts of the world associated to the spread of its vector, the Aedes aegypti mosquito, into urban areas. In this context, the fused tetrahydroquinoline derivative golgicide A (105) is of great interest because it is a highly specific, reversible inhibitor of one of the proteins involved in the COPI vesicle transport system, which is necessary for the digestion of blood by female mosquitoes. Following the separation of the exo and endo diastereomers and their resolution into individual enantiomers, the eutomer was identified as compound 106 (Figure 17). Some analogues of this structure, including 107 and 108, showed an activity comparable with that of the reference compound.98 In a similar study, cis-(2R,4S)-109 showed ca. 55 times more activity against mosquito larvae in vivo than its cis-(2S,4R) enantiomer.99

Scheme 3. Generalization of the Pd(II)-Catalyzed Oxidative Synthesis of Tetrahydroquinolines

4. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES BY INTRAMOLECULAR REACTIONS Among the variety of approaches developed for the synthesis of 1,2,3,4-tetrahydroquinolines that will be discussed in this review, intramolecular cyclization reactions deliver 1,2,3,4-THQs by generating just one new bond starting from suitable arylamine derivatives. Such intramolecular reactions may involve the creation of all possible bonds of the dihydropyridine ring, namely the N−C2, C2−C3, C3−C4, C4−C4a, and N−C8a bonds.

occurs more efficiently on substrates with electron-rich substituents than in the presence of electron-withdrawing groups. For 2,3-disubstituted compounds, very high trans diastereoselectivities were observed. In the context of work toward the synthesis of FR900482 and the mitomycins, Trost and co-workers devised a method for the preparation of benzazocine derivatives from allenes 114 via the 8-endo cyclization of a palladium π-allyl complex. However, they obtained 1,2,3,4-tetrahydroquinolines 115 via 6-exo-dig cyclization, in excellent yields and good diastereoselectivities (Scheme 4).102 When, instead of allenes, the same authors used allylic carbonates 116 as starting materials, they again obtained sixmembered 1,2,3,4-tetrahydroquinoline 117 with excellent yields and good diastereoselectivities (Scheme 5).4 Chowdhury and co-workers demonstrated a method for the synthesis of (E)-2-arylmethylidene-N-tosyl/nosyl-1,2,3,4-tetrahydroquinolines 120 through cyclocondensation of aryl iodides 119 with readily available 1-(2-tosylaminophenyl)prop-2-yn-1ols 118, in the presence of PdCl2 as catalyst (Scheme 6).103 The

4.1. Formation of the N−C2 Bond

Zhang and co-workers developed a straightforward method for the synthesis of 2-substituted 1,2,3,4-tetrahydroquinolines 111 with a halide functionality through a Pd(II)-catalyzed oxidative cyclization reaction (Scheme 2).100 The synthetic precursor 110 was prepared from 2-aminobenzyl alcohol by tosylation of the Scheme 2. Pd(II)-Catalyzed Oxidative Synthesis of 2Bromomethyl-1,2,3,4-tetrahydroquinolines

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of the N−CN bond and vicinal addition of the sulfonamide and nitrile groups across the alkene. Che and co-workers employed the commercially available iron catalyst [Fe(F20TPP)Cl] (H2F20TPP = meso-tetrakis(pentafluorophenyl)porphyrin) for achieving the conversion of aryl azides 123 into the corresponding tetrahydroquinolines 124 in moderate to excellent yields and moderate diastereoselectivities via an intramolecular amination (Scheme 8).105

Scheme 4. Synthesis of Tetrahydroquinolines by PdCatalyzed Cyclization of Precursors with a Tethered Allene Moiety

Scheme 8. Iron-Catalyzed Transformation of Aryl Azides into Tetrahydroquinolines Scheme 5. Synthesis of Tetrahydroquinolines by PdCatalyzed Cyclization of Precursors with a Tethered Allyl Carbamate Moiety

This approach was extended to the synthesis of other types of biologically significant nitrogen heterocycles such as indoles, indolines, dihydroquinazolinones, and quinazolinones. Regarding the mechanistic aspects of this transformation, aryl azide 123 was proposed to form an iron-nitrene/imido complex with [Fe(F20TPP)Cl], followed by intramolecular hydrogen atom abstraction to generate a benzylic radical that then leads to C−N bond formation. Recently, Guttroff and co-workers developed additional conditions to achieve the Fe-catalyzed intramolecular C−Hamination of aryl azides. They found that, in the presence of Bu4N[Fe(CO)3(NO)] (TBA[Fe]) in DMF and DCE as cosolvent and under microwave conditions at 120 °C, the azidoarylalkanes 125 furnished mixtures of five- and sixmembered heterocycles in moderate yields (Scheme 9).106

Scheme 6. Synthesis of Tetrahydroquinolines by PdCatalyzed Cyclocondensation of Aryl Iodides with 1-(2Tosylaminophenyl)prop-2-yn-1-ols

proposed reaction mechanism involves oxidative addition of aryl iodide with a Pd(0) complex generated in situ from palladium chloride and triphenyl phosphine. This palladium intermediate activates the alkyne, which then undergoes intramolecular nucleophilic attack by the sulfonamide nitrogen through transaminopalladation, deprotonation by base resulting in a (E)-vinyl palladium species, and a final reductive elimination to furnish the products with E configuration. This regio- and stereoselective method was applicable to a broad class of substrates and furnishes tetrahydroquinolines 120 in moderate to good yields. Douglas and co-workers developed an efficient method allowing the synthesis in excellent yields of the 2,2-disubstituted tetrahydroquinoline 122 via a Lewis acid-promoted intramolecular aminocyanation of alkenes from readily available cyanamide 121 (Scheme 7).104 This transformation may proceed through activation of N-sulfonyl cyanamide group by the Lewis acid B(C6F5)3, followed by intramolecular nucleophilic attack of the alkene to the central cyanamide with cleavage

Scheme 9. Additional Studies on the Synthesis of Tetrahydroquinolines by Iron-Catalyzed Cyclization of Aryl Azides

The ratio of five- to six-membered rings depends on the nature of the substituent, with more acidic C−H bonds leading to the preferential formation of 2,2′-disubstituted tetrahydroquinolines 126. Nevertheless, in most cases the indolines 127 were the major products. Radical clock experiments indicated that this TBA[Fe]-catalyzed transformation did not follow a radical reaction pathway but instead it was characterized by a ligandbased two-electron-transfer event. Liang and co-workers described an efficient and highly regioselective synthetic access to the polysubstituted tetrahydroquinoline scaffold 129/130 through a iodine-mediated reaction starting from aromatic amines bearing a propargyl

Scheme 7. Synthesis of Tetrahydroquinolines by Lewis AcidCatalyzed Intramolecular Aminocyanation of Alkenes

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alcohol side chain 128 (Scheme 10).107 Starting materials substituted at R1 with electron-releasing groups showed slightly

asymmetric synthesis of 3,3,4-trisubstituted dihydroquinolin-2one derivatives 136 via acid-promoted hydrolysis of the Npivaloyl group followed by intramolecular amidation (Scheme 12).109 The reduction of compounds 136 with lithium

Scheme 10. Synthesis of 4-Iminotetrahydroquinolines by Iodine-Mediated Cyclization of Aromatic Amines with a Tethered Propargyl Alcohol Chain

Scheme 12. Synthesis of Tetrahydroquinolines by Intramolecular Amidation

aluminum hydride provided 3,3,4-trisubstituted tetrahydroquinoline derivatives 137 in moderate yields but with excellent enantioselectivities. In a related transformation, the enantiomerically pure compound 138 underwent a ready hydrolytic cyclization in acidic or basic conditions to form tetrahydroquinolinone 139. This was followed by reduction of 139 with borane−THF under reflux condition to provide the chiral 4-methyltetrahydroquinoline 140 in moderate yield (Scheme 13).110

better results than those with electron-withdrawing groups for this transformation, and the presence of a strong electronwithdrawing substituent (acyl) abolished the reaction. 1H NMR data and X-ray diffraction analysis revealed that the major products had an E (trans) relative configuration at the imine CN bond. The same authors further extended the scope of this method by employing anilines 131 and propargyl alcohol-bearing anilines 132 as starting materials (Scheme 11). They observed

Scheme 13. Additional Example of Synthesis of Tetrahydroquinolines by Intramolecular Amidation of an Enantiomerically Pure Precursor

Scheme 11. Generalization of the Synthesis of 4Iminotetrahydroquinolines

a maximum yield of the 2,2-disubstituted tetrahydroquinoline derivatives 133/134 by using 3 equiv of anilines 131 and a good to excellent diastereoselectivity in favor of the E-isomer. Similar chemistry has allowed the regioselective synthesis of pyrano[3,2f ]quinoline and phenanthroline derivatives using molecular iodine as a promoter.108 Park and co-workers synthesized highly enantioenriched tertiary alcohols 135 by (+)-sparteine-mediated lithiation− substitution of o-benzyl-N-pivaloylaniline with various ketones. These compounds were then used as starting materials for the

Reductive cyclizations starting from nitroarenes and leading to tetrahydroquinolines are also well established. Thus, Pedotti and co-workers reported the use of 2-nitrochalcones 141 for the synthesis of 2-substituted 1,2,3,4-tetrahydroquinolines 142 by a one-pot reductive intramolecular cyclization in a hydrogen atmosphere (Scheme 14).111 Benzo[h]tetrahydroquinolines were also obtained in good to excellent yields by this method. Recently, another reductive cyclization sequence, mediated by Zn/AcOH, was also established for the synthesis of 1,2,3,4THQs. Thus, the nitro group present in the ester-substituted L


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Scheme 14. Synthesis of 2-Substituted 1,2,3,4Tetrahydroquinolines by Reductive Cyclization of 2Nitrochalcones

Scheme 17. Synthesis of Spiro-tetrahydroquinolines by an Intramolecular Base-Catalyzed Mannich Reaction

dihydrofurans 143 was reduced into an amine using Zn/AcOH in ethanol under reflux conditions. This was followed by removal of Zn through filtration, and the reaction mixture was then heated to 150 °C in a microwave reactor to afford quinolone derivatives 144 (Scheme 15).112 Scheme 15. Synthesis of Fused Dihydroquinolin-2-(1H)ones by Reductive Cyclization

In closely related work, acyl-substituted dihydrofurans 145 were treated with Zn/AcOH in ethanol under reflux condition. In this case, due to the presence of a ketone function in the starting material, an intramolecular reductive amination took place to generate intermediate imine derivatives B via species A. Subsequent opening of the dihydrofuran ring via acid-promoted hydrolysis of the enol ether afforded imines C. These unstable compounds were reduced in crude form in the presence of NaBH4 in methanol to furnish tetrahydroquinolines 146 in 32− 40% yields and diastereoselectivities up to 71:29 (Scheme 16).

reduced by lithium aluminum hydride in tetrahydrofuran to generate in situ an amino group that underwent intramolecular cyclization with an iminium species arising from the reduction of the lactam carbonyl to afford the fused tetrahydroquinoline derivative 150 in moderate yield. Hydrolytic removal of the chiral auxiliary by treatment with trifluoroacetic acid furnished alcohol 151 in good yield. On the other hand, when the reduction of the nitro group was carried out by catalytic hydrogenation, the resulting amino derivative of 149 was treated with aromatic aldehydes 152 to generate imine intermediates A, which were cyclized via base-induced intramolecular 1,6addition of a carbanion to the imino group. A final removal of the chiral auxiliary with trifluoroacetic acid afforded spiro compounds 153, whose absolute configuration was established by X-ray crystallography. The hexahydro-1H-pyrrolo[3,2-c]quinoline skeleton inherent to the martinelline natural products was prepared in two steps by Comesse and co-workers (Scheme 18).114 The starting N-Cbz β-gem-difunctionalized pyrrolidine 154 was reduced using iron powder in glacial acetic acid at 80 °C to yield tricyclic compound 155 in quantitative yield. Its N-deprotection was performed in acetic acid in the presence of hydrobromic acid and led to the formation of the martinelline-related scaffold 156 in 83% yield. Reiser and co-workers successfully developed an atomtransfer radical addition (ATRA) process between substituted o-nitrobenzyl bromide and styrene derivatives for the synthesis of compounds 157 by irradiating the starting materials with a green light-emitting diode in the presence of 1 mol% of Cu(dap)2Cl. Precursors 157 were then treated with FeCl3/Zn in refluxing DMF−H2O (1:1) to reduce the nitro group to amino, which then cyclized via an intramolecular nucleophilic substitution to afford 2-aryltetrahydroquinolines 158 in good yields (Scheme 19).115

Scheme 16. Synthesis of Fused Tetrahydroquinolines by Reductive Amination

Sen and co-workers developed the synthesis of complex fused and spiro-tetrahydroquinolines in the context of a diversityoriented synthesis project (Scheme 17).113 The starting bicyclic lactam 147 was alkylated with 2-nitrobenzyl bromide 148 in the presence of LDA to yield compound 149 in 80% yield and 98:2 diastereomeric ratio. The nitro group present in 149 was M


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promote the same reaction sequence to deliver tetrahydroquinolines in good to excellent yields.118 Kim and co-workers also described the first intramolecular version of sequences comprising oxidative enamine catalysis and 1,5-hydride transfer/cyclization for the synthesis of tetrahydroquinolines incorporating five- to nine-membered azacycles with moderate to high yields and high diastereoselectivities.119 The same group demonstrated a related Lewis acid-catalyzed 1,5-hydride shift for the synthesis of 3-nitrotetrahydroquinolines 162 from 2-(o-(dialkylamino)aryl)nitroalkenes 161 (Scheme 21).120 Following Lewis acid optimization, these precursors

Scheme 18. Synthesis of Fused Tetrahydroquinolines by Reductive Amidation

Scheme 21. Synthesis of 3-Nitrotetrahydroquinolines via the tert-Amino Effect

Scheme 19. Synthesis of Tetrahydroquinolines by Nitro Reduction/Intramolecular Nucleophilic Displacement

were treated with Sc(OTf)3 in acetonitrile at 80 °C and underwent the same 1,5-hydride shift/6-endo cyclization sequence described in previous cases to afford 3-nitrotetrahydroquinolines in moderate to excellent yields and diastereoselectivities up to >20:1. The same authors achieved a similar transformation, leading to nitrotetrahydroquinolines, using thiourea (10 mol%) as an organocatalyst in toluene at 110 °C.121 Briones and Basarab established the use of Mg(OTf)2 as a Lewis acid catalyst for the synthesis of polysubstituted tetrahydroquinolines 164 through the tert-amino effect, i.e., 1,5-hydride transfer/ring closure, starting from compounds 163 (Scheme 22).122 The 3-amino tetrahydroquinoline-3-carbox-

4.2. Formation of the C2−C3 Bond

Kim and co-workers reported the synthesis of tetrahydroquinolines 160 in high yields, starting from aldehydes 159, via a secondary amine-catalyzed intramolecular tert-amino effect, i.e., a 1,5-hydride transfer followed by enamine-iminium ring closure (Scheme 20). These authors have also demonstrated the first Scheme 20. Synthesis of 3-Formyltetrahydroquinolines via the tert-Amino Effect

Scheme 22. Synthesis of Tetrahydroquinolines Having an αNitroester Function at C-3 through the Lewis Acid-Catalyzed tert-Amino Effect

ylate esters 165, obtained by the reduction of 164, were converted into biologically relevant spirohydantoin derivatives 166 in two steps, namely conversion of the amine into urea by acylation with potassium isocyanate in acetic acid followed by base-mediated ring closure with sodium ethoxide in ethanol (Scheme 23). Recently, a related cyclization reaction was achieved using a thiourea catalyst, and 1,2,3,4-THQs were obtained in good to excellent yields (up to 99%).123 Zhang and co-workers reported a Sc(OTf)3-catalyzed domino 1,5-hydride shift/cyclization reaction of enynes 167 for the synthesis of a variety of heterocycle-fused tetrahydroquinolines 168 in good yields (Scheme 24).124 Morpholine and piperidinefused tetrahydroquinolines were obtained with high diaster-

organocatalytic enantioselective version of the tandem 1,5hydride transfer/ring closure process for the synthesis of enantio-enriched THQs in the presence of a chiral secondary amine catalyst and (−)-CSA, in good yields and with enantioselectivities in the 85−99% range.116 Subsequently, the same reaction was performed under microwave irradiation to give the corresponding THQs in excellent yields.117 Later, a combination of benzylamine and triflic acid was also found to N


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Scheme 23. Transformation of 3-Aminotetrahydroquinoline3-carboxylates into Tetrahydroquinoline-3-spirohydantoins

Scheme 26. Alternative Synthesis of Spirotetrahydroquinolines Using the tert-Amino Effect

Scheme 24. Synthesis of Tetrahydroquinolines with an AllCarbon Quaternary Stereocenter at C-3 Using the tert-Amino Effect

catalysts, Sc(OTf)3 afforded the tetrahydroquinoline derivatives in excellent yields (up to 99%) in mesitylene at 190 °C with moderate diastereoselectivities. Compounds 172 were further treated with NaOMe in methanol to provide the corresponding ring-opened 3-amino-3-carboxy-tetrahydroquinolines bearing amino and carboxylic functionalities. Liang and co-workers employed PtCl2 as a Lewis acid catalyst to promote an intramolecular cyclization process that allowed the synthesis of benzo[a]quinolizidines 174, containing a ringfused tetrahydroquinoline fragment, from 3-aryl-1-(2-(piperidin-1-yl)aryl)prop-2-ynyl esters 173, in moderate to good yields and with moderate diastereoselectivity (Scheme 27).127

eoselectivity, which, on the other hand, was inferior when eightmembered amines or acyclic secondary amines were employed as starting materials. Yuan and co-workers developed an efficient FeCl3-catalyzed stereoselective intramolecular tandem 1,5-hydride transfer/ring closure reaction of compounds 169 for the synthesis of structurally diverse spirooxindole-tetrahydroquinolines 170 in high yields (up to 98%) with good to excellent levels of diastereoselectivity (up to 99:1 dr) (Scheme 25).125 They also

Scheme 27. Synthesis of Benzo[a]quinolizidines Using a 1,3OAc Migration/1,5-Hydride Shift/Cyclization Sequence

Scheme 25. Direct Synthesis of SpirooxindoleTetrahydroquinolines Using the tert-Amino Effect

This domino transformation proceeds through a sequence of 1,3-OAc migration, 1,5-hydride shift, and intramolecular cyclization via intermediates 175 and 176 and was followed by a separate deacylation step with K2CO3 in MeOH. LiCl was used as an additive to enhance the catalytic activity of PtCl2, and the presence of dehydrating agents such as molecular sieves or CaO was shown to increase the yield. Wang and co-workers identified a DDQ-mediated, metal-free intramolecular oxidative cross-coupling reaction for the preparation of dibenzo[af ]quinolizidines 178, containing a ring-fused tetrahydroquinoline system, under mild conditions (Scheme 28).128 The proposed mechanism for this oxidative coupling was hydride transfer from the C1 position of the starting isoquinoline 177 to DDQ to generate an iminium

described a single example of a catalytic asymmetric version of this process in the presence of a chiral BINOL-derived phosphoric acid that gives access to an enantioenriched spirooxindole-tetrahydroquinoline in 95% yield with 94:6 dr and 54% ee. Yuan and co-workers described a Sc(OTf)3-catalyzed intramolecular tandem 1,5-hydride transfer/cyclization reaction for the synthesis of spiro-fused tetracyclic and pentacyclic tetrahydroquinoline derivatives 172 (Scheme 26).126 The (Z)alkylidene azalactones 171 were treated with various triflates, including Zn(OTf)2, CuOTf, Cu(OTf)2, Sc(OTf)3, and other Lewis acids such as NiCl2, FeCl3, Mg(ClO4)2, Ni(OAc)2, and AgNO3 for the synthesis of THQs 172. Among the tested O


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Scheme 28. Synthesis of Dibenzo[af ]quinolizidines by a DDQ-Mediated Intramolecular Oxidative Cross-Coupling Reaction

Scheme 31. Photocatalytic Redox Route to 2-Substituted Tetrahydroquinolines from Selenide Precursors

involving a sequence of reactions that comprises a diastereoselective copper-catalyzed dialkylzinc conjugate addition to 2imino nitrostyrenes 186 in the presence of 5 mol% Cu(OTf)2 and an intramolecular nitro-Mannich reaction promoted by trifluoroacetic acid via intermediate 188 (Scheme 32).131 The

cation, followed by cyclization via an intramolecular electrophilic addition of an enolate generated at the α-carbonyl position to the iminium ion to give the ring-fused tetrahydroquinolines 178. Yan and co-workers reported a KO-t-Bu-mediated cyclization process for the synthesis of the same type of fused tetrahydroquinoline derivatives (Scheme 29).129 Thus, the

Scheme 32. Synthesis of cis,cis-2,3,4-Trisubstituted Tetrahydroquinolines Using a Dialkylzinc Conjugate Addition/Intramolecular Nitro-Mannich Protocol

Scheme 29. Alternative Synthesis of Dibenzo[af ]quinolizidines by a Single-Electron-Transfer Mechanism Promoted by Potassium tert-Butoxide

two-reaction sequence was carried out in one pot, and the rather sensitive synthetic precursors 186 were obtained through the radical nitration of the corresponding 2-iminostyrenes. The Anderson group also demonstrated the diastereoselective synthesis of a series of 3-nitrotetrahydroquinolines 191 through an intramolecular nitro-Mannich reaction (Scheme 33).132 The

synthetic precursor N-2-(ethenylphenyl)tetrahydroisoquinoline 179 in the presence of KOt-Bu in dimethylformamide under reflux conditions underwent cyclization to provide compounds 180 in good yields. A single-electron-transfer mechanism was proposed, based on the observation that radical scavengers significantly inhibited the reaction. This method was further extended to the use of ovinylarylmethylamine derivatives 181 as starting materials, which provided good yields of N-methyl tetrahydroquinolines 182 via 6-endo cyclization and/or N-methyl indolines 183 through 5-exo cyclization (Scheme 30).

Scheme 33. Synthesis of 3-Nitrotetrahydroquinolines by an Intramolecular Nitro-Mannich Reaction

Scheme 30. Synthesis of Tetrahydroquinolines by SingleElectron-Transfer-Promoted Cyclization

2-(2-nitroethyl)phenylamine 189 precursor was treated with aldehydes in ethanol to generate the imine 190, which subsequently reacted with NH4OH to deliver 2,3-disubstituted THQs 191 in high yields and with up to >9:1 transdiastereoselectivity. Saikia and co-workers established an imine-ene cyclization strategy for the diastereoselective synthesis of 2,3-disubstituted 1,2,3,4-THQs. The reaction between o-allylic anilines 192 and aldehydes 193 in the presence of BF3·OEt2 under mild conditions furnished THQs 194 in good yields (up to 95%). The mechanism of the reaction involved the initial formation of imine A from arylamine 192 and aldehyde 193 followed by

The selenide compounds 184 underwent a photocatalytic redox reaction to provide 2-substituted tetrahydroquinolines 185 (Scheme 31).130 The same reaction could be applied to the synthesis of indolines by reducing the length of the alkyl chain of selenide to one carbon. Anderson and Rundell reported a methodology for the synthesis of cis,cis-2,3,4-trisubstituted tetrahydroquinolines 187 P


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deuterium-labeling experiment suggested that the α-hydrogen of the dialkylamine was transferred intramolecularly into the terminal methylene. Thus, the mechanism of the reaction involved an intramolecular ene cyclization of the iminium ion formed between the aldehyde and the dialkylamine with the copper-coordinated terminal alkyne, followed by hydrolysis to give the desired product. Bakthadoss and co-workers successfully established a simple and efficient protocol for the synthesis of substituted tri- and tetracyclic pyrrolo/pyrrolizino quinoline ring system starting from Baylis−Hillman products (Scheme 37).136 Thus, treat-

Lewis acid-mediated intramolecular attack of the alkene to the imine to afford THQs 194 (Scheme 34).133 Scheme 34. Synthesis of Tetrahydroquinolines from α-Allylic Anilines and Aldehydes

Scheme 37. Synthesis of Ring-Fused Tetrahydroquinolines by an Intramolecular [3+2] Dipolar Cycloaddition

4.3. Formation of the C3−C4 Bond

Ray and co-workers disclosed the synthesis of 4-benzylidene-3methylene-1,2,3,4-tetrahydroquinolines 198, containing a bisexocyclic diene fragment, via a Pd-catalyzed intramolecular Heck reaction (Scheme 35).134 The Heck precursors 197 were Scheme 35. Synthesis of 4-Benzylidene-3-methylene-1,2,3,4tetrahydroquinolines by an Intramolecular Heck Reaction

ment of N-allylated aldehyde 201 with N-methyl glycine 202 or proline in acetonitrile under reflux conditions afforded tricyclic pyrrolo[3,2-c]quinoline 203 or tetracyclic pyrrolizino quinolines, respectively, in excellent yields. The reaction pathway that was proposed to take place started with the formation of intermediate A, followed by an intramolecular [3+2] dipolar cycloaddition. The trans relative configuration of the phenyl group and the adjacent ester moiety was due to the trans geometry of olefin 201. This was verified when the same authors extended the methodology to cis-N-allylated aldehydes 204 containing nitrile functionality and obtained the products 205 with cis-stereochemistry (Scheme 38). Continuing with their study of the synthetic applications of Baylis−Hillman adducts, the Bakthadoss group synthesized synthesized in good yield from the corresponding alkynes 195 and 2,3-dibromoprop-1-ene 196. Compounds 197 then underwent intramolecular cyclization upon treatment with Pd(OAc)2, PPh3, and HCO2Na in DMF at 80 °C to provide compounds 198 in good yields via intermediate A. The reaction between N-propargyl-2-aminobenzaldehydes 199 and dialkylamines in the presence of copper(I) iodide and PCy3 afforded 4-(alkylamino)-3-methylene-1,2,3,4-tetrahydroquinoline derivatives 200 in good yields (Scheme 36).135 A

Scheme 38. Intramolecular [3+2] Dipolar CycloadditionBased Synthesis of Ring-Fused Tetrahydroquinolines with Alternative Relative Stereochemistry

Scheme 36. Cu-Catalyzed Reaction between N-Propargyl-2aminobenzaldehydes and Dialkylamines

Q


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tricyclic tetrahydroisoxazoloquinoline scaffolds 207 in good yields via an intramolecular 1,3-dipolar nitrile oxide cycloaddition strategy (Scheme 39).137 The N-allylated amino-

Scheme 40. Synthesis of Ring-Fused Tetrahydroquinolines by a Solid-State Melt Reaction Comprising Knoevenagel and Intramolecular Hetero-Diels−Alder Steps

Scheme 39. Synthesis of Ring-Fused Tetrahydroquinolines by Intramolecular 1,3-Dipolar Nitrile Oxide Cycloadditions

Scheme 41. Previous Reaction with in Situ Preparation of the Pyrazolone Starting Material

aldehyde 206 was treated with hydroxylamine hydrochloride in the presence of 50% sodium hydroxide in ethanol to obtain aldoximes A. After solvent evaporation, these intermediates were treated with N-chlorosuccinimide and triethylamine in carbon tetrachloride at room temperature to furnish non-isolated nitrile N-oxides B that were transformed into compounds 207 in a highly regio- and diastereoselective 1,3-dipolar cycloaddition. The same group also established a related straightforward synthesis of highly functionalized tetrahydroquinolinoisoxazoles in excellent yields (up to 90%) and with high diastereoselectivity via a nitrone formation−intramolecular nitrone 1,3-dipolar cycloaddition reaction cascade.138 Bakthadoss also developed a solvent-free, solid-state melt reaction (SSMR) for the synthesis of tetracyclic octahydropyrazolo[4′,3′:5,6]pyrano[3,4-c]quinolones 210 by melting together at 200 °C Baylis−Hillman derivatives 208 and 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 209. This diastereoand regioselective domino process takes place via an initial Knoevenagel condensation to give intermediate A followed by an intramolecular hetero Diels−Alder reaction (Scheme 40).139 Almost simultaneously, Pandit and Lee described a closely related transformation.140 In a related work, starting from aldehydes 211 and leading to the same framework 214, the pyrazolone derivative was generated in situ from a β-ketoester 212 and phenylhydrazine 213, as shown in Scheme 41.141 Bakthadoss later extended this chemistry to the synthesis of pentacyclic frameworks 217 by using 4-hydroxycoumarin 216 as the starting material, together with the previously employed Baylis−Hillman derivatives 215 (Scheme 42). Xu and co-workers synthesized benzo-fused tetracyclic aziridines 219, bearing a tetrahydroquinoline moiety, in a good yield of 76% by heating the phenyl-conjugated dienyl vinyl azide 218 in toluene at 100 °C (Scheme 43).142 The tetracyclic product was formed through an intramolecular aza-Diels−Alder reaction between the pending diene unit and the in situgenerated 2H-azirine A.

Scheme 42. Extension of the Knoevenagel/Intramolecular Hetero-Diels−Alder Strategy to the Synthesis of Pentacyclic Frameworks

Scheme 43. Synthesis of Tetracyclic Aziridines Bearing a Tetrahydroquinoline Moiety by an Intramolecular HeteroDiels−Alder Reaction

Wan and co-workers reported a transition-metal controlled diastereodivergent synthesis of azido pyrrolo[3,4-c]R


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quinolinones (Scheme 44).143 These compounds were obtained with trans geometry (221) by treating the starting compounds

Scheme 45. Mechanism Proposed To Explain the Isolation of Azido Pyrrolo[3,4-c]quinolinones

Scheme 44. Transition-Metal-Catalyzed Synthesis of Azido Pyrrolo[3,4-c]quinolinones

Scheme 46. Synthesis of Azaspirocyclic Dihydroquinolin-2ones

220 with TMSN3 in acetonitrile at 80 °C in the presence of Mn(OAc)3 as a catalyst and N-fluorodibenzenesulfonimide (NFSI), whereas the use of Cu(ClO4)2/BiPy as a catalyst system and tert-butyl peroxybenzoate (TBPB) as an oxidant provided exclusively the cis-isomer 222 in moderate to good yields. The substituents on the phenyl ring had only minimal effect on the reactivity regardless of their steric effects. The mechanistic studies revealed the formation of LnM-N3 species. Thus, the reaction was proposed to proceed through the oxidation of TMSN3 by high-valent transition metals to produce a free azidyl radical, which then attacks the 1,7-enyne system in 220 to trigger a 6-exo-dig cyclization that leads to the formation of alkyl radical A, followed by cyclization with concomitant loss of N2 to form alkyl radical C, which is intercepted by LnM-N3 species leading to azide transfer with high diastereoselectivity. In the case of the Mn-catalytic system, Mn−N3 probably coordinates with the nitrogen atoms of intermediate C, followed by azide transfer to give the trans-product 221. In the presence of Cu, the steric repulsion between the phenyl and azide groups enables the azide attack from the opposite side, thus providing cis-product 222 (Scheme 45). Shi and co-workers demonstrated the synthesis of CF3substituted azaspirocyclic dihydroquinolin-2-ones 225 from a similar starting material 223, again containing a 1,7-enyne system (Scheme 46).144 Intermediate A was obtained by reacting the enyne 223 with Togni’s reagent 224, used as the trifluoromethyl source, and commercially available TMSN3, used as the azide source, in the presence of copper(I) thiophene2-carboxylate (CuTc, 5 mol%) as the catalyst in refluxing acetonitrile. The intermediate readily rearranged to form a three-membered azirine ring by extrusion of nitrogen to provide CF3-containing azaspirocyclic dihydroquinolin-2-ones in good to excellent yields. The reaction proceeded well irrespective of the identity of the N-protecting group and the electronic nature of the substituent in the aryl ring and alkyne. The azaspirocyclic products 225 were further transformed into synthetically useful furoindoline derivatives and multifunctionalized aziridine compounds.

A variety of 2,3-quaternary fused indolines were synthesized diastereoselectivity in good yields starting from alkynyl tethered oximes and diaryliodonium salts under mild metal-free conditions. This approach was also extended for the synthesis of THQ derivatives 227 and 228. The alkynyl-tethered oxime 226 would initially undergo a selective arylation with a diaryliodonium salt in the presence of potassium hydroxide as base to give nitrone A, which would then experience a regioselective intramolecular [3+2] cycloaddition to deliver intermediate B. A subsequent [3,3]-sigmatropic rearrangement of species B followed by aromatization through isomerization would furnish indoline 227. Alternatively, intermediate B may have undergone a [1,3′]-sigmatropic rearrangement to provide C, which would have given product 228 via a ring-expansion process (Scheme 47).145 4.4. Formation of the C4−C4a Bond

Intramolecular Friedel−Crafts alkylations have been widely employed to generate tetrahydroquinoline rings. Thus, Kouznetsov and co-workers synthesized homoallylamines 230 via the Grignard reaction of aldimines 229 with allyl magnesium bromide or using the Barbier reaction of the same aldimines with allyl bromide in the presence of powdered indium (Scheme 48).146 Compounds 230 were converted into 1,2,3,4-tetrahyS


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Scheme 47. Synthesis of Fused Tetrahydroquinolines from Alkynyl Tethered Oximes and Diaryliodonium Salts

Scheme 49. Synthesis of 1,2,3,4-Unsubstituted 1,2,3,4Tetrahydroquinolines by Intramolecular Friedel−Crafts Alkylation

the exclusive formation of the tetrahydroquinoline products. As an application of their method, the authors also demonstrated the synthesis of bioactive compounds containing tetrahydroquinoline fragments such as 9-nitrojulolidine and 1,5diazaoctahydroanthracene derivatives. Bunce reported that tertiary alcohols 236 underwent intramolecular Friedel−Crafts cyclization to afford 4,4′dimethyltetrahydroquinolines 237 with excellent yields in refluxing chloroform containing bismuth triflate as a Lewis acid catalyst (Scheme 50).149 The same reaction has been described in the presence of FeCl3 as the Lewis acid.150

Scheme 48. Synthesis of 2-(2-Pyridyl)-1,2,3,4tetrahydroquinolines by Intramolecular Friedel−Crafts Alkylation

Scheme 50. Synthesis of Tetrahydroquinolines by Bismuth Triflate-Catalyzed Intramolecular Friedel−Crafts Alkylation

N-Glycosylanilines 238 undergo intramolecular Friedel− Crafts alkylation in the presence of scandium triflate, acting as a Lewis acid, via in situ generated intermediate oxonium ion A to produce N-alkylated tetrahydropyrano[3,2-c]quinolines 239 in moderate to good yields and with full diastereoselectivity (Scheme 51).151 Reductive intramolecular Friedel−Crafts alkylations have also found some use in the synthesis of tetrahydroquinolines. In one

droquinolines 231 by treatment with sulfuric acid at 80−90 °C. The α-pyridyl-substituted tetrahydroquinolines 231 thus obtained, and also the corresponding homoallylamines 230, showed good antifungal activities. The related cyclization was achieved using the combination of AuCl3 and AgOTf as catalysts for the synthesis of dihydrobenzopyrans, tetralins, and tetrahydroquinolines.147 Thibaudeau and co-workers developed a chemodivergent method for the synthesis of β-fluorinated anilines 233 and their cyclization products 1,2,3,4-tetrahydroquinolines 234 or 3methylindolines 235 starting from N-allylanilines 232(Scheme 49).148 These reactions were performed in the HF/SbF5 superacid system, and the outcome of the reaction was found to depend on SbF5 concentration and on temperature. Thus, at low concentrations of SbF5 (3.8 mol%) and low temperatures (−50 °C), compounds 232 undergo hydrofluorination of the olefin moiety to form β-fluorinated anilines 233, whereas at 0 °C and a higher concentration of SbF5 (21.6 mol%), the cyclized 1,2,3,4-tetrahydroquinolines 234 or 3-methylindolines 235 were the main reaction products, formed via intramolecular Friedel− Crafts cyclization. Under these cyclization conditions, an increase in the electronic density on the aromatic ring led to an increase of indoline product formation, but the introduction of the highly electron-withdrawing trifluoromethyl group led to

Scheme 51. Intramolecular Friedel−Crafts Alkylation of NGlycosylanilines

T


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example, compound 240, obtained by Hii using an enantioselective Pd-catalyzed aza-Michael reaction in the presence of a dicationic chiral diphosphine Pd(II) complex, was stereoselectively transformed into tetrahydroquinoline 241 by means of a reductive intramolecular Friedel−Crafts-type alkylation, using sodium borohydride in the presence of magnesium or calcium chloride in ethanol/water (Scheme 52).152 Not unexpectedly, two regioisomers were obtained for the case of the meta-substituted system.

Scheme 54. Synthesis of 4-Ferrocenyl-1,2,3,4tetrahydroquinolines Using an Intramolecular Reductive Friedel−Crafts Alkylation

Scheme 52. Synthesis of a Tetrahydroquinoline Derivative by Reductive Intramolecular Friedel−Crafts Alkylation starting materials 245 followed by treatment with acetic acid in ultrasonic conditions. In a more complex Friedel−Crafts-based process, a highly stereoselective synthesis of 3-azidotetrahydroquinolines 248 from aniline-derived allylic azides 247 was developed by Topczewski and co-workers (Scheme 55).155 Upon treatment Scheme 55. Synthesis of Tetrahydroquinolines by a Domino Allylic Azide Rearrangement/Intramolecular Friedel−Crafts Alkylation

The BET (bromodomain and extra-terminal domain) family of proteins is a promising target for a variety of therapeutic areas. Recently, Potter and co-workers synthesized a small library of tetrahydroquinoline-based BET inhibitors using a closely related cyclization onto a reductively generated acyliminium cation as the key step for the construction of the THQ system (Scheme 53).153 THQ 243 was synthesized starting from compound 242 by generating the new C4−C4a bond, which was further transformed into BET inhibitors 244. Scheme 53. Intramolecular Friedel−Crafts-Based Synthesis of Tetrahydroquinoline Derivatives as Precursors of BET Inhibitors

with a catalytic amount of AgSbF6, compounds 247 underwent a domino process comprising an allylic azide rearrangement followed by the intramolecular Friedel−Crafts alkylation of the aromatic ring to provide 1,2,3,4-THQs 248 with excellent diastereoselectivity. The authors also synthesized 3-azidotetralins and -chromanes using similar reaction conditions. Intramolecular Friedel−Crafts acylations have also been employed for the preparation of tetrahydroquinolines. Thus, Mosberg and co-workers synthesized a series of μ-opioid receptor (MOR) agonistic and δ-opioid receptor (DOR) antagonistic peptidomimetics featuring a tetrahydroquinoline core (compounds 253) in 11 steps from p-toluidine (Scheme 56).64 The alkyl bromides 249, synthesized from p-toluidine in a few straightforward steps, underwent an intramolecular SN2 cyclization in the presence of NaOt-Bu in DMF to form βlactams 250, which rearranged into tetrahydroquinolones 251 under acidic conditions via an intramolecular Friedel−Crafts acylation. The Boc-protected analogues of 251 were subsequently converted into the corresponding imines with (R)(+)-2-methyl-2-propanesulfinamide, the Elman chiral auxiliary, and Ti(OEt)4 and reduced in situ with NaBH4 to give tertbutanesulfinyl-protected amines 252 as single diastereomers. The enantiopure target molecules 253 were prepared in five steps from THQs 252. Fernández, Sierra, and co-workers have studied two different and competitive reaction pathways involving a nucleophilic addition reaction and/or an enolate α-arylation from (2haloanilino)ketones 254 and leading, respectively, to tetrahydroquinolines 255 or 256 (Scheme 57).156 Detailed DFT

Vukićević and co-workers developed a high-yielding reductive Friedel−Crafts process for the synthesis of novel 4-ferrocenyl1,2,3,4-tetrahydroquinolines 246 starting from the corresponding ferrocenoylethylanilines 245 (Scheme 54).154 This method involved the cyclization of an α-ferrocenyl carbenium ion intermediate, generated by sodium borohydride reduction of the U


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Scheme 56. Synthesis of a Tetrahydroquinolin-4-one by an Intramolecular Friedel−Crafts Acylation

Scheme 58. Synthesis of Trisubstituted Tetrahydroquinolines by Reductive Cyclization of Epoxyketimines

Scheme 57. Pd-Catalyzed Cyclization of (2Iodoanilino)ketones

Scheme 59. Synthesis of 2-Indolyl-1,2,3,4tetrahydroquinolines by Hydroarylation/CrossDehydrogenative Coupling

studies supported the formation of a palladaaminocyclobutane intermediate that is a common intermediate for both cases. There are two main factors that influence these processes, namely the length of the chain that attaches the carbonyl to the amino group and the electronic nature of the substituent attached to the nitrogen atom (R). Thus, the formation of 4hydroxytetrahydroquinolines 255 through the nucleophilic addition reaction was favored for the case of shorter chains (two CH2) while longer ones (three CH2) favor the formation of 4-acyltetrahydroquinolines 256 via the enolate α-arylation process. When electron-withdrawing groups were attached to the aniline nitrogen atom (R = CO2Me), the nucleophilic addition pathway becomes slightly disfavored, and the enolate R-arylation reaction is facilitated. This is translated into a small computed barrier energy difference of these competitive reaction pathways that should lead to a mixture of reaction products, as found experimentally. Anderson and Mo discovered an efficient method for the synthesis in excellent yields of trans-α,β-epoxyketimines 258 from the (E)-α,β-unsaturated arylnitrone intermediates 257 in the presence of a CuCl-1,10-phenanthroline catalytic system (Scheme 58).157 These compounds were valuable synthetic precursors, as demonstrated by the preparation of the trisubstituted tetrahydroquinolines 259 by treatment of the corresponding epoxyketimines 258 with sodium borohydride in the presence of BF3·OEt2. Nakamura and co-workers synthesized diversely substituted 2-indolyl-1,2,3,4-tetrahydroquinolines 262 in good to excellent yields by zinc(II) acetate-catalyzed intramolecular hydroarylation−redox cross-dehydrogenative coupling of various Npropargylanilines 260 with indoles 261 (Scheme 59).158 From the mechanistic point of view, it was proposed that activation of the alkyne 260 by Zn coordination allows the formation of a

dihydroquinoline framework via an intramolecular hydroarylation. This intermediate isomerizes to generate an iminium cation that traps the nucleophilic indole 261, yielding the final products 262. Lin and co-workers illustrated a method for the synthesis of 2,3-dihydroquinolin-4-imines 264 from N-propargylanilines 263 via Cu-catalyzed reactions (Scheme 60).159 In this method, Scheme 60. Cu-Catalyzed Synthesis of 2,3-Dihydroquinolin4-imines from N-Propargylanilines

the starting propargylanilines 263 were treated with tosyl azide in the presence of the CuCl and K2CO3 in refluxing dichloromethane to furnish compounds 264 in moderate to good yields. France and co-workers developed a general and efficient method for the synthesis of functionalized pyrrolo[3,2,1ij]quinolin-4-ones 266 in good to excellent yields and very good diastereoselectivities through an indium triflate-catalyzed intramolecular vinylogous Friedel−Crafts annulation starting from indoles 265 (Scheme 61).160 Using this strategy, biologically relevant derivatives of the julodinine alkaloid V


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Scheme 61. Synthesis of Pyrrolo[3,2,1-ij]quinolin-4-ones by an Intramolecular Vinylogous Friedel−Crafts Reaction

Scheme 64. Synthesis of 1,2,3,4-Tetrahydroquinolines or 3,4Dihydro-1H-quinolin-2-ones by Radical Cyclization

led only to recovered starting material, which supports a radical mechanism and rules out nucleophilic aromatic substitution as a competing mechanism. The same group extended this strategy to the double cyclization of 1,4-diaminobenzene derivatives 274 to furnish bis-3,4-dihydro-1H-quinolin-2-one 275 as a single product in 59% yield (Scheme 65).

skeleton (compounds 268) were prepared with trans-diastereoselectivity in excellent yields from 1,2,3,4-tetrahydroquinoline derivatives 267 (Scheme 62). Scheme 62. Synthesis of Benzo[ij]quinolizidines by an Intramolecular Vinylogous Friedel−Crafts Reaction

Scheme 65. Synthesis of Bis-3,4-dihydro-1H-quinolin-2-ones by Double Radical Cyclization

Fagnou and co-workers described the palladium(0)-catalyzed intramolecular arylation of the cyclopropane methylene C−H bonds in compounds 269 to generate 1,4-dihydroquinolines 270 via in situ ring-opening (Scheme 63).161 The optimum Scheme 63. Synthesis of 1,4-Dihydroquinolines by PdCatalyzed Intramolecular Arylation of a Cyclopropane Ring Koolman and co-workers showed that, when an acetone solution of the acrylanilide derivative 276 was subjected to a photochemical [6π]-cyclization by treatment with quartz-glassfiltered UV light from a mercury middle-pressure lamp in a mesoscale tube-based flow reactor, the fused dihydroquinolinones 277 were obtained in good yields (Scheme 66).163 These Scheme 66. Synthesis of Fused Dihydroquinolinones by Photochemical Cyclization of Acrylanilide Derivatives

reaction condition involved the use of a combination of palladium acetate (5 mol%), di-tert-butyl(methyl)phosphine (10 mol%), cesium pivalate (30 mol%), and potassium phosphate (1.5 equiv) in mesitylene at 90 °C for 16 h. The catalytic hydrogenation of 1,4-dihydroquinolines 270 afforded tetrahydroquinolines 271. Taylor and co-workers showed that 1,2,3,4-tetrahydroquinolines and 3,4-dihydro-1H-quinolin-2-ones 273 were accessible via a copper(II)-catalyzed radical cyclization from aniline- and anilide-derived substrates 272, respectively (Scheme 64).162 Control experiments performed for 4-chloro and 3-nitro substrates 272 in the absence of copper(II) 2-ethylhexanoate W


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compounds were further reduced with borane−THF and treated with trifluoroacetic acid to remove the Boc protection to furnish (±)-trans-vabicaserin and related 4,4′-disubstituted tetrahydroquinolines 278 in excellent yields. The photochemical step was shown to tolerate well the presence of substituents on the aromatic ring, as well as on the acrylic moiety. The authors extended this strategy to the synthesis of C4-cyclobutane spiro-tetrahydroquinolone derivatives, albeit in moderate yields. Whiting and co-workers also reported the intramolecular cyclization of suitable N-substituted anilines into the corresponding THQs in the presence of acidic reagents under Friedel−Crafts conditions.164 Lete and co-workers readily prepared substituted 4alkylidene-tetrahydroquinoline derivatives 280 from N-alkenyl-substituted 2-haloanilines 279 via Pd(0)-catalyzed Heck reactions (Scheme 67).165 When nonsubstituted alkenes (R2 =

Scheme 68. Synthesis of Tetracyclic Ring-Fused Tetrahydroquinolines by a Cu(OTf)2-Catalyzed Domino Cyclization Reaction

Scheme 67. Synthesis of 4-Alkylidenetetrahydroquinolines by Intramolecular Heck Reactions

Scheme 69. Synthesis of Tetrahydroquinolines by a Domino Heck−Suzuki Reaction

H) were used, 4-methylenetetrahydroquinolines were obtained together with their isomeric 4-methyldihydroquinolines, but the authors found that the endocyclic product could be avoided by the addition of silver salts such as silver carbonate. If R2 was substituted by an amide moiety such as diethylamines or Weinreb amides, intramolecular cyclization was favored and provided selectively the exocyclic double bond with E geometry. Li and co-workers reported an approach to the stereoselective synthesis of natural product-like tetracyclic tetrahydroquinolines 282, involving the generation of five stereocenters in single step, from easily accessed homopropargylamines 281 by means of a Cu(OTf)2-catalyzed domino cyclization reaction (Scheme 68).166 The products were obtained in high yields and with excellent diastereoselectivities. The reaction sequence that was proposed to explain the formation of 282 started with the intramolecular hydroamination of compounds 281 to give the dihydropyrrole intermediate A, followed by a formal inverseelectron-demand hetero-Diels−Alder reaction between an in situ formed intermediate A and an iminium cation B, arising from an in situ isomerization of the dihydropyrrole A. By applying this protocol, the authors carried out the synthesis of the aglycon of incargranine B using a mixture of hexafluoroisopropanol (HFIP) and 2-propanol as the reaction solvents. Rao and Periasamy also reported a related approach for the synthesis of the tetracyclic compounds 282 starting from Narylpyrrolidine derivatives using 70% aqueous tert-butyl hydroperoxide (TBHP) in the presence of sodium acetate.167 Wilson described a Heck−Suzuki domino reaction for the diastereoselective synthesis of tetrahydroquinolines 284 by treating 2-bromo-N-(3-methyl-1-phenylbut-3-en-1-yl)anilines 283 with aryl boronic acid in the presence of Pd2(dba)3/P(tBu)3 and potassium phosphate (Scheme 69).168 The reaction proceeded through oxidative addition of Pd(0) to bromo compound 283 to generate intermediate A followed by the

insertion into the olefin to produce an alkyl-palladium(II) intermediate B, that then undergoes transmetalation with boronic acid, followed by reductive elimination to afford the final products 284 via the intermediacy of C (Scheme 70). The starting materials 283 were prepared by Grignard addition of 2methylallylmagnesium chloride to the imine generated from 2bromoanilines and aromatic aldehydes. Doucet and co-workers developed a facile synthesis of 4-aryl3-substituted tetrahydroquinolines 287 from N-allyl-N-arylsulfonamides 285 and benzenesulfonyl chlorides 286 using a Scheme 70. Mechanism Proposed for the Heck−Suzuki Domino Reaction

X


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ligand-free Pd-catalyzed domino reaction that involved the successive insertion of an alkene into a Pd−Ar bond and an intramolecular sp2C−H bond functionalization (Scheme 71).169 This chemo- and diastereoselective transformation worked well for a variety of substituents on the aromatic ring, allyl moiety, and benzenesulfonyl group.

Scheme 73. Synthesis of Tetrahydroquinolines by Intramolecular Epoxide Ring Opening

Scheme 71. Synthesis of 4-Aryl-3-substituted Tetrahydroquinolines by a Pd-Catalyzed Domino Reaction

Scheme 74. Synthesis of Tetrahydroquinolines by an Intramolecular Pd-Catalyzed N-Arylation Reaction of Trifluoroacetamides

Koolman and co-workers performed a direct synthesis of spirocyclic substituted 4,4′-cyclobutyl tetrahydroquinolines 289 in a microfluidic flow photoreactor via a [6π] cyclization of an acrylanilide precursor 288 (Scheme 72).163 Scheme 72. Synthesis of Spirocyclic Tetrahydroquinolines by a Photochemical [6π] Cyclization

tetrahydroquinolines 294 in high yield and diastereoselectivity.171 In related work, Š imůnek and co-workers demonstrated a simple procedure for the synthesis of 2-aroylmethylidene1,2,3,4-tetrahydroquinolines 296 from enaminones 295 using the Pd2(dba)3/X-Phos or t-BuX-Phos catalytic systems, with Cs2CO3 as base in toluene or t-AmOH via intramolecular C−N cross-coupling (Scheme 75).172

A regio- and diastereoselective synthesis of bridged benzothiaoxazepine-1,1-dioxides containing an embedded tetrahydroquinoline unit was achieved in three steps from readily available starting materials (Scheme 73).170 The starting N-aryl-2-fluorobenzenesulfonamides were alkylated with trans2,3-epoxycinnamyl alcohol-derived tosylates in the presence of K2CO3 in DMF at 60 °C to give the N-alkyl sulfonamides 290, which underwent an intramolecular epoxide ring-opening in the presence of p-toluenesulfonic acid in toluene at 80 °C to form trans-4-aryl-3-hydroxytetrahydroquinoline derivatives 291. Then, without purification, compounds 291 were further treated with NaH in DMF and thus underwent an intramolecular SNAr reaction at room temperature to afford bridged benzosultams 292 in moderate yields. The synthesis of compounds 292 in enantiomerically pure form was also developed starting from the corresponding enantiopure epoxy tosylate derivative.

Scheme 75. Synthesis of Tetrahydroquinolines by Intramolecular Pd-Catalyzed N-Arylation of Enamines

Ghorai and co-workers developed a two-step method for the synthesis of 3-aryl-4-cyanotetrahydroquinolines 300 starting with the regio- and diastereoselective ring opening of N-tosyl aziridines 298 with the anion derived from arylacetonitriles 297. This was followed by Pd-catalyzed intramolecular N-arylation of intermediates 299 in the presence of Pd(OAc)2, (±)-BINAP, and K2CO3 (Scheme 76).173 2-Bromophenyl γ-amino alcohols 301 were cyclized to pyrrolo[1,2-a]quinolines (benzoindolizines) under Cu catalysis conditions (Scheme 77).174 The reaction proceeds well using CuI/Cu and L-proline as the catalyst system, K3PO4 as the base,

4.5. Formation of the N−C8a Bond

Anderson prepared 1,2-diamines 293 via an aza Henry reaction between nitroalkanes bearing an o-halo-aromatic group and N-pmethoxyphenyl-protected aldimines, followed by Zn/HCl reduction of the nitro group to amine (Scheme 74). The diamines 293 underwent an intramolecular N-arylation in the presence of tetrakis(triphenylphosphine)palladium, potassium carbonate, and toluene at 100 °C to furnish 3-amino-1,2,3,4Y


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the presence of Pd(OH)2 provided enantiomerically pure 1,2,3,4-tetrahydroquinolines 306. Yus and co-workers converted homoallylamine derivatives 307 (n = 1−3) into 2-allyl-substituted heterocycles 308 (five- to seven-membered ring) in the presence of palladium acetate, triphenyl phosphine, cesium carbonate, and toluene at 110 °C (Scheme 79).176 They demonstrated the synthesis of the natural

Scheme 76. Synthesis of Tetrahydroquinolines by Intramolecular Pd-Catalyzed N-Arylation of Sulfonamides

Scheme 79. Synthesis of Tetrahydroquinolines by Intramolecular Pd-Catalyzed N-Arylation of a Primary Amine

Scheme 77. Synthesis of Tetrahydroquinolines by Intramolecular Cu-Catalyzed N-Arylation

and a 1:1 mixture of t-BuOH/H2O as solvent to afford tetrahydroquinolines 302. The ring closure of γ-amino alcohols by intramolecular N- arylation was achieved under microwave or thermal conditions in moderate to good yield. The regioselective cleavage of the aziridine ring in compound 303 with AcOH in dichloromethane followed by saponification of the acetate in the presence of lithium or potassium hydroxide provided amino alcohols 304 (Scheme 78).175 After protection of the alcohol as a silyl ether, a subsequent intramolecular C−N bond formation with Pd2(dba)3, XPhos, and NaOt-Bu in toluene at 110 °C, followed by deprotection of TBS group by TBAF, led to the formation of 1,2,3,4-tetrahydroquinolines 305. Finally, debenzylation by catalytic hydrogenation in methanol in

alkaloid (−)-angustureine 1 from 2-allyl tetrahydroquinolines in two steps, the first of which was N-methylation using paraformaldehyde, sodium cyanoborohdride, acetic acid and methanol. Cross-metathesis of the resulting 2-allyl-N-methyltetrahydroquinoline 309 with cis-3-hexene in the presence of the Hoveyda−Grubbs ruthenium catalyst in dry CH2Cl2, followed by reduction of alkene by Pd/C in methanol under a hydrogen atmosphere, provided (−)-angustureine 1 in 54% yield. Chen and co-workers developed a new palladium-catalyzed picolinamide (PA)-directed iodination reaction of ε-C(sp2)−H bonds of γ-arylpropylamines 310 (Scheme 80).177 Thus, when N-picolinyl-γ-arylpropylamines 310 were treated with 2 equiv of molecular iodine, Pd(OAc)2 as the catalyst, KHCO3 as base and PhI(OAc)2 as oxidant in DMF, the PA-directed ε-iodinated

Scheme 78. Synthesis of Tetrahydroquinolines by Intramolecular Pd-Catalyzed N-Arylation of Secondary Amines

Scheme 80. Synthesis of Tetrahydroquinolines by Intramolecular Cu-Catalyzed N-Arylation of Picolinamides

Z


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PhI(OAc)2, and toluene or HFIP as solvent at 100 °C. Mechanistic studies revealed that this oxalylamide-directed intramolecular C(sp2)−H amination occurred by a PdII/IV catalytic cycle, involving a sequence of C−H palladation, PdII/IV oxidation, and C−N reductive elimination. Bower and co-workers found that the in situ deprotection of Ts-activated N-Boc hydroxylamines 319 in the presence of a Rh catalyst and in a solvent system formed by a trifluoroacetic acid (TFA)/trifloroethanol (TFE) mixture allowed an intramolecular C−H amination to provide tetrahydroquinolines 320 (Scheme 84).181 The C−H amination process was also achieved

products 311 were obtained. These compounds were readily converted into their corresponding 1,2,3,4-tetrahydroquinolines 312 in the presence of CuI and CsOAc in DMSO via an intramolecular C−N aryl coupling with excellent yields. The authors also demonstrated the PA-directed iodination/CuIcatalyzed cyclization sequence for the synthesis of the alkaloid (+)-angustureine 1.178 Shi and co-workers generalized the synthesis of tetrahydroquinolines 314 via formation of the N−C8a bond by dispensing with the need for an ortho-halogen substituent. In their method, the remote C−H bond activation due to the presence of the trifluoromethanesulfonamide group allowed to perform the desired cyclization of compounds 313 using the AgOAc/4,4′-di-t-butyl-2,2′-bipyridine (dtdpy), PhI(OTFA)2 catalytic system (Scheme 81).179 This strategy was also applied

Scheme 84. Synthesis of Tetrahydroquinolines by Intramolecular Rh-Catalyzed N-Arylation of Toluenesulfonamides

Scheme 81. Synthesis of Tetrahydroquinolines by Intramolecular Ag-Catalyzed N-Arylation of Triflic Acid Amides

in the absence of the Rh catalyst in those cases where the starting material had an electron-releasing group at the meta-position, although in lower yields.

5. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES INVOLVING THE GENERATION OF TWO BONDS In addition to the intramolecular approaches discussed in the previous section for the synthesis of THQs involving the generation of one new bond, a considerable number of intermolecular reactions have also been established to access diverse THQs by generating two new bonds in a single operation.

to a double amination of compounds 315 that afforded in a single step compound 316, corresponding to the tricyclic core of the martinelline alkaloid (Scheme 82). Scheme 82. Synthesis of Fused Tetrahydroquinolines by a Double Intramolecular C−H Activation Reaction

5.1. Formation of the N−C2 and C2−C3 Bonds

Sriramurthy and Kwon demonstrated the construction of benzannulated heterocycles such as tetrahydroquinolines, indolines, dihydropyrrolopyridines, etc. via mixed double-Michael domino sequences starting from simple arylamine derivatives 321 bearing two nucleophilic centers and ynones 322, under metal-free conditions (Scheme 85).182 The diphenylphosphiScheme 85. Synthesis of Tetrahydroquinolines by a Michael− Michael Domino Reaction

Palladium-catalyzed intramolecular C−N amination through remote C−H bond activation was also achieved by use of oxalylamide (OA) as the directing group (Scheme 83).180 Tetrahydroquinolines 318 were synthesized by treating phenylpropylamine oxalylamide derivatives 317 with Pd(OAc)2, Scheme 83. Oxalylamide as a Remote Directing Group in PdCatalyzed, C−H Activation-Based Intramolecular Aminations Leading to Tetrahydroquinolines

nopropane (DPPP)-catalyzed reaction between the dinucleophiles 321 and the electron-deficient alkynes 322 delivered excellent yields of diverse heterocyclic compounds via [5+1] annulation, including two examples of THQs 323. Wang and Ready demonstrated a method for the synthesis of tetrahydroquinolines 326 bearing a C-3 allene functionality starting from amino-propargyl silanes 324 and carbonyl compounds 325 through a diphenyl phosphate-catalyzed imino Diels−Alder reaction (Scheme 86).183 These THQs were further functionalized into biologically important complex AA


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Scheme 86. Synthesis of Tetrahydroquinolines Bearing an Allene Functionality at C-3

Scheme 88. Synthesis of Tetrahydroquinolines by an Imine Formation/Intramolecular Aldol Sequence

heterocyclic compounds. This reaction proceeded through imine formation between the amino-propargyl silanes 324 and carbonyl compounds 325, followed by an intramolecular Sakurai reaction with loss of the easily leaving trimethylsilyl group, to furnish the allene-bearing tetrahydroquinolines 326. Hydrazones 327, derived from 2-aminoacetophenones and phenylhydrazine, were treated with aryl aldehydes 328 under acidic conditions to provide 4-hydrazonotetrahydroquinolines 329 in moderate yields (Scheme 87).184 In the presence of BF3−

5.2. Formation of the N−C2 and C3−C4 Bonds

The conversion of suitably substituted benzyl chlorides 335 into 3-substituted fused-tetrahydroquinoline derivatives 336 was achieved under mild conditions in the presence of K3PO4 via an intramolecular aza Diels−Alder reaction (Scheme 89).186 The

Scheme 87. Synthesis of 4-Hydrazonotetrahydroquinolines from o-Hydrazonoanilines

Scheme 89. Synthesis of Tetrahydroquinolines by Intramolecular Hetero-Diels−Alder Reactions of o-Quinone Methides

OEt2, acting as a Lewis acid, intermediate A was formed from the starting materials and underwent imine−enamine tautomerism at the hydrazone moiety to yield B; this was followed by an intramolecular cyclization via an intramolecular Mannich reaction to afford hydrazonotetrahydroquinolines 329. Aryl aldehydes bearing electron-withdrawing groups (-Cl, di-Cl, -Br, -CN, and -NO2) or electron-donating groups at different positions reacted smoothly with hydrazones 327. An aliphatic aldehyde (propionaldehyde) afforded the desired product in a similar yield. trans-2,4-Diaryl-1,2,3,4-THQs 334 were synthesized via a Lewis acid-catalyzed reaction of a derivative of azaflavan-4-ol (2aryl-1,2,3,4-tetrahydroquinolin-4-ol) with several nucleophiles. The 4-hydroxytetrahydroquinoline 333 required as the starting material for this transformation was synthesized from 2′aminoacetophenone 330 and 4-chlorobenzaldehyde 331 in the presence of L-proline, followed by reduction of the carbonyl functionality with sodium borohydride via intermediate 332. A variety of nucleophiles including phenols, naphthols, indoles, and furan were treated with compound 333 in the presence of boron trifluoride etherate to access 2,4-diaryltetrahydroquinolines 334 by displacement of the C-4 hydroxyl substituent (Scheme 88).185

allyl carbamate derivatives 335 were transformed into the quinone methide imine A by dehydrohalogenation under basic conditions. This intermediate subsequently underwent an intramolecular hetero Diels−Alder reaction to afford the desired tetrahydroquinolines 336 in moderate yields. The starting materials 335 were accessed from (2-chloromethylphenyl)carbamic acid allyl ester and alkenes through cross-metathesis reactions in the presence of the Hoveyda−Grubbs catalyst. In an intermolecular example of a similar Diels−Alder strategy involving o-quinone methides, Takanami and co-workers developed an efficient and convenient stereoselective synthetic approach to 2,4-substituted 1,2,3,4-tetrahydroquinolines (Scheme 90).187 This catalytic procedure involves a sequential reaction of 2-aminobenzyl alcohol 337 with styrenes 338 in the presence of Hf(OTf)4 as a catalyst to give a variety of cis-2,4substituted tetrahydroquinolines 339 in good yields and diastereoselectivities. Wang and co-workers synthesized a series of fullerotetrahydroquinolines 341 from N-(o-chloromethyl)aryl sulfonamides 340 and [60]-fullerene via a [4+2] cycloaddition reaction with in situ-generated aza-o-quinone methides in anhydrous chlorobenzene at 120 °C and in the presence of the catalytic system formed by copper oxide and 1,10-phenanthroline (Scheme AB


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Scheme 90. Lewis Acid-Promoted Synthesis of Tetrahydroquinolines from 2-Aminobenzyl Alcohols and Styrenes

Scheme 93. Synthesis of Tetrahydroquinolines by an Intermolecular Aza Michael/Intramolecular Michael Sequence

91).188 This methodology provided a broad substrate scope and excellent functional group tolerance, although the yields obtained were only moderate (20−36%). Scheme 91. Synthesis of Fullerotetrahydroquinolines by Hetero-Diels−Alder Reactions of o-Quinone Methides with Fullerene

lines 346 in good to excellent yields and with diastereoselectivities >99:1. The presence of electron-donating groups at the α,βunsaturated carbonyl compounds 345 led to better yields than the corresponding electron-withdrawing groups. The reaction proceeded through an intermolecular aza Michael/intramolecular Michael domino sequence, with participation of two molecules of 345. The authors also identified suitable reaction conditions for the asymmetric synthesis of tetrahydroquinolines 348 in the presence of the chiral phosphoric acid 347, together with the K3PO4/Mg(OTf)2 combination. As shown in Scheme 94, Shishido and co-workers demonstrated a regioselective synthesis of vinyltetrahydroquinolines 351 and 352 starting from 2-amidoarylmalonates 349

Related transformations could be achieved under photochemical conditions. Thus, the unusual β-lactam derivatives 343 and 344 were obtained from precursor 342 by irradiation in a Rayonet photoreactor equipped with 16 W RPR-3500 UV lamps (broadband 300−400 nm UV source) in 75% aqueous methanol, degassed by an argon purge (Scheme 92).189 In Scheme 92. Synthesis of Fused Tetrahydroquinolines by a Photochemically Induced Hetero-Diels−Alder Reaction

Scheme 94. Pd-Catalyzed Synthesis of Tetrahydroquinolines from 2-Amidoarylmalonates

these conditions, photoprecursor 342 is proposed to form intermediate A, which would undergo competing intramolecular [4+2] cycloaddition to give the tetrahydroquinoline derivative 343 and [4+4] cycloaddition, leading to the bridged azocine derivative 344. Song and co-workers developed a simple and efficient method for the synthesis of 2,3,4-trisubstituted tetrahydroquinolines 346 from readily available starting materials such as Nsubstituted-2-aminoaryl-α,β-unsaturated carbonyl compounds 345 (Scheme 93).190 The reaction proceeded in toluene in the presence of potassium phosphate and benzyltriethylammonium chloride as a phase-transfer catalyst to provide tetrahydroquinoAC


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and 1,4-diacetoxy-2-butene 350 under palladium catalysis.191,192 The nature of the substituents present in the amino functionality decided the regioselectivity. Thus, if strongly electron-withdrawing groups were present, 3-vinyl-substituted tetrahydroquinolines 351 were obtained. On the other hand, 2-vinyl THQs 352 arose from the corresponding compounds 349 bearing electron-releasing substituents. The Pd-catalyst was proposed to form a π-allylpalladium complex with 1,4-diacetoxybut-2-ene 350, which furnished intermediates A or B by reacting with compounds 349 depending upon the nature of the Nsubstituents (R2). Subsequent intramolecular cyclizations delivered the corresponding THQs 351 and 352. The authors extended a similar strategy to the enantioselective synthesis of vinyl tetrahydroquinolines using (S)-BINAP as the chiral ligand with excellent diastereo- and enantioselectivity. Sahani and Liu described that gold-catalyzed [4+2] annulation/cyclization cascades between benzisoxazoles 353 and propiolate derivatives 354 provide quinoline epoxides 355 efficiently. Subsequently, these compounds were cyclized to yield the highly oxygenated bridged tetrahydroquinolines 356 using gold or zinc(II) catalysts, in a transformation that could be performed in one pot (Scheme 95).193 Thus, a mixture of

96).194 The enantioselective synthesis of 2,4-disubstituted tetrahydroquinolines was also achieved by using Boc-protected Scheme 96. Synthesis of Tetrahydroquinolines Initiated by a Rh-Catalyzed Conjugate Addition of Boronic Acids

pinacolboronate with a range of α,β-unsaturated ketones in the presence of [Rh(nbd)Cl]2 as catalyst and either (S,S,R,R)- or (R,R,S,S)-Duanphos as ligand, with cis-diastereoselectivity (>95:5) and excellent enantioselectivity (up to 98% ee). Cheng and co-workers demonstrated a new cobalt-catalyzed C−H/N−H [3+3] annulation of anilides 362 with allenes 363 to provide 1,2-dihydroquinolines 364. One of the synthesized 1,2-dihydroquinolines was further reduced to tetrahydroquinoline 365 in the presence of Pd/C/H2 (Scheme 97).195

Scheme 95. Synthesis of Tetrahydroquinolines Based on a Gold-Catalyzed [4+2] Annulation/Cyclization Cascade

Scheme 97. Synthesis of Tetrahydroquinolines Initiated by a Cobalt-Catalyzed [3+3] Annulation of Anilides with Allenes

benzisoxazoles 353 and propiolates 354 was heated with (PhO)3AuCl/AgSbF6 in hot dichloroethane until complete consumption of the propiolate. Zn(OTf)2 (20 mol%) was then added to this solution, which was heated until complete disappearance of intermediate epoxides 355, yielding compounds 356 bearing aryl (4-XC6H4, X = Cl and Br) and alkyl (R = cyclopropyl and isopropyl) substituents in 62−95% yields. In one of the reactions, corresponding to R2 = cyclopropyl, the quinolin-4-one derivative 357 was obtained as a side product.

The mechanism proposed for the formation of 1,2dihydroquinolines 364 is shown in Scheme 98. Initial ortho C−H metalation of the amide 362 by an active cobalt(III) complex, generated from [Cp*Co(CO)I2], Cu(OAc)2·H2O, and AgSbF6, followed by allene insertion, would furnish intermediate B. Subsequent β-hydride elimination-reductive elimination steps would deliver intermediate C and Co(I). Finally, Co(I) oxidation by the silver ion, followed by deprotonative coordination of N−H to Co(III) and a 1,4addition of N−Co to the diene group, would afford the final product 364. A related Rh-catalyzed four-component reaction was developed for the synthesis of 2-substituted tetrahydroquino-

5.3. Formation of the N−C2 and C4−C4a Bonds

As shown by Marsden and co-workers, the 2-aminophenylboronic ester 358 or the boronic acid 359 underwent conjugate addition with α,β-unsaturated carbonyl compounds 360 in the presence of [RhCl(cod)]2 and KOH, followed by intramolecular condensation, to furnish dihydroquinolines. These intermediates were further reduced by adding an excess of sodium triacetoxyborohydride to afford 2,4-disubstituted tetrahydroquinolines 361 in high yields (up to 96%) and diastereoselectivities (dr = 88:12 to 95:5) in favor of the cis-isomer (Scheme AD


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catalysts (Scheme 100).197 The N-protected (N-trifluoroacetyl, benzoyl, Boc, and CBz) dihydroquinoline scaffolds 373 were

Scheme 98. Mechanism Proposed for the Isolation of 1,2Dihydroquinolines by C−H/N−H Cobalt-Catalyzed [3+3] Annulations

Scheme 100. Synthesis of Tetrahydroquinolines Based on a Cu-Catalyzed Reaction of Anilines and 3-Chloro-3methylbut-1-yne

lines 370 from arylamines 366, carboxylic acid anhydrides 367, allyl alcohol 368, and alcohols 369 in the presence of a rhodium catalyst, AgSbF6, PivOH, and Cu(OAc)2 (Scheme 99).196 The

subjected to epoxidation with m-CPBA for the synthesis of the corresponding THQs 374. A related asymmetric epoxidation was also achieved from a chiral iminium salt, using oxone or tetraphenylphosphonium monoperoxysulfate (TPPP) as the oxidants. The tetrahydroquinoline-based glucocorticoid receptor agonists 380 were synthesized in four steps by Zhi and co-workers (Scheme 101).74,75 The substituted anilines 375 and acetone were heated to 120 °C in a sealed tube in the presence of iodine to provide dihydroquinolines 376, which were submitted to

Scheme 99. Synthesis of Tetrahydroquinolines by a RhCatalyzed Four-Component Reaction

Scheme 101. Synthesis of Tetrahydroquinolines Based on an Iodine-Promoted Reaction between Anilines and Acetone

formation of compounds 370 was proposed to comprise a rhodium(III)-catalyzed C−H bond functionalization via intermediates A and B, leading to the formation of aldehyde C. Its acid-promoted cyclization followed by exchange with alcohol 369 would furnish the final product 370. Chan and co-workers reported the synthesis of dihydroquinolines 373 starting from arylamines 371 and 3-chloro-3-methylbut-1-yne 372 using cuprous chloride and copper powder as AE


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proposed mechanism for this transformation involved Lewis acid activation of cyclopropane derivatives 386 by coordinating with the ester functionality followed by stereoselective opening of the cyclopropane ring at the benzylic position by the bromide ion to generate the corresponding enolate, which further reacted with the nitrosobenzene 387 to provide intermediate A. The electron-donating effect of the alkoxy group aided the cleavage of the N−O bond by forming a reactive iminoquinone-type intermediate, which afforded intermediate B through nucleophilic addition of bromide. B then underwent cyclization through an intramolecular Friedel−Crafts-type alkylation to provide 8-bromo-1,2,3,4-tetrahydroquinolines 388. More recently, Luo and co-workers developed a related Ni/ Al-catalyzed domino process for the synthesis of tetrahydroquinolines 391 starting from cyclopropane-1,1-diesters 389 and arylamines 390 (Scheme 104).202 The cyclopropane-1,1-diester

hydroboration-oxidation to give the hydroxy derivatives 377. These compounds were brominated at C-6 using NBS to obtain compounds 378, and a final Suzuki coupling with indole-6boronic acid 379 provided the target compounds 380. The synthesis of diastereomeric bridged THQs 384 and 385 was achieved using the reaction between arylamines 381 and 2deoxy-D-ribose 382 or glycals 383 catalyzed by montmorillonite KSF or InCl3/InBr3 (Scheme 102).198 In the case of 2-deoxy-DScheme 102. Synthesis of Bridged Tetrahydroquinolines from Anilines and 2-Deoxy-D-ribose or Glycals

Scheme 104. Ni/Al-Catalyzed Synthesis of Tetrahydroquinolines from Cyclopropanes and Nitrosoarenes

ribose 382, nearly 1:1 diastereomeric mixtures of the fused THQs were obtained. On the other hand, the InBr3-catalyzed reaction between arylamines 381 and glycals 383 afforded the products with high diastereoselectivity. The structure of one of the diastereomers, which had been reported incorrectly in the literature, was rectified.199,200 Studer and co-workers developed a MgBr2-catalyzed [3+3]annulation involving donor−acceptor cyclopropanes 386 and nitrosoarenes 387 for the synthesis of 1,2,3,4-tetrahydroquinolines 388 (Scheme 103).201 These authors explored various Scheme 103. MgBr2-Catalyzed Synthesis of Tetrahydroquinolines from Cyclopropanes and Nitrosoarenes

389 undergoes a Ni(II)-catalyzed nucleophilic ring opening with the arylamine 390 to yield intermediate A, which then cyclized to the azetidine derivative B by intramolecular diester αamination. This intermediate underwent ring expansion in the presence of aluminum triflate to afford tetrahydroquinoline derivatives 391 in moderate to good yields. The ring expansion step is facilitated by the fact that cyclopropane-1,1-diesters 389 containing an electron-rich aryl group. Wang and co-workers developed Mn(I)/Ag(I) based relay catalysis for the one-pot domino synthesis of indenoquinoline 394 through a formal [3+2] and [4+2] cyclization reaction of diaryl imines 392 and allenes 393 (Scheme 105).203 This domino process involves the imine-directed ortho-allylic C−H Scheme 105. Synthesis of Indenoquinolines from Imines and Allenes

Lewis acids, including MgCl2, NiCl2, CuBr2, ZnBr2, FeBr3, InBr3, MgI2, and Cu(OTf)2, but none of them provided the expected [3+3]-annulation products. However, the reaction took place in moderate yields in the presence of 2 equiv of MgBr2, which acted as a Lewis acid as well as bromide source, and 0.2 equiv of 3,5-ditert-butyl-4-hydroxytoluene (BHT) as an additive. The AF


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serotonin 5-HT2C receptor, which is involved in the regulation of appetite and is therefore considered as an interesting target to combat obesity.205

activation by the Mn(I)/NaOAc catalyst, followed by a Povarovtype reaction catalyzed by silver triflate. Other Lewis acids such as BiCl3, Sc(OTf)3, Cu(OTf)2, and Zn(OTf)2 led to significant hydrolysis of ketimine 392 to the corresponding amine and ketone. The use of trifluoroethanol as cosolvent also increased the yield of the desired product. A variety of substituted imines, regardless of the electronic nature, at different positions of aryl ring were well tolerated, and the coupling with unsymmetric allenes resulted in a mixture of diastereoisomers with the bulky substituent preferentially positioned trans to the angular methyl group.

5.5. Formation of the C2−C3 and C3−C4 Bonds

The reaction between 2-dialkylaminobenzaldehydes 402 and benzoylacetonitrile under reflux provided the Knoevenagel condensation product, which cyclized through a 1,5-hydride shift (tert-amino effect) to afford 3-benzoyl-1,2,3,4-tetrahydroquinoline-3-carbonitriles 403 (Scheme 108).206The benzoyl Scheme 108. tert-Amino Effect-Based Synthesis of Fused Tetrahydroquinolines from 2-Dialkylaminobenzaldehydes

5.4. Formation of the N−C2 and N−C8a Bonds

2-Fluoro-5-nitrophenyl derivatives 395 reacted with primary amines 396 to afford arylamine coupling products via a domino process comprising SNAr and intramolecular aza-Michael addition, to furnish 1-alkyl-6-nitro-1,2,3,4-tetrahydroquinoline2-acetates 397 in good to excellent yields (Scheme 106).204 The Scheme 106. Synthesis of 6-Nitro-1,2,3,4tetrahydroquinolines by an SNAr/Intramolecular AzaMichael Domino Process

group present in compound 403 was removed by treatment with hydroxylamine hydrochloride to deliver compounds 404, and the nitrile group was hydrolyzed into amide under acidic conditions, leading to the formation of tetrahydroquinolinecarboxamides 405. 3-Aminomethyltetrahydroquinoline derivatives 409 were synthesized in a facile three-step procedure, in order to develop a library of inhibitors of the enzyme semicarbazide-sensitive amine oxidase (SSAO) (Scheme 109).207 The Knoevenagel condensation between carbonyl compounds 406 and malononitrile was carried out under different conditions to provide 2dicyanovinyl-tert-anilines. A cis-diastereoselective cyclization was achieved via the tert-amino effect under microwave-assisted solvent-free conditions or in trifluoroacetic acid at 150−180 °C. The cyclized intermediates 407 thus obtained underwent decyanation in the presence of tributyltin hydride and AIBN in toluene at 80 °C to deliver compounds 408. The remaining cyano group was reduced by treatment with sodium borohydride−nickel chloride in the presence of Boc2O in methanol to provide carbamate derivatives. The deprotection of the N-Boc group was carried out in HCl/EtOAc and provided the target biologically active 3-aminomethyl-1,2,3,4-tetrahydroquinoline derivatives 409. Using microwave irradiation conditions at high temperature in butanol, the 2-dialkylaminobenzaldehydes 410 react with cyanothioacetamide 411 to form 2-vinyldialkylanilines from a Knoevenagel condensation, which further cyclized in situ via the tert-amino effect to give tetrahydroquinolin-3-carbothioamides 412 (Scheme 110).208 These compounds were employed as starting materials for further transformations, and thus they reacted with α-bromoacetophenone to give 3-(1,3-thiazol-2yl)tetrahydroquinolines, again under microwave conditions. The Knoevenagel condensation between o-(tert-amino)benzaldehydes 413 and N-monoalkyl barbituric acids 414 generated intermediate 1-alkyl-5-(2-(tert-amino)benzylidene)

nitro group present in the para position to fluoro substituent facilitated the SNAr reaction. This method worked well for both aliphatic and aromatic amines; however, α-branched amines provided low yields. The starting materials 395 were synthesized from the corresponding aldehydes and ylides via a Wittig reaction. In a similar domino approach based on the combination of intramolecular SNAr and aza-Michael steps, treatment of 1,2- or 1,3-diamines 398 with the fluorinated precursors 399 allowed the one-pot construction of the tricyclic compounds 400 (Scheme 107). This work led to the identification of pyrimidinediazabicyclo[3.3.0]octane derivatives 401 as agonists of the Scheme 107. Synthesis of Fused Tetrahydroquinolines Based on an SNAr/Intramolecular Aza-Michael Reaction

AG


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zaldehydes 417 and isoxazol-5-ones 418 in the presence of ZnCl2 (Scheme 112).210 The reaction was initiated by a Lewis

Scheme 109. Synthesis of 3-Aminomethyl-1,2,3,4tetrahydroquinoline Derivatives

Scheme 112. tert-Amino Effect-Based Synthesis of Spirotetrahydroquinolines from o-Dialkylaminobenzaldehydes

acid-catalyzed Knoevenagel condensation, followed by 1,5hydride shift and cyclization. The products were obtained in good to high yields (up to 97% yield) and with good to excellent diastereoselectivities (up to >95:5 dr). 5.6. Formation of the C2−C3 and C4−C4a Bonds

This strategy will be discussed in detail in section 6, devoted to the Povarov and Povarov-like reactions. 5.7. Formation of the N−C8a and C4−C4a Bonds

Dai and co-workers demonstrated the synthesis of Naryltetrahydroquinolines 422 through reaction between arynes, generated in situ from triflates 420 in the presence of potassium fluoride and 18-crown-6, and β-amino ketones 421 (Scheme 113).211 A range of differently substituted β-amino ketones

Scheme 110. Microwave-Assisted tert-Amino Effect for the Synthesis of Ring-Fused Tetrahydroquinolines

Scheme 113. Synthesis of N-Aryltetrahydroquinolines from Arynes and β-Amino Ketones

barbiturates, which then underwent an in situ domino 1,5hydride transfer/ring closure process to give the spiro derivatives 415/416 in good to excellent yields with 415 as the major diastereoisomer (Scheme 111).209 Wang and co-workers constructed spiroisoxazol-5-one tetrahydroquinoline derivatives 419 from o-dialkylaminoben-

smoothly underwent the tandem reaction to afford the corresponding tetrahydroquinolines 422 with excellent diastereoselectivity. An efficient inverse electron demand aza-Diels−Alder reaction between easily accessible 1-azadienes 423 and arynes generated in situ from compounds 424 was developed by He and co-workers (Scheme 114).212 Using an excess of the aryne component 424, a domino [4+2]/[2+2] double cycloaddition process took place to provide dihydrocyclobutaquinolines 425 in a single step and in 63−82% yield. The reaction was

Scheme 111. Synthesis of Spiro-Ring-Fused Tetrahydroquinolines Using a Knoevenagel/1,5-Hydride Shift/Cyclization Sequence

Scheme 114. Synthesis of Fused Tetrahydroquinolines by Aza-Diels−Alder Reactions of Arynes and Imines

AH


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the formation of the first stereogenic center in the initial allylation process, assuming a stepwise mechanism. A mechanism was proposed for the formation of 1,2,3,4-THQs 428 via cationic intermediates A and B (Scheme 116).

performed using KF in the presence of 18-crown-6 as an additive in acetonitrile at room temperature. The scope of the reaction was examined by varying the electronic and steric properties of both the 1-sulfonyl-1-azadienes 423 and the aryne component 424, finding that the best results were obtained with both electron-withdrawing and -donating substituents at the metaposition of the aryl ring. The reaction stopped at the [4+2] cycloaddition stage by using 1 mol of aryne component 424, and in this case it provided isothiazole dioxide-fused dihydroquinolines in moderate yields.

Scheme 116. Lewis Acid-Catalyzed Povarov Reactions of Allyltrimethylsilanes

6. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES VIA THE POVAROV REACTION The formal [4+2] cycloaddition reaction between N-arylimines, derived from arylamines and aldehydes, and electron-rich olefins under acid catalysis is known as the Povarov reaction, discovered in the 1960s by the Russian chemist L. S. Povarov (Scheme 115). Scheme 115. Two- and Three-Component Povarov Reactions

Glyoxylate and arylglyoxal imines 429, derived from 12aminodehydroabietic acid, underwent hetero-Diels−Alder reaction with cyclopentadiene 430 in the presence of BF3· OEt2 in trifluoroethanol to afford diastereomeric fused naphtho[1,2-f ]quinolines 431 and 432 in moderate to excellent yields (up to 96%) (Scheme 117).226 Similar reaction conditions were Scheme 117. Povarov Reactions of Imines Derived from 12Aminodehydroabietic Acid

In our 2011 review,6 we summarized the main catalysts employed to trigger the Povarov reaction, including Lewis and Brønsted acids and metal-salt related catalysts,, and its synthetic applications. We also discussed in detail the mechanistic aspects of the reaction, which was initially proposed to follow a mechanism involving a concerted [4+2] cycloaddition; later, on the basis of experimental evidence, a stepwise mechanism involving a cationic intermediate was also widely accepted. In recent years, researchers have thoroughly studied the mechanism of the Povarov reaction with the aid of theoretical, and experimental studies.213−220 Glushkov221 and Kouznetsov222 have also previously reviewed the synthetic applications of the Povarov reaction, in addition to overviews by da Silva,223 which partially covered the recent literature, and by Dudley,224 which described the synthesis of natural THQs including angustureine and related alkaloids. In this section, we will update the recent literature on Povarov reactions, in both racemic and enantioselective versions.

also applied to the reaction between arylglyoxal imines 429 and other dienophiles, including ethyl vinyl ether and indene, to form the corresponding [4+2] cycloadducts. In 2014, Molchanov and co-workers employed for the first time fulvenes as dienophiles in the Povarov reaction, using hydroquinone as an additive to minimize fulvene polymerization. Thus, the [4+2] cycloaddition between imines 433 and dimethylfulvene 434 was carried out in the presence of Yb(OTf)3 to obtain the corresponding cyclopenta[c]quinolines 435 in low yields (Scheme 118).227 On the other hand, the imines 433 failed to react with 6-adamantylidene-, tetramethylene-, pentamethylene-, 6-ethyl-6-methyl-, and 6,6diphenylfulvenes. Recently, Radhakrishnan and co-workers reported the synthesis of related compounds in improved yields using Yb(OTf)3 as catalyst in acetonitrile.228

6.1. Two-Component Povarov Reactions

Hilt and co-workers used the reaction between imine 426 and allyltrimethylsilane 427 in the presence of the Lewis acids AlCl3, TiCl4 and BCl3 to determine the order of activity of these compounds as catalysts, with the help of NMR experiments.225 Among the studied Lewis acids, BCl3 showed the highest rate constant, which translates into a half-life time of t1/2 = 1227 s. Based on the rate constants obtained, the authors proposed that BCl3 would be a good platform for the design of an asymmetric version of the Povarov reaction, where the catalyst would control AI


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Scheme 118. Povarov Reactions Employing Fulvenes as Dienophiles

Scheme 120. Trityl Tetrafluoroborate (TrBF4) as an Organocatalyst for the Povarov Reaction

Dobbelaar and Marzabadi first reported the application of the Povarov reaction between imines 436 and exo-glycals 437 for the synthesis of carbohydrate-derived quinoline derivatives 440(Scheme 119).229,230 The initial reaction between imines Scheme 119. Povarov Reactions Employing exo-Glycals as Dienophiles

Scheme 121. Mechanism Proposed for the TrBF4-Catalyzed Povarov Reactions

436 and exo-glycals 437 in the presence of Lewis acids, including Sc(OTf)3, Yb(OTf)3, and Tb(OTf)3, furnished a mixture of diastereomeric glucose−spiroanellated tetrahydroquinolines 438/439 and quinolines 440. Subsequently, the THQs 438/ 439 were transformed into the corresponding quinoline derivatives 440 using MnO2 for the dehydrogenation step. Similarly, several electron-rich dienophiles were combined with the imine obtained from 2,4-O-benzylidene-D-erythrose and p-anisidine, furnishing enantiomerically pure tetrahydroquinolines.231 Guo and co-workers demonstrated the use of trityl tetrafluoroborate (TrBF4) as an organocatalyst for the synthesis of diastereomeric THQ derivatives 443 and 444 via Povarov reactions (Scheme 120).232 Benzylideneanilines 441 and electron-rich olefins such as 3,4-dihydro-2H-pyran or 2,3dihydrofuran 442 reacted in the presence of TrBF4 to deliver the corresponding tetrahydroquinolines 443 and 444 in good to excellent yields, whereas cyclopentadiene and indene under the same reaction conditions gave only traces of the products. A catalytic cycle that accounts for these results is depicted in Scheme 121, and starts with the reaction of imine 441 with the trityl cation to form intermediate A, which subsequently would undergo nucleophilic addition of the electron-rich dienophile 442 to deliver intermediate B. Loss of a trityl cation from B would close the cycle while furnishing the cyclized intermediate

C, and a final [1,3]-hydrogen shift would then afford the final products 443/444. In connected work, Jia and co-workers had previously synthesized hexahydrofuro[3,2-c]quinoline derivatives under radical cation-induced conditions using the commercially available, stable radical cation salt tris(4-bromophenyl)aminium hexachloroantimonate (TBPA+•) as the catalyst.233 A variety of 2-pentafluorophenyl THQ derivatives 447 and 448 were synthesized by treating fluorinated imines, such as pentafluorobenzylidineanilines 445, with 3,4-dihydro-2H-pyran or 2,3-dihydrofuran 446 as electron-rich olefins, using molecular iodine as the catalyst in CF3CH2OH at room temperature (Scheme 122).234 This reaction provides an easy access to pyrano- and furano-fused THQs as a mixture of cis- and transdiastereomers in moderate yields. Under similar conditions, the one-pot, three-component reaction between pentafluorobenzaldehyde, arylamines, and 3,4-dihydro-2H-pyran afforded the same products in comparable yields. The inverse electron demand aza-Diels−Alder reaction between Schiff bases 449, containing a highly electron-donating phenothiazinyl group, and 3,4-dihydro-2H-pyran 450 was achieved under microwave irradiation conditions in the presence of just 1 mol% of molecular iodine to access AJ


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Scheme 125. Povarov Reactions Employing α-Diazo Olefins as Dienophiles

Scheme 122. Iodine-Catalyzed Povarov Reactions

biologically significant 2-phenothiazinyl-substituted THQ derivatives 451 (Scheme 123).235 In the case of imines derived Scheme 123. Additional Iodine-Catalyzed Povarov Reactions, Involving Starting Phenothiazinyl Imines The cycloadducts 457 were subsequently transformed into Zconfigured esters 458 upon treatment with Rh2(OAc)4 in good yields. On the other hand, the E-configured esters 459 were obtained directly from the starting compounds in the presence of [P(t-Bu)2(o-biphenyl)AuNTf2]. The mechanism of this reaction involved an initial formal [4+2] cycloaddition between the diazo species 456 and N-aryl imines 455 to give isolable diazo-containing cycloadducts 457, and the subsequent formation of their metal carbenes from the corresponding Au and Rh catalysts allowed the production of six-/sevenmembered aza heterocycles, including the tetrahydroquinoline derivatives 458 and 459 and tetrahydro-1H-benzo[b]azepines. Wang and co-workers studied the utility of thioureas 460− 463 as co-catalysts of the ethanedisulfonic acid-promoted Povarov reaction between benzylideneanilines and 2,3-dihydrofuran (Figure 18).238 The bis-thiourea macrocycle 460, with multiple and convergent H-bonding sites, was found to be highly efficient to catalyze the Povarov reactions that deliver 1,2,3,4THQs in yields up to 95%. However, the acyclic monothiourea

from electron-rich arylamines (R1 is electron-releasing), the initial THQ product underwent aromatization to deliver the corresponding quinolines. The starting phenothiazinyl Schiff bases 449 were obtained in excellent yields by the microwaveassisted condensation of the corresponding aldehyde and arylamines in MeCN. The [4+2]-cycloaddition reactions between heterodiene 452 and furfuryl vinyl ether 453 were carried out in acetic acid or 2,2,3,3-tetrafluoropropan-1-ol, without any additional catalyst, resulting in 4-furfuryloxy-2-phenyl-1,2,3,4-tetrahydroquinoline 454 in 58 and 65% yields, respectively. In both solvents, the formation of 2-phenylquinoline was also observed (Scheme 124).236 Liu and co-workers demonstrated the reaction of diazo compounds 456 with various N-benzylideneanilines 455 to achieve the diastereoselective synthesis of THQs 457 in the presence of a catalytic amount of triflic acid (Scheme 125).237 Scheme 124. Povarov Reactions Employing Furfuryl Vinyl Ethers as Dienophiles

Figure 18. Thiourea co-catalysts for the acid-promoted Povarov reactions. AK


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analogues 461−463 had little effect on the acid-catalyzed Povarov reaction. Interestingly, oxalic acid supported on powdered marine sponge was found to be an excellent catalyst system for the imino Diels−Alder reaction between N-arylimines and various electron-deficient alkenes, including maleic anhydride and quinones. For instance, the reaction between imines 464 and maleic anhydride 465 furnished the corresponding 1,2,3,4tetrahydroquinolines 466 and 467, where the trans-diastereomer was the major product (Scheme 126).239

Scheme 128. Synthesis of the Anticoagulant BMS-593214 with a Povarov Reaction as the Key Step

Scheme 126. Povarov Reactions Catalyzed by Oxalic Acid Supported on Powdered Marine Sponge

underwent a Povarov reaction with indane 475 in the presence of indium triflate and acetonitrile to give the 1,2,3,4-THQ derivative 476, which was converted into BMS-593214 (99) in three steps. N-Vinylpyrrolidin-2-one is one of the most widely studied dienophiles in the Povarov reaction, and it introduces nitrogen functionality at C-4. The SbCl3-catalyzed reaction between Nbenzylideneanilines 477 and N-vinylpyrrolidin-2-one 478a (n = 1) or N-vinyl-ε-caprolactam (n = 3) in acetonitrile produced tetrahydroquinolines 479 in good to excellent yields under mild experimental conditions (Scheme 129).241 From spectral

A straightforward method for the synthesis of substituted 5,6,6a,11b-tetrahydrobenzofuro[2,3-c]quinolines 470/471 was achieved by the reaction between N-benzylideneanilines 468 and benzo[b]furan 469 using BF3·OEt2 as a catalyst in acetonitrile. The reaction afforded the products in good to excellent yields under mild experimental conditions. The stereoselectivity of benzo[b]furan resembled that of indene, and a high endo selectivity was observed (Scheme 127).240

Scheme 129. Povarov Reactions Catalyzed by SbCl3

Scheme 127. Povarov Synthesis of 5,6,6a,11bTetrahydrobenzofuro[2,3-c]quinolines

analysis, a cis-structure was confirmed for tetrahydroquinolines 479. The reaction tolerated a variety of substituents in both aryl rings of the imine, and excellent yields were obtained irrespective of the electronic nature of this starting material. In addition, Arai and Ohkuma investigated a photochemical protocol for the Povarov reaction between N-benzylideneanilines and N-vinylpyrrolidin-2-one. The reaction was catalyzed by Cr(III)/bipyridine complex under the irradiation of blue light with a substrate-to-catalyst ratio (S/C) of 1000, affording 1,2,3,4-THQs in excellent yields (up to 97%).242 Using the same type of dienophiles, Cameron and co-workers developed a method for the regioselective synthesis of isoindolo[2,1-a]quinolone derivatives 482 starting from Naryl-3-hydroxyisoindolinones 480 and dienophiles 481 via an in situ generated N-acyliminium ion intermediate in the presence

Wexler and co-workers demonstrated the use of a Povarov reaction as the key step of a gram-scale route for the construction of BMS-593214 (99), a potent inhibitor of the coagulation factor VIIa (Scheme 128).92 In the presence of ZnCl2, 4cyanoaniline 472 and aldehyde 473 reacted to form imine 474 under reflux conditions in toluene. The heterodiene 474 then AL


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of BF3·OEt2 (Scheme 130).243 The reaction afforded exclusively the endo-products, where the hydrogen atoms on the stereogenic centers are in a cis-orientation with respect to each other.

selectivity, in a ratio that depended upon the nature of the substrates involved in the reaction (Scheme 132).249 Scheme 132. An Intramolecular Hydroamination/Povarov Domino Process

Scheme 130. Synthesis of Isoindolo[2,1-a]quinolone Derivatives by Povarov Reactions of in Situ Generated NAcyliminium Cations

The combination of two processes, each of which is able to generate several bonds in a single operation, is one of the most efficient ways to the fast generation of molecular diversity and complexity. We have developed a Yb(OTf)3-catalyzed reaction between imines 483, derived from arylamines and aldehydes, and electron-rich 1,4-dihydropyridines 484, which in turn are available via a multicomponent reaction from readily available, noncyclic starting materials (Scheme 131).244,245 This Povarov

The same authors synthesized a series of octahydrofuro[3,2c]pyrrolo[1,2-a]quinoline derivatives 492 and 493 from the homopropargylic amines 490 and electron-rich olefins 491 in the presence of Al2O3 and Cu(OTf)2 as a Lewis acid catalyst in anisole at 60 °C (Scheme 133).250 An in situ-generated

Scheme 131. Povarov Reactions Employing Electron-Rich 1,4-Dihydropyridines as Dienophiles

Scheme 133. Synthesis of Octahydrofuro[3,2-c]pyrrolo[1,2a]quinolone by a Domino Intramolecular Hydroamination/ Povarov Process

reaction was based on prior work by Lavilla, who used as starting materials dihydropyridines prepared by reduction of pyridinium salts derived from commercially available pyridines.246 The reaction gives access to hexahydrobenzo[h][1,6]-naphthyridine derivatives 485 in good yields under mild conditions, affording a 2:1 diastereomeric mixture where the all-cis-stereoisomer was found to be the major one.247 Khan and Khan also employed 1,4-dihydropyridines as dienophiles for the BF3·OEt2-catalyzed Povarov reaction for the synthesis of naphthyridine derivatives in moderate yields.248 Similarly, Li and co-workers demonstrated a copper triflatecatalyzed highly efficient one-pot domino process for the synthesis of pyrroloquinoline derivatives 488/489. Homopropargylic amines 487, previously prepared by means a multicomponent reaction, initially reacted with Cu(OTf)2 to generate the highly reactive dihydropyrrole intermediate A via an intramolecular hydroamination reaction. This compound subsequently reacted with imines 486 to furnish the corresponding THQs 488/489. A diastereomeric mixture of compounds 488 and 489 was obtained with good endo:exo

cycloenamine intermediate isomerizes into an iminium cation, which undergoes a hetero Diels−Alder reaction with electronrich olefins to form the desired products in good yields with diastereoselectivities up to >25:1. The role of the Al2O3 additive, which is activated by water, is to reduce a competitive selfdimerization reaction of the starting of homopropargylic amines 490 by enhancing their isomerization to cycloiminium cations. This strategy was used for the synthesis of diastereomeric THQs 496 and 497, potentially interesting for lung cancer treatment, starting from amine 494 and 2,3-dihydrofuran 495. AM


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In this particular case, the reaction proceeded in moderate yield and with only 69:31 endo/exo diastereoselectivity (Scheme 134).

Scheme 136. Synthesis of Cyclopropane-Fused Tetrahydroquinolines by Povarov Reaction between NBenzylideneaniline and Cyclopropenes

Scheme 134. Synthesis of Tetracyclic Compounds Potentially Useful for Lung Cancer Treatment by a Domino Intramolecular Hydroamination/Povarov Process

Tang and co-workers utilized readily available 1,2-dihydroquinolines 499 as dienophiles for the direct synthesis of spirocyclic bitetrahydroquinolines 500 in good to excellent yields starting from imines 498 (Scheme 135).251 Several Lewis

enol diazoacetates 502 by a dirhodium carboxylate catalyst, which underwent cycloaddition with imines 504 to furnish tetrahydroquinolines 505. Furthermore, tetrahydroquinolines 505 underwent ring opening when treated with tetrabutylammonium fluoride (TBAF) to generate 1H-benzazepine derivatives 506 with a high diastereoselective ratio (9:1) in good to excellent yields. The dirhodium(II)-catalyzed nitrogen extrusion from enol diazoacetate 502 would generate a metal enol carbene, which would then undergo intramolecular cyclization to deliver the donor−acceptor cyclopropene 503. A subsequent Sc(OTf)3-catalyzed Povarov-type reaction with imines 504 would finally afford the exo-product. Alternatively, a Mannich addition of cyclopropene 503 with imines 504 could generate a reactive oxonium ion, which would undergo further intramolecular electrophilic aromatic addition to provide the cyclopropane-fused tetrahydroquinoline 505. Reddy and Grewal generated in situ an azadiene from N[methyl-N-(trimethylsilyl)methyl]aniline 507 in the presence of a catalytic amount of molecular iodine, and this intermediate underwent [4+2] cycloaddition with electron-rich enol ethers, such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran 508, in dichloromethane at room temperature to afford the corresponding hexahydropyrano- and furo[3,2-c]quinolines derivatives 509, respectively, in good to excellent yields with cis-stereoselectivity (Scheme 137).253 A plausible mechanism for this

Scheme 135. Synthesis of Spirocyclic Bitetrahydroquinolines Based on the Use of 1,2-Dihydroquinolines as Povarov Dienophiles

Scheme 137. Povarov Reactions from N-[Methyl-N(trimethylsilyl)methyl]aniline acid catalysts and solvents were screened for this transformation, and indium chloride in toluene at 40 °C was established as the best one. In addition, the reaction could be selectively stopped at the first stage of its mechanism by using the Brønsted acid TsOH as the catalyst. Under these conditions, 1,2-dihydroquinolines 501 were obtained in the 45−93% yield range. Doyle and co-workers developed a novel regio- and diastereoselective Lewis acid-catalyzed Povarov reaction between N-benzylideneanilines 504 and donor−acceptor cyclopropenes 503 that provided direct access to functionalized cyclopropane-fused tetrahydroquinolines 505 and 1H-benzazepine derivatives 506 (Scheme 136).252 In this transformation, the donor−acceptor cyclopropenes are generated in situ from AN


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transformation involved the initial reaction of iodine with Narylamino-N-alkylsilane 507 to generate an iminium ion A, which would subsequently undergo a [4+2] cycloaddition with the enol ethers 508 to deliver THQs 509. Recently, a series of 4-aminoaryl tetrahydroquinolines 511 were synthesized in 52−82% yields and excellent diastereoselectivities from N-aryl-α-alkyl α-amino acids 510 through an aerobic decarboxylative Povarov-type reaction via photoredox catalysis using two 1 W blue light-emitting diodes as the energy source and a dicyanopyrazine-derived chromophores 512 (DPZ) as the catalyst (Scheme 138).254

three-component Povarov reaction was also employed for the one-pot synthesis of aromatic quinoline derivatives via sequential Povarov-oxidation steps.264,265 The InCl3-catalyzed, three-component reaction between compounds 518, aryl aldehydes 519, and cyclic enol ethers 520 was described for the diastereoselective synthesis of 4-(2benzofuranyl)furano[3,2-c]tetrahydroquinolines and 2-alkoxy4-heteroaromatic-substituted furano[3,2-c]tetrahydroquinolines 521 and 522 in good to excellent yields (Scheme 140).266 Interestingly, the reaction between arylamine 518 and 2 Scheme 140. Povarov-Based Synthesis of 4-(2Benzofuranyl)furano[3,2-c]tetrahydroquinolines and 2Alkoxy-4-heteroaromatic-Substituted Furano[3,2c]tetrahydroquinolines

Scheme 138. Synthesis of 4-Aminotetrahydroquinolines via Photoredox Catalysis in a Povarov Reaction

6.2. Three-Component Povarov Reactions

6.2.1. Lewis Acid-Catalyzed Povarov Reactions. The Lewis acid-catalyzed three-component Povarov reaction between aryl aldehydes 513 arylamines 514 and cyclic vinyl ethers 515 is very well studied, with numerous reports in the literature. Nevertheless, a considerable number of new catalysts have been recently identified that promote it. For instance, 25 mol% of GdCl3 triggered the three-component reaction to deliver excellent yields of the corresponding THQs 516 and 517 with good diastereoselectivity (Scheme 139).255 In addition, Sc(OTf)3,256 BF3·OEt2,257 NbCl5,258,259 Sm(OTf)3,260 ceric ammonium nitrate (CAN),261 CeCl3·7H2O/NaI,262 and Al(OTf)3263 were also employed as catalysts for the same reaction. This chemistry was applied to the synthesis of hexahydro 2Hpyrano[3,2-c]quinolines as selective σ1 receptor ligands.65 The

equiv of dihydrofuran in the presence of InCl3 furnished the tetrahydroquinoline derivatives 523 in high yields with an excellent diastereomeric ratio (>20:1). Similarly, Jiang and co-workers found a convenient method for the synthesis of 4-substituted furano[3,2-c]tetrahydroquinoline derivatives 525/526 with anticancer activities from heteroaryl-substituted anilines 524, aldehydes, and 2,3-dihydro-2H-furan in the presence of indium chloride, using acetonitrile as solvent (Scheme 141).55 These reactions proceeded in moderate to good yields with cis-/transdiastereoselectivities from 67:33 to 87:13. In addition, two more furo[3,2-c]tetrahydroquinoline derivatives 527/528 were synthesized via a ABB′-type reaction between the suitable anilines 524 and two molecules of dihydro-2H-furan. Related heterocycle-fused 1,2,3,4-THQs were also synthesized involving Lewis acid (Sc(OTf)3 or BF2·OEt2)-catalyzed three-component reaction.267 Dehaen and co-workers developed a three-component Povarov reaction by using ethyl-5-aminobenzothiophene-2carboxylate 529, a heterocyclic amine, aromatic aldehydes 530, and cyclic enol ethers 531 in the presence of BiCl3 for the synthesis of tetrahydrothieno[3,2-f ]quinolines 532 (Scheme 142).268 The authors also performed the reaction between amine 529 and 2 equiv of cyclic vinyl ethers 531 in the absence of aryl aldehydes for the synthesis of the corresponding THQs using BiCl3 or molecular iodine as catalyst.

Scheme 139. Three-Component Povarov Reactions Catalyzed by GdCl3

AO


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Scheme 141. Synthesis of Anti-cancer 4-Substituted Furo[3,2-c]tetrahydroquinolines through the Povarov Reaction

Scheme 143. Povarov Reactions Catalyzed by SnCl2

Scheme 144. Povarov Reactions Using Norbornene Derivatives as Dienophiles

Scheme 142. Synthesis of Tetrahydrothieno[3,2-f ]quinolines through the Povarov Reaction

reactions with norbornene. Formation of the diastereomers 541 and 542 could be visualized through the attack of the Narylimine dienes from the exo-face of the norbornene ring as shown in Scheme 145. In most cases, the formation of exo/exo diastereomers was observed, and for the case of ortho- or metasubstituted arylamines, the exo/endo adducts were also obtained. The synthesis of phosphino- and phosphine sulfide-1,2,3,4tetrahydroquinolines was achieved from 2-phosphinoaniline or 2-phosphine sulfide-aniline, aldehydes, and styrenes via the Povarov reaction (Scheme 146).270 The in situ-generated N-(2diphenylphosphino)aldimine from 2-(diphenylphosphino)aniline 543 and aldehyde 544 undergoes a formal [4+2] cycloaddition with alkenes 545 in the presence of BF3·OEt2 in chloroform at reflux condition to yield phosphine-1,2,3,4tetrahydroquinolines 546 in moderate yields. Similarly, phosphine sulfide-1,2,3,4-tetrahydroquinolines 547 were prepared from 2-phosphine sulfide-aniline under the same reaction conditions in 48−95% yields. Alternatively, compounds 547 were prepared by treating the crude 546 with molecular sulfur in refluxing chloroform. The G protein-coupled estrogen-receptor-selective agonist 551/552 and its analogues were synthesized in excellent yields and diastereoselectivities using a simple Sc(OTf)3-catalyzed three-component Povarov reaction, and the structure of the

A SnCl2-catalyzed one-pot imino-Diels−Alder reaction for the synthesis of novel diastereomeric hexahydro-2H-pyrano[3,2-c]quinoline 536 and 537 was developed by Sriram and coworkers (Scheme 143).39 The imines generated in situ from aromatic amines 533 and dibenzo[b,d]furan-2-carbaldehyde or 9-methyl-9H-carbazole-3-carbaldehyde 534 were reacted with 3,4-dihydro-2H-pyran 535 in a diastereoselective manner to deliver 1,2,3,4-THQs 536 and 537 in acetonitrile at room temperature in the presence of SnCl2·2H2O. Some of the isomeric pyranoquinoline analogues 536 and 537 thus obtained were active in vitro against Mycobacterium tuberculosis H37Rv. A large number of diastereomeric THQs 541 and 542 were synthesized via three-component Povarov reactions, using ringstrained bicyclo[2.2.1]heptenes (norbornenes) as dienophiles. The in situ-generated imines from arylamines 538 and aryl aldehydes 539 reacted with norbornenes 540 under mild conditions to produce highly functionalized natural product-like tetrahydroquinolines, using BF3·OEt2 as catalyst (Scheme 144).269 In addition, more reactive ethyl glyoxylate-derived imines were also utilized to achieve faster, room temperature AP


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Scheme 145. Explanation of the Stereochemical Outcome of the Norbornene Povarov Reactions

Scheme 147. Povarov-Based Synthesis of an Agonist of the G Protein-Coupled Estrogen Receptor

Scheme 146. Synthesis of Phosphino- and Phosphine Sulfide1,2,3,4-tetrahydroquinolines through the Povarov Reaction

Figure 19. Biologically relevant iodinated fused tetrahydroquinolines prepared through the Povarov reaction.

receptor for estrogens, in comparison to the classical nuclear estrogen receptors. Papke and co-workers demonstrated the use of microwaveassisted conditions for the construction of racemic cis-4-(4bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide via the Povarov reaction in the presence of 20 mol% of InCl3 in acetonitrile from compounds 557−559 (Scheme 148).84 They also studied the separation of enantiomers 560 and 561 through HPLC using a chiral column and found that the (+)-enantiomer 560 (GAT107), having the 3aR,4S,9bS absolute configuration, was the eutomer and the most potent positive allosteric modulator of α7 nicotinic acetylcholine receptors known at the time of publishing. The related compounds were also synthesized using a threecomponent Povarov reaction in the presence of Lewis acid catalysts.88,274,275

compound was confirmed by single-crystal X-ray analysis. The reaction between 4-aminoacetophenone 548, 6-bromopiperonal 549, and cyclopentadiene 550 in the presence of 10 mol% of Sc(OTf)3 in acetonitrile at room temperature afforded the target compound 551 in nearly quantitative yield with a diastereomeric ratio of 94:6 (Scheme 147).271 Related compounds were also synthesized using InCl3 as catalyst under microwave irradiation,272 and also with Yb(OTf)3 as catalyst under reflux conditions or sonication.273 Arterburn and co-workers also functionalized tetrahydro-3Hcyclopenta[c]quinolines 551 to access the pharmacologically significant iodo-substituted heterocyclic compounds 553−556 (Figure 19).68 The iodinated compounds exhibited a high affinity and selectivity toward GPR30, a G protein-coupled AQ


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Scheme 148. Povarov-Based Synthesis of a Fused Tetrahydroquinoline Acting as a Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Scheme 150. Povarov Reactions Catalyzed by Cu(OTf)2

We have described a hetero-Diels−Alder reaction between diaryl imines and α,β-unsaturated dimethylhydrazones, acting as dienophiles, for the diastereoselective synthesis of THQs bearing a quaternary stereocenter and a carbonyl equivalent functionality at C-4.285 Subsequently we extended the scope of the reaction to the chemodivergent synthesis of functionalized THQs 574 and hexahydropyrrolo[3,2-b]indoles 575 (Scheme 151).286 The one-pot reaction between in situ generated diaryl

Takahashi and co-workers developed an efficient Povarov reaction for the synthesis of THQ derivatives 565 and 566 from arylamines 562, aldehydes 563, and alkene 564 promoted by a Sn(IV) species that was generated in situ from redox reaction of SnCl2 and FeCl3 (Scheme 149).276 This method provided

Scheme 151. Povarov Reactions Employing α,β-Unsaturated Dimethylhydrazones as Dienophiles

Scheme 149. Povarov Reactions Catalyzed by an in SituGenerated Sn(IV) Species

excellent yields of the products for arylamines bearing either electron-withdrawing or electron-donating groups and also worked well for aliphatic and aromatic aldehydes, which significantly expanded the scope of substrates accessible through the Povarov reaction. It is relevant to note that this method allowed access to THQs with a quaternary stereocenter at C-4. 2,4-Diaryl-1,2,3,4-tetrahydroquinoline derivatives 570 were diastereoselectively synthesized in good to excellent yields via a Cu(OTf)2-catalyzed three-component reaction between arylamines 567, aromatic aldehydes 568, and commercial transanethole 569 as the dienophile (Scheme 150).277,278 The related 2,4-diaryl-THQs were also accessed by various research groups using FeCl3 as catalyst under ball-milling conditions,279 and also with eugenol as the dienophile in the presence of BF3· OEt2,280,281 and with formaldehyde as the aldehyde component in the presence of molecular iodine.282−284Similar reactions were used for the synthesis of tetrahydroquinoline derivatives with anti-trypanosomal,44,45 anticancer,52 and antifungal43 properties.

imines from arylamines 571, aryl aldehydes 572, and α,βunsaturated N,N-dimethylhydrazones 573 in acetonitrile in the presence of InCl3 led to the formation of C-4 functionalized biologically relevant THQs 574 as a single diastereomer with small quantities of hexahydropyrrolo[3,2-b]indoles 575 and hydrazones 576. On the other hand, the reaction delivered hexahydropyrrolo[3,2-b]indoles 575 in good yields (38−93%) using BF3·OEt2 as catalyst in chloroform via an ABB′C fourcomponent reaction. Thus, this chemodivergent approach furnished two structurally diverse molecules by simply changing the catalyst and reaction solvent. Subsequently, we extended this chemistry by studying the InCl3-catalyzed hetero Diels−Alder reaction between arylamines 577, aldehydes 578, and α,β-unsaturated N,Ndimethylhydrazones 580 to give 2-acyl-1,2,3,4-tetrahydroquinolines 581 bearing a dimethylhydrazone function at C-4, followed by oxidation of the latter to a nitrile (compounds 582) with magnesium monoperoxyphthalate hexahydrate (MMPP) at AR


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Scheme 152. Application of the Povarov Reactions Starting from α,β-Unsaturated Dimethylhydrazones to the Synthesis of 2Acyl-1,2,3,4-tetrahydroquinolines

room temperature. Compounds 582 were easily aromatized, which was a significant finding in view of the scarcity of methods for the synthesis of 2-acylquinolines. The isatin-derived imines 584 were also treated with α,β-unsaturated N,N-dimethylhydrazones 580 under the optimized conditions to yield spiroTHQs 585 as single diastereomers (Scheme 152).287 Zhu and co-workers demonstrated a two-step synthesis of 5,6dihydroindolo[1,2-a]quinolines 591 via Yb(OTf)3-catalyzed three-component Povarov reaction between arylamines 586, α-oxo aldehydes 587, and dienophiles 588 to generate 2-acyltetrahydroquinolines 589 followed by a heteroannulation reaction between the Povarov adducts and in situ generated benzynes from compounds 590 in the presence of tetrabutylammonium difluorotriphenylsilicate (TBAT).288 As shown in Scheme 153, structurally diverse products were obtained in good yields under mild experimental conditions. Lavilla and co-workers developed a methodology for the synthesis of diastereomeric fused THQs 595/596 via a threecomponent Povarov reaction using oxa-, thia-, and imidazolones as electron-rich olefins. A wide variety of natural product-like THQs were synthesized regioselectively by using arylamines 592, aldehydes 593, and the heteroatom-substituted electronrich olefins 594 in the presence of a catalytic amount of Sc(OTf)3 in acetonitrile (Scheme 154).289 Subsequent oxidation of these THQs into the corresponding quinolines was achieved using DDQ. Koutnezsov found that the environmentally friendly BiCl3 is an excellent catalyst to trigger the three-component reaction between arylamines 597, (hetero)aryl aldehydes 598, and Nvinylamides, including N-vinylacetamide 599 and N-vinylpyrrolidin-2-one 601, to furnish cis-2,4-disubstituted THQs 600 and 602 in good to excellent yields (Scheme 155).290 The same group subsequently employed this catalyst for the synthesis of other types of THQs.291−294 San Martiń and co-workers synthesized in a single step tetrahydroquinoline 606, with moderate acetylcholinesterase inhibition activity, using a Povarov reaction from aniline 603, piperonal 604, and N-vinylpyrrolidin-2-one 605 in acetonitrile (Scheme 156).80 Related 1,2,3,4-THQs with potential antibacterial295 and antifungal42 activities were also synthesized via

Scheme 153. Alternative Synthesis of 2-Acyl-1,2,3,4tetrahydroquinolines and Their Heteroannulation with Benzynes

InCl3-catalyzed three-component reactions. Highly fluorescent quinolines, employed for the detection of both Gram-positive and Gram-negative bacteria, were synthesized via Sc(OTf)3catalyzed three-component Povarov reaction followed by DDQ mediated aromatization.40 A series of bistetrahydroquinolines 610 was synthesized in 25−72% yields via double Povarov reactions between anilines 607, dialdehydes 608, and N-vinyl-2-pyrrolidone 609 using acetonitrile as solvent in the presence of bismuth trichloride as catalyst at room temperature, and their activities as inhibitors of the AChE and BuChE cholinesterase enzymes were predicted computationally (Scheme 157).81 Roy and Reiser synthesized pharmacologically important fused THQs in high yields by a simple Sc(OTf)3-catalyzed three-component approach, as summarized in Scheme 158.296 This methodology involved the reaction between aniline 611, AS


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Scheme 154. Povarov Reactions Employing Oxa-, Thia-, and Imidazolones as Dienophiles

Scheme 157. Double BiCl3-Catalyzed Povarov Reactions

Scheme 158. Povarov Reactions Employing CyclopropaneFused Pyrrolines as Dienophiles

Scheme 155. Povarov Reactions Catalyzed by BiCl3

Scheme 159. A Povarov/Cyclopropane Ring-Opening Domino Process

Scheme 156. Additional Povarov Reactions Catalyzed by BiCl3

bonds, as dienophiles for the Sc(OTf)3-catalyzed, threecomponent Povarov reaction to afford diastereomeric THQ derivatives 621 and 622 in moderate yields from arylamines 618 and aldehydes 619. Although the overall diastereoselectivity of the reaction was poor, a single diastereomer was isolated in the case of the 2-furyl-substituted system (Scheme 160).297 A large number of arylamines 618 and aldehydes 619 were successfully employed to deliver the corresponding THQs 621 and 622 under mild conditions. By employing dienophile 623, bearing an exocyclic double bond, the same authors extended this methodology to the synthesis of spiro-THQs 624 and 625 in 1:1 ratio under microwave irradiation (Scheme 161). Tu and co-workers developed a metal-free imino Diels−Alder reaction for the synthesis of exo-indolo[3,2-c]quinoline derivatives. In this three-component reaction, a variety of aromatic amines, including naphthalen-2-amine 626a, 1H-

aryl aldehydes 612, and the monocyclopropanated adduct of NBoc-pyrrole 613 under microwave irradiation conditions to obtain THQs 614 and 615. The structure of the products was established by single-crystal X-ray analysis of a representative compound. The authors extended this strategy to a fourcomponent reaction by introducing pyrrole 616 as external nucleophile that added to the imine functionality present in Diels−Alder adduct 614 to furnish compound 617 as the major product (Scheme 159). Lavilla and co-workers demonstrated the feasibility of using unsaturated lactams 620, with endo- and exo-cyclic C−C double AT


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An interesting three-component Povarov reaction was developed involving electron-deficient indolylnitroalkenes as dienophiles. 4-Indolyl-2,3,4-trisubstituted THQs 633 were synthesized as single diastereomers in good yields starting from arylamines 630, aldehydes 631, and indolylnitroalkenes 632 in the presence of FeCl3 (Scheme 163).299 This

Scheme 160. Povarov Reactions Employing Unsaturated Lactams as Dienophiles

Scheme 163. Povarov Reactions Employing Indolylnitroethylene Derivatives as Dienophiles

methodology was applicable to a broad class of substrates, since it showed a good functional group tolerance, and was used to prepare biologically active, highly fused indolo-benzonaphthyridine derivatives. Kinfe and co-workers developed an approach for the synthesis of highly substituted pentacyclic N-heterocycles including benzopyran-fused pyranoquinolines 637 consisting of a Ferrier rearrangement and the Povarov reaction domino sequence (Scheme 164).300 In this transformation, a wide range of

Scheme 161. Povarov Reactions Employing Methylenepyrrolidinones as Dienophiles for the Synthesis of Spiro-tetrahydroquinolines

Scheme 164. Synthesis of Benzopyran-Fused Pyranoquinolines via a Ferrier Rearrangement/Povarov Sequence

indazol-5-amine 626b, and 9-ethyl-9H-carbazol-3-amine 626c, aryl aldehydes 627, and substituted indoles 628 as dienophile were treated with 5 mol% molecular iodine at room temperature in toluene to yield the corresponding fused THQs 629 in good yields (Scheme 162).298 Scheme 162. Povarov Reactions Employing Indoles as Dienophiles

arylamines 634 and salicylaldehyde derivatives 635 reacted with glycols 636 in the presence of Sc(OTf)3 in acetonitrile to deliver the pentacyclic compounds 637. Chandrasekhar and co-workers established a synthetic route for the construction of compound 643, in 13 steps, corresponding to the pentacyclic core of a family of structurally complex Melodinus alkaloids such as maloscine 644 through a CAN-catalyzed three-component Povarov reaction (Scheme 165).301 The THQ intermediate 641 was synthesized in 68% yield starting from aniline 638, ethyl 2-oxoacetate 639, and cyclopentadiene 640 in the presence of CAN catalyst. 6.2.2. Brønsted Acid-Catalyzed Povarov Reactions. The reaction between arylamines 645, aryl aldehydes 646, and cyclic vinyl ethers 647 in the presence of Brønsted acid catalysts, including HClO4−SiO2,302 HCl−EtOH,303 PANI−PTSA,304 and TPA/MCM-41,305 and cellulose sulfuric acid38 furnished the diastereomeric mixture of pyrano- or furano-tetrahydroquiAU


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THQs were achieved starting from arylamines, aryl aldehydes, and dienophiles. The THQs were assayed as ligands of the GPER receptor, which has recently emerged as a promising target to treat a number of diseases. Some compounds showed interesting activity in these preliminary in vitro assays. Cao, Ye, and co-workers established a triflic acid-catalyzed three-component reaction for the synthesis of cyclopropanefused dihydroquinolines 653 similar to those in Scheme 136 by reaction between arylamines 650, aldehydes 651, and cyclopropenes 652 as the dienophiles (Scheme 167).306,307 Ring

Scheme 165. Synthesis of the Pentacyclic Core of the Melodinus Alkaloids Starting with a CAN-Catalyzed ThreeComponent Povarov Reaction

Scheme 167. Povarov Reactions Employing Cyclopropene Derivatives as Dienophiles

Scheme 166. Brønsted Acid-Catalyzed Povarov Reactions

opening of compounds 653 was achieved in the presence of Tf2O and lutidine to access benzazepine derivatives, and one of the dihydroquinolines 653 was converted into the corresponding THQ 654 in 91% yield under reductive conditions. A simple, solvent-free imino Diels−Alder/intramolecular amide cyclization domino sequence was established for the synthesis of highly functionalized 6,6a-dihydroisoindolo[2,1a]quinolin-11(5H)-one derivatives 658/659. This cascade was carried out in the presence of catalytic amorphous milled cellulose sulfonic acid (AMCell-SO3H) using substituted anilines 655, 2-formylbenzoic acid 656, and olefins 657 in acetonitrile at 90 °C (Scheme 168).308 The reaction afforded good yields with high regioselectivity (up to 99%) and diastereoselectivity (up to 100%). The authors screened a variety of catalysts including Lewis acids, Brønsted acids, and polymer-supported catalysts and identified AMCell-SO3H as the optimal one. The p-TsOH-catalyzed synthesis of 2-(2-nitrophenyl)1,2,3,4-tetrahydroquinolines 663 was performed via a Povarov reaction from arylamines 660, 2-nitroarylaldehydes 661, and electron-rich alkenes 662, in acetonitrile at room temperature (Scheme 169).309 A variety of dienophiles were employed in the

noline derivatives 648 and 649 (Scheme 166, Table 1). Although in all the cases excellent yields of the products were isolated, the diastereomeric ratio varied depending on the catalytic system. L-Tartrate boronic acid was also employed as the catalyst for the synthesis of a couple of pyrano- or furanotetrahydroquinoline derivatives.37 Cyclic vinyl ethers and N-protected enamines are among the most commonly employed dienophiles to test Povarov reactions under new conditions. Gioiello and co-workers developed flow conditions to carry out this standard Povarov reaction.67 A three-component flow synthesis of diastereomeric 1,2,3,4Table 1. Brønsted Acid-Catalyzed Povarov Reactions entry

catalyst

solvent

yield (%)

no. of examples

cis:trans ratio(648:649)

1 2 3 4 5

HClO4−SiO2 HCl−EtOH PANI−PTSA TPA/MCM-41 cellulose sulfuric acid

MeCN MeCN none MeCN MeCN or H2O

up to 95 up to 83 up to 90 up to 95 up to 89

22 18 20 8 18

20:80 to 10:90 100:0 to 5:95 100:0 to 0:100 55:45 to 11:89 79:21 to 29:71

AV


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and 2,3-dihydrofuran 667 under microwave-assisted reaction conditions (Scheme 170).311

Scheme 168. Solvent-Free Povarov/Intramolecular Amidation Sequence

Scheme 170. Double Povarov Reactions Catalyzed by pSulfonic Acid Calix[4]arene

Fernandes and co-workers also employed a diastereoselective three-component cascade reaction, catalyzed by the Brønsted acidic p-sulfonic acid calix[4]arene 670, for the synthesis of julolidines 674 from arylamines 671, 2 equiv of formaldehyde 672, and 2 equiv of olefin 673 (Scheme 171).312 The reaction

Scheme 169. Povarov Synthesis of 2-(2-Nitrophenyl)-1,2,3,4tetrahydroquinolines as Precursors for Fused Tetraheterocyclic Frameworks

Scheme 171. Calixarene-Catalyzed Double Povarov Reactions for the Synthesis of Julolidines

was also tested in the presence of other Brønsted acids, including trifluoroacetic acid, acetic acid, p-toluenesulfonic acid (PTSA), and sulfuric acid, but they gave inferior yields and diastereoselectivities. The authors subsequently extended their approach to the synthesis of quinolines via a domino Povarov− hydrogen transfer process.313 The mechanism involved the initial reaction between arylamines 671 and formaldehyde 672 to generate the iminium cation A, which subsequently reacted with olefin 673 to give tetrahydroquinolinium ion B. The second equivalent of formaldehyde and olefin reacted with intermediate B to afford the final julolidines 674 via the intermediacy of species C and D (Scheme 172). Mantlo and co-workers synthesized a series of isoxazolyl-, pyrazolyl-, and tetrazoyl-substituted tetrahydroquinoline derivatives 679 and 680 as potent inhibitors of the cholesteryl ester transfer protein (CETP) using a Povarov reaction to generate the required tetrahydroquinoline ring (Scheme 173).90 To this end, commercially available 4-(trifluoromethyl)aniline 675 was converted into tetrahydroquinolines 678 by reaction with a

reaction to deliver the corresponding products in high yields. These 2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinolines were subsequently converted into indazolo[2,3-a]quinoline derivatives 664 by an intramolecular cyclization that involved forming the N−N bond of the indazole ring via photoredox catalysis using Ru(bpy)3Cl2 catalyst in acetonitrile at room temperature, under visible light irradiation. The same transformation was subsequently achieved using choline chloride/CuCl as a photocatalyst.310 Similarly, Fernandes and co-workers developed a one-pot double Povarov reaction catalyzed by a p-sulfonic acid calix[4]arene 670 and allowing the synthesis of julolidine derivatives 668 and 669 in good to excellent yields but low diastereoselectivity using arylamines 665, formaldehyde 666, AW


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Scheme 172. Mechanism for the Generation of the Dibenzo[ij]quinolizine Framework of the Julolidines

Scheme 174. Povarov-Based Synthesis of 4-Aryl-3-methyl1,2,3,4-tetrahydroquinolines

Scheme 173. Synthesis of Tetrahydroquinoline-Derived Cholesteryl Ester Transfer Protein Inhibitors

component cationic Povarov reaction between N-allylanilines 686, formaldehyde 687 (37% solution in methanol), and Nvinyl-2-pyrrolidinone 688 with p-TsOH (20 mol%) as catalyst, in acetonitrile (Scheme 175).79 N-Propargylated derivatives Scheme 175. Povarov Reaction between N-Allylanilines, Formaldehyde, and N-Vinyl-2-pyrrolidinone

variety of aldehydes 676 and vinyl acetamide 677 in the presence of p-toluenesulfonic acid. A simple, inexpensive, and mild one-pot Povarov reaction for the synthesis of 4-aryl-3-methyl-1,2,3,4-tetrahydroquinolines derivatives 684 was developed using aqueous HCl as catalyst. This reaction proceeded through an iminium ion intermediate, generated through the condensation of N-benzylanilines 681 and formaldehyde 682 and dienophiles 683 including isoeugenol and trans-anethole (Scheme 174).314 This method afforded tetrahydroquinolines with good to excellent yields and high trans-diastereoselectivity. The debenzylated THQs 685 were obtained via catalytic hydrogenolysis with Pd/C in methanol. An acetic acid-catalyzed three-component reaction between arylamines, arylaldehydes, and trans-isoeugenol was also established to access 2,4-diaryl-3-methyl-THQs in good yields, and the synthesized compounds were screened for their multifunctional activities including microbial, cancer, retinoic acid receptor, inflammatory, cholesterol ester transferase, and parasitic diseases.315 Romero-Bohórquez and co-workers described the efficient synthesis of N-allyl 4-substituted-1,2,3,4-tetrahydroquinoline derivatives 689 in good to excellent yields using a three-

were also synthesized using N-propargyl aniline as staring material, in this case in the presence of InCl3(20 mol%) as a Lewis acid. Both series of compounds were examined for their inhibitory activity against BChE, and the N-allyl derivatives were found to be more active. In related work, Castillo, Abonia, and co-workers found that this chemistry could be carried out in catalyst-free conditions (Scheme 176).316 A set of 1,4-disubstituted THQs 693 was synthesized from amines 690, paraformaldehyde 691, and dienophiles 692 in high yields. Nine of the compounds were evaluated for antiproliferative activity, and it was found that one of them (R1 = 6-MeO, R2 = p-ClC6H4, and n = 1) had a remarkable activity against a panel of 57 cancer cell lines. The same group extended the scope of the reaction to include heterocyclic substrates containing an aniline fragment such as dibenzoazepine 694 and tetrahydroquinoline 695 to access the corresponding fused THQs 697 and 698. When a primary aromatic amine (p-toluidine, 696) was employed, a double Povarov reaction took place to deliver compound 699 in a AX


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activity relationship of the synthesized tetrahydroquinoline as the membrane bound large-conductance, calcium-activated potassium channel (BKCa) agonists.87 The TFA-catalyzed approach was also extended to the synthesis of THQ-based nonsteroidal selective androgen receptor modulators (SARMs).69,71 The 1,2,3,4-THQ derivatives 709, possessing a parasubstituted aromatic ring attached through an amide linkage, were prepared in two steps (Scheme 179).72 The first one was a

Scheme 176. Catalyst-Free Povarov Reaction between NAlkylanilines, Formaldehyde, and N-Vinyl-2-pyrrolidinone

Scheme 179. Povarov-Based Synthesis of Modulators of the Non-steroidal Selective Androgen Receptor

modest 32% yield, which increased to 61% upon addition of 0.2 mL of acetic acid (Scheme 177). Scheme 177. Povarov Reaction between N-Heterocycles, Formaldehyde, and N-Vinyl-2-pyrrolidinone

TFA-mediated Povarov reaction between 4-cyanoaniline 704, N-Boc-3-amino-2,2-dimethylpropanal 705, and cyclopentadiene 706 in acetonitrile to provide 1,2,3,4-THQ 707 in 65% yield. Boc deprotection and coupling with the suitable aromatic carboxylic acid 708 afforded the required amide products 709 in good to excellent yields. As mentioned in section 3, these compounds showed good in vitro activity as modulators of the non-steroidal selective androgen receptor, a relevant target for the treatment of osteoporosis. Odinokov and co-workers studied the reaction of lower aliphatic aldehydes (formaldehyde, acetaldehyde, and propanal) with arylamines 710 and cyclopentadiene 711 in the presence of TFA. In the case of formaldehyde 712, fused julolidine derivatives 713, arising from a double Povarov reaction, were obtained as the major product in excellent yield (Scheme 180).318 However, ortho-substituted anilines gave only the intermediate tricyclic product arising from the first cycloaddition. On the other hand, the reaction involving aniline 710a, cyclopentadiene 711, and acetaldehyde 714 gave a complex

The diastereoselective synthesis of tetrahydro-1,7- and tetrahydro-1,8-phenanthroline derivatives 703 was achieved in moderate yields based on a TFA-catalyzed reaction between 5aminoquinoline or 5-aminoisoquinoline 700 with aromatic aldehydes 701 and cyclopentadiene 702 in trifluoroethanol (Scheme 178).317 Gore and co-workers also synthesized related 1,2,3,4-THQs involving a trifluoroacetic acid-catalyzed threecomponent Povarov reaction and investigated the structure− Scheme 178. Povarov-Based Synthesis of Tetrahydro-1,7and Tetrahydro-1,8-phenanthroline Derivatives

Scheme 180. TFA-Catalyzed Double Povarov Reactions of Anilines, Formaldehyde, and Cyclopentadiene

AY


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the 2-vinylindole acting as the diene and the imine as the dienophile was observed, leading to tetrahydro-γ-carbolines. Oruganti and co-workers reported an Amberlyst-15-promoted Povarov reaction between an imine, derived from 1Hindazol-6-amine 726 and aryl/heteroaryl aldehydes 727, and indole/5-bromoindole 728 (Scheme 184).91 This reaction

mixture of 715, 716, and 717, while aniline, cyclopentadiene, and propanal gave the tricyclic system as the only product, but in a low yield of 17% (Scheme 181). Scheme 181. TFA-Catalyzed Povarov Reactions of Anilines, Acetaldehyde, and Cyclopentadiene

Scheme 184. Povarov Reactions Starting from 1H-Indazol-6amine, Aldehydes, and Indoles

Golgicide A (GCA, 721) was synthesized in 70% yield via a three-component Povarov reaction between 2,4-difluoroaniline 718, pyridine-3-carbaldehyde 719, and cyclopentadiene 720 in the presence of oxalic acid as catalyst in refluxing acetonitrile. The major cis product was evaluated in larval and adult mosquito assays (Scheme 182).98 The procedure was extended for the synthesis of a library of 18 GCA analogues under similar conditions.

allowed the synthesis of library of exo-1,6,7,7a,12,12ahexahydroindolo[3,2-c]pyrazolo[3,4-f ]quinolines 729, which were tested for sirtuin (Sir-2) inhibitory activity using a yeastbased assay. Yan and co-workers demonstrated a hetero Diels−Alder reaction between isatin-derived imines 733 and β-enamino esters 732 for the synthesis of polysubstituted spiro[indoline3,2′-quinolines] 734 (Scheme 185).320 The β-enamino esters

Scheme 182. Synthesis of Golgicide A through a Povarov Reaction

Scheme 185. Povarov Reactions from Anilines, Propiolates, and Isatin-Derived Imines

Xiao and co-workers reported a chemoselective synthesis of 4(2-indolyl)-substituted THQs 725 by a Povarov reaction from aromatic amines 722, aldehydes 723, and N-unsubstituted 2vinylindoles 724 as the dienophile, carried out in the presence of 30 mol% of 3,5-dinitrobenzoic acid as a Brønsted acid catalyst in dichloroethane at room temperature (Scheme 183).319 Interestingly, when N-protected 2-vinylindoles were used under similar reaction conditions, a Diels−Alder reaction with 732, prepared from arylamines 730 and methyl propiolate 731 in ethanol, underwent nucleophilic addition to imine 733 in the presence of TsOH followed by intramolecular electrophilic aromatic substitution at the ortho-position of N-aryl ring to give spiro[indoline-3,2′-quinoline] 734. The reaction tolerated a wide range of substituents on all three aryl rings to deliver the products without any significant change in yields regardless of the nature of the substituents. Beifuss and co-workers established a one-pot domino process for the synthesis of tetrahydroquinolines from nitrobenzenes, aldehydes, and cyclopentadiene involving a nitro reduction/ Povarov reaction sequence of reactions that allowed the replacement of anilines with nitrobenzenes as substrates for the Povarov reaction. Thus, the three-component reaction

Scheme 183. Povarov Reactions Employing 2-Vinylindole Derivatives as Dienophiles

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achieved by the reaction between arylamines 745 and 2 equiv of N-vinylpyrrolidin-2-one or N-vinylcaprolactam 746 in acetonitrile under reflux conditions (Scheme 188).323 This domino

between nitrobenzenes 735, aldehydes 736, and cyclopentadiene 737 was performed in aqueous citric acid at 40 °C and delivered cyclopenta[c]quinolines 738 and 739 in good to excellent yields and very high endo-selectivity (Scheme 186).321 The domino reaction was performed with numerous nitrobenzenes and aromatic, heteroaromatic, and aliphatic aldehydes.

Scheme 188. Synthesis of 2-Methyl-1,2,3,4tetrahydroquinolines by Povarov Reactions of Anilines and 2 Equiv of N-Vinyl Lactams

Scheme 186. Reductive Povarov Reactions from Nitrobenzenes, Aldehydes, and Cyclopentadiene

process involves the initial reaction of arylamines 745 and 1 equiv of 746 to give the corresponding N-arylimines, which in the presence of Lewis acid catalyst then yield the imino Diels− Alder adduct with another equivalent of 746, which acts as dienophile, to afford the tetrahydroquinolines 747. The reaction was also achieved in excellent yields in the presence of a variety of catalytic systems, including SbCl3,324 phosphotungstic acid,325 and InCl3 in water,326 CuPy2Cl2,327 polyaniline salt,328 and iron oxide nanoparticles,329 and Sb2(SO4)3,93 and also under catalyst-free conditions in water.330 The mechanism of the reaction was proposed to involve the formation of N-vinylaniline A via Lewis acid-catalyzed reaction between arylamine 745 and N-vinylpyrrolidin-2-one 746 (Scheme 189). The enamine A tautomerized into imine B,

6.2.3. Enzyme-Catalyzed Povarov Reactions. In addition to the Lewis and Brønsted acids, some enzymes, such as αchymotrypsin from bovine pancreas (BPC), have also been found to trigger the three-component Povarov reaction. He and co-workers reported this enzyme to be an excellent catalyst for the reaction between arylamines 740, aromatic aldehydes 741, and 2,3-dihydropyran or 2,3-dihydrofuran 742 in acetonitrile− water medium to afford the corresponding 1,2,3,4-THQs 743 and 744 in high yields and excellent diastereoselectivities (Scheme 187).322

Scheme 189. Mechanism Proposed for the ABB′ Reaction between Anilines and N-Vinyl Lactams

Scheme 187. Three-Component Povarov Reactions Catalyzed by Bovine α-Chymotrypsin

6.2.4. ABB′ Povarov Reactions. Because of their special features, we devote a separate section to ABB′ Povarov reactions. ABB′ three-component reactions are defined as those that have only two starting materials, but one of them takes part in the reaction with two different roles. For instance, an ABB′ three-component reaction between arylamines and 2 equiv of dienophiles, including vinyl ethers and N-vinylpyrrolidin-2-one, is known to afford 2-methyl-1,2,3,4-tetrahydroquinolines. Thus, the FeCl3-catalyzed synthesis of 2-methyl4-substituted-1,2,3,4-tetrahydroquinoline derivatives 747 was BA


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underwent a formal [4+2] cycloaddition with another equivalent of the enol ether in the presence of TBPA•+ to afford tetrahydroquinolines as a diastereomeric mixture. Other catalytic systems, including nanoporous aluminosilicate,336 cellulose−SO3H,337 AlCl3/H2O,338 Sm(NO3)3,339 and lanthanide halides,340 also effectively catalyzed the ABB′ threecomponent reaction between arylamines and cyclic enol ethers. A simple ABB′ three-component Povarov reaction between 3amino- and 1-aminocarbazoles 756, and ethyl vinyl ether 757 was carried out in the presence of CAN under mild conditions to access tetrahydroquinolines 758 in high yields. These compounds were subsequently transformed into pyrido[2,3c]carbazoles 759.341 Mechanistically, arylamine 756 was proposed to react with one molecule of the ethyl vinyl ether 757 in the presence of CAN to afford imine A, which would then react in imino Diels−Alder fashion with a second molecule of ethyl vinyl ether 757, now acting as an electron-rich dienophile, to give the observed tetrahydroquinolines 758 (Scheme 192).

which is equivalent to the imine derived from arylamine and acetaldehyde. Subsequent Lewis acid-catalyzed imino Diels− Alder reaction with the second equivalent of N-vinylpyrrolidin2-one 746 furnished 2-methyl-THQs 747 and 748. The formation of the major cis diastereomer 747 could be visualized through the less sterically hindered exo intermediate C and minor trans isomer 748 is formed via the endo intermediate D. Kouznetsov and co-workers developed a green protocol for the synthesis tetrahydroquinoline derivatives 751, using for the first time the surfactant sodium dodecyl sulfate (SDS) as catalyst. The reaction between arylamines 749 and N-vinyl acetamides 750 in the presence of SDS at micellar concentration afforded the tetrahydroquinoline derivatives 751 (Scheme 190).331 This methodology provided cis 2,4-disubstituted Scheme 190. Synthesis of 2-Methyl-1,2,3,4tetrahydroquinolines by Povarov Reactions of Anilines and 2 Equiv of N-Vinylamides

Scheme 192. CAN-Catalyzed ABB′ Three-Component Povarov Reaction between 3-Amino- and 1-Aminocarbazoles and Ethyl Vinyl Ether

tetrahydroquinolines in excellent yields under the influence of SDS micelles, which formed above the critical micellar concentration (12 mM). Phthalic acid332 and Ce(SO4)2333 were also found to be excellent catalysts to promote this ABB′ three-component reaction. This reaction was also achieved under high-speed vibratory ball-milling conditions using phosphomolybdic acid as catalyst, and the THQs were obtained in 56−76% yield.334 As summarized in Scheme 191, Jia and co-workers developed an efficient approach for the synthesis of diastereomeric Scheme 191. ABB′ Povarov Reaction between Anilines and Cyclic Vinyl Ethers

Kouznetsov and co-workers reported a variation of a previously known342 ABB′-type three-component reaction between anilines 760 and 2 mol of ethyl vinyl ether 761 for the synthesis of cis-4-ethoxy-2-methyl-1,2,3,4-tetrahydroquinolines 762, which they performed in the presence of phthalic acid as catalyst in aqueous methanol (Scheme 193).343 Subsequently, THQs 762 were aromatized into 2-methylquinolines that were transformed into 2-styrylquinolines. Fustero and co-workers described a Povarov-type ABB′ threecomponent reaction between fluorinated imino esters 763 and 2 equiv of furan derivatives 764 with either AuCl3 or SIPrAuOTf as the catalysts in dichloromethane at room temperature to afford fluorinated tetrahydrofuran-fused tetrahydroquinolines 765 in good yields, although with moderate diastereoselectivity (Scheme 194).344 Surprisingly, the more activated 2-methoxyfuran did not give the product under the reaction conditions whereas the presence in the furan ring of other 2-alkyl

tetrahydroquinoline derivatives 754 and 755 by reaction between arylamines 752 and 2 equiv of cyclic enol ethers 753 in the presence of tris(4-bromophenyl)aminium hexachloroantimonate (TBPA•+, 5 mol%) at ambient temperature.335 As in the previous case, arylamines reacted with 1 equiv of the enol ethers to give the corresponding N-arylimines, which then BB


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Scheme 193. Phthalic Acid-Catalyzed ABB′ ThreeComponent Povarov Reaction

Scheme 195. Mechanism Proposed for the Gold-Catalyzed Povarov/Furan Addition Domino Process

Scheme 194. Gold-Catalyzed Povarov/Furan Olefin Addition Sequence

substituents, such as a benzyl group, allowed the formation of the Friedel−Crafts product in 65% yield. A plausible mechanism for this transformation would involve the activation of imino ester 763 by the gold catalyst (acting as a σ-Lewis acid) for the attack of the furan ring 764 through its position 5 (Scheme 195). This attack would generate intermediate B, which would generate the aza-Diels−Alder product tricyclic intermediate C through the nucleophilic attack by the ortho position of the aromatic ring. Upon [1,3]-proton shift and coordination of the gold salt with the enol ether moiety (intermediate D), the nucleophilic addition of a second molecule of furan 764 would take place in a formal Friedel− Crafts-type process, subsequently releasing the final product 765 and regenerating the gold catalytic species. It is noteworthy that this tandem protocol constitutes a good example of the dual σand π-Lewis role of gold catalysts. 6.2.5. Miscellaneous Three-Component Povarov Reactions. As summarized in Scheme 196 and Table 2, some uncommon catalysts, including N,N-diethyl-1,1,1-trifluoro-λ4sulfanamine,345 nano silica chromic acid,346 Fe2(SO4)3· xH2O,347,348 and the ionic liquid [bmim]BF4,349catalyzed the classical Povarov reaction between arylamines 766, aryl aldehydes 767, and cyclic vinyl ethers 768 to deliver the corresponding diastereomeric THQs 769 and 770. A one-pot, catalyst- and solvent-free, microwave-assisted, three-component reaction allowed the synthesis of 3-spirotetrahydroquinolines 774 from 1-aminonaphthalene 771, aromatic aldehydes 772, and 5-benzylidene-1,3-dimethyl pyrimidine-2,4,6-trione 773 in high yields (Scheme 197).350 The reaction was found to be general and tolerated a broad range of substituents in the aldehyde and dienophile components. Rajanarendar and co-workers demonstrated a L-prolinecatalyzed, one-pot, three-component aza-Diels−Alder reaction for the synthesis of isoxazolyl-tetrahydroquinolines 778/779 and isoxazolo[2,3-a]pyrimidines starting from arylamines 775,

Scheme 196. Three-Component Povarov Reactions Promoted by Uncommon Catalysts

Table 2. Three-Component Povarov Reactions Promoted by Uncommon Catalysts

aldehydes 776, and nitrostyrylisoxazoles 777 (Scheme 198).351 The reaction was highly efficient and gave high yields of the products diastereoselectively. In this organocatalytic protocol, the arylamines 775 reacted with L-proline-activated aldehydes BC


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Scheme 197. Povarov Reactions Employing Knoevenagel Products as Dienophiles

Scheme 200. Ultrasound-Promoted Povarov Reaction of Anilines, Isatins, and Maleic Anhydride

Scheme 198. Povarov Reaction Catalyzed by L-Proline

with maleic anhydride 783 in the presence of InCl3 in PEG 400 as a green solvent under ultrasonication, or under reflux conditions. The formation of the complex spiro-tetrahydroquinoline products 784 was achieved in good yields, in short reaction times, and without the generation of any side products. The synthesized compounds were evaluated for their antimicrobial and analgesic activities, and some of the compounds showed promising results. Propylphosphonic anhydride (T3P) was found to be an efficient catalyst for the Povarov reactions of aldimines generated from arylamines 785 and aryl aldehydes 786 with dihydropyran or dihydrofuran 787 to afford the corresponding pyrano- and furo[3,2-c]quinolines 788 and 789 in high yields with high diastereoselectivity in a short reaction time (Scheme 201).353 The broad functional group tolerance, low tendency toward epimerization, and easy workup due to the good water solubility of side products make this reagent interesting in the development of synthetic methodology.

776 to give aldimines, which then reacted with nitrostyrylisoxazoles 777 to furnish the desired products. The mechanism proposed by the authors to explain the formation of compounds 778 and 779 is summarized in Scheme 199. Proline would promote the reaction between arylamines Scheme 199. Mechanistic Proposal To Explain the ProlineCatalyzed Povarov Reaction

Scheme 201. Povarov Reactions Catalyzed by Propylphosphonic Anhydride

775 and aldehydes 776 via iminium catalysis to deliver the imine intermediate A. Subsequently, proline would promote a Michael−Mannich domino process between intermediate A and compounds 777 to generate intermediate B containing all stereocenters, which would finally cyclize with loss of proline. Ultrasound irradiation promoted the reaction of arylamines 780, indole-2,3-diones 781, and maleic anhydride 783 (Scheme 200).352 The in situ-generated imine intermediate 782 reacted BD


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6.3. Four-Component Povarov Reactions

Scheme 204. Mechanistic Explanation of the Isolation of 2Aryl-4-arylamino-1,2,3,4-tetrahydroquinoline Derivatives

We have developed a CAN-catalyzed AA′BC four-component reaction for the synthesis of trans-2-aryl-4-arylamino-1,2,3,4tetrahydroquinolines 793 from 2 equiv of 3,5-dimethylaniline 790, aromatic aldehydes 791, and vinyl ethers 792. Interestingly, the conventional Povarov adduct, namely cis-2-aryl-4-alkoxy1,2,3,4-tetrahydroquinolines 794, was not formed (Scheme 202).354 Subsequently, this methodology was extended to an Scheme 202. CAN-Catalyzed AA′BC Four-Component Povarov Reaction for the Synthesis of trans-2-Aryl-4arylamino-1,2,3,4-tetrahydroquinolines

ABCD four-component reaction involving two different arylamines. As shown in Scheme 203, 3,5-dimethylaniline 790 with ethyl vinyl ether 792 in the presence of CAN to generate the oxonium ion intermediate B. The expected intramolecular Friedel−Crafts-type reaction could not be achieved due to the steric interaction with the methyl substituent to deliver cis-2aryl-4-alkoxy-1,2,3,4-tetrahydroquinolines 794. Subsequent attack of the second arylamine 795 to intermediate B furnished iminium cation C, which again could not be cyclized to form the corresponding cis THQ derivative 797 for the steric reasons. On the other hand, owing to the hydrogen-bonding stability, intermediate C underwent conformational change to intermediate D, which cyclized to generate trans-2-aryl-4-arylamino1,2,3,4-tetrahydroquinoline derivatives 796. The previously mentioned commercially available, stable radical cation salt tris(4-bromophenyl)aminium hexachloroantimonate (TBPA•+) was investigated as a catalyst for the synthesis of 2-methyl-4-anilino-1,2,3,4-tetrahydroquinolines 800 and 801. Arylamines 798 reacted with a variety of Nvinylamines 799 in the presence of TBPA•+ to furnish the target molecules 800/801 via initial formation imines from 1 equiv of the amine and 1 equiv of N-vinylamine 799 (Scheme 205).356 In this transformation, TBPA•+ acted as both Lewis acid and oneelectron oxidant. A one-pot synthesis of quinolines via a TBPA•+-catalyzed THQ formation−aromatization sequence was also reported.357 Jia and co-workers developed a simple and efficient AA′BB′ Povarov reaction for the synthesis of 2,3,4-trisubstituted tetrahydroquinolines 804 from readily available arylamines 802 and aldehydes 803 and in the absence of additional reagents or catalysts (Scheme 206).358 A possible mechanism for this

Scheme 203. CAN-Catalyzed ABCD Four-Component Povarov Reaction for the Synthesis of trans-2-Aryl-4arylamino-1,2,3,4-tetrahydroquinolines

reacted with benzaldehyde 791a, ethyl vinyl ether 792, and the second arylamine 795 to afford trans-2-aryl-4-arylamino-1,2,3,4tetrahydroquinoline derivatives 796 in good to excellent yields. Stevenson and co-workers later reported a related approach for the synthesis of THQs involving yttrium triflate or triflic acid as catalysts.355 The formation of the 2-aryl-4-arylamino-1,2,3,4-tetrahydroquinoline derivatives 796 and the observed unusual trans diastereoselectivity could be explained via the proposed mechanism shown in Scheme 204. The imine A, generated from 3,5-dimethylaniline 790 and aryl aldehydes 791, reacted BE


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Scheme 205. Povarov Synthesis of 2-Methyl-4-anilino1,2,3,4-tetrahydroquinolines Catalyzed by Tris(4bromophenyl)aminium Hexachloroantimonate

Scheme 207. Application of a Tetrahydroquinoline Arising from the AA′BB′ Povarov Reaction to the Synthesis of Martinelline and Martinellic Acid

Scheme 208. Fe-Catalyzed AA′BB′ Povarov Reaction between Arylamines and Aliphatic Aldehydes Scheme 206. Catalyst-Free AA′BB′ Povarov Reaction between Arylamines and Aliphatic Aldehydes

3-methoxy group. The increase in the length of the aldehyde chain caused a decrease in yield of the reaction. The domino sequence leading to 804 or 811 is shown for the case of the latter compounds and presumably involved a stepwise Povarov mechanism, i.e., a Mannich reaction and an intramolecular Friedel−Crafts alkylation, followed by an intermolecular Friedel−Crafts alkylation. N-Substituted anilines 809 and aldehyde 810 would react to give iminium ion A, which would then react with iron(III) enolate B generated from aldehyde to deliver the Mannich adduct C. A subsequent FeCl3catalyzed intramolecular Friedel−Crafts ring closure would furnish the benzyl alcohol intermediate D, which would then generate the carbocation intermediate E. A final nucleophilic addition of another molecule of the starting N-substituted aniline 809 to E would finally afford tetrahydroquinolines 811 (Scheme 209). Huang and co-workers described a similar four-component AA′BB′ Povarov reaction between arylamines 812 and cyclopropyl aldehyde 813 for the synthesis of hexahydropyrroloquinolines 814 in high yields in the presence of NH4Br as the catalyst (Scheme 210).362 In almost all cases, a nearly 1:1 mixture of exo and endo diastereomers was obtained. In the proposed mechanism, the initially formed imine B underwent rearrangement to generate N-aryldihydropyrrole A, which upon [4+2] cycloaddition with another molecule of B afforded hexahydropyrroloquinolines 814. This domino protocol is advantageous in that the direct use of dihydropyrroles suffers

transformation involved the formation of a heterodiene (imine) starting from 1 equiv of the amine and the aldehyde, which would tautomerize into the corresponding enamine, acting as a dienophile. These intermediates would then undergo a [4+2] cycloaddition to afford the observed products 804. Subsequently this methodology was applied to the formal synthesis of the natural products (±)-martinelline and martinellic acid (Scheme 207). The bromination of THQ 805 with NBS in DCM provided the corresponding dibromo compound 806 in 80%. Subsequent treatment with hydrazine hydrate followed by 1 N HCl afforded the tricyclic skeleton of (±)-martinellic acid 807. An additional sequence of five straightforward steps afforded Ma’s intermediate 808359,360 for the synthesis of martinellic acid 36 and martinelline 37 (Figure 6, section 2) in good overall yields. Later, Liang and co-workers studied the use of FeCl3 as a catalyst for this transformation for the synthesis of polysubstituted tetrahydroquinolines 811 from simple N-substituted anilines 809 and aldehydes 810 (Scheme 208).361These authors screened the reaction with different Lewis acids such as Fe(NO3)3, Fe(acac)3, FeCl3, FeBr2, Sc(OTf)3, and InCl3 as well as Brønsted acids HSbF6·6H2O, TFA and TsOH and found that 0.3 equiv of FeCl3 in dry anisole was the optimal reaction conditions for this transformation. Aromatic amines with electron-donating groups on the benzene rings gave higher yields than those with electron-withdrawing groups, except the BF


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yields by generating two C−C and two C−N bonds. The mechanism proposed for the reaction involved a formal [4+2] cycloaddition reaction between β-enamino ester A, generated from arylamine 815 and methyl propiolate 816, and diarylimine B, obtained from arylamine 815 and aldehyde 817 (Scheme 212).

Scheme 209. Mechanism of the Fe-Catalyzed AA′BB′ Povarov Reaction

Scheme 212. Mechanism Proposed for the AA′BC Povarov Reaction

Scheme 210. AA′BB′ Povarov Reaction between Arylamines and Cyclopropyl Aldehyde

6.4. Intramolecular Povarov Reactions

Suitably substituted arylamines and aldehydes bearing tethered dienophiles undergo imine formation−intramolecular [4+2] cycloaddition sequences in the presence of a wide variety of catalysts to deliver complex fused tetrahydroquinoline derivatives in a single operation. Raghunathan and co-workers demonstrated an intramolecular Povarov reaction between arylamines 819 and N-allyltethered aldehydes 820 in the presence of InCl3 in acetonitrile at room temperature to generate pyrrolo-tetrahydroquinolines 821via intermediate A (Scheme 213).364,365 The structures of compounds 821 were characterized by spectroscopic techniques and single-crystal X-ray diffraction analysis of some of the products. The allylaminopyrimidine-5-carbaldehydes 822, bearing a C4 phenylthio group, reacted with arylamines to generate imine A, which underwent intramolecular hetero Diels−Alder cyclizations in the presence of a stoichiometric amount of p-TsOH in polar solvents such as acetonitrile/water at ambient temperature

from limitations in terms of low stability, which makes the presence of an N-protecting group indispensable. Yan and co-workers successfully established an AA′BC fourcomponent imino Diels−Alder reaction for the stereoselective synthesis of 2,3,4-trisubstituted THQs 818 (Scheme 211).363 The domino reaction of 2 equiv of arylamines 815, methyl propiolate 816, and aromatic aldehydes 817 in the presence of TsOH as a Brønsted acid furnished THQs 818 in moderate

Scheme 213. Intramolecular Povarov Reaction between Anilines and N-Allyl-Tethered Aldehydes

Scheme 211. AA′BC Povarov Reaction between Anilines, Methyl Propiolate, and Aromatic Aldehydes

BG


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to deliver benzo[b]pyrimido[4,5-h][1,6]naphthyridines 823 chemoselectively. On the other hand, epiminopyrimido[4,5b]azepine 824 was obtained from the same starting materials through an ene cyclization by using catalytic amounts of pTsOH in less polar solvents like benzene and toluene at elevated temperature (Scheme 214).366 DFT theoretical calculations

Scheme 215. Ph3P−HClO4-Catalyzed Intramolecular Povarov Reaction

Scheme 214. Acid-Controlled Divergent Processes Involving an Intramolecular Povarov Reaction and an Imine Formation/Intramolecular Ene Reaction Sequence

Scheme 216. CuBr2-Catalyzed Synthesis of 5,6Dihydrodibenzo[b,h][1,6]naphthyridines

showed that an iminium intermediate favors the low-energy intramolecular imino Diels−Alder pathway under acidic conditions. In the absence of acid, the imine intermediate favors the thermal ene-type cyclization reaction via transfer of an allylic proton from the allylic amine to the imine, followed by a nucleophilic addition process. The Ph3P−HClO4-catalyzed intramolecular Povarov reaction of arylamines 825 and 2-(N-alkenyl-N-aryl)aminochromone-3carbaldehyde 826 produced chromenonaphthyridines 827 and 828 (Scheme 215).367 The substituent on the alkenyl part of aminochromone controls the mode of reaction as well as the stereochemistry of the product. An endo approach of the dienophile is favored when R5 = Me, whereas the exo approach led to the formation of the trans-fused product when R5 = Ph. Nagaiah and co-workers also demonstrated a related synthesis of chromeno[4,3-b]quinoline derivatives involving Yb(OTf)3catalyzed intramolecular [4+2] imino-Diels−Alder reactions of 2-azadienes derived in situ from arylamines and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones in good yields, and the synthesized compounds were evaluated for their antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cells.56 We have reported a highly efficient synthesis of 5,6dihydrodibenzo[b,h][1,6]naphthyridines 831 by the reaction between 2-(N-propargylamino)benzaldehydes 829 and arylamines 830 in the presence of CuBr2(Scheme 216).368 The in situ generated electron-deficient heterodienes bearing a tethered

alkyne partner underwent an intramolecular Povarov reaction followed by air oxidation to furnish the desired products in high yields. This strategy was also extended to the synthesis of fused tetrahydroquinolines including 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones, which were obtained in high yields starting from 3-amino-2H-chromen-2-one. Recently, Beifuss and co-workers established a one-pot domino reduction−imine formation−intramolecular azaDiels−Alder reaction sequence for the diastereoselective synthesis of tetrahydrochromano[4,3-b]quinolines in good yields.369 Aryl nitro compounds 832 and 2-(cinnamyloxy)benzaldehydes 833 were treated with iron powder, citric acid, and montmorillonite K10 clay in water at 80 °C furnished the target compounds 834 in 69−87% yield (Scheme 217). An initial reduction of the nitro compounds to amines followed by reaction with aldehydes to generate the azadiene and a subsequent intramolecular Povarov reaction explains the formation of the observed products. 6.5. Oxidative Povarov Reactions

Miura and co-workers developed a facile synthesis of tetrahydroquinolines 837 and 839 through oxidative cyclization of N-methylanilines 835 with electron-deficient olefins 836 and 838 respectively (Scheme 218).370 N-Methylanilines 835 reacted with maleimide 836 in MeCN in the presence of BH


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Scheme 217. Intramolecular Povarov Reactions Starting from Nitroarenes and 2-(Cinnamyloxy)benzaldehydes

Scheme 219. Mechanism Proposed To Explain the Isolation of Tetrahydroquinolines from N-Methylanilines and Electron-Deficient Olefins

Scheme 218. Synthesis of Tetrahydroquinolines from NMethylanilines and Electron-Deficient Olefins by a CuPromoted Radical Process Scheme 220. Synthesis of Tetrahydroquinolines from Tertiary Amines Based on a Photoinduced Electron Transfer (PET) Process

A series of tetrahydroquinolines 845 with amido-substituted quaternary carbon centers were synthesized through an ironcatalyzed dehydrogenative [4+2] cycloaddition of tertiary anilines 843 and enamides 844 in the presence of FeCl3 as catalyst and TBHP as oxidant (Scheme 221).372 A possible Scheme 221. Synthesis of Tetrahydroquinolines by FeCatalyzed Dehydrogenative [4+2] Cycloaddition of Tertiary Anilines and Enamides

CuCl2 using air as the oxidant to furnish THQs 837 in high yields. Two examples of THQs 839 were also synthesized from N-methylanilines 835 and benzylidene malononitrile 838 under slightly modified conditions (CuCl2, O2, EtCN). The authors proposed a mechanism for this transformation initiated by a single electron transfer from N-methylaniline 835 to the copper complex, followed by deprotonation to generate the N-methylene radical B via radical cation A. Subsequent electrophilic radical addition to maleimide 836 and cyclization onto the aromatic ring would afford the corresponding cyclohexadienyl radical D via radical intermediate C, which would then readily rearomatize by a second electron transfer/ proton elimination step, leading to the formation of product 837 (Scheme 219). Similarly, Singh and co-workers reported a tetrahydroquinoline synthesis based on a photoinduced electron transfer (PET) process, allowing the sp3 C−H functionalization of tertiary amines. In this photocatalytic protocol, 1,3,4-trisubstituted tetrahydroquinolines 842 were obtained from tertiary amines 840 and α,β-unsaturated carbonyl compounds 841 (Scheme 220).371 The N,N-dimethylaniline precursors 840 were irradiated with a blue LED in the presence of the Ru(bpy)3Cl2 photocatalyst in degassed dry pyridine−MeOH (3:1) to generate α-amino alkyl radicals, which further underwent an alkylation/cyclization sequence with the α,β-unsaturated carbonyl compounds 841 to produce tetrahydroquinolines 842 in moderate yields.

mechanism for this reaction involves the generation of iminium species A by dehydrogenation of N-methylaniline 843 in the presence of [Fe]/TBHP system, followed by a Povarov reaction of enamide 844 and iminium cation A to give the final tetrahydroquinolines 845. In similar transformations, Zhang and co-workers developed a nanoporous catalytic system based on poly benzobisthiadiazole and employed it for the synthesis of fused 1,2,3,4-tetrahydroquinolines under photochemical conditions in high yields.373 A related synthesis of THQs was achieved involving the bis(1,10-phenanthroline)-copper(I) [Cu(dap)2]+-catalyzed direct α-C− H bond functionalization of amines under visible light and trifluoroacetic acid as cocatalyst. A variety of THQs were synthesized in moderate to good yields, and a free radical BI


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mechanism was proposed for the transformation.374 In addition, Eosin Y was also employed as a photocatalyst to trigger the radical reaction between N,N-dimethylanilines and maleimides to yield the corresponding THQs.375 Concurrently, Yadav and Yadav reported a similar transformation in the presence of K2S2O8 as the oxidant that led to THQs in very high yields.376 A number of authors have described additional Povarov-type reactions performed from N-alkylanilines under oxidative conditions for the synthesis of THQs 848. In one example of this kind of transformations, summarized in Scheme 222, Huo

Scheme 224. Alternative Mechanism That Explains the Isolation of Fused Tetrahydroquinolines from N,NDimethylanilines and Dihydrofuran

Scheme 222. Cobalt-Catalyzed Synthesis of Fused Tetrahydroquinolines from N,N-Dimethylanilines and Dihydrofuran

Scheme 225. Cu-Catalyzed Synthesis of Fullerene-Fused Tetrahydroquinolines and co-workers377 and Sakai and co-workers378 disclosed almost simultaneously a cobalt-catalyzed oxidative annulation of N,Ndimethylanilines 846 and olefins such as dihydrofuran 847 or maleimide. Two types of mechanisms were proposed to account for these results. In the first one, a cobalt-mediated oxidation of one of the N-methyl units of 846 in two one-electron-transfer steps leads to the formation of an iminium derivative A that subsequently gives a Povarov reaction with dihydrofuran 847 to deliver 1,2,3,4THQ 848 (Scheme 223). Alternatively, the radical species B, arising from the initial one-electron oxidation of the starting material 846, may add to the dihydrofuran 847 to furnish radical intermediate C, which would then become the final products 848 upon loss of one proton and one electron (Scheme 224). Chu and co-workers applied a similar reaction to achieve the synthesis of fullerene-fused tetrahydroquinolines 851 starting from N,N-dimethylanilines 849 and [60]-fullerene 850 using the CuCl2/air catalytic system (Scheme 225).379 The reaction was proposed to take place through a CuCl2-mediated singleelectron-transfer (SET) process for Csp3−H bond activation followed by a radical mechanism similar to the one summarized in Scheme 219. The same transformations, with maleimides as the dienophile component, have been achieved under photochemical con-

ditions, using visible light with chlorophyll as a catalyst380 or using UV-CFL bulbs in the absence of catalyst.381 In the latter case, the reaction was driven by the photochemical activity of an electron donor−acceptor (EDA) complex. In the same vein, Guan and co-workers developed a photochemical synthesis of tetrahydroquinoline derivatives 854 from N,N-dimethylanilines 852 and Knoevenagel adducts 853 using Rose Bengal 855 as catalyst under visible light (Scheme 226).382 Rose Bengal (RB) absorbs a photon to form the excited-state RB*, which interacts

Scheme 223. Mechanistic Proposal To Explain the Isolation of Fused Tetrahydroquinolines from N,N-Dimethylanilines and Dihydrofuran

BJ


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Scheme 226. Visible Light-Promoted Photochemical Synthesis of Tetrahydroquinolines from N,NDimethylanilines and Knoevenagel Adducts

Scheme 228. Alternative Cu-Catalyzed Synthesis of Tetrahydroquinolines from N,N-Dialkylanilines through a Povarov-like SET Process

the combination of CuBr with TBHB was identified as the ideal system for proposed transformation. The N-arylamine precursors 859 generated iminium ion in the presence of CuBr/ TBHP catalytic system, which further underwent inverse electron-demand aza-Diels−Alder cyclizations with enamides and enol ethers 860 to afford tetrahydroquinolines 861 in moderate yield and diastereoselectivity. Xu and co-workers described a visible-light photocatalyzed oxidation for an inverse electron-demand aza-Diels−Alder reaction via an iminium intermediate (Scheme 229).387 This

with O2 to generate singlet oxygen (1O2) via energy transfer. The 1 O2 thus generated then reacts with N,N-dimethylaniline 852 via SET, initiating a radical Povarov-like reaction similar to the one summarized in Scheme 224. Tummatorn and co-workers discovered that benzylic azides can generate transient N-aryliminium species under acidic conditions at room temperature.383 In the course of efforts to apply this chemistry to the synthesis of heterocyclic systems, these authors developed a regio- and diastereoselective Povarovlike synthesis of 3,4-disubstituted tetrahydroquinolines 858 via a formal [4+2] cycloaddition of N-aryliminium ions A, generated in situ from benzylic azides 856 and nucleophilic alkenes 857 in the presence of triflic acid under mild conditions (Scheme 227).384 The reaction of trans-stilbene gave the corresponding

Scheme 229. Synthesis of Dibenzo[af ]quinolizines Based on a Ru-Catalyzed Photocatalytic Oxidation of N,NDialkylanilines

Scheme 227. Synthesis of Tetrahydroquinolines by [4+2] Cycloaddition of N-Aryliminium Ions Generated in Situ from Benzylic Azides reaction proceeded through simultaneous functionalization of both sp3C−H and sp2C−H bonds. The precursor N-aryl1,2,3,4-tetrahydroisoquinolines 862 underwent photocatalytic oxidation to form iminium ion intermediates and their subsequent [4+2] cycloaddition with various alkenes 863 (cyclic and acyclic enamides and enol ethers) in the presence of Ru(bpy)3Cl2 and BrCCl3 under blue LED to deliver the corresponding fused THQs 864. Electron-withdrawing substituents in the phenyl ring gave better yields (72−90%) than the respective electron-donating groups. The reaction was found to be highly diastereoselective and afforded the products with dr >20:1 in all cases. In related work, additional polycyclic systems derived from the dibenzo[af ]quinolizine framework and containing a tetrahydroquinoline subunit (compounds 867) were obtained via metal-free, amine-catalyzed oxidative cross-dehydrogenative coupling/intramolecular hydroarylation of N-aryltetrahydroisoquinolines 865 and crotonaldehyde 866 (Scheme 230).388 After a detailed optimization study, the authors successfully employed catalyst 868, together with benzoic acid and DDQ, to afford the products in good yields and diastereoselectivities. The aldehyde function was subsequently reduced with sodium borohydride to afford the stable compounds 867 in good yields.

tetrahydroquinolines as a single trans diastereomer in good yields, whereas cis-stilbene provided a mixture of cis- and transtetrahydroquinolines in 1:1 ratio and in moderate combined yield. Previously, Gigant and Gillaizeau also reported a related approach for the diastereoselective synthesis of poly-functionalized fused tetrahydroquinolines starting from benzyl azides and enamides in moderate to good yields under acidic conditions.385 Seidel and co-workers reported the synthesis of THQs 861 via activation of both sp3C−H and aryl sp2C−H bonds of N-aryl dialkylamines 859 through a SET process (Scheme 228).386 After a detailed optimization study involving various catalysts that included CuCl, CuBr, CuI, CuCl2, CuBr2, and Cu(OTf)2, BK


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reaction published almost simultaneously.390 Consequently, in this section we will update the progress of the enantioselective Povarov reaction by covering the papers published after this period. 6.6.1. Reactions Catalyzed by Chiral Phosphoric Acids. Brønsted acids are in principle good catalysts for the Povarov reaction since they can promote both the formation of imines from aldehydes and amines and their reaction with nucleophiles, and hence the interest in the study of chiral Brønsted acids as catalysts for the Povarov reaction. With the aim of performing the first enantioselective Povarov reaction using indole as the dienophile, Zhu and Sun examined the reaction of indole, benzaldehyde, and 3,5-dimethoxyaniline in the presence of chiral phosphoric acids, but they obtained only complex mixtures. Reasoning that the presence of an ortho hydrogen bond acceptor such as an ether group on the aldehyde component may orient the transition state and facilitate the desired process, they eventually found that the presence of an oxetane ring promotes the three-component reaction. Using the optimized conditions, they were able to synthesize a broad range of polycyclic alkaloid-type molecules that contain indoline, tetrahydroquinoline, and tetrahydroisoquinoline moieties and bear four stereogenic centers (compounds 875) from anilines 871, o-(oxetan-3-yl)benzaldehydes 872, and indoles 873, in the presence of the chiral phosphoric acid derivative 876 via the intermediacy of 874 (Scheme 232).391

Scheme 230. Organocatalyzed Synthesis of Dibenzo[af ]quinolizines from NAryltetrahydroisoquinolines in the Presence of DDQ

The mechanism proposed for this transformation is summarized in Scheme 231 and started with the activation of Scheme 231. Mechanistic Explanation of the DDQ-Promoted Organocatalytic Synthesis of Dibenzo[af ]quinolizines

Scheme 232. Enantioselective Brønsted Acid-Catalyzed Povarov Reactions Using Indole as the Dienophile

crotonaldehyde 866 by the organocatalyst 868 to generate dienamine A. This intermediate then trapped the iminium derivative B, arising from DDQ oxidation of the starting material 865, and afforded the unsaturated iminium ion C, which underwent an intramolecular hydroarylation to furnish 869. Finally, hydrolysis of the enamine function in the latter intermediate furnished the aldehyde 870 and closed the catalytic cycle by regenerating the catalyst 868.

Liu has developed an enantioselective domino hydroamination/Povarov reaction in the presence of a chiral metal phosphate 879, starting from secondary aminoalkynes 877. This method, which can be viewed as a enantiospecific version of a reaction developed simultaneously by Li and discussed previously (Scheme 66),164 provided atom-economical access to tetracyclic octahydro-dipyrroloquinoline frameworks 878 (Scheme 233) and was applied to achieve the first synthesis of the biologically active alkaloids incargranine B aglycone epimer in two steps.392 The Ag salt of the phosphoric acid was the

6.6. Asymmetric Synthesis of Chiral 1,2,3,4-Tetrahydroquinolines via the Povarov Reaction

Bernardi and co-workers reviewed in 2014 the application of catalytic asymmetric Povarov reactions to the synthesis of chiral 1,2,3,4-THQs, covering the literature until mid-2013,389 and Waldmann and co-workers also gave some coverage to the topic in a more general review of the asymmetric hetero-Diels−Alder BL


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step of the hydroamination/Povarov domino sequence was probably stepwise, in view of the isolation of the Mannich intermediate in one of the experiments. Min and Seidel envisioned a catalytic kinetic resolution method for the enantioselective intramolecular Povarov reaction using a chiral phosphonic acid catalyst 883. The Oallylsalicylaldehyde derivatives 880 and 2-arylindolines 881 afforded polycyclic tetrahydroquinoline derivatives 882, with four stereogenic centers (Scheme 235).393 In this process, one enantiomer of the indoline reacts preferentially, resulting in a high enantio- and diastereoselectivity (>20:1 dr, up to 98% ee).

Scheme 233. Enantioselective Domino Intramolecular Hydroamination/Povarov Reaction Catalyzed by a Chiral Metal Phosphate

Scheme 235. Catalytic Kinetic Resolution Based on an Enantioselective Intramolecular Povarov Reaction

optimal catalyst. The corresponding copper(I), copper(II), and gold phosphates showed a lower reactivity, although the stereoselectivity was excellent. As shown in Scheme 234, the stereochemical outcome of this transformation was controlled by the formation of a chiral counteranion-iminium ion pair. The formal [4+2] cycloaddition Scheme 234. Mechanism Proposed for the Hydroamination/ Povarov Domino Process

Mazzanti and co-workers synthesized three chiral phosphoric acid catalysts, 890a−c, which exhibited atropisomerism in the 3,3′-positions, and compared their reactivity with that of commercially available chiral phosphoric acid catalysts 887− 889 by testing them in an enantioselective Povarov reaction between N-4-methoxyphenyl aldimine 884 and 2-vinylindole 885a or 1-amidodiene 885b. The highly hindered catalyst 887 affords very good enantioselectivity (98%, ee), whereas the 9anthracenyl derivative 888, bearing flat substituents, is less efficient (66%, ee), and the 1-naphthyl-substituted catalyst 889 affords intermediate results (81% ee). The 2-methyl-1-naphthylderived catalysts 890a−c were found to give 1,2,3,4-tetrahydroquinolines 886 in moderate to good enantioselectivities (Scheme 236).394 As summarized in Scheme 237, Shi and co-workers described the use of chiral phosphoric acid 895 as a catalyst for asymmetric Povarov reactions between anilines 891, aldehydes 892, and 3methyl-2-vinylindoles 893. These reactions provided access to chiral indole-derived tetrahydroquinolines 894 with three contiguous stereogenic centers in high yields (up to 99%) and with excellent diastereo- and enantioselectivities (>95:5 dr, up to 96% ee). In most cases, electron-poor benzaldehydes displayed much higher reactivity and enantiocontrol.395 Shi and co-workers also developed an asymmetric Povarov reaction from isatin-derived imines 896 and 3-vinylindoles 897 in the presence of the chiral phosphoric acid 899 in o-xylene at 45 °C to furnish indolyl-substituted spiro[indolin-3,2′-quinolines] 898 in high yields (Scheme 238). This protocol tolerated a wide range of substrates with generally excellent diastereoseBM


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Scheme 236. Enantioselective Povarov Reactions Catalyzed by Atropoisomeric Brønsted Acids

Scheme 237. Enantioselective Povarov Reactions from Anilines, Aldehydes, and 2-Vinylindoles Catalyzed by a Chiral Phosphoric Acid

Scheme 238. Enantioselective Synthesis of IndolylSubstituted Spiro[indolin-3,2′-quinolines] from IsatinDerived Imines and 3-Vinylindoles

lectivities (up to >95:5 dr) and good enantioselectivity (89:11 er).396 Moran and co-workers developed a two-step, one-pot procedure for the enantioselective synthesis of tetrahydroquinolines 902 involving the isomerization of N-allylcarbamates 900 by a nickel catalyst, followed by an enantioselective phosphoric acid-catalyzed Povarov reaction with imines 901 in the presence of 10 mol% of the commercially available BINOL-derived phosphoric acid 903. This reaction afforded a series of enantioenriched tetrahydroquinolines 902 in good yields and good diastereomeric and enantiomeric ratios (Scheme 239).397 Recently, the BINOL-derived chiral phosphoric acids 907 were investigated as catalysts for Povarov reactions starting from ferrocenecarbaldehyde-derived imines 904 and several electronrich dienophiles 905, such as N-vinyl carbamate, (E)-prop-1-en1-ylcarbamate, dienecarbamate, and 2-vinyl- and 3-vinylindoles (Scheme 240).398 Thus, the reactions catalyzed by chiral phosphoric acid derivative 907c, at 0.1−1 mol% amounts, in toluene at room temperature, afforded ferrocenyl-1,2,3,4tetrahydroquinolines 906 in good to excellent yields, almost exclusively as the 2,4-cis-diastereoisomer (dr >95:5) and with

90−99% enantiomeric excess. Similar yields and enantioselectivities were observed for a three-component process under similar reaction conditions. In this case, a decrease in the amount of catalyst from 0.1 mol% to 0.01 mol% also gave satisfactory results, although it required an increase in the reaction time from 6 to 24 h. Similarly, Retich and Bräse used glyoxylate imines 908, derived from electron-rich arylamines and 3-vinylindoles 909, for the synthesis of indole-substituted tetrahydroquinolines 910 and 911 using 10 mol% of a chiral phosphoric acid 912 in dichloromethane at room temperature (Scheme 241).399 On the other hand, related glyoxylate imines gave bisindole piperidine derivatives when reacted with 3-vinylindoles under similar reaction conditions. The chiral catalyst (S)-912 gave enantiomer 910, whereas (R)-912 gave the opposite enantiomer 911 BN


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Masson and co-workers synthesized a series of trisubstituted tetrahydrochromeno[4,3-b]quinolin-6-ones and tetrahydrodibenzo[1,6]naphthyridin-6-ones 915 via enantioselective intramolecular Povarov reactions in the presence of the chiral phosphoric acid catalyst 916 (Scheme 242).400 2-Aminophenols

Scheme 239. Enantioselective Synthesis of Tetrahydroquinolines by an N-Allylcarbamate Isomerization/Asymmetric Povarov Sequence

Scheme 242. Enantioselective Synthesis of Tetrahydrochromeno[4,3-b]quinolin-6-ones and Tetrahydrodibenzo[1,6]naphthyridin-6-ones via Intramolecular Povarov Reactions

Scheme 240. Enantioselective Povarov Reactions from Ferrocenecarbaldehyde-Derived Imines and Several Electron-Rich Olefins

913 and 2-formyl phenyl acrylates 914a (X = O) were successfully transformed into the corresponding tetrahydrochromeno[2,3-d]pyrimidines 915a in good yields and with excellent diastereo- and enantioselectivities. The methodology was then extended to linear amide substrates 914b (X = N) for the synthesis of enantiomerically enriched hexahydrobenzo[1,6]naphthyridinone derivatives 915b. These compounds 915 were further functionalized into chemically diverse heterocycles through well-established reactions. 6.6.2. Reactions Catalyzed by Chiral (Thio)ureas. Compounds containing an acidic functionality in addition to an anion-recognition site act as powerful conjugate basestabilized Brønsted acid catalysts. In this context, Seidel and co-workers reported the application of this concept to the Povarov reaction, achieving the first catalytic enantioselective three-component reaction of indolines 917 and other secondary aromatic amines with aldehydes 918 and N-vinylpyrrolidin-2one 919 for the synthesis of fused tetrahydroquinoline derivatives 920 in the presence of catalyst 921 with good to excellent yields and enantioselectivities (ee = 79 to 99%), as shown in Scheme 243.401 The same group next applied their conjugate-base-stabilized carboxylic acid chiral catalyst concept to intramolecular Povarov reactions by studying the reaction of indolines 922 and other secondary-aniline-type amines with O-allylsalicylaldehyde derivatives 923 or their sulfur analogues to afford bioactive tetrahydrochromanoquinolines 924 with high diastereo- and enantioselection (Scheme 244).402 O-Allylsalicylaldehyde derivatives with different substituents, thiosalicylaldehyde-derived starting materials and indolines with both electron-withdrawing and electron-releasing groups were tolerated.

Scheme 241. Enantioselective Povarov Reactions from Aromatic Glyoxylate Imines and 3-Vinylindoles

and, as expected, a racemic mixture was obtained using racemic phosphoric acid as catalyst. BO


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Scheme 243. Enantioselective Synthesis of Fused Tetrahydroquinolines from Indolines, Aldehydes, and NVinylpyrrolidin-2-one in the Presence of a Chiral Thiourea

Scheme 245. Enantioselective Povarov Reactions Using a Dual Brønsted Acid/Chiral Thiourea Catalytic System

Scheme 244. Synthesis of Complex Fused Tetrahydroquinolines Based on an Intramolecular Povarov Reaction the Si face of the imine, since the Re face is shielded by both the triisopropylsilyl and tert-butyl groups of the catalyst, leading to the preferential formation of endo-tetrahydroquinolines (Scheme 246).404 Scheme 246. Enantioselective Povarov Reactions Catalyzed by a Chiral Cobalt Complex

Jacobsen and co-workers developed dual catalytic systems comprising a chiral sulfinamidourea 930 and an achiral strong Brønsted acid (o-nitrobenzenesulfonic acid 931) for the highly enantioselective synthesis of tetrahydroisoquinolines. The enantioselective Povarov reactions of benzaldimines 925 with vinylpyrrolidinone 926 in the presence of this catalytic system afforded the corresponding trans-pyrrolidinyl-substituted tetrahydroquinolines 927 with high enantioselectivities and diastereoselectivities. Similarly, exo-tricyclic hexahydropyrrolo-[3,2c]quinolines 929 were obtained under the same conditions through the cyclization of N-Cbz-protected 2,3-dihydropyrroles 928 (Scheme 245).403 6.6.3. Cobalt-Catalyzed Enantioselective Reactions. Gong and co-workers have demonstrated that the sodium salts of anionic chiral Co(III) complexes 935 are good catalysts for the asymmetric Povarov reaction of imines 932 with various dienophiles 933, such as 2,3-dihydrofuran, ethyl vinyl ether, and an N-protected 2,3-dihydropyrrole, furnishing structurally diverse endo-tetrahydroquinolines 934 with excellent diastereoselectivities (up to >20:1 dr) and high enantioselectivities (up to 95:5 er). The sodium cation, in combination with the weakly coordinating chiral anion, acts as a Lewis acid to activate the intermediate imine by coordinating with its nitrogen. The [4+2] cycloaddition with 2,3-dihydrofuran preferentially occurs from

́ 6.6.4. Enantioselective Domino Reactions. Rodriguez de Lera and co-workers demonstrated a straightforward new three-component cascade reaction catalyzed by a gold complex 940 and a chiral BINOL-derived phosphoric acid 941 for the enantioselective synthesis of hexahydrofuro[3,2-c]quinolines 939 (Scheme 247). This process involves the in situ generation of dihydrofurans that will act as dienophiles from alkynols 938 by intramolecular hydroalkoxylation in the presence of an Au catalyst. These intermediates, then form the chiral hexahydrofuro[3,2-c]quinolines 939 with in situ generated BP


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Scheme 247. Domino Process Comprising an Intramolecular Hydroalkoxylation and an Enantioselective Povarov Reaction

Scheme 248. Enantioselective Synthesis of Spirooctahydroacridine-3,3′-oxindoles

imines from arylamines 936 and aldehydes 937 in the presence of the BINOL-derived phosphonic acid 941. A wide range of substrates with different substitution patterns reacted smoothly to afford the corresponding products with excellent yields, diastereoisomeric ratios ranging from 20:1 to 3:1, and good to excellent enantioselectivities (99:1 to 92:8 er). In contrast to previous related reports, this method allows access to the exo isomer of compounds 939.405 Wu and Wang developed a domino reaction for the enantioselective synthesis of spirooctahydroacridine-3,3′-oxindole scaffolds 945 from 3-substituted oxindoles 942, α,βunsaturated aldehydes 943, and aniline derivatives 944 using the Hayashi diphenylprolinol silyl ether 946 as catalysts and chiral phosphonic acid 947 as additives. All these reactions proceeded smoothly, affording the desired spirooctahydroacridine-3,3′oxindole derivatives 945 in good yields (30−89% yield) with excellent diastereoselectivities (5:1 to >20:1 dr) and excellent enantioselectivities (84 to >99% ee). Irrespective of the substituent present in the aniline and the chain length of α,βunsaturated aldehydes, the domino reaction proceeded efficiently and stereoselectively, although lower yields and decreased stereocontrol were observed when cinnamaldehyde was used (Scheme 248).406

Scheme 249. Synthesis of Tetrahydroquinolines via a SingleElectron-Transfer (SET) Process

Scheme 250. Mechanism Proposed for the SET-Based Synthesis of Tetrahydroquinolines

7. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES INVOLVING THE GENERATION OF THREE OR MORE BONDS: MISCELLANEOUS APPROACHES N-Substituted anilines 948 reacted with 2 equiv of N-substituted lactams 949 through a SET process in the presence of FeCl3 as catalyst and TBHP as oxidant to afford the ring-fused tetrahydroquinoline derivatives 950 (Scheme 249).407 In this method, three new bonds (two C−C, one C−N bond) were generated via multiple cross-dehydrogenative-coupling reactions in a single operation. The iminium ions A and B were generated from lactam 949a in the presence of the FeCl3/t-BHP catalytic system via a SET process (Scheme 250). Subsequently, aniline 948a gave a Friedel−Crafts reaction with iminium ion A, followed by nucleophilic attack on the iminium ion B to deliver intermediate C. Finally, C underwent pyrrolidone elimination to produce

intermediate D, which afforded ring-fused tetrahydroquinoline 950a after a further SET oxidative process. Lee and co-workers achieved the synthesis of diversely substituted tetrahydroquinolines 953 using a one-pot, threecomponent reaction between arenediazonium salts 951, styrenes 952, and nitriles (Scheme 251).408 The first step is the formation of arylnitrilium intermediates A, which were attacked by styrenes 952 via a Povarov-like reaction to provide intermediate 3,4-dihydroquinolinium salts B. Finally, these BQ


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generated in situ from copper(II) chloride, sodium tetrakis[3,5bis(trifluoromethyl)phenyl]borate (NaBArF), and chiral spirobisoxazoline ligands 959 (Scheme 253). This reaction provided the first example of a highly enantioselective intramolecular N−H bond insertion.412

Scheme 251. Synthesis of Tetrahydroquinolines by a ThreeComponent Reaction between Arenediazonium Salts, Styrenes, and Nitriles

Scheme 253. Asymmetric Synthesis of Tetrahydroquinolines by an Enantioselective Intramolecular N−H Bond Insertion

iminium intermediates were reduced in situ in the presence of sodium borohydride to afford the tetrahydroquinolines 953 in moderate to good yields. Other alkylnitriles such propionitrile, 2-methylpropionitrile, and butyronitrile provided yields of tetrahydroquinoline in the 60−78%, range, but in the case of higher alkyl (R = butyl, hexyl) and aromatic (R = Ph) nitriles, product formation was not observed. A similar transformation was promoted by UV light in the presence of N-methyldihydroacridine as a photocatalyst.409

Zhao reported the first enantioselective synthesis of tetrahydroquinolines based on the borrowing hydrogen (hydrogen autotransfer) methodology, which involves a domino sequence of oxidation, condensation, and reduction reactions without the use of an external reductant or oxidant. Thus, in the presence of a chiral phosphoric acid 962 and an achiral iridacycle complex 963 as catalysts, aminoalcohols 960 were transformed into enantioenriched tetrahydroquinolines 961 (Scheme 254).

8. ADDITIONAL METHODS FOR THE ASYMMETRIC SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES 8.1. One-Bond Formation

Scheme 254. Enantioselective Synthesis of Tetrahydroquinolines Based on the Borrowing Hydrogen Concept

8.1.1. Formation of the N−C2 Bond. Sző llő si and coworkers showed that 2-nitrophenylpyruvates 954 could be transformed into 3-hydroxy-3,4-dihydroquinolin-2(1H)-ones 955 in enantioselectivities up to 90% by catalytic hydrogenation of both the nitro and keto groups using a Pt catalyst in the presence of a Cinchona alkaloid derivative 956, followed by spontaneous lactonization (Scheme 252).410 The same group later disclosed a detailed study of the influence of reaction conditions on this asymmetric heterogeneous domino reaction.411 The enantioselective synthesis of chiral 2-carboxytetrahydroquinoline derivatives 958 was achieved by Zhu and Zhou from the diazo derivatives 957 in the presence of a chiral species Scheme 252. Enantioselective Synthesis of 3-Hydroxy-3,4dihydroquinolin-2(1H)-ones by Reduction of 2Nitrophenylpyruvates

The proposed mechanism involves oxidation of the alcohol by hydrogen transfer to the Ir catalyst, intramolecular imine formation, and asymmetric reduction of the latter by the reduced iridium catalyst under the influence of the chiral Brønsted acid.413 Liao and co-workers have described a regio- and enantioselective conjugate addition of arylboronic acids to β,γunsaturated α-ketoamides such as 964 in the presence of a combination of a rhodium salt and a simple chiral sulfinylphosphine ligand 967. This reaction furnished γ,γ-diaryl BR


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hydrogenation using the Hantzsch ester 975 as a hydride donor (Scheme 257).416 After optimizing the reaction in batch

ketoamide 965, which is a useful synthetic building block and was readily transformed into enantiomerically pure tetrahydroquinoline-2-carboxylamide 966 by reductive cyclization (Scheme 255).414

Scheme 257. Enantioselective Photocyclization−Reduction Process from Aminochalcones

Scheme 255. Enantioselective Synthesis of Tetrahydroquinolines Based on a Regio- and Enantioselective Conjugate Addition of Arylboronic Acids to β,γ-Unsaturated α-Ketoamides

conditions, and due to the advantages of microflow photochemical processes, the authors also developed a flow setup for carrying out the reaction.417 Denmark has developed a method for the sulfeno functionalization of an alkene with an electrophilic sulfur reagent 979, with concomitant intramolecular attack by a tosylaniline nucleophile, which allows the enantioselective transformation of substrates 977 into tetrahydroquinolines 978. The enantioselectivity of the method is due to the use of a chiral selenophosphoramide basic catalyst 980, which was coupled to a Brønsted acid cocatalyst (Scheme 258). Besides tetrahydroquinolines, other chiral benzo-fused nitrogen heterocycles were accessible by this method, including indolines and tetrahydrobenzazepines.418

Lautens and co-workers achieved a domino process giving access to enantioenriched tetrahydroquinolinone building blocks 970.415 This transformation is initiated by a Rh-catalyzed conjugate arylation of an arylboronic acid 969 onto the unsaturated amide moiety in 968, followed by a Pd-catalyzed C−N cross-coupling process (Scheme 256). In this reaction, it is Scheme 256. Enantioselective Arylboronic Acid Conjugate Arylation/Pd-Catalyzed N-Arylation Process

Scheme 258. Synthesis of Tetrahydroquinolines by Olefin Sulfeno-Functionalization/Intramolecular Nucleophilic Attack by a Tosylaniline

noteworthy that a compatible combination of achiral and chiral ligands (971 and 972) was used for the sequential Rh/Pd catalysis, allowed by the absence of ligand interference and different rates of catalysis. Rueping developed an asymmetric photocyclization−reduction domino process from aminochalcones 973 using the chiral phosphoric acid catalyst 976. The photocyclization of the starting chalcone yielded the chiral ion pair A, which was transformed on the target compounds 974 by transfer

Fustero and Sánchez-Roselló developed an intramolecular aza-Michael reaction starting from carbamates 981 tethered to a conjugated ketone moiety that acts as a Michael acceptor. This organocatalytic strategy allowed the enantioselective synthesis of a number of nitrogen heterocycles, including tetrahydroquinolines 982 (Scheme 259). The transformation was performed in the presence of 9-amino-9-deoxyepihydroquinine 983 as the catalyst and pentafluoropropionic acid (PFP) as a co-catalyst.419 BS


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Scheme 259. Enantioselective Synthesis of Tetrahydroquinolines Based on an Intramolecular Michael Addition

Scheme 261. Enantioselective Synthesis of 2-Substituted Tetrahydroquinolines by Intramolecular Hydroamination/ Transfer Hydrogenation

In a related strategy, Liu and Feng reported a one-pot process comprising an intramolecular aza-Michael reaction and a bromination, which afforded enantio-enriched 2-substituted-3bromo-1,2-dihydroquinolin-4-ones 985 from starting materials 984. The good to excellent level of enantioselection achieved in this transformation came from the use of the chiral bisguanidine derivative 986 as an organocatalyst (Scheme 260).420

Sudalai has developed an organocatalytic method for the synthesis of chiral derivatives of 3-hydroxy-1,2,3,4-tetrahydroquinolines in good to excellent yields and ee values up to 99%.424 The enantioselective α-aminooxylation of compounds 991 was achieved by their treatment with nitrosobenzene in the presence of L-proline, and that was followed by reductive cyclization with concomitant hydrogenolysis of the N−O bond, leading to compounds 992 (Scheme 262). A similar organocatalytic

Scheme 260. Synthesis of 3-Bromo-1,2,3,4tetrahydroquinolines by Enantioselective Intramolecular Michael Addition/Bromination

Scheme 262. Enantioselective Synthesis of 3-Substituted Tetrahydroquinolines by α-Aminooxylation/Reductive Cyclization

Gold catalysis has been widely employed to cyclize o(alkynylmethyl)anilines 987 to tetrahydroquinolines 988 via hydroamination/transfer hydrogenation. When these reactions are performed in the presence of chiral catalysts, they give access to enantiomerically enriched 2-substituted tetrahydroquinolines. Thus, Han has described the transformation of substrates 987 into compounds 988 in the presence of the Hantzsch ester as a hydrogen donor and a chiral gold catalyst generated in situ from IMesAuMe (IMes: 990) and a BINOL-based phosphoric acid 989 (Scheme 261). In this case, the gold catalyst promotes both the hydroamination step, acting as a π-Lewis acid, and the asymmetric hydrogen-transfer process, acting as a chiral Lewis acid.421,422 Similarly, Shi and co-workers have recently demonstrated the synthesis of 4-acyloxy-1,2-dihydroquinolines via a gold(I)-catalyzed tandem [3,3]-rearrangement−intramolecular hydroamination sequence of propargylic esters in good yields and enantioselectivities. One of the synthesized compounds was hydrogenated into the corresponding 1,2,3,4THQs using LAH.423

process using an azodicarboxylate as the electrophile afforded derivatives of the 3-amino-1,2,3,4-tetrahydroquinoline framework, and this method was applied to the synthesis of compounds with pharmacological interest, including the inotropic agent (S)-903 (993). In another example of the synthesis of chiral tetrahydroquinoline derivatives by cyclization of a chiral precursor, Ramachary has described the use of a combination of L-phenylalanine with the quinidine-thiourea derivative 997 as an organocatalyst for the Michael addition of acetone to o-azidonitrostyrenes 994. The resulting adducts 995 were then cyclized into THQs 996 by reductive amination, induced by their treatment with BT


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triethylsilyl hydride in the presence of indium trichloride (Scheme 263).425

Scheme 264. Enantioselective Synthesis of Tetrahydroquinolin-2-ones by N-Deprotection− Lactamization of a Chiral Precursor

Scheme 263. Enantioselective Synthesis of 2,4-Disubstituted Tetrahydroquinolines by Reductive Cyclization of a Chiral Precursor

Scheme 265. Enantioselective Synthesis of Tetrahydroquinolines by Asymmetric Conjugate Addition− Cyclization of N-Protected o-Aminophenyl α,β-Unsaturated Aldehydes In a related method, Wennemers found that the quinidineurea catalyst 1002 promoted the enantioselective Michael addition of a β-dicarbonyl compound 999 onto the N-protected o-aminonitrostyrenes 998. Compounds 1000 thus generated were then cyclized by one-pot N-deprotection−lactamization, under acidic conditions, to give 1,2,3,4-THQs 1001 (Scheme 264). By using protected phenols as starting materials instead of compounds 998, this method could also be applied to the synthesis of dihydrocoumarins.426 Cinnamaldehyde derivatives bearing an ortho nitrogen function are also suitable substrates for the preparation of chiral tetrahydroquinolines as single enantiomers. Thus, Kim carried out the asymmetric conjugate addition-cyclization reaction of Nprotected o-aminophenyl α,β-unsaturated aldehydes 1003 and malonic ester derivatives 1004 in the presence of the Hayashi− Jørgensen catalyst 1007 to furnish 1,2,3,4-THQs 1005. Their deoxygenation with triethylsilane as a hydride donor, in the presence of boron trifluoride etherate, led to 4-substituted chiral tetrahydroquinolines 1006 (Scheme 265).427 In a somewhat more complex example starting from the same type of materials, the same group achieved the synthesis of chiral cyclopropane-fused tetrahydroquinolines 1010 from compounds 1003 and α-bromomalonic esters 1008 using the method summarized in Scheme 266. Treatment of 1003 and 1008 with triethylamine in the presence of the Hayashi− Jørgensen catalyst 1007 afforded the chiral formylcyclopropane intermediates 1009, which were finally transformed into the final products 1010 by base-induced intramolecular attack of the carbamate nitrogen onto the formyl group.428 The bioactive alkaloid (+)-angustureine 1 was synthesized by Pandey and co-workers using the strategy summarized in Scheme 267. An initial Sonogashira coupling of o-iodonitrobenzene 1011 and chiral alkyne 1012 was followed by catalytic

hydrogenation, which achieved the one-pot reduction of the triple bond, transformation of the nitro group into a primary amine, and deprotection of the benzyl group. The resulting amino alcohol 1013 was cyclized under Mitsunobu conditions to yield norangustureine, which was finally transformed into the natural product (+)-angustureine 1 by reductive methylation with formaldehyde.429 Hopkins and Wolfe demonstrated the use of a catalyst composed of Pd2(dba)3 and (S)-Siphos-PE 1017 for promoting enantioselective Pd-catalyzed alkene carboamination reactions between anilines derivatives 1014 with an alkene function tethered to the aromatic o- position and aryl or alkenyl halides BU


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Scheme 266. Enantioselective Synthesis of CyclopropaneFused Tetrahydroquinolines

Scheme 268. Enantioselective Synthesis of Tetrahydroquinolines by Enantioselective Pd-Catalyzed Alkene Carboamination Reactions

Scheme 269. Enantioselective Synthesis of Fused Tetrahydroquinolines Based on the Asymmetric tert-Amino Effect Induced by a Cinchona-Derived Secondary Amine Scheme 267. Enantioselective Synthesis of (+)-Angustureine from a Chiral Alkyne

1015 for the synthesis of chiral THQs 1016 (Scheme 268).430 These reactions are particularly efficient in that they generate a C−N bond, a C−C bond, and a stereocenter. 8.1.2. Formation of the C2−C3 Bond. Kim has developed an organocatalytic domino process that allows the enantioselective transformation of compounds 1018, containing both a cyclic amine and an α,β-unsaturated ketone, into ring-fused tetrahydroquinolines 1019. The reaction products arose from a Csp3−H bond functionalization at an α-N position and were isolated in moderate yields and diastereoselectivities but with high levels of enantioselectivity (up to 97% ee).431 The reaction was proposed to start with the formation of an iminium species A from 1018 and the catalyst 1020, followed by an intramolecular 1,5-hydride transfer to yield B, which finally becomes the final product 1019 by enantioselective enamineiminium 6-endo-trig cyclization (Scheme 269). The same group later reported a similar transformation using an aldehyde 1021 as a substrate lacking the side-chain unsaturation. They generated the conjugated CC double bond in situ using a catalytic Saegusa oxidation, and in this case,

following precedent from their own laboratory,116 they employed the Hayashi−Jørgensen catalyst 1023 to promote the enantioselective hydride transfer/cyclization step to access the chiral THQs 1022 (Scheme 270).432 In a related procedure, they also reported the use of IBX under acidic conditions as an oxidant to generate the required enal moiety.433 Finally, as yet another alternative, the same group showed that the enal function could be generated in situ by oxidation of an allylic alcohol 1024 with a catalytic amount of the Ley−Griffith TPAP catalyst in the presence of oxygen to regenerate the perruthenate species (Scheme 271).434 Akiyama described another example of an asymmetric Csp3− H bond functionalization mediated by an internal redox process, catalyzed in this case by a chiral phosphoric acid. Thus, treatment of the starting arylmethylene malonate derivative 1025 with either biphenyl phosphoric acid derivatives (S)-1027 or binaphthyl phosphoric acids (R)-1028 in toluene afforded BV


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quinolizine derivatives 1030 from suitable starting materials 1029 using chiral phosphoric acid catalyst 1031 (Scheme 273).436

Scheme 270. Enantioselective Synthesis of Fused Tetrahydroquinolines Based on the Asymmetric tert-Amino Effect Induced by the Hayashi Catalyst

Scheme 273. Enantioselective Synthesis of Dibenzo[af ]quinolizines Based on the Asymmetric tertAmino Effect Induced by a Chiral Brønsted Acid

Scheme 271. Related Method Including the in Situ Generation of the Starting Enal

Almost simultaneously with the Akiyama study, Feng described a similar 1,5-hydride transfer/cyclization sequence of o-dialkylamino-substituted benzylidene malonates 1032 to give tetrahydroquinolines 1033 in the presence of a catalytic amount of the chiral bispiperidine-N,N′-dioxide Co(II) complex 1034 (Scheme 274).437

tetrahydroquinolines 1026.435 By studying the stereochemical outcome of reactions having as substrates the two possible enantiomers of a compound bearing a methyl group at the benzylic position of 1025, the authors proved that the initial internal redox process involves the enantioselective activation of proton Hα, leading to A. A final 6-endo-trig cyclization completes the formation of the observed products 1026 (Scheme 272). One year later, Luo disclosed the application of the same methodology to the synthesis of natural product-like dibenzo-

Scheme 274. Enantioselective Synthesis of Tetrahydroquinolines Based on the Asymmetric tert-Amino Effect Induced by a Chiral Bispiperidine-N,N′-dioxide Co(II) Complex

Scheme 272. Enantioselective Synthesis of Tetrahydroquinolines Based on the Asymmetric tert-Amino Effect Induced by a Chiral Brønsted Acid

The related chiral catalyst 1037 was later employed by Feng to achieve the synthesis of spiro-tetrahydroquinolines 1036 from 3-arylmethylene oxindoles 1035, as shown in Scheme 275.438 Other groups have carried out the same transformation using alternative catalysts, such as chiral Brønsted acids.439 Finally we will mention the work by Anderson on the reductive cyclization of 2-iminonitrostyrenes 1038 with a Hantzsch ester 1040 as hydride donor in the presence of a bifunctional thiourea catalyst 1041 to give the cis-2-aryl-3nitrotetrahydroquinolines 1039 as single diastereoisomers, in high yields and enantioselectivities (Scheme 276).440 This BW


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Scheme 275. Enantioselective Synthesis of 3-Spirotetrahydroquinolines Based on the Asymmetric tert-Amino Effect Induced by a Chiral Bispyrrolidine-N,N′-dioxide

Scheme 277. Enantioselective Synthesis of Tetrahydroquinolines by an Asymmetric Intramolecular Benzoin Reaction Catalyzed by an N-Heterocyclic Carbene

Scheme 278. Enantioselective Synthesis of Tetrahydroquinolines by a Pd-Catalyzed Domino Process from Tethered Allenyl Aldehydes and Arylboronic Acids

Scheme 276. Enantioselective Synthesis of Tetrahydroquinolines from 2-Iminonitrostyrenes in the Presence of a Bifunctional Thiourea Catalyst

8.1.4. Formation of the C4−C4a Bond. Giera and Schneider studied the InCl3-catalyzed Friedel−Crafts reactions of chiral compounds 1047, with an allyl chloride tethered to an N-aryl moiety. These reactions provided 1,2,3,4-tetrahydroquinolines 1048 with good yields, moderate to excellent diastereoselectivities, and good to excellent enantioselections (Scheme 279).443

transformation took place by initial conjugate hydride addition to the nitroolefin moiety, followed by an intramolecular nitroMannich reaction, with simultaneous generation of two stereocenters. 8.1.3. Formation of the C3−C4 Bond. Jia and You carried out the synthesis of chiral tetrahydroquinolines 1043 starting from aldehydes 1042 via an enantioselective intramolecular benzoin reaction catalyzed by a N-heterocyclic carbene generated in situ by deprotonation of the chiral δ-camphorderived triazolium salt 1044 (Scheme 277).441 The main challenge found in developing intramolecular benzoin reactions as a route to tetrahydroquinolines and other cyclic systems is the possibility of a competing use of a intramolecular aldol reaction, but the authors found that this problem was minimized when the transformation was performed in the presence of a weak base such as sodium acetate. Han and co-workers reported a Pd-catalyzed domino process starting from tethered allenyl aldehydes 1045 and arylboronic acids that yields chiral tetrahydroquinolines 1046 in good to excellent diastereoselectivities in favor of the cis isomer and good to excellent enantiomeric excesses, although the absolute configuration of the favored product was not determined. After studying several chiral phosphines, the authors chose (R)BINAP as the source of chirality due to its commercial availability (Scheme 278).442

Scheme 279. Enantioselective Synthesis of Tetrahydroquinolines by Intramolecular Friedel−Crafts Reactions on a Chiral Substrate

Saget and Cramer explored the synthesis of chiral tetrahydroquinolines by Pd-catalyzed enantioselective intramolecular C−H arylations of cyclopropanes using chiral ligand 1051.444 In the course of this work, the reaction summarized in Scheme 280 was developed, leading to chiral cyclopropanefused tetrahydroquinolines 1050 from substrates 1049 via the formation of seven-membered palladacycle intermediates. This transformation was presumably facilitated by the higher sBX


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Scheme 280. Enantioselective Synthesis of Tetrahydroquinolines by Pd-Catalyzed Asymmetric Intramolecular C−H Arylations of Cyclopropanes

Scheme 282. Enantioselective Synthesis of Tetrahydroquinolines by Ir-Catalyzed Asymmetric Allylic Alkylation/Intramolecular Heck Coupling

character of the cyclopropane C−H bonds, which increases their acidity in comparison to other similar aliphatic bonds.445 Feringa has investigated the synthesis of chromenes and tetrahydroquinolines via a sequence of allylic alkylation and intramolecular Heck coupling reactions. Thus, the coppercatalyzed asymmetric allylic alkylation of compounds 1052 with Grignard reagents was achieved in the presence of the chiral ligand Taniaphos 1056 with excellent regio- and enantioselectivities to access compounds 1053. A subsequent intramolecular Heck reaction afforded the tetrahydroquinoline derivatives 1054, together with small amounts of their isomers with an endocyclic double bond 1055 (Scheme 281).446

approach to chiral 2-substituted tetrahydroquinolines that was applied to the total syntheses of the alkaloids (+)-angustureine 1 and (−)-cuspareine 2 (Scheme 283).

Scheme 281. Enantioselective Synthesis of Tetrahydroquinolines by Pd-Catalyzed Asymmetric Allylic Alkylation/Intramolecular Heck Coupling

Scheme 283. Enantioselective Total Synthesis of the Alkaloids (+)-Angustureine and (−)-Cuspareine

Hii has used a related procedure to achieve the synthesis of (+)-angustureine 1, (−)-galipinine 4, and the structure proposed at that time for (−)-galipeine 3a, another member of the same family of alkaloids. In this case, the key tetrahydroquinoline C-2 stereocenter was established by a Pdcatalyzed aza-Michael reaction of aniline onto substrate 1061 in the presence of the (R)-BINAP complex 1064 as a chiral Lewis acid. The resulting compound 1062 was cyclized in reductive conditions to yield tetrahydroquinoline 1063, which was transformed into the natural products using an eight-step sequence (Scheme 284).448 The authors noted that the optical rotation of an enantiomerically pure sample of synthetic galipeine thus obtained is larger than that reported for the natural isomer, an observation that was explained by a subsequent revision of the structure of (−)-galipeine to the

In a conceptually similar approach, Satyanarayana studied the iridium-catalyzed regio- and stereoselective allylic amination of allylic carbonates with 2-haloanilines. This reaction furnished chiral allylic N-substituted anilines 1057, which were transformed into the corresponding terminal boranes A by treatment with 9-BBN; finally, an intramolecular Suzuki−Miyaura coupling yielded tetrahydroquinolines 1058 (Scheme 282).447 This strategy provides a protecting-group-free, two-step BY


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genation of the initially obtained dihydroquinoline (Scheme 286).450

Scheme 284. Enantioselective Synthesis of 2,4-Disubstituted Tetrahydroquinolines by Asymmetric Pd-Catalyzed AzaMichael Reaction/Reductive Friedel−Crafts Alkylation

Scheme 286. Enantioselective Synthesis of Tetrahydroquinolines by Pt-Catalyzed Intramolecular Electrophilic Hydroarylation of a Chiral Precursor

8.1.5. Formation of the N−C8a Bond. Davies has used his chiral lithium amide conjugate addition methodology to synthesize the proposed structure of (−)-galipeine, finding, as previous authors,448 a discrepancy in the optical rotation value, and also some subtle differences in the spectral data of the synthetic material and the reported data for the natural product. In an effort to explain these discrepancies, the synthesis of a regioisomer of the proposed structure was carried out as shown in Scheme 287. The aza-Michael addition of the lithium amide

regioisomeric 3-methoxy-4-hydroxyphenyl derivative (see Scheme 287 below).10 Sotomayor has described the synthesis of 4-substituted tetrahydroquinolines 1066 by intramolecular Michael addition of aryllithium species obtained by iodine−lithium exchange on N-alkenyl 2-iodoanilines 1065. When the reaction was carried out in the presence of (−)-sparteine or a sparteine surrogate, modest levels of enantioselection were observed (Scheme 285).449

Scheme 287. Synthesis and Structural Reassignment of (−)-Galipeine Initiated by a Chiral Lithium Amide Conjugate Addition

Scheme 285. Synthesis of 4-Substituted Tetrahydroquinolines by Intramolecular Michael Addition of an Aryllithium

Palomo has described an asymmetric Mannich reaction of aldehydes 1067 and unactivated imines 1068 in the presence of a combination of a Brønsted acid and chiral α,α-dialkyl prolinol derivatives 1071. This organocatalytic transformation provides anti adducts 1069 with 9:1 diastereoselectivity and ee values usually above 95% for the major diastereomer. One of these compounds was transformed into the fused tetrahydroquinoline 1070 by N,O-double protection of the amino alcohol moiety in the presence of carbonyldiimidazole followed by Pt-catalyzed intramolecular electrophilic hydroarylation and catalytic hydroBZ


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1072 onto the unsaturated Weinreb amide 1073 gave compound 1074, which, following partial nitrogen deprotection by selective removal of the N-α-methyl-p-methoxybenzyl group to give 1075, was submitted to an intramolecular Buchwald− Hartwig amination that furnished the chiral tetrahydroquinoline 1076. From this point, a three-step sequence of reactions afforded compound 3b, which was identical to the natural (−)-galipeine in all respects, leading to the structural reassignment of this alkaloid.10 In a work primarily addressed at the synthesis of enantiomerically pure indolines, Yu and Cai have reported a method that allows the highly enantioselective synthesis of tetrahydroquinolines 1078 by desymmetrization of 1,3-bis(2-iodoaryl)pentan-2amines 1077via a copper-catalyzed intramolecular Ullmann C− N coupling in the presence of the chiral BINOL-derived catalyst 1079 (Scheme 288).451 Cai later showed that these conditions

Scheme 289. Synthesis of a Chiral Tetrahydroquinoline by an Intramolecular Copper-Catalyzed Ullmann C−N Coupling

Scheme 288. Enantioselective Synthesis of Tetrahydroquinolines by a Desymmetrization Process Based on an Enantioselective Intramolecular Ullmann C−N Coupling

Scheme 290. Synthesis of a Chiral Tetrahydroquinoline by an Intramolecular Copper-Catalyzed Ullmann C−N coupling

Scheme 291. Enantioselective Synthesis of Spiro OxindoleTetrahydroquinolines Based on an Aza-Michael/Michael Domino Reaction Catalyzed by a Chiral Bifunctional Cinchona-Squaramide Catalyst

were adequate for performing kinetic resolutions of the starting materials and related prochiral secondary amines.452 Subsequent work by the Cai group showed that, by starting with the cyanobearing substrate 1080, the asymmetric desymmetrization strategy was also useful for the construction of tetrahydroquinolines bearing an all-carbon quaternary stereocenter 1081 (Scheme 289).453,454 Within the scope of work aimed at the asymmetric synthesis of chiral heterocyclic amino acids, Wang and Liu reported one example of an intramolecular copper-catalyzed Ullmann C−N coupling reactions that afforded the chiral tetrahydroquinoline 1084 from substrate 1083 (Scheme 290).455 Similarly, Foubelo, Yus, and co-workers used a Pd-catalyzed intramolecular Narylation reaction as the key step for the synthesis of alkaloids (−)-angustureine and (−)-cuspareine from chiral tert-butylsulfinyl imines.456

alized spiro oxindole-tetrahydroquinolines 1087 in excellent yields and diastereoselectivities (>25:1 dr), and also with high enantioselectivities (up to 94% ee). Zhao and co-workers explored a related formal [4+2] annulation strategy for the diastereoselective construction of spiro oxindole-tetrahydroquinolines 1091 starting from o-(pmethylbenzenesulfonamide)-α,β-unsaturated ketones 1089 and methyleneindolinones 1090 involving a chiral thiourea catalyst. After a detailed screening, the authors identified that the catalyst 1092 was the most efficient to deliver the products in high yields (up to 99%) and enantioselectivities up to 94% (Scheme 292).458

8.2. Two-Bond Formation

8.2.1. Formation of the N−C2 and C3−C4 Bonds. Yang and Du described a similar aza-Michael/Michael domino process starting from of (2-tosylaminophenyl)enones 1085 and 3-ylidenoxindoles 1086, catalyzed by a chiral bifunctional Cinchona-related tertiary amine-squaramide catalyst 1088 for the synthesis of chiral spiro-THQs 1087 (Scheme 291).457 This reaction proceeded under mild conditions and yielded functionCA


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Scheme 292. Enantioselective Synthesis of Spiro OxindoleTetrahydroquinolines Based on an Aza-Michael/Michael Domino Reaction Catalyzed by a Chiral Thiourea Catalyst

Figure 20. Transition state proposed to explain the isolation of the spiro pyrazolone-tetrahydroquinolines.

Scheme 294. Enantioselective Synthesis of Tetrahydroquinolines by an Aza-Michael−MichaelLactonization Strategy Using a Chiral N-Heterocyclic Carbene as Catalyst

In related work, the same group has disclosed a reaction of the starting materials 1093 with unsaturated pyrazolones 1094 to furnish chiral spiro pyrazolone-tetrahydroquinolines 1095 with three contiguous stereocenters in excellent yields, with generally good diastereo- and enantioselectivities (Scheme 293). As in the Scheme 293. Enantioselective Synthesis of Spiro PyrazoloneTetrahydroquinolines Based on an Aza-Michael/Michael Domino Reaction Catalyzed by a Chiral Bifunctional Cinchona-Squaramide Catalyst

By changing the nature of the electrophile, Du has also discovered a method for the preparation of highly enantiomerically enriched tetrahydroquinolines bearing a 3-nitro quaternary stereocenter (compounds 1103) from (2-tosylaminophenyl)enones 1101 and nitro olefins 1102 via a Michael−Michael sequence in the presence of catalyst 1104 (Scheme 295),461 which other authors have also performed in a supercritical fluid.462 Using similar Michael−Michael chemistry but employing a catalyst where squaramide had been replaced by a thiourea fragment (1108), Kim and co-workers have reported the preparation of chiral 3-nitro-1,2,3,4-tetrahydroquinolines 1107 Scheme 295. Enantioselective Synthesis of Tetrahydroquinolines by a Michael−Michael Strategy in the Presence of a Bifunctional Quinidine-Squaramide Catalyst

previous example, this domino aza-Michael/Michael process was performed in the presence of a chiral bifunctional organocatalyst 1096 containing both a Cinchona alkaloid framework and a squaramide fragment, which was proposed to generate the transition state depicted in Figure 20.459 Hui has developed an enantioselective aza-Michael−Michaellactonization domino sequence of reactions that transforms (2′tosylaminophenyl)enones 1097 and 2-bromoenals 1098 into functionalized chiral tetrahydroquinolines 1099, using as catalyst a N-heterocyclic carbene generated by deprotonation of compound 1100 (Scheme 294).460 CB


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starting from compounds 1105 and 1106 (Scheme 296).463,464 Recently, Wang and co-workers reported the synthesis of

Scheme 297. Enantioselective Synthesis of Tetrahydroquinolines from by 2-Amino-β-nitrostyrenes and Aldehydes in the Presence of the Hayashi Catalyst

Scheme 296. Enantioselective Synthesis of Tetrahydroquinolines by a Michael−Michael Strategy in the Presence of a Bifunctional Quinidine-Thiourea Catalyst

1117 in the presence of a dihydroquinidine derivative as catalyst gave spiro-tetrahydroquinoline-oxindole derivatives 1118 via an enantioselective Michael−Michael domino process (Scheme 298).468

tetrahydroquinolines containing a 2-CF3 substituent using a related approach in high yields and excellent enantio- and diastereoselectivities.465 Zlotin has used this reaction to test the efficiency of bifunctional tertiary amine-squaramides designed to work as catalysts in reactions performed in carbon dioxide. Among them, compounds 1109 and 1110 promoted the desired reaction at significantly lower pressure (75 bar) and temperature (35 °C) than previously known, less lipophilic catalysts (Figure 21).466

Scheme 298. Enantioselective Synthesis of SpiroTetrahydroquinoline-Oxindoles from Tosylamino-βnitrostyrenes and Oxindole Derivatives

Figure 21. Chiral bifunctional tertiary amine-squaramides catalysts tested for the synthesis of tetrahydroquinolines by Michael−Michael strategy.

An enantio- and diastereoselective organocatalytic intramolecular nitro-Mannich reaction was developed starting from ortho-functionalized nitroalkanes 1119 and aldehydes 1120. In the presence of a bifunctional tertiary amino-thiourea catalyst 1122, trans-2-aryl-3-nitro-tetrahydroquinoline products 1121 were obtained in high yields and generally good enantioselectivities (Scheme 299).469 The chiral transition state formed due to supramolecular interactions between an intermediate imine (arising by condensation of 1119 and 1120) and the catalyst 1122 is shown in Figure 22. Jørgensen has reported an interesting synergistic combination of palladium catalysis and organocatalysis for the enantioselective synthesis of highly substituted tetrahydroquinolines 1125 from vinyl benzoxazinanones 1123 and acrolein derivatives 1124 (Scheme 300).470 The proposed mechanism starts with the formation of palladium intermediate A from the starting vinyl benzoxazinanone 1123 followed by acid-promoted decarboxylation to yield the palladium−π-allyl complex B. This

Nitrostyrenes bearing a suitable amino or protected-amino group at the phenyl ortho position are also good substrates for the synthesis of tetrahydroquinolines by enantioselective organocatalytic domino reactions. Thus, Kim and Lee studied the reaction of 2-amino-β-nitrostyrenes 1111 with aldehydes 1112 in the presence of diphenylprolinol TMS ether 1115 to yield fully substituted chiral tetrahydroquinolines 1113 via an enamine Michael addition/hemiaminal formation domino process (Scheme 297).467 The presence of the 2-hydroxy substituent made these compounds suitable starting materials for the synthesis of chiral 1,4-dihydroquinolines 1114, which are not readily accessible using other methodologies. In a related transformation described by Zhu, the reaction of 2-tosylamino-β-nitrostyrene 1116 and oxindole derivatives CC


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Scheme 299. Enantioselective Synthesis of Tetrahydroquinolines by an Organocatalytic Intramolecular Nitro-Mannich Reaction

Scheme 301. Mechanism Proposed for the Combination of Transition-Metal Catalytic and Organocatalytic Cycles

Figure 22. Chiral transition state formed by the bifunctional organocatalyst in the enantioselective intramolecular nitro-Mannich reaction.

this intermediate, the Re face of the enolate is shielded by the methyl group, and it is thus the Si face of the enolate that attacks the less sterically hindered Re face of A, creating two stereocenters in the same step (Scheme 302). Interestingly, Gong reported almost simultaneously the preparation of very similar chiral 1,2,3,4-tetrahydroquinolin-2ones by employing as nucleophiles ammonium enolates, generated in situ from the attack of tertiary amines onto the starting carboxylic acid, previously activated as a mixed anhydride.472 Another synthesis of closely related chiral 1,2,3,4-tetrahydroquinolin-2-ones 1134 in the presence of the P-chiral monophosphorus ligand 1135 (BI-DIME)has been described by Tang and Deng (Scheme 303).473 As continuation of their work on the chemistry of Cu− allenylidene species generated in situ from 4-ethynylbenzoxazinanones, Cao and Wu have demonstrated the synthesis of unusual frameworks containing a tetrahydroquinoline core fused with a butyrolactone moiety 1138 and featuring three adjacent stereogenic centers. Their method involved the use of compounds 1136 and 5-substituted 2-silyloxyfurans 1137 as starting materials in the presence of chiral ligand 1139 (Scheme 304).474 In related work, Shao You proved that indole derivatives 1141 were also efficient nucleophiles for this transformation, allowing the synthesis of tetrahydro-5H-indolo[2,3-b]quinolines 1142, a framework that is of significance because it constitutes the core structure of some families of indole alkaloids such as the communesins using ligands 1143 and CuI (Scheme 305).475 Using a similar concept and starting from the benzoxazinanone starting materials 1144 and methyleneindolinones 1145, Mei and Shi have developed a synthesis of chiral spirotetrahydroquinolines 1146, structurally related to compounds 1118 described above, in good yields and with excellent

Scheme 300. Enantioselective Synthesis of Tetrahydroquinolines by Combination of Pd Catalysis and Organocatalysis

intermediate then undergoes an enantioselective 1,4-addition to the iminium-ion activated α, β-unsaturated aldehyde C furnishing intermediate D. Finally, an enamine-catalyzed ringclosure reaction, with concomitant release of the catalyst, yields the final product 1125 (Scheme 301). From similar starting materials 1127 and arylacetic acids 1128, Cao and Wu have developed a synthesis of the chiral 3aryl-4-ethynyl-1,2,3,4-tetrahydroquinolin-2-ones 1129 in the presence of a combination of the chiral catalysts 1130 and 1131, which also act in a synergistic fashion by combining transitionmetal catalysis and organocatalysis.471 Thus, the reaction of the ethynylbenzoxazinanones 1127 and chiral pyridinyl-bis(oxazoline) ligand (Pybox) 1130 in the presence of Cu(I) was proposed to furnish the Cu−allenylidene complex A. On the other hand, the arylacetic acid 1128 would react with the benzotetramisole-type Lewis base 1131 to furnish Z-enolate B, where the oxygen atom is positioned syn to the sulfur atom. In CD


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Scheme 302. Enantioselective Synthesis of 3-Aryl-4-ethynyl1,2,3,4-tetrahydroquinolin-2-ones by Synergistic TransitionMetal Catalysis and Organocatalysis

Scheme 304. Enantioselective Synthesis of Tetrahydrofuro[3,2-b]quinolin-2(3H)-ones in the Presence of a Bis-oxazoline Chiral Ligand

Scheme 305. Enantioselective Synthesis of Tetrahydro-5Hindolo[2,3-b]quinolines in the Presence of a Bis-oxazoline Chiral Ligand

Scheme 303. Enantioselective Synthesis of 1,2,3,4Tetrahydroquinolin-2-ones via Intermediate Ammonium Enolate Nucleophiles

of optically active 1,2,3,4-THQs. The reaction involved a Lewis acid-catalyzed Friedländer reaction between 2-aminoarylaldehydes or ketones 1153 and enolizable carbonyl compounds 1154 to deliver quinolines 1155, followed by a transfer hydrogenation from the Hantzsch ester catalyzed by the chiral Brønsted acid to afford THQs 1156 via intermediate A (Scheme 308).479 Thus, the enantiomerically enriched chiral tetrahydroquinolines 1159 were obtained by the combination of a Friedländer synthesis of quinolines, achieved from compounds 1157 and 1158, with their in situ asymmetric reduction with Hantzsch ester 1161 as a hydride donor in the presence of chiral Brønsted acids 1160 (Scheme 309). Hodik and Schneider described an enantioselective method for the synthesis of 1,4-dihydroquinoline-3-carboxylates 1164 from o-quinone methide imines, generated in situ from o-

diastereo- and enantioselectivities in the presence of the chiral phosphine 1147 (Scheme 306).476 Another aza-Michael−Michael reaction sequence allowed the combination of o- amino α, β-unsaturated ketones 1148 with nitrostyrenes 1149 in the presence of the quinidine-thiourea organocatalyst 1152. This reaction afforded the diastereomeric tetrahydroquinolines 1150/1151 in moderate to excellent diastereo- and enantioselectivities (Scheme 307).477,478 Gong and co-workers explored a relay catalytic Friedländer condensation/transfer hydrogenation process for the synthesis CE


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Scheme 306. Enantioselective Synthesis of Spirotetrahydroquinolines in the Presence of a Chiral Phosphine Catalyst

Scheme 308. Concept of a Tetrahydroquinoline Synthesis by Sequential Friedländer Reaction/Enantioselective Hydrogenation

Scheme 309. Enantioselective Synthesis of Tetrahydroquinolines by Combination of a Friedländer Reaction with in Situ Asymmetric Reduction with a Hantzsch Ester in the Presence of a Chiral Brønsted Acid

Scheme 307. Enantioselective Synthesis of Tetrahydroquinolines from o-Amino α,β-Unsaturated Ketones and Nitrostyrenes

311),481 and Patil has achieved a similar synthesis of chiral 2substituted tetrahydroquinolines 1175 using a complex, threecomponent catalytic system formed by Au(I) catalyst 1177, an amine, and a chiral Brønsted acid 1176 (Scheme 312).482 Scheidt has developed a synthesis of chiral 3-substituted 1,2,3,4-tetrahydroquinolin-2-ones 1180 based on a dual activation approach. In this method, carboxylic acids 1179 acted as precursors to N-heterocyclic carbene enolates by in situ activation in the presence of catalyst 1181. Simultaneously, a reactive aza-o-quinone methide was generated from precursor 1178 under the basic reaction conditions, and the final products would be generated by a formal [4+2] process, either concerted or proceeding by a stepwise Michael addition−annulation sequence (Scheme 313).483 Recently, Mei and Shi described another approach to chiral tetrahydroquinolines based on the formation of intermediate oquinone methide imines, which in this case arose from the dehydration of precursors 1182. The [4+2] cycloaddition

aminobenzhydryl alcohols 1162, and β-keto esters 1163 under chiral phosphoric acid catalysis 1166 (Scheme 310).480 One of the compounds 1164 was hydrogenated and deprotected to furnish the corresponding tetrahydroquinoline 1165 in good yield and diastereoselectivity using hydrogen in combination with both palladium on charcoal and Pearlman’s catalyst. The relative configuration of the hydrogenated products 1165 was confirmed by NOESY experiments. In related methods, Che has almost simultaneously developed a one-pot asymmetric process based on a gold(I)/Brønsted acid cooperative system, again using Hantsch ester 1172 as a hydride donor, to provide highly enantio-enriched tetrahydroquinolines 1169/1170 with one or two stereogenic centers (Scheme CF


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Scheme 310. Enantioselective Synthesis of 1,4Dihydroquinoline-3-carboxylates from in Situ-Generated oQuinonimine Methides

Scheme 312. Enantioselective Synthesis of Tetrahydroquinolines Based on the Use of a ThreeComponent Catalytic System

Scheme 313. Enantioselective Synthesis of 1,2,3,4Tetrahydroquinolin-2-ones by a Formal [4+2] Cycloaddition onto an Aza-o-quinone Methide

Scheme 311. Gold(I)/Brønsted Acid Cooperative Catalysis for the Enantioselective Synthesis of Tetrahydroquinolines

Scheme 314. Alternative Approach to Chiral Tetrahydroquinolines Based on the Formation of Intermediate Aza-o-quinone Methides

reaction of these intermediates with styrene derivatives 1183 in the presence of the chiral Brønsted acids 1185 afforded the final products 1184 with excellent diastereoselection and acceptable enantioselections (Scheme 314).484 8.2.2. Formation of N−C8a and C2−C3 Bonds. Guo has combined an asymmetric Zn-mediated allylation of chiral N-tertbutylsulfinyl imines with an intramolecular C−N cross-coupling reaction to achieve the synthesis of 2,3-disubstituted-4methylene-1,2,3,4-tetrahydroquinolines 1189 with excellent diastereoselections and good to excellent enantioselectivities (Scheme 315).485 The required precursors 1188 were prepared

from allyl bromides 1186 and chiral imines 1187 in the presence of Zn and LiCl. CG


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Scheme 315. Enantioselective Synthesis of Tetrahydroquinolines by Zn-Mediated Allylation of Chiral N-tert-Butylsulfinyl Imines/Intramolecular C−N CrossCoupling

Scheme 317. Enantioselective Synthesis of Tetrahydroquinolines by an Asymmetric Michael−Mannich Domino Process with Malononitrile as the Nucleophile

the presence of DDQ as an oxidant to deliver THQs 1199 (Scheme 318).488 Scheme 318. Synthesis of Tetrahydroquinolines by Intramolecular Cross-Dehydrogenative Coupling of a Chiral Precursor in the Presence of DDQ

8.2.3. Formation of C2−C3 and C3−C4 Bonds. Michael− aza Henry domino processes starting from aromatic imines bearing an o-enone side chain (compounds 1190) were used for the asymmetric synthesis of tetrahydroquinolines 1191. In one example of the application of this strategy, the starting material 1190 was made to react with nitromethane in the presence of the quinidine-thiourea catalyst 1192 (Scheme 316).486 In a closely related example (Scheme 317), the nucleophile was malononitrile, and stereoselection came from the use of the chiral thiourea bifunctional catalyst 1195.487 Scheme 316. Enantioselective Synthesis of Tetrahydroquinolines by an Asymmetric Michael−Aza Henry Domino Process with Nitromethane as the Nucleophile

8.3. Formation of Three Bonds

Luo and Huang reported the efficient synthesis of chiral tetrahydroquinolines 1203 containing two quaternary stereogenic centers via a four-component AA′BB′ Povarov-type cyclization reaction catalyzed by a chiral phosphoric acid 1204. The initial study was carried out with anilines 1201 and pyruvates 1202 (Scheme 319), but the authors later showed that “hybrid” AA′BC reactions using two different anilines are also possible (Scheme 320).489 Sun has developed a four-component domino sequence comprising asymmetric α-aminoxylation, aza-Michael and Mannich steps via two organocatalytic cycles. This reaction allows the construction of chiral 1,2-oxazine derivatives 1212 from aldehydes 1207, nitrosobenzene 1208, arylamines 1209, and unsaturated aldehydes 1211, in the presence of L-proline and prolinol ether 1210. In a separate step, the acid-promoted Friedel−Crafts-type cyclization of compounds 1212 afforded

Kim described a procedure for the synthesis of enantioenriched ring-fused tetrahydroquinolines 1199. The enantioselective conjugate addition reaction of malonates to o(tetrahydroisoquinolinyl)-substituted cinnamaldehyde derivatives 1196, to access compounds 1198, was achieved in the presence of the diphenylprolinol TMS ether 1200 and was followed by intramolecular cross-dehydrogenative coupling in CH


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catalyst. In this specific case, the oxidant was the oxopiperidinium species 1216, the reductant was Hantzsch ester 1217, and 1218 was used as a chiral phosphoric acid catalyst. Interestingly, the oxidant and reductant could be present simultaneously thanks to the use of phase separation (Scheme 322).491

Scheme 319. Enantioselective Synthesis of Tetrahydroquinolines by a Four-Component Povarov-Type Reaction from Anilines and Pyruvates Catalyzed by a Chiral Phosphoric Acid

Scheme 322. Deracemization of Tetrahydroquinolines by an Asymmetric Redox Approach

Scheme 320. Chiral Phosphoric Acid-Catalyzed Enantioselective Synthesis of Tetrahydroquinolines Using Two Different Starting Anilines

The deracemization of 2-methyl-1,2,3,4-tetrahydroquinoline using mutant cyclohexylamine oxidase, obtained by iterative saturation mutagenesis, has also been described.492 In related work, Turner and Marsden have described the use of Escherichia coli expressing CHAO, a recombinant cyclohexylamine oxidase variant, to perform the final desymmetrization step of the synthesis of several 2-arylalkyltetrahydroquinoline alkaloids.493

the fused tetrahydroquinolines 1213 in excellent diastereo- and enantioselectivities (Scheme 321).490

9. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES BY REARRANGEMENT REACTIONS In addition to the more conventional methods for the synthesis of 1,2,3,4-THQs discussed in the previous sections, some rearrangement reactions have also been developed to access highly functionalized THQs. For instance, Feng and co-workers established the catalytic asymmetric ring-expansion reaction of isatins 1219 and α-alkyl-α-diazoesters 1220 for the synthesis of highly functionalized C4-quaternary 2-quinolones 1221 in high yields (up to 94%) and enantioselectivities (up to 99% ee). As depicted in Scheme 323, the reaction was carried out in the

8.4. Deracemization of Tetrahydroquinolines

Toste has achieved the deracemization of tetrahydroquinolines 1214 in a single operation via an asymmetric redox approach, in which the substrate reacts with an oxidant and yields an oxidized intermediate that then reacts with a reductant, and at least one of those steps is enantioselective owing to the presence of a chiral Scheme 321. Synthesis of Fused Tetrahydroquinolines by Friedel−Crafts-Type Cyclization of Chiral Precursors

Scheme 323. Enantioselective Synthesis of Tetrahydroquinolines by Asymmetric Ring-Expansion Reaction of Isatins and α-Alkyl-α-diazoesters

CI


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presence of Sc(OTf)3 as the catalyst, in the presence of an N,N′dioxide-based chiral ligand 1222.494 The reaction tolerated a range of substituents on all the diversity points and required a very low catalyst loading. The reaction pathway proposed to explain the enantioselective ring-expansion is shown in Scheme 324, where the initial

Owing to the poor yield and complications associated with the reaction shown in Scheme 325, the authors designed an alternative precursor 1227 (Scheme 326). Oxone oxidation of Scheme 326. Synthesis of Sespenine

Scheme 324. Mechanism Proposed To Explain the Enantioselective Isatin Ring-Expansion

step is the attack of the diazo compound 1220 to isatin 1219 to generate intermediate A. Between the two potentially competitive 1,2-aryl migration (path a) and 1,2-carbonyl migration (path b) reaction pathways, only the former rearrangement took place regioselectively to yield the observed functionalized 2,3-quinolinedione derivatives 1221. The first bioinspired total synthesis of sespenine, a rare indole sesquiterpenoid bearing a spiro-tetrahydroquinoline scaffold, was developed by Li.495 The required precursor 1224 was obtained from simple starting materials by a multistep route, and the key THQ moiety-generating step for the synthesis of the compound 1226, containing the target framework, was achieved by treatment of 1224 with oxaziridine 1225 and acetic acid (Scheme 325). The formation of compound 1226 from intermediate A can be visualized as an acid-catalyzed azaPrins/Friedel−Crafts/retro Friedel−Crafts reaction sequence where the THQ ring was generated by rearrangement of the indole scaffold.

compound 1227 followed by acetic acid treatment furnished the THQ derivative 1230 in good overall yields in two steps via the C-3 epimers 1228 and 1229. Krapcho demethoxycarbonylation followed by hydrolysis furnished sespenine 1232 in good yield through the intermediacy of compound 1231. A Lewis acid-catalyzed one-pot strategy was established for the synthesis in high yields of spiro-pyranoquinolone derivatives 1235 starting from 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1methylindolin-2-one 1233 and aldehydes 1234 (Scheme 327).496 A variety of aryl/alkyl aldehydes 1234 were treated Scheme 327. Synthesis of Spiro-tetrahydroquinolines Based on a 3-Hydroxyoxindole Ring Expansion

Scheme 325. Synthesis of Tetrahydroquinolines by an AcidCatalyzed Aza-Prins/Friedel−Crafts/Retro-Friedel−Crafts Reaction sequence

with compounds 1233 in the presence of BF3·OEt2 under mild conditions to furnish the desired products as single diastereomers. The mechanism of the reaction was proposed to involve Prins pinacol reactions (Scheme 328). Initial attack of the primary alcohol 1233 to the Lewis acid-activated aldehyde 1234 generated the oxo-carbenium ion A, which underwent intramolecular cyclization to deliver the tertiary carbocation B, and the final pinacol 1,2-shift would afford the spiro-pyranoquinolone derivatives 1235, while the potentially competing acyl migration leading to compounds 1236 was not observed. CJ


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Scheme 328. Prins Pinacol Mechanism Proposed To Explain the 3-Hydroxyoxindole Ring Expansion

Scheme 330. Mechanism Proposed To Explain the Ring Expansion of 1-Aminoindanes

intermediate B. A final addition of organolithium or magnesium reagents explains the formation of THQs 1238. Recently, Ulikowski and Furman explored the Schwartz’s reagent-mediated synthesis of 2,3-disubstituted indoles from isatins. During this investigation, the authors observed that their reaction intermediate 1239 underwent an aza Diels−Alder reaction with cyclopentadiene 1240 obtained from the catalyst (Cp2ZrHCl), followed by a rearrangement reaction leading to the formation of unexpected 1,2,3,4-THQ 1241 through the intermediacy of A (Scheme 331).498 Miyata and co-workers established an efficient protocol for the synthesis of 1,2,3,4-THQs comprising an alkylative ring expansion strategy.497 A domino reaction of N-indanyl(methoxy)amines 1237 with organolithium or magnesium reagents delivered the corresponding THQs 1238 in good yields, and one of these derivatives was employed as the starting material for the stereoselective formal synthesis of (±)-martinellic acid 36 (Scheme 329).

Scheme 331. Synthesis of Fused Tetrahydroquinolines by an Aza-Diels−Alder/Rearrangement Reaction Sequence

Scheme 329. Synthesis of Tetrahydroquinolines Based on an Alkylative Ring Expansion of 1-Aminoindane Derivatives

10. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES BY CONSTRUCTION OF THE ARYL RING OR BOTH RINGS Gillaizeau and co-workers reported the synthesis of conjugated enamides starting from enamines and olefins via palladiumcatalyzed Fujiwara−Moritani cross-coupling reaction in good yields. One of these cyclic analogues 1242 was treated with dienophiles 1243 to deliver compounds 1244 by constructing the carbocyclic ring via an intermolecular Diels−Alder reaction. Finally, a MnO2-mediated aromatization delivered the corresponding fused tetrahydroquinoline 1245 (Scheme 332).499 Cooper and Booker-Milburn established a palladium(II)catalyzed C−H bond activation process for the construction of polycyclic systems containing pyrrole, indole, furan, thiophene, and THQ moieties.500 The 1,3-dienyl-substituted heterocycles 1246 were transformed into polycyclic compounds 1247, bearing a THQ core, in the presence of a palladium catalyst and 3,5-di-tert-butyl-o-benzoquinone 1248 (Scheme 333). The mechanism proposed for this reaction comprises C−H activation and syn-carbometalation steps involving a Pd0/II catalytic cycle.

The mechanistic pathway proposed for this reaction is summarized in Scheme 330. An initial coordination of Nindanyl(methoxy)amines 1237 with the organolithium or Grignard reagent would generate intermediate A, which subsequently would undergo elimination of an alkoxy group followed by rearrangement of an aryl group to deliver the imine CK


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Scheme 332. Synthesis of Fused Tetrahydroquinolines by a Diels−Alder Reaction of a Conjugated Enesulfoamide

Scheme 334. Synthesis of Tetrahydroquinolines by Fe(OTf)2-Catalyzed Transfer Hydrogenation of Quinolines

Scheme 335. Synthesis of Tetrahydroquinolines by Transfer Hydrogenation Quinolines, Catalyzed by an N-Heterocyclic Carbene-Supported Ruthenium Catalyst

Scheme 333. Synthesis of Fused Tetrahydroquinolines by Pd(II)-Catalyzed C−H Activation of 1,3-Dienyl-Substituted Heterocycles

propanol.502 The reaction was found to be chemoselective and reduced exclusively the heterocyclic ring when the trihydride Cp(IPr)RuH3 was the active species. Recently, Süss-Fink and co-workers demonstrated the partial hydrogenation of quinolines into the corresponding 1,2,3,4THQs in excellent yields in the presence of metallic ruthenium nanoparticles intercalated in hectorite and sodium borohydride in aqueous solution. Interestingly, 2-phenylquinoline was hydrogenated to the corresponding 5,6,7,8-tetrahydroquinoline under the same conditions. In addition, isoquinoline and quinoxalines were also hydrogenated effectively.503 RuCu nanocages and Cu@Ru core−shell catalysts supported on commercial carbon were employed for the partial hydrogenation of quinoline into 1,2,3,4-THQ. Although the commercial Ru/C system afforded a mixture of 1,2,3,4tetrahydro-, 5,6,7,8-tetrahydro-, and octahydroquinoline, RuCu nanocages synthesized via a modified galvanic replacement reaction showed excellent activity and selectivity to deliver 100% of 1,2,3,4-tetrahydroquinoline.504 Li, Wang, and co-workers also demonstrated the partial hydrogenation of quinoline in the presence of Ru-SiO2@mSiO2, a well-dispersed core−shell nanocatalyst, in water.505 Other notable ruthenium catalysts involved in the partial hydrogenation of quinolines to 1,2,3,4-THQs include ruthenium supported on low-cost nanoporous HT-C12A7506 and the Ru(acac)3-triphos complex.507 11.1.2. Partial Hydrogenation with Co, Rh, and Ir Catalysts. Beller and co-workers demonstrated the partial hydrogenation of quinolines and other N-heterocycles such as acridines, benzo[h]- and 1,5-naphthyridines, and indoles, using cobalt oxide/cobalt-based nanoparticles.508 The cobalt nanoparticles having core−shell structure and nitrogen-doped

11. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINES BY PARTIAL HYDROGENATION OF QUINOLINES 11.1. Racemic Hydrogenations

The partial hydrogenation of quinolines into their 1,2,3,4tetrahydro derivatives has been achieved using a variety of transition metal catalysts, including Ru, Co, Rh, Ir, Ni, Pd, Pt, and Au species. In addition, organocatalysts and boron reagents have also been employed for the regioselective hydrogenation of quinolines and other related N-heterocycles. In this section, we will summarize the approaches established for the transformation of quinolines into racemic 1,2,3,4-THQs. 11.1.1. Partial Hydrogenation with Fe and Ru Catalysts. Transfer hydrogenation of quinolines in the presence of Fe(OTf)2 with Hantzsch ester 1251 as the hydrogen source was achieved under mild conditions (Scheme 334).501 Quinolines 1249 bearing a wide range of substituents were partially hydrogenated into the corresponding 1,2,3,4-THQs 1250 in good to excellent yields without affecting other reducible functional groups, including some that are potentially sensitive to reduction such as the chloro and nitro substituents. Mai and Nikonov studied the transfer hydrogenation of nitriles, olefins, and nitrogen heterocycles, including quinolines, by means of N-heterocyclic carbene-supported ruthenium as catalyst. As summarized in Scheme 335, the half-sandwich complex of ruthenium 1254 effectively hydrogenates compounds 1252 in the presence of potassium tert-butoxide in 2CL


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melamine-2@C-700 showed high activity and selectivity for the dehydrogenation of formic acid to generate molecular hydrogen and carbon dioxide and for the partial hydrogenation of quinolines 1260 to deliver the N-formyl-1,2,3,4-THQ derivatives 1261 in good yields (Scheme 338).511 The reaction tolerated a large number of functionalities potentially susceptible to reduction on the heteroaryl ring.

graphene layers on alumina were prepared by the pyrolysis of Co(OAc)2/phenanthroline and employed for the partial hydrogenation of N-heterocycles 1255 to the corresponding products 1256 in good to excellent yields (Scheme 336). In Scheme 336. Synthesis of Tetrahydroquinolines by Partial Hydrogenation of Quinolines and with Cobalt Oxide/ Cobalt-Based Nanoparticles

Scheme 338. Synthesis of Tetrahydroquinolines by Partial Hydrogenation of Quinolines Catalyzed by Heterogeneous Supported Cobalt Catalysts

order to prove the flexibility of the method, some THQs synthesized by this approach were later transformed into three biologically significant compounds including (6-methoxy-3,4dihydroquinolin-1(2H)-yl)(3,4,5-trimethoxyphenyl)methanone (a tubulin polymerization inhibitor), the antibacterial flumequine, and the alkaloid (±)-galipinine. Beller and co-workers also reported the cobalt-catalyzed hydrogenation of a variety of quinolines 1257 into 1,2,3,4THQs 1258. The reaction was screened in the presence of a range of phosphines, and it was found that the tris(2(diphenylphosphino)phenyl)phosphine) ligand 1259 was superior to the others (Scheme 337).509 The reaction tolerated

Ti(III)-oxo clusters in a metal organic framework support single-site Co(II) hydride catalysts (Ti8-BDC-CoH) were also employed for the hydrogenation of arenes, including quinolines.512 The catalytic hydrogenation of a wide variety of quinoline derivatives 1262 was achieved using [(Cp*RhCl2)2] as the catalyst in the presence of potassium iodide and a formic acid− triethylamine azeotrope to obtain the corresponding THQs 1263 in excellent yields (Scheme 339).513 The addition of

Scheme 337. Synthesis of Tetrahydroquinolines by CobaltCatalyzed Partial Hydrogenation of Quinolines in the Presence of Phosphine Ligands

Scheme 339. Synthesis of Tetrahydroquinolines by Partial Hydrogenation of Quinolines Catalyzed by Nitrogen-Doped Graphene Layers Encapsulating Cobalt Nanoparticles

iodide was essential to generate the active anionic diiodo Rh−H hydride to effect the hydrogenation, and a S/C ratio up to 10,000 was achieved. In addition to quinolines, isoquinolines and quinoxalines were also converted into the corresponding 1,2,3,4-tetrahydro derivatives under similar conditions. Recently, Xu and co-workers employed (pentamethylcyclopentadienyl)rhodium dichloride in the presence of 2,2′bipyridine for the transfer hydrogenation of N-heterocycles including quinolines, quinoxalines, quinoxalinones, and indoles to afford the corresponding partially hydrogenated compounds.514 HCO2H/HCO2Na was employed as the hydrogen source in aqueous medium, with an excellent S/C ratio. Recently, porous nitrogen-doped graphene layers encapsulating cobalt nanoparticles were synthesized and employed for the transformation of quinolines into 1,2,3,4-THQs in high yields.515 A recyclable rhodium catalyst immobilized on bipyridine-periodic mesoporous organosilica was also developed and tested for the transfer hydrogenation of nitrogen heterocycles. This catalyst showed good activity to deliver the corresponding hydrogenated compounds in high yields and was recycled and reused several times.516 Quinolines and other N-heterocycles were successfully converted into their partially hydrogenated derivatives in the

the presence of a variety of functional groups, including reducible functions, and furnished the products in good to excellent yields. Compound 1258a, the key intermediate for the preparation of the natural product galipinine, was also obtained by this method. Although other heterocyclic substrates such as naphthyridine, quinoxaline, acridine, isoquinoline, and benzoquinolines afforded the corresponding hydrogenated products in good yields, indole and pyridine derivatives gave only moderate to low yields. The authors also examined the use of the Co(BF4)2·6H2O/1259 system for the hydrogenation of quinolines using formic acid as the hydrogen source.510 Recently, Beller and co-workers also demonstrated the catalytic activity of nitrogen-modified heterogeneous cobalt catalysts supported on carbon, using melamine or melamine resins as the nitrogen source, for the asymmetric transfer hydrogenation of heteroarenes. The optimal catalyst Co/ CM


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presence of cyclometalated Ir(III) complexes obtained from Naryl ketimines. As demonstrated in Scheme 340, quinolines

mesoporous silica (SBA-15)-supported iridium catalyst 1273 was prepared by grafting cyclometalated iridium 2-aryl benzoxazole complexes with the linker 3-(triethoxysilyl)propyl isocyanate (TEPIC) and employed for the transfer hydrogenation of quinolines to 1,2,3,4-THQs with formic acid in water (Figure 23).520 The corresponding N-formyl THQs were

Scheme 340. Synthesis of Tetrahydroquinolines by Partial Hydrogenation of Quinolines Catalyzed by Cyclometalated Ir(III) Complexes Obtained from N-Aryl Ketimines

1264 bearing a variety of substituents were transformed into the corresponding 1,2,3,4-THQs 1265 in the presence of the iridium catalyst 1266 in excellent yields (up to 99%).517 The reaction was carried out under mild conditions (1 atm H2) and tolerated a variety of potentially reducible functional groups. A detailed optimization revealed that the choice of ligand and the use of TFE as solvent were crucial to achieve this transformation efficiently. A tandem hydrogenation-reductive alkylation process starting from 2-methylquinoline 1267 was achieved involving the use of 3 equiv of aryl aldehydes 1268 in the presence of the benzoquinoline-iridium catalyst 1272. This reaction afforded a mixture of the intermediate 2-methyl-1,2,3,4-THQ 1269, Nbenzyl-2-methyl-1,2,3,4-THQ 1270, and benzyl alcohols 1271 (Scheme 341).518 Iridium(IV) oxide nanoparticles, prepared by a ball-milling reaction between iridium trichloride hydrate and sodium hydroxide, showed remarkable catalytic activity in the hydrogenation of nitrogen heterocycles, including quinolines.519 The

Figure 23. Some Ir catalysts used for the partial hydrogenation of quinolines.

also accessible by simply changing the quantity of formic acid used, and their preparation involved a one-pot transfer hydrogenation/N-formylation sequence. The catalyst was reused 12 times without significant loss in its activity. The N-heterocyclic carbene-based iridium catalysts 1274 and 1275 were also prepared and utilized for the partial hydrogenation of quinolines in water (Figure 23).521 Previously, airand moisture-stable iridium(I) NHC catalysts had been developed for the partial hydrogenation of quinolines having functionalities at the 2-, 6-, and 8- positions in high yields.522 11.1.3. Partial Hydrogenation with Ni, Pd, and Pt Catalysts. Török and co-workers established a Raney-type Ni− Al alloy as a catalyst for the hydrogenation of N-heterocycles in an aqueous medium.523 A variety of indoles and quinolines were transformed into the corresponding indolines and 1,2,3,4-THQs in excellent yields, under both conventional and microwave irradiation conditions. The Ni−Al alloy reacted with water to generate hydrogen, and the Raney Ni system acted as the hydrogenation catalyst. A number of polycyclic aromatic hydrocarbons and heteroaromatic compounds, including quinolines, were partially hydrogenated in the presence of quenched skeletal Ni (QS Ni) catalyst.524 Murugesan and co-workers demonstrated the synthesis of 3(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives 1279 with potential activity as inhibitors of the HIV-1 reverse transcriptase (Scheme 342).36 6-Methoxyquinoline 1276 was hydrogenated into THQ 1277 using Ni−Al alloy and aqueous sodium hydroxide in ethanol and a subsequent N-alkylation followed by introduction of piperazyl fragment furnished the target compounds 1279 via the carboxylic acid intermediate 1278. Rivara and co-workers explored the synthesis of the tetrahydroquinoline-based potent and selective MT2 melatonin receptor full agonists 1282. The key intermediates 1281 were obtained from the corresponding 2-cyanoquinolines 1280 by hydrogenation in the presence of Raney-Ni (Scheme 343).61

Scheme 341. Synthesis of Tetrahydroquinolines by a Tandem Hydrogenation−Reductive Alkylation Process from 2Methylquinoline

CN


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Scheme 342. Synthesis of Tetrahydroquinolines Active as HIV-1 Reverse Transcriptase Inhibitors, Initiated by the Partial Hydrogenation of a Quinoline Derivative

Scheme 344. Synthesis of 2-Methyl-1,2,3,4tetrahydroquinoline by Reduction of the Corresponding Quinoline

Scheme 345. Reductive Alkylation of Quinolines with Alcohols in the Presence of Pd/C and Zn

Scheme 343. Synthesis of Tetrahydroquinolines Active as MT2 Melatonin Receptor Agonists, Initiated by the Partial Hydrogenation of a Quinoline Derivative

Lee and co-workers identified 1,2,3,4-THQ derivatives 1291 as potent inhibitors of lipopolysaccharide (LPS)-induced NF-κB transcriptional activity. For their preparation, the quinoline precursors 1289 were hydrogenated into THQs 1290 in the presence of Pd/C under mild conditions (Scheme 346).47 Subsequently, THQs 1290 were transformed into a library of biologically active compounds 1291 in good yields. Scheme 346. Synthesis of Tetrahydroquinolines by Reduction of Quinolines in the Presence of Pd/C The 2-methyl-1,2,3,4-THQ derivative 1284 was obtained from the corresponding quinoline 1283 by reduction with NaBH4 and NiCl2·6H2O in methanol. Subsequently, compound 1283 was transformed into a set of antiparasitic THQs 1285 in good yields (Scheme 344).46 This catalytic system was also employed for the preparation of antifungal 5-alkyl-1,2,3,4tetrahydroquinoline in good yield.13 The synthesis of several 1-arylsulfonyl-6-(N-hydroxyacrylamido)tetrahydroquinolines with potent histone deacetylase (HDAC) inhibitory activity was achieved using a method having as the key step the hydrogenation of quinolines into the corresponding THQs by means of the Pd/C and ammonium formate system in methanol.54 Similarly, Abarca and co-workers showed that the combination of Pd/C and Zn with alcohols could be employed for the one-pot transfer hydrogenation and N-alkylation of quinolines. Thus, treatment of quinolines 1286 with several alcohols in the presence of a catalytic amount of Pd/C and 1.5 equiv of Zn metal furnished a mixture of 1,2,3,4-THQs 1287 and N-alkyl1,2,3,4-THQs 1288 in good yields (Scheme 345).525 Here the alcohols acted as hydrogen donors in the presence of the Pd/C/ Zn mixture and the reaction proceeded via zinc alkoxide and palladium hydride intermediates.

1-Aryl-2-(8-quinolinyloxy)ethanones 1292 were cyclized under reductive conditions using Pd/C and H2 to afford the corresponding fused THQs 1293 bearing a benzoxazine core (Scheme 347).94 The authors screened these fused compounds for their antioxidant properties and found some of them to have potent activity. CO


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Scheme 347. Synthesis of 1-Aryl-2-(8quinolinyloxy)ethanones by a Reductive Cyclization Strategy

Scheme 349. Synthesis of Tetrahydroquinolines by PdCatalyzed Three-Component Reaction between NAlkylquinolinium Salts, Diazo Compounds, and Anilines

Hydroxyapatite-supported Pd(0) nanoparticles (Pd 0 HAP),526 Pd nanoparticles supported on amine-rich silica hollow nanospheres,527 and a polymer-supported palladium catalyst,528,529 obtained by copolymerization of Pd(AAEMA)2 (AAEMA = 2-(acetoacetoxy)ethyl methacrylate) with ethyl methacrylate and ethylene glycol dimethacrylate, were found to be excellent catalysts for the partial hydrogenation of quinolines to give the corresponding 1,2,3,4-THQs in excellent yields. Wu and co-workers synthesized modular metal−carbon stabilized palladium nanoparticles from palladium salts and substituted binaphthyl diazonium salts in the presence of sodium borohydride and employed them for the catalytic hydrogenation of N-heterocycles including quinolines in good to excellent yields under mild conditions.530 Xuan and Song demonstrated a diboron-assisted transfer hydrogenation of N-heterocycles catalyzed by palladium acetate.531 The N-heterocyclic compounds 1294 such as imidazo[1,2-a]pyridine, quinolines, and quinoxaline derivatives were partially hydrogenated using B2 pin2 as mediator and water as hydrogen donor and solvent. In the case of quinolines, up to 95% yield of the corresponding 1,2,3,4-THQs 1295 (X = CH2) were obtained under mild conditions (Scheme 348). After some detailed experimental studies, the authors proposed a mechanism involving Pd−H as the key intermediate.

Scheme 350. Mechanism Proposed for the Pd-Catalyzed Three-Component Synthesis of THQs

Scheme 348. Synthesis of Tetrahydroquinolines by PdCatalyzed Diboron-Assisted Transfer Hydrogenation of Quinolines

A Pd(II)-catalyzed three-component reaction between Nalkylquinolinium salts 1296, diazo compounds 1297, and arylamines 1298 delivered polyfunctional polycyclic 1,2,3,4THQ derivatives 1299 and 1300 in excellent yields (Scheme 349).532 The reactions were found to be highly regioselective, and moderate to good diastereoselectivity was observed. On the basis of several control experiments, the authors proposed a mechanism for this transformation involving the generation of electrophilic palladium carbene intermediates and 1,4-conjugate addition−intramolecular nucleophilic cyclization steps (Scheme 350). The reaction between diazo compound 1297 and palladium catalyst generates electrophilic palladium carbene intermediates A, which react with arylamines 1298 to deliver enolate C via species B. 1,4-Conjugate addition of species B/C with quinolinium salt 1296 to provide 1,4-dihydroquino-

lines D by regenerating the palladium catalyst. Final protonation and intramolecular nucleophilic cyclization steps furnish the products 1299/1300. The regio- and diastereoselectivity of the process could be visualized through the transition states I and II. CP


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The syn isomers form via more stable transition state I, which is stabilized by π−π stacking and hydrogen bonding. Cao, Gu, and co-workers developed a platinum nanowire catalyst for the reversible hydrogenation-oxidative dehydrogenation of quinolines under mild conditions.533 Thus, the hydrogenation of quinolines 1301 into the corresponding THQs 1302 was achieved in the presence of platinum nanowire catalyst and hydrogen in methanol. On the other hand, the partially hydrogenated products were also successfully oxidized using the same catalyst in the presence of oxygen in methanol (Scheme 351). In addition to quinolines, isoquinolines 1,10phenanthroline and 9,10-dihydroacridine were also hydrogenated effectively.

the same authors had explored the catalytic activity of gold nanoparticles supported on TiO2 for the partial hydrogenation of N-heterocycles such as quinolines, isoquinolines, acridines, and 7,8-benzoquinolines in good yields.538 Gold nanoparticles supported on TiO2 were also employed by Stratakis and coworkers for the partial hydrogenation of quinolines into 1,2,3,4THQs using hydrosilanes/ethanol as the reducing system under solvent-free conditions, in good yields.539 Jin and co-workers also reported a related unsupported nanoporous gold catalyst for the reduction of quinolines into 1,2,3,4-THQs using organosilane with water as a hydrogen source in excellent yields (78−98%). The catalyst was recovered and reused several times without a significant loss in its activity.540 11.1.5. Miscellaneous Hydrogenation Reactions. Oxazino- and oxazepino-fused tetrahydroquinolines were synthesized via Zn/AcOH-mediated reductive amidation of ω-(8quinolyloxy)alkyl esters. The esters 1306, derived from 8hydroxyquinoline, were transformed into the corresponding fused THQs 1307 under mild conditions in excellent yields (Scheme 353).541 An initial reduction of the pyridine ring by

Scheme 351. Platinum Nanowire-Catalyzed Hydrogenation of Quinolines

Scheme 353. Synthesis of Ring-Fused Tetrahydroquinolines by Reductive Amidation of ω-(8-Quinolyloxy)Alkyl Esters Nagarajan and co-workers reported the development of THQ-based inhibitors of EPAC proteins, which are therapeutic targets potentially interesting for the treatment of cardiac hypertrophy and cancer metastasis, where the Pt/C/H2 system was employed for the hydrogenation of the quinoline precursor.534 Similarly, quinoline was converted into 1,2,3,4THQ in the presence of Pt/C/H2 in 84% yield together with 6% of trans-decahydroquinoline.535 Recently, Pt nanoparticles supported on CeO2 nanorods (Pt/NR-CeO2) were identified as efficient catalysts for the partial hydrogenation of quinolines.536 11.1.4. Partial Hydrogenation with Au Catalysts. Cao and co-workers established the use of single-phase rutile titaniasupported gold nanoparticles (Au/TiO2-R) for the conversion of quinolines 1303 into the corresponding 1,2,3,4-THQs 1304 via regioselective transfer hydrogenation, using formic acid as the hydrogen source (Scheme 352).537 The activity of the catalyst system was excellent, and a S/C ratio of 1000 was achieved. Cao and co-workers also synthesized n-formyl-1,2,3,4tetrahydroquinolines 1305 directly from quinolines 1303 in one-pot in the presence of gold nanoparticles using a 3:10 mixture of Et3N and water as the reaction medium. Previously,

Zn/AcOH was followed by intramolecular amide formation in the presence of an in situ-generated Zn(II) catalyst via an intermediate 1,2,3,4-tetrahydro-8-quinolyloxy alkyl ester A. Soós and co-workers established the partial hydrogenation of quinolines into 1,2,3,4-THQs using the frustrated Lewis pairs (FLP) concept.542 Thus, the transition-metal-free hydrogenation of quinolines 1308 was achieved in the presence of the weak Lewis acid MesB(C6F4H)2, 1310 (Scheme 354). In addition to a variety of substituted THQs 1309, the alkaloid raccuspareine was also synthesized. The mechanism for the formation of the THQs 1309 was established by employing NMR spectroscopic and computational techniques where the interaction of quinoline and borane was investigated, leading the authors to suggest the existence of an organohydride intermediate. A silylative reduction of quinolines 1311 in the presence of a boron catalyst was established to obtain THQs 1312, with the concomitant formation of a C(sp3)−Si bond exclusively β to nitrogen, allowing the construction of a library of 3-silylated THQs bearing a variety of substituents (Scheme 355).543 The triarylborane was found to be an excellent catalyst for this transformation, and silanes served as both a silyl source and a reducing reagent. Based on detailed experimental and theoretical studies, the authors proposed a mechanism involving 1,4-addition and hydrosilylation steps starting from boron-

Scheme 352. Hydrogenation of Quinolines Catalyzed by Single-Phase Rutile Titania-Supported Gold Nanoparticles

CQ


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borylated intermediate A, together with small quantities of the corresponding 2-hydroxy derivatives 1318 (Scheme 357). On

Scheme 354. Partial Hydrogenation of Quinolines in the Presence of Lewis Pairs

Scheme 357. Synthesis of 3-Hydroxy-1,2,3,4tetrahydroquinolines by Hydroboration/Oxidation

Scheme 355. Silylative Reduction of Quinolines in the Presence of a Triarylborane the other hand, 2- and 4-substituted quinolines 1319 afforded exclusively high yields of 3-hydroxy-1,2,3,4-THQs 1320, where the trans-isomer was the major product (Scheme 358). This approach was employed for the synthesis of the antibodytargeted peptidomimetic compounds FISLE-412 (1321 and 1322), potentially useful for the treatment of lupus. Scheme 358. Synthesis of a 3-Hydroxy-1,2,3,4tetrahydroquinoline as a Key Step of the Synthesis of the Peptidomimetics FISLE-412

coordinated quinolines. The authors subsequently demonstrated the partial hydrogenation of related heterocyclic compounds including quinoline N-oxides and quinoxalines in the presence of the B(C6F5)3/Et2SiH2 system.544 The partial hydrogenation of quinolines and other related heterocycles was also performed in high yields using the B(C6F5)3/NH3·BH3545and B(C6F5)3/ H2546systems. The key intermediate for the synthesis of a library of myeloid cell leukemia-1 (Mcl-1)inhibitors 1315, methyl 1,2,3,4-tetrahydroquinoline-3-carboxylate 1314, was obtained from the corresponding quinoline 1313 in good yield via its reduction with the pyridine-borane complex in acetic acid under mild conditions (Scheme 356).547 Scheme 356. Partial Reduction of Quinolines with the Pyridine−Borane Complex in Acetic Acid

Coldham and co-workers reported the preparation of N-Boc2-aryl-1,2,3,4-tetrahydroquinolines 1324 in two steps involving the NaBH3CN reduction of 2-arylquinolines 1323 in acetic acid followed by the introduction of N-Boc group (Scheme 359).549 Subsequently, efficient lithiation at the 2-position was achieved using n-BuLi, and the resulting organolithium species were trapped with a variety of electrophiles to give 2,2,-disubstituted 1,2,3,4-THQs 1325 bearing a C-2 quaternary center. You and co-workers established the synthesis of spiro-THQs 1327 starting from quinoline derivatives 1326 in the presence of

3-Hydroxy-1,2,3,4-THQs were synthesized from the corresponding quinolines bearing no substituent on the heterocyclic ring by hydroboration with chloroboranes followed by oxidation.548 The starting materials 1316 reacted with BCl3/ BH3 and a subsequent oxidation with NaBO3·H2O to deliver 3hydroxy-1,2,3,4-THQs 1317 as the major product, via the CR


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Scheme 359. Partial Reduction of 2-Arylquinolines with NaBH3CN

Scheme 361. Reductive Synthesis of 2,4-Diphosphono1,2,3,4-tetrahydroquinolines

A 2-substituted N-carbamoyl 1,2-dihydroquinoline 1333, obtained via oxidative C−H bond functionalization of Ncarbamoyl-1,2-dihydroquinolines using potassium trifluoroborates and TEMPO oxoammonium salt as an oxidant, was transformed into functionalized tetrahydroquinolines (Scheme 362).557 The diastereoselective dihydroxylation, hydrogenation, phosphoric acid catalyst 1328 and Hantzsch ester 1329 (Scheme 360).550 A domino reaction comprising hydrogenative

Scheme 362. Several Pathways for the Functionalization of 2Substituted N-Carbamoyl 1,2-Dihydroquinolines

Scheme 360. Reductive Synthesis of Spirotetrahydroquinolines

dearomatization of quinoline and intramolecular aza-Friedel− Crafts alkylation reaction sequence was proposed to explain the formation of the products. In almost all cases, excellent yields of compounds 1327 were obtained under mild conditions. An enantioselective version of the reaction was also attempted for a couple of substrates using a chiral phosphoric acid and a moderate ee of 77% was achieved. Thiourea-catalyzed transfer hydrogenation of 2-substituted quinolines with Hantzsch ester as the hydrogen source was also established for the synthesis of 1,2,3,4-THQs in good to excellent yields.551 In related work, Zhang and co-workers reported the transfer hydrogenation of quinolines, benzoxazines, and benzothiazines in the presence of thiourea dioxide and Hantzsch ester as the hydrogen source to access the partially hydrogenated heterocyclic compounds including 1,2,3,4-THQs.552 The same group also demonstrated the utility of cyclopentadiene-based Brønsted acid and Hantzsch ester for the transfer hydrogenation of 2substituted quinoline.553 A synthesis of 2,4-diphosphono-1,2,3,4-tetrahydroquinolines 1332 was developed in one-pot starting from quinolines 1330 and H-phosphonates 1331(Scheme 361).554 The formation of the products could be explained involving two consecutive hydrophosphonylation steps of the quinoline derivatives with Hphosphonates. Related diphosphonylation reactions were also reported under nickel catalysis555 or in acidic media.556

and diastereoselective epoxidation of 1,2-dihydroquinolines 1333 were achieved in the presence of OsO4, Pd/C/H2, and mCPBA, respectively, to provide THQs 1334−1336 in high yields. 11.2. Asymmetric Hydrogenations

In addition to the strategies summarized in section 6.6 and section 8 for the asymmetric synthesis of chiral 1,2,3,4-THQs, the direct asymmetric partial hydrogenation of quinolines remain one of the simplest approaches to access these compounds as single enantiomers. Quinolines and other related heteroarenes have been effectively hydrogenated in the presence of various catalysts, including chiral Brønsted acids and transition metal catalysts. Besides Zhou’s comprehensive review on this topic in 2012,558 this area is covered in other related reviews with detailed mechanistic analysis.559−562 In this section, we will summarize the catalysts employed for the synthesis of chiral 1,2,3,4-THQs via asymmetric hydrogenation. 11.2.1. Brønsted Acid-Catalyzed Asymmetric Hydrogenation. Rueping and co-workers demonstrated the chiral phosphoric acid-catalyzed asymmetric hydrogenation of 4substituted quinolines 1337 to give the corresponding 4-alkylCS


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and 4-aryl-1,2,3,4-THQs 1338 in good yields and enantioselectivities (Scheme 363).563,564 After a detailed catalyst

Scheme 365. Asymmetric Transfer Hydrogenation of 3Trifluoromethylthioquinolines Catalyzed by a Chiral Brønsted Acid

Scheme 363. Asymmetric Transfer Hydrogenation of 4Substituted Quinolines Catalyzed by a Chiral Phosphoric Acid

catalytic system was also employed for the transfer hydrogenation of 3-(trifluoromethyl)quinolines to access chiral 2,3disubstituted 1,2,3,4-tetrahydroquinolines containing a trifluoromethyl group.568 Transfer hydrogenation of 1,2-dihydroquinolines to chiral 1,2,3,4-THQs was achieved using a related phosphoric acid catalyst and Hantzsch ester, where enantioselectivities up to 94% were achieved.569 Synthesis of optically active 3-tosylaminoquinolines 1346 was achieved by means of asymmetric transfer hydrogenation of the corresponding 3-substituted quinolines 1345 using chiral phosphoric acid 1347 as the catalyst and Hantzsch ester 1348 as the hydrogen donor (Scheme 366).570 The products were

screening, the authors identified the triphenylsilyl-substituted phosphoric acid 1339 as the suitable catalyst to afford maximum yield and enantioselectivity in the presence of Hantzsch ester 1340 as the hydrogen source via transfer hydrogenation.565 The mechanism proposed for this reaction involved the initial protonation of quinoline 1337 by the chiral Brønsted acid to generate the iminium ion A, followed by hydride transfer from Hantzsch ester from the less hindered side to afford the chiral species B. Isomerization of chiral enamine intermediate B delivered the iminium ion C, and the second hydride transfer afforded the chiral THQs 1338 after regenerating the catalyst (Scheme 364).

Scheme 366. Asymmetric Transfer Hydrogenation of 3Tosylaminoquinolines Catalyzed by a Chiral Phosphoric Acid

Scheme 364. Mechanism Proposed To Explain the Chiral Phosphoric Acid-Catalyzed Reduction of 4-Substituted Quinolines

Recently, an asymmetric transfer hydrogenation of 3trifluoromethylthioquinolines 1341 was achieved in the presence of the chiral Brønsted acid 1343 and Hantzsch ester 1344 to access chiral 2,3-disubstituted-1,2,3,4-tetrahydroquinoline derivatives 1342 bearing a stereogenic trifluoromethylthio group in excellent yields (up to 98%) and enantioselectivities up to 99% (Scheme 365).566 More and Bhanage also reported the transfer hydrogenation of 2-substituted quinolines using chiral catalyst 1343 and Hantzsch ester 1344 in diethyl carbonate as a sustainable solvent, with excellent yields and enantioselectivities.567 This

obtained in good yields (up to 96%) and enantioselectivities (up to 90%). Based on this method, the parent 3-tosylaminoquinoline could be transformed in five steps into (R)-sumanirole 1349, the first selective agonist of the dopamine D2 receptor.571 Shi and co-workers elaborated the SPINOL-derived phosphoric acid-catalyzed transfer hydrogenation N-heterocyclic compounds, including 2-arylquinolines, 2-(naphthalen-2-yl)quinoline-1-oxide, 3-aryl-1,4-benzoxazines, 3-(4-methoxyphenyl)-2H-1,4-benzthiazine, and 3-phenyl-2H-1,4-benzoxazin-2CT


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one.572 As shown in Scheme 367, a variety of 2-arylquinolines 1350 were transformed into the corresponding chiral THQs

Scheme 369. Proposed Reaction Pathway for the Asymmetric Transfer Hydrogenation-Based Dynamic Kinetic Resolution

Scheme 367. Asymmetric Transfer Hydrogenation of 2Arylquinolines in the Presence of a SPINOL-Derived Chiral Phosphoric Acid

prepared from 1,8-dibromobiphenylene using a chiral phosphorodiamidate as the phosphorylating agent, showed significant activity in the desired transformation and afforded the chiral 1,2,3,4-THQs 1359 with enantioselectivities up to 90% (Scheme 370).

1351 in high yields and enantioselectivities in the presence of chiral phosphoric acid 1352 and Hantzsch ester 1353. The authors explained this transformation using a mechanism related to the one shown in Scheme 364. An efficient transfer hydrogenation procedure was developed that allowed the synthesis of chiral THQs bearing three contiguous stereogenic centers. 1,2,3,4-Tetrahydroacridines 1354 were reduced to the corresponding derivatives 1355 in the presence of phosphoric acid 1356 and Hantzsch ester 1357 via a dynamic kinetic resolution process (Scheme 368).573 The

Scheme 370. Asymmetric Transfer Hydrogenation of 2Arylquinolines Catalyzed by Phosphoric Acids with Chiral Paracyclophane Scaffolds

Scheme 368. Asymmetric Transfer Hydrogenation of 1,2,3,4Tetrahydroacridines Catalyzed by a Chiral Phosphoric Acid

Tang and co-workers reported the enantioselective partial hydrogenation of challenging 3-susbtituted quinoline substrates using a cyclopentadiene-based chiral Brønsted acid as catalyst and Hantzsch ester as hydrogen donor. A large number of 3susbtituted quinolines 1362 bearing a wide range of substituents were treated with the chiral Brønsted acid catalyst 1364 and Hantzsch ester 1365 to obtain the corresponding optically active 3-substituted 1,2,3,4-THQs 1363 in good yields and moderate enantioselectivities (Scheme 371).575 11.2.2. Asymmetric Hydrogenation by Rh and Ir Catalysts. In addition to chiral Brønsted acid catalysts, homogeneous metal catalysts containing Rh, Ir, Ru, etc. were also developed for the enantioselective partial hydrogenation of heteroaryl compounds including quinolines.559−562 In this context, the asymmetric hydrogenation of a series of isoquinolines and quinolines was studied in the presence of a chiral Rhthiourea phosphine complex. The rhodium catalyst was prepared in situ from [Rh(COD)Cl]2, and the chiral thiourea ligand (S,R)-1368 was found to be highly efficient in triggering the partial hydrogenation of the N-heterocycles in excellent yields and enantioselectivities. For instance, quinoline hydro-

products were obtained in good yields and enantioselectivities and with excellent diastereoselectivities (dr > 20:1). The interaction of compound 1354 with chiral Brønsted acid generates the chiral ion pair, which undergoes 1,4-hydride addition to deliver intermediate A. Subsequent imine−enamine isomerization in the presence of chiral Brønsted acid provides intermediates B1−B4, and the final highly diastereoselective 1,2-hydride addition affords the desired compound 1355. The driving force for this reaction is a rapid Brønsted acid-catalyzed enamine/imine isomerization between the intermediates A−C (Scheme 369). Marinetti and co-workers synthesized phosphoric acids with planar chiral paracyclophane scaffolds and investigated their catalytic activity for the transfer hydrogenation of 2-arylquinolines in the presence of Hantzsch esters.574 The catalyst 1360, CU


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Scheme 371. Asymmetric Transfer Hydrogenation of 3Susbtituted Quinolines Catalyzed by a CyclopentadieneBased Chiral Brønsted Acid

Scheme 373. Iridium-Catalyzed Asymmetric Hydrogenation of Quinolines Using the C3*-TunePhos Chiral Diphosphine Ligands

Scheme 374. Iridium-Catalyzed Asymmetric Hydrogenation of Quinolines Using the Difluorphos Chiral Diphosphine Ligand

chlorides 1366 were hydrogenated to give the corresponding chiral THQs 1367 in high yields and enantioselectivities up to 99% (Scheme 372).576 Anion binding between the substrate and Scheme 372. Asymmetric Hydrogenation of Quinolines Catalyzed by a Chiral Rh-Thiourea Phosphine Complex The catalytic system was employed for the asymmetric hydrogenation of trisubstituted pyridines to give the corresponding hydrogenated compounds in high yields and enantioselectivities up to 98%. Agbossou-Niedercorn and co-workers also investigated a series of bisphosphine ligands for the asymmetric hydrogenation of 2-functionalized quinolines in combination with [Ir(COD)Cl]2/I2, achieving enantioselectivities up to 96%.579,580 The most significant ligands that afforded high yields and enantioselectivities (compounds 1375−1377) are shown in Figure 24.

the ligand was achieved in the presence of strong Brønsted acid HCl. On the basis of deuterium labeling experiments, a mechanism was proposed involving an enamine−iminium tautomerization after the first hydride-transfer step. Zhang, Liang, and co-workers developed an efficient iridiumcatalyzed asymmetric hydrogenation of quinolines using the C3*-TunePhos chiral diphosphine ligands to access the chiral 1,2,3,4-THQs in good yields. After screening a set of ligands, the combination of the iridium catalyst with diphosphine ligand 1371 was identified as a good choice to transform quinolines 1369 into the optically active THQs 1370 in good yields (84− 99%) with enantioselectivities up to 93% (Scheme 373).577 The catalytic system formed by the chiral bisphosphine ligand difluorphos 1374 and [Ir(COD)Cl]2 was employed for the asymmetric hydrogenation of 2,6-disubstituted quinolines 1372 to obtain the corresponding THQs 1373 in excellent yields (up to 99%) and enantioselectivities (up to 96%, Scheme 374).578 The reaction proceeded in high yields with very low catalytic loadings (0.05 to 0.002%) and remarkable catalytic activities (TOF up to 1510 h−1) and productivities (TON up to 43,000).

Figure 24. Some bisphosphine ligands combined with [Ir(COD)Cl]2/ I2 for the asymmetric hydrogenation of 2-functionalized quinolines.

Zhou and co-workers also utilized the [Ir(COD)Cl]2, I2/(R)Difluorphos system for the asymmetric hydrogenation of 3aminoquinolines into the corresponding optically active THQs in high yields with enantioselectivity up to 94%.581 A set of chiral THQs holding potential as cytotoxic compounds was also prepared via Ir-catalyzed asymmetric hydrogenation in the presence of related chiral phosphine ligands.48 CV


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Fan and co-workers synthesized an iridium−diamine catalyst 1380 and employed it to achieve the asymmetric hydrogenation of quinolines 1378 to 1,2,3,4-THQs 1379 (Scheme 375).582 A large number of 2-substituted quinolines were transformed into chiral THQs in high yields and enantioselectivities (up to 99%).

Scheme 377. Ir-Catalyzed Asymmetric Hydrogenation of Quinolines in the Presence of a Chiral Phosphite Ligand

Scheme 375. Asymmetric Hydrogenation of Quinolines in the Presence of a Chiral Iridium−Diamine Catalyst

Scheme 378. Asymmetric Hydrogenation of Quinolines in the Presence of Chiral N-Ferrocenyl NHC-Iridium Catalyst

You and co-workers developed an Ir-catalyzed intramolecular asymmetric allylic dearomatization reaction of heterocyclic compounds including pyridines, pyrazines, quinolines, and isoquinolines. In this report, the authors demonstrated the synthesis of a THQ derivative (compound 1382) starting from quinoline 1381 in the presence of [Ir(COD)Cl]2 and the chiral ligand 1383via quinolinium species A in a modest 22% yield with 27% ee (Scheme 376).583 Scheme 376. Ir-Catalyzed Asymmetric Hydrogenation of Quinolines in the Presence of a Chiral Dioxaphosphepine Ligand

(up to 94%) and enantioselectivities (up to 90:10 er). This procedure was the first one to achieve the low-pressure outersphere asymmetric hydrogenation of quinolines for the synthesis of chiral 1,2,3,4-THQs using an iridium complex bearing a chiral monodentate NHC ligand.586 11.2.3. Asymmetric Hydrogenation by Ru Catalysts. In addition to iridium catalysts, chiral ruthenium catalysts were also involved in the asymmetric hydrogenation of quinolines into the corresponding optically active 1,2,3,4-THQs. Thus, the asymmetric hydrogenation of quinolines and isoquinolines was achieved in the presence of a chiral cationic ruthenium complex Ru(TsDPEN) [TsDPE = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine] in an ionic liquid. A wide variety of 2-alkylsubstituted quinolines 1390 and 1-alkyl-substituted isoquinolines were transformed into the corresponding partially hydrogenated products 1391 in >99% ee with complete conversion (Scheme 379).587 Notably, the reaction was selective

The asymmetric hydrogenation of quinolines and 2,4,5,6tetrahydro-1H-pyrazino[3,2,1-j,k]carbazole was achieved in the presence of iridium catalyst combined with chiral phosphitetype ligands. The quinoline hydrochlorides 1384, upon treatment with [Ir(COD)2]BARF (BARF = tetrakis(3,5trifluoromethylphenyl)borate) and ligand 1386, delivered chiral 1,2,3,4-THQs 1385 in moderate yields and enantioselectivities (Scheme 377).584,585 Metallinos and co-workers synthesized planar annulated chiral N-ferrocenyl NHC-iridium complexes for the asymmetric hydrogenation of quinolines. As shown in Scheme 378, the cationic iridium complex 1389 was employed for the synthesis of optically active THQs 1388 from the corresponding quinoline derivatives 1387 under mild conditions using only 1 mol% complex and PPh3 under 1−5 atm of H2 in good yields

Scheme 379. Asymmetric Hydrogenation of Quinolines in the Presence of a Chiral Cationic Ruthenium Complex

CW


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for the quinoline CN bond over CO bonds, since quinolines containing additional carbonyl functionality were selectively hydrogenated without affecting the carbonyl groups. The catalyst was recycled by simple filtration and reused at least six times with no significant loss in its activity. The asymmetric hydrogenation of quinolines was also achieved in oligo(ethylene glycol)s (OEGs) and poly(ethylene glycol)s (PEGs) in the presence of Ru(TsDPEN) catalyst in excellent yields and enantioselectivities.588 The recycling of the catalyst was demonstrated both in pure 3-OEG and in a biphasic 3-OEG/n-hexane system. Related chiral cationic ruthenium-diamine catalysts were employed for the asymmetric hydrogenation of quinolines in water, and the key intermediate 6-fluoro-2-methyl-1,2,3,4tetrahydroquinoline, a starting material for the preparation of the antibacterial agent (S)-flumequine, was also obtained with 98% ee.589 Fan, Yu, and co-workers previously demonstrated the catalytic activity of other η6-arene-N-tosylethylenediamine-Ru(II) complexes for the asymmetric hydrogenation of quinolines 1393 to 1,2,3,4-THQs 1394 (Scheme 380).590 A large number of

Scheme 381. Asymmetric Hydrogenation of Quinolines Using [Ru(η3-methallyl)2(COD)]/Ph-TRAP System

Zhou and co-workers reported the reduction of 2-substituted quinolines into 1,2,3,4-THQs in the presence of the [Ru(pcymene)Cl2]2/I2 system, and the racemic THQs were resolved using commercial tartaric acid derivatives. Moderate yields of both enantiomers were obtained with enantiomeric excess values above 99%.592 11.2.4. Asymmetric Hydrogenation by Other Metal Catalysts. Tu and Gong explored the catalytic activity of gold phosphates for the asymmetric transfer hydrogenation of quinolines 1401 to obtain chiral 1,2,3,4-THQs 1402(Scheme 382).593 The chiral catalyst generated in situ from binol-based

Scheme 380. Asymmetric Hydrogenation of Quinolines in the Presence of η6-Arene-N-tosylethylenediamine−Ru(II) Complexes

Scheme 382. Asymmetric Transfer Hydrogenation of Quinolines in the Presence of Gold Phosphates

quinoline derivatives such as 2-alkylquinolines, 2-arylquinolines, and 2,3-disubstituted quinoline derivatives were transformed into the corresponding 1,2,3,4-THQs in the presence of the catalysts 1395 or 1396 in excellent yields with >99% ee. These authors explored the mechanistic pathway of the reaction via experimental and theoretical calculations and proposed a mechanism involving 1,4-hydride addition, isomerization, and 1,2-hydride addition reactions. Kuwano and co-workers demonstrated an interesting approach for the partial hydrogenation of quinolines where the reduction took place on the carbocyclic ring to afford 5,6,7,8tetrahydroquinolines as the major products. The combination of [Ru(η3-methallyl)2(COD)] catalyst with Ph-TRAP 1400 was identified as optimal for the selective reduction of the carbocyclic ring of quinolines 1397 to furnish 5,6,7,8tetrahydroquinolines 1398 in good yields with enantiomeric ratios up to 91:6, together with small quantities of 1,2,3,4-THQs 1399(Scheme 381).591 The unusual chemoselectivity of the reaction was presumably due to the trans-chelating property of the chiral ligand. On the basis of some control experiments, the authors suggested that the aromaticity-breaking step is accompanied by the chiral induction in the present asymmetric hydrogenation of quinoline carbocycles.

phosphoric acid 1403 and (IMes)AuMe was effective to trigger the transfer hydrogenation of quinolines 1401 in the presence of Hantzsch ester 1405 to afford the optically active THQs 1402 in excellent yields and enantioselectivities (ee up to 98%). The coordination of the Au(I) phosphate to quinoline was visualized as the first step, and the reaction proceeded via asymmetric transfer hydrogenation−protonation−asymmetric transfer hydrogenation−metathesis steps through the intermediacy of a dihydroquinoline. Ito and co-workers demonstrated a dearomatization− enantioselective borylation reaction sequence for the synthesis of chiral 1,2,3,4-THQs 1408 starting from quinolines 1406via dihydroquinoline 1407(Scheme 383).594 Partial reduction of the quinoline derivatives 1406 using NaBH4 followed by copper(I)-catalyzed regio- and enantioselective protoborylation of 1,2-dihydroquinolines in the presence of chiral ligand (R,R)CX


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of 3-phthalimido-substituted quinolines 1415 to access the chiral 1,2,3,4-THQs 1416, bearing two contiguous stereogenic centers (Scheme 385).597 A wide range of substituted quinolines

Scheme 383. Asymmetric Synthesis of Tetrahydroquinolines by a Dearomatization−Enantioselective Borylation Reaction Sequence

Scheme 385. Homogeneous Palladium-Catalyzed Asymmetric Hydrogenation of 3-Phthalimido-Substituted Quinolones in the Presence of a Chiral Phosphine

QuinoxP* 1409 furnished chiral 3-boryl-tetrahydroquinolines 1408 in good yields and enantioselectivities. The synthesis of functionalized chiral tetrahydroquinolines was also explored through derivatization of the borylation products. Recently, Hou, Zhang, and co-workers also reported the related copper-catalyzed enantioselective hydroboration of 1,2dihydroquinolines in high yields and excellent enantioselectivities (up to 98% ee), and the approach was extended to the synthesis of compounds with pharmacological significance, such as sumanirole and the inotropic agent (S)-903.595 An effective approach based on dual catalysis was established by combining a Lewis acid and chiral Lewis base for the asymmetric addition of aldehydes to quinolinium acetals.596 The dihydroquinoline derivatives 1410 were treated with aldehydes 1411 in the presence of In(OTf)3, and the chiral cyclic amine catalyst 1414 furnished the corresponding chiral dihydroquinolines 1412 in good yields and enantioselectivities (Scheme 384). Subsequently one of the synthesized dihydroquinolines was transformed into the optically active 1,2,3,4-THQ 1413 under standard conditions. Zhou and co-workers developed the first example of an homogeneous palladium-catalyzed asymmetric hydrogenation

were transformed into the corresponding optically active THQs in the presence of Pd(OCOCF3)2 and the chiral phosphine ligand 1417 in high yields with enantioselectivities up to 90%. Similarly, Wu and co-workers reported the use of binaphthylstabilized palladium nanoparticles (BIN-PdNPs) with chiral modifiers for the asymmetric hydrogenation of N-heterocycles, including quinolines, in good to excellent yields and moderate enantioselectivities.598 After establishing a method for the silver-catalyzed biomimetic transfer hydrogenation in excellent yields of various Nheterocycles such as quinolines, quinoxalines, and 1,10phenanthroline with Hantzsch ester,599 the asymmetric version of the reaction was also studied. This reaction involved the use of Ag catalysts and chiral phosphine ligands and gave the target chiral THQs in good yields but with moderate enantioselectivities. 11.2.5. Miscellaneous Approaches for the Synthesis of Chiral Tetrahydroquinolines from Quinolines. Zhang and Du accomplished the cis-hydrogenation of 2,3,4-trisubstituted quinolines 1418 with chiral borane catalysts generated in situ from chiral diene 1420, allowing the first synthesis of optically active 2,3,4-trisubstituted 1,2,3,4-THQs 1419 (Scheme 386).600 The reaction was accomplished under metal-free conditions to

Scheme 384. Synthesis of Tetrahydroquinolines Based on the Asymmetric Addition of Aldehydes to Quinolinium Acetals

Scheme 386. Asymmetric Hydrogenation of Quinolines with in Situ-Generated Chiral Borane Catalysts

CY


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access a wide range of chiral THQs containing three contiguous stereogenic centers in high yields (up to >99%) and enantioselectivities (82−99%). Subsequently the authors extended their study to the diastereo- and enantioselective synthesis of 2,3- and 2,4-disubstituted 1,2,3,4-THQs from the corresponding quinolines.601 Cozzi and co-workers reported the direct organocatalyzed enantioselective alkylation of aldehydes with quinolines activated with benzyl chloroformate for the synthesis of chiral dihydroquinolines.602 Treatment of quinolines 1421 with CbzCl followed by the addition of aldehydes to activated quinolines in the presence of Jørgensen catalyst 1426 furnished the diastereomeric dihydroquinolines 1422 and 1423 with small quantities of 4-substituted 1,4-dihydroquinolines 1424 in good yields (Scheme 387). The ratio of compounds 1422 and 1423

Scheme 388. Asymmetric Synthesis of Tetrahydroquinolines Based on the Asymmetric Borylation/Kinetic Resolution of the Racemic 2-Substituted 1,2-Dihydroquinolines

Scheme 387. Asymmetric Hydrogenation of Quinolines Based on an Organocatalyzed Enantioselective Alkylation of Aldehydes with Activated Quinolines

dihydroquinolines 1429 was recovered with high yields and excellent enantiopurities. A three-component reaction between quinoline 1431, phenyl acetylene 1432, and ethyl chloroformate in the presence of a copper catalyst and the StackPhos ligand 1434 provided the C-2 alkynylated dihydroquinolines 1433 with excellent enantioselectivities of 90−98% (Scheme 389).605 These dihydroquinoScheme 389. Asymmetric Synthesis of Tetrahydroquinolines Based on an Asymmetric Copper-Catalyzed ThreeComponent Reaction

was up to 17:83 in favor of the syn isomer with excellent enantioselectivity (up to 99%). Representative examples of the dihydroquinolines were converted in the corresponding 1,2,3,4THQs. For instance, 1,2,3,4-THQ 1425 was obtained in 79% yield as a 2.9:1 diastereomeric mixture upon hydrogenation of the corresponding dihydroquinoline. The synthesis of chiral 2-substituted 1,2,3,4-THQs was established via a chemo-enzymatic deracemization by combining muteins of a bacterial cyclohexylamine oxidase (CHAO) and ammonia−borane with the Turner deracemization strategy. A set of chiral THQs was obtained with good yields (58−92%) and ee values up to 99%.603 Hou and co-workers established the asymmetric borylation/ kinetic resolution of the racemic 2-substituted 1,2-dihydroquinolines 1427 via Cu-catalyzed borylation (Scheme 388).604 One enantiomer of racemic 1,2-dihydroquinolines 1427 selectively undergoes borylation in the presence of the CuCl/(R,Sp)JosiPhos-1 catalytic system (1430) and potassium methoxide in THF/MeOH solvent system to provide chiral 3-boryltetrahydroquinolines 1428 bearing two vicinal stereogenic centers with excellent diasteroselectivities >99:1 and enantioselectivities up to 99%. The other enantiomer of 2-substituted 1,2-

lines were transformed into naturally available tetrahydroquinoline alkaloids such as (−)-angustureine 1, (+)-cuspareine 2, and (+)-galipinine 4 in two steps with good yields. Wang and co-workers established a dearomative C-2 arylation of quinolinium salts 1435 with aryl boronic acids using the [Rh(COD)2]BF4/(R)-BINAP catalytic system to access 2-aryl dihydroquinolines 1436 with good to excellent enantioselectivities (Scheme 390).606 Furthermore, one of the 2-aryl dihydroquinolines 1436 was reduced using tosylhydrazine to afford the tetrahydroquinoline derivative 1437 in 90% yield and CZ


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and ammonium acetate, are the key intermediates for the formation of the target compounds. Shang, Song, and co-workers developed a Yb(OTf)3catalyzed four-component reaction for the synthesis of antimicrobial 5,6,7,8-tetrahydroquinolines (Scheme 392).609

Scheme 390. Asymmetric Synthesis of Tetrahydroquinolines Based on an Asymmetric Dearomative C-2 Arylation of Quinolinium Salts

Scheme 392. Synthesis of 5,6,7,8-Tetrahydroquinolines by a Hantzsch-like Reaction Starting from (+)-Nopinone

This approach involved the Hantzsch-like reaction among ammonium acetate, (+)-nopinone 1442, arylaldehydes 1443, and ethyl cyanoacetate or malononitrile 1444 in the presence of Yb(OTf)3 in ethanol to furnish 5,6,7,8-tetrahydroquinolines 1445. The reaction between intermediate A, obtained via Knoevenagel condensation between aldehyde 1443 and active methylene compounds, and the enamine B, derived from (+)-nopinone 1442 and ammonium acetate, delivered 5,6,7,8tetrahydroquinolines 1444 via successive Michael addition, intramolecular cyclization, and aromatization steps. Another Hantzsch-like process, allowing the preparation of pyridines from cyclohexanone oxime acetates, was applied to the synthesis of some Sceletium alkaloids containing a fused 5,6,7,8tetrahydropyridine core.610 2-Aryl-5,6,7,8-tetrahydroquinoline derivatives 1451, designed as ligands for the construction of multilayer organic lightemitting diodes (OLEDs) by preparation of a series of bluegreen to red light-emitting phosphorescent platinum(II) complexes, were synthesized by means of a three-step protocol (Scheme 393).611,612 The Mannich reaction between aryl methyl ketones 1446 and N,N-dimethylmethyleneiminium chloride 1447 generated β-amino ketones 1448, which further reacted with cyclohexanone enamine 1449 to afford 1,5diketones 1450. The final construction of the pyridine moiety

88% ee. This compound is relevant because it is a key intermediate in the preparation of tetrahydroquinoline-derived selective estrogen receptor modulator 1438. The authors proved the versatility of this methodology by its application to the synthesis of naturally occurring alkaloids (+)-cuspareine 2, and (−)-angustureine 1 using alkenylboronic acids. The oxidative resolution of racemic 2-susbtituted 1,2,3,4THQs was achieved by whole cell studies of Pseudomonas monteilii ZMU-T01 strains, which showed up to 50% conversion and >99% enantioselectivity.607

12. SYNTHESIS OF TETRAHYDROQUINOLINES WITH OTHER HYDROGENATION PATTERNS 12.1. Synthesis of 5,6,7,8-Tetrahydroquinolines by Generation of the Pyridine Ring

A highly efficient water-mediated, three-component reaction was developed for the synthesis of polysubstituted pyridines and 5,6,7,8-tetrahydroquinolines. As shown in Scheme 391, the reaction between enolizable ketones 1439, Mannich bases 1440, and ammonium acetate afforded 5,6,7,8-tetrahydroquinolines 1441 in the presence of montmorillonite K-10 in water at 80 °C, in high yields (up to 96%).608 Enone A, generated in situ from Mannich bases 1440, and enamine B, arising form ketone 1439

Scheme 393. Synthesis of 2-Aryl-5,6,7,8tetrahydroquinolines from 1,5-Dicarbonyl Compounds and Hydroxylamine

Scheme 391. Synthesis of 5,6,7,8-Tetrahydroquinolines by a Three-Component Reaction from Ketones, Mannich Bases, and Ammonium Acetate

DA


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was achieved by reacting the 1,5-dicarbonyl compounds 1450 with hydroxylamine hydrochloride in ethanol. Ceylan and co-workers reported a related synthesis of a variety of 2,4-diaryl-5,6,7,8-tetrahydroquinoline derivatives 1454 starting from chalcones 1452 and cyclohexanone (Scheme 394).613

Scheme 396. Synthesis of 5,6,7,8-Tetrahydroquinolines by an Enamine Formation−Michael Addition−Intramolecular Cyclocondensation Sequence

Scheme 394. Synthesis of 2,4-Diaryl-5,6,7,8tetrahydroquinolines from 1,5-Dicarbonyl Compounds and Ammonia

like reaction between cyclohexanone 1462, arylaldehydes 1463, ethyl cyanoacetate 1464, and ammonium acetate followed by treatment with POCl3 of the intermediate 5,6,7,8-tetrahydroquinoline-2-one 1465 (Scheme 397).57 The authors also Scheme 397. Synthesis of 5,6,7,8-Tetrahydroquinolin-2-ones by a Four-Component Reaction between Cyclohexanone, Arylaldehydes, Ethyl Cyanoacetate, and Ammonium Acetate The base-catalyzed Michael addition of cyclohexanone with chalcones 1452 in the presence of a phase-transfer catalyst delivered the intermediate 1,5-diketone 1453, which was subsequently transformed into 2,4-diaryl-5,6,7,8-tetrahydroquinoline derivatives 1454 using ammonium acetate as the nitrogen source. Acetophenone derivatives 1456 were reacted with cyclic 1,3diketones 1455 and ammonium acetate under microwave irradiation using KHSO4 as catalyst in aqueous media to obtain the 2-aryl-5,6,7,8-tetrahydroquinoline derivatives 1457 in excellent yields (Scheme 395).614 Kantevari and co-workers also reported a related procedure for the synthesis of compounds 1457 in the presence of the CeCl3·7H2O−NaI catalytic system in refluxing i-PrOH.615 Scheme 395. Synthesis of 2-Aryl-5,6,7,8tetrahydroquinolines by a Michael/Cyclocondensation Process

explored the synthesis of the corresponding 2-amino derivatives using cyclic ketones, Knoevenagel condensation product of arylaldehydes and malononitrile, and ammonium acetate under similar experimental conditions. In related work, the reaction of arylidene malononitriles with cyclohexanone in an alcohol as solvent and in the presence of sodium, under microwave irradiation, was found to afford 2alkoxy-5,6,7,8-tetrahydroquinoline-3-carbonitriles in excellent yields.617 Similarly, a library of 2-amino-5,6,7,8-tetrahydroquinolines 1470, potential precursors for the synthesis of biologically relevant heterocyclic compounds, were prepared in one pot from cyclic ketone 1467, aldehydes 1468, malononitrile 1469, and ammonium acetate in good yields (Scheme 398).58−60 In addition, similar transformations were achieved starting from ethyl cyanoacetate or cyanoacetamide.618 3-Cyano-5,6,7,8-tetrahydroquinoline derivatives are also accessible via an ANRORC-type oxygen−nitrogen exchange, by treatment of the corresponding 5,6,7,8-tetrahydrobenzopyran derivatives with ammonium acetate in refluxing DMSO.619

2,6-Disubstituted 5,6,7,8-tetrahydroquinolines containing trifluoromethyl groups 1461 were synthesized from cyclic ketone 1458, enone 1460, and ammonium acetate by a reaction comprising enamine formation−Michael addition−intramolecular cyclocondensation steps via the intermediacy of enamine 1459 (Scheme 396).616 The racemic 2,6-disubstituted tetrahydroquinolines thus obtained were then separated by chiral HPLC to obtain their enantiomers. 2-Chloro-5,6,7,8-tetrahydroquinolines 1466 were synthesized in good yields by means of a four-component HantzschDB


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13. FUNCTIONALIZATION OF TETRAHYDROQUINOLINES

Scheme 398. Synthesis of 5,6,7,8-Tetrahydroquinolines from Cyclic Ketones, Aldehydes, Malononitrile, and Ammonium Acetate

13.1. N-Functionalization of Tetrahydroquinolines

Xie and co-workers synthesized a series of N-heteroarylsubstituted tetrahydroquinolines 1478 and evaluated them for antitumor activity and drug-like properties (Scheme 400).50 NScheme 400. SNAr Reactions from a Tetrahydroquinoline and 2,4-Dichloroquinazoline The Friedländer reaction provides another approach for the construction of fused 5,6,7,8-tetrahydroquinolines. In this context, CuSO4-D-glucose was identified as an eco-efficient catalytic system for the Friedländer reaction allowing the synthesis of a set of fused 5,6,7,8-tetrahydroquinolines from cyclic ketones and in situ-generated 2-aminoarylaldehydes/ ketones.620 Compounds containing a 2-aminonitrile structural fragment are good starting materials for the construction of 4-aminoquinolines via a Friedländer-type reaction with cyclohexanone derivatives. This chemistry has found broad application in the synthesis of acetylcholinesterase inhibitors for their study as potential anti-Alzheimer agents and is exemplified by the preparation of compounds 1474 summarized in Scheme 399.621 Scheme 399. Synthesis of Fused 5,6,7,8Tetrahydroquinolines by a Friedländer-Type Reaction of 2Aminobenzonitriles with Cyclohexanone

Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines 1477 were synthesized by coupling 6-methoxy-1,2,3,4-tetrahydroquinoline 1475 and 2,4-dichloroquinazoline 1476 in the presence of NaHCO3 in anhydrous EtOH at reflux. Subsequently, the 2-chloro substituent in 1477 was converted into a substituted amino group by SNAr reactions with 3-aminopropanol, cyclopropylamine, or cyclopentylamine in ethanol under microwave irradiation at 150 °C to afford the corresponding compounds 1478, which behaved as tubulin polymerization inhibitors. The authors also synthesized N-substituted quinolines, isoquinoline, and 9H-purine-substituted tetrahydroquinoline derivatives in good yields using similar strategies. The same group also described the Pd-catalyzed N-arylation of tetrahydroquinolines with bromo- or iodobenzene derivatives in the presence of BINAP as a ligand and cesium carbonate as a base, to be tested as antitumor agents targeting the colchicine site on tubulin.49 Tetrahydroquinoline derivatives 1482 were synthesized in three steps as inhibitors of HIV-1 reverse transcriptase and were also evaluated for antifungal activity against Candida albicans and Aspergillus niger fungal strains (Scheme 401).623 The intermediate 1481 in this route was synthesized by treating tetrahydroquinoline 1479 with 4-chlorophenacyl bromide 1480 in Et3N/DMF, followed by reduction of the keto group to hydroxyl using sodium borohydride. The intermediate 1481 was reacted with several substituted phenyl isocyanates in the presence of sodium hydride as base in THF to afford the final compounds 1482 in good to excellent yields. Ling and co-workers synthesized a series of pyrazole derivatives containing a 1,2,3,4-tetrahydroquinoline structural fragment and evaluated their fungicidal activities (Scheme 402).97 The substituted-1H-pyrazole-5-carboxylic acid 1484 was converted into the corresponding acid chloride with thionyl chloride and further coupled with tetrahydroquinoline 1483 in

The required 2-aminonitrile 1473 was synthesized via a threecomponent reaction between aldehydes 1471, 8-hydroxyquinoline 1472, and malononitrile under basic conditions. Subsequent treatment with cyclohexanone in the presence of AlCl3 delivered the polycyclic compounds 1474 bearing 5,6,7,8-THQ core. Finally, it is relevant to mention in this section that iridium(III) complexes of 8-amino-5,6,7,8-tetrahydroquinolines have found utility as catalysts for the asymmetric transfer hydrogenation of ketones.622 DC


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compound 1487 was then coupled with methyl 2-thiophene thioimidate 1488 to give the final compounds 1489. The authors synthesized some additional derivatives for the biological studies by varying the N-substituted side chain with cyclic and acyclic substituted amines. 6-Amino-1,2,3,4-tetrahydroquinoline 1490 underwent chemoselective sulfonylation with a variety of aryl sulfonyl chlorides 1491 in TFA/DCM to afford N-arylsulfonated 1,2,3,4tetrahydroquinolines 1492, some of which exhibited cytotoxic effects against several cancer cell lines (Scheme 404).53

Scheme 401. Alkylation of Tetrahydroquinoline with 4Chlorophenacyl Bromide

Scheme 404. Chemoselective Sulfonylation of 6-Amino1,2,3,4-tetrahydroquinolines

Scheme 402. Acylation of Tetrahydroquinoline with 1HPyrazole-5-carboxylic Acid

A series of long alkyl chain-substituted N-alkyl tetrahydroquinoline derivatives 1494 were prepared from THQ 1493 to evaluate their antimicrobial activity (Scheme 405).41 ComScheme 405. Synthesis of Long-Alkyl-Chain-Substituted Nalkyl Tetrahydroquinolines

pyridine to provide the required pyrazole-linked 1,2,3,4tetrahydroquinolines 1485 in excellent yields. Ramnauth and co-workers synthesized a 1,2,3,4-tetrahydroquinoline derivative containing a 6-substituted thiophene amidine group (compound 1489) from 6-amino-1,2,3,4tetrahydroquinolin-2-one derivatives 1486 in two steps, for their evaluation as inhibitors of human nitric oxide synthase (Scheme 403).86 The starting tetrahydroquinolone 1486 was reduced using lithium aluminum hydride, and the resulting Scheme 403. Synthesis of a 1,2,3,4-Tetrahydroquinoline Derivative Containing a 6-Substituted Thiophene Amidine Group

pounds 1494 were prepared either by direct alkylation of 1493 or by its acylation followed by reduction. Their corresponding hydrochloride salts 1495 were then precipitated by treatment with HCl gas to facilitate their biological study. Similarly, N-alkyl perhydroquinoline derivatives were obtained from transperhydroquinoline. Benzoyl isocyanates 1498 were prepared from benzoic acid in three steps, namely transformation into the corresponding acid chloride, then amide, and finally treatment with phosgene (Scheme 406).624 The reaction of isocyanate 1498 with tetrahydroquinoline 1497 in refluxing toluene afforded Nsubstituted benzoyl-1,2,3,4-tetrahydroquinolyl-1-carboxamides 1499, some of which exhibited excellent fungicidal activities. Cholesteryl ester transfer protein (CETP), a plasma protein that facilitates the transport of cholesteryl esters, is a potential target in the treatment of atherosclerosis, as discussed in section 3. In the course of their preclinical and clinical studies, the CETP inhibitors 1501(R,S) and 1502(R,R) were synthesized in DD


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Scheme 406. Synthesis of Acylureas by Reaction of Benzoyl Isocyanates with Tetrahydroquinoline

Scheme 409. Kinetic Resolution of Chiral 2-Substituted Tetrahydroquinolines by N-Acylation

quantitative yield in multi-hundred-gram scale by Li and coworkers via regiospecific and diastereoselective ring-opening of (S)-2-(trifluoromethyl)oxirane with (R)-1500 in hexafluoro-2propanol, without catalyst (Scheme 407). 625 Similarly, 1501(S,S) and 1502(S,R) were synthesized in excellent yield by treating (R)-2-(trifluoromethyl)oxirane with (S)-1500 under the same reaction conditions. Scheme 407. Regiospecific and Diastereoselective RingOpening of (S)-2-(Trifluoromethyl)oxirane with a Tetrahydroquinoline Derivative

Scheme 410. Enantioselective Synthesis of Tetrahydroquinolines via an Aza-Henry Reaction in the Presence of a Chiral Ammonium Betaine

N-Aryl tetrahydroquinolines 1505 were obtained in yields up to 94% by coupling tetrahydroquinoline 1503 with a variety of aryl halides 1504 in refluxing toluene in the presence of the Pd2(dba)3/BINAP catalytic system, with sodium tert-butoxide as base (Scheme 408).626

Indoles 1516 undergo a ready nucleophilic substitution reaction with dihydroquinoline 1515 in the presence of Brønsted acids to provide tetrahydroquinolines. Enhancing the electron density of the phenyl ring of starting compounds 1515 facilitates the protonation of the alkene group by the Brønsted acid affording a highly reactive aza-o-xylylene (AOX) intermediate 1519, which reacts effectively with the indoles to yield compounds 1517. This method was examined in the presence of chiral phosphoric acids 1518 as catalysts to afford tetrahydroquinolines containing a quaternary all-carbon center in high yields with good to excellent enantioselectivities (Scheme 411).630 Iridium-catalyzed photochemical reactions of N-phenyl1,2,3,4-tetrahydroquinolines (X = CH2) 1520 with di-tertbutyl azodicarboxylate 1521 afforded tetrahydroquinoline derivatives 1522 via direct sp3C−H amination (Scheme 412).631 The photoredox catalysis-mediated formation of αaminoalkyl radicals is a key step in this transformation. The N,Nacetals 1522 thus obtained easily undergo nucleophilic substitution with carbon nucleophiles to provide 2-substituted tetrahydroquinolines 1523 through C−C bond formation. Other six-membered benzocyclic amines 1520, such as 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-1,4-benzoxazine, and 3,4-dihydro-2H-benzo-1,4-thiazine derivatives also undergo a smooth reaction to give corresponding N,N-acetals 1522 in moderate yields.

Scheme 408. Pd-Catalyzed N-Arylation of Tetrahydroquinolines

N-Acylation reactions have been used as the basis for kinetic resolution protocols of chiral 2-substituted tetrahydroquinolines 1506 and related heterocycles (Scheme 409). These methods are based on the differential reactivity of both enantiomers toward chiral acyl chlorides such as compounds 1507627 and 1510.628 13.2. Functionalization of Carbon Atoms at the Tetrahydropyridine Ring

Ooi and co-workers demonstrated a highly enantioselective synthesis of tetrahydroquinoline derivatives 1513 via an azaHenry reaction between 3-nitro-dihydro-2(1H)-quinolones 1511 and N-Boc-aldimines 1512, using a chiral ammonium betaine 1514 as the catalyst (Scheme 410).629 This method provides a direct access to quinolone derivatives 1513 bearing a tetrasubstituted stereogenic center at the C-3 position. DE


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radical process initiated by a ketyl radical attack onto the nitrile, which leads to the formation of the methylene-bridged eightmembered ring to furnish the target tricyclic compounds 1528 (Scheme 413).632

Scheme 411. Enantioselective Synthesis of 4-(3Indolyl)tetrahydroquinolines in the Presence of Chiral Phosphoric Acids

Scheme 413. Synthesis of Methylene-Bridged Bridged Tetrahydroquinolines

Scheme 412. Ir-Catalyzed Photochemical Reactions of NPhenyl-1,2,3,4-tetrahydroquinoline with Di-tert-butyl Azodicarboxylate

Guingant and co-workers reported a 12-step total synthesis of (−)-(R)-sumanirole 1534, a highly selective D2 receptor full agonist, from a dihydroquinoline precursor 1529 (Scheme 414).633 The first step of this synthesis involves the epoxidation of the C-3−C-4 double bond in 1,2-dihydroquinoline 1529 through Jacobsen’s enantioselective epoxidation, followed by Scheme 414. Synthesis of (−)-(R)-Sumanirole Based on a Jacobsen Enantioselective Epoxidation

Streuff and co-workers developed a two-step method for the synthesis of methylene-bridged tricyclic building blocks 1528 that started with the titanium(III)-catalyzed reductive crosscoupling of quinolones or chromones 1525 with Michael acceptors 1526 to give tetrahydroquinolin-4-ones (X = NR) or chromanones (X = O) 1527. The formation of 1527 can be explained by a titanium(III)-catalyzed reaction, involving the generation of an allylic radical by an in situ-formed titanium(III) catalyst. This radical then attacks the Michael acceptors forming the new carbon−carbon bond. For the case of tetrahydroquinolin-4-ones (X = NR), the relative configuration at C-2/C-3 of compounds 1527 was exclusively syn, which was attributed to the steric repulsion between the C-2-functionalized alkyl chain and the nitrogen substituent. On the other hand, in the case of chromones (X = O) the anti-diastereomer was the major product because of the absence of steric repulsion. Compounds 1527 then underwent reductive ketonitrile cyclization in a DF


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Scheme 416. Ir-Catalyzed α-Functionalization of Tetrahydroquinolines with Indoles

reduction to provide 3-hydroxytetrahydroquinoline 1530. This compound was then transformed into the target (−)-(R)sumanirole 1534 via intermediates 1531−1533. An alternative synthesis of (−)-(R)-sumanirole is summarized in Scheme 367 and the accompanying discussion. The acetohydrazide derivative 1535, containing a 5,6,7,8tetrahydroquinoline ring, was treated with a variety of electrophiles as part of a research program aimed at the search for new antileishmanial and antitumor compounds. All reactions were carried out under reflux conditions and gave yields in the range of 55−77%, affording the heterocyclic systems 1536− 1543 summarized in Scheme 415.634 Scheme 415. Synthetic Transformations Starting from a 5,6,7,8-Tetrahydroquinoline Acetohydrazide Derivative

Scheme 417. Enantioselective C-4 Hydroxylation of Tetrahydroquinolines with Whole Cells of Rhodococcus equi

buffer (50.0 mM Na2HPO4/KH2PO4) containing racemic 2substituted-1,2,3,4-tetrahydroquinolines 1547, Rhodococcus equi ZMU-LK19 and DMSO at 30 °C. The products were isolated in moderate yields and good to excellent stereoselectivities.

Tetrahydroquinolines and heteroaryl-fused cyclic secondary amines 1544 were α-functionalized utilizing an iridium catalyst to synthesize the corresponding 2-indole-substituted derivatives 1546 with moderate to good yields (Scheme 416).635 Thus, compounds 1544 were coupled with various indoles 1545 in the presence of [Cp*IrCl2]2 as catalyst, with TBHP as oxidant and Cs2CO3 as base, in refluxing toluene. The reaction proceeded through partial dehydrogenation of the starting materials 1544 to give an imine that is then trapped by the indole nucleophiles to deliver the α-functionalized products 1546. Chen co-workers developed a biocatalytic method, using whole cells of Rhodococcus equi ZMU-LK19, for the enantioselective synthesis of chiral 2-substituted-1,2,3,4-tetrahydroquinolin-4-ols 1548 and 1549 and chiral 2-substituted2,3-dihydroquinolin-4(1H)-ones 1550 and 1551 from (±)-2substituted-tetrahydroquinolines 1547 through a sequential asymmetric hydroxylation/diastereoselective oxidation process (Scheme 417).636 The reaction was performed at pH = 7, in PBS

13.3. Functionalization of the Aryl Ring

The benzene ring in tetrahydroquinolines has the usual reactivity found in electron-rich benzene derivatives. For instance, N- alkyl-2,2,4-trimethyltetrahydroquinolines 1552 undergo Vilsmeier−Haack formylation at their most electronrich C-6 position to afford 6-formyltetrahydroquinolines 1553 in moderate yields (Scheme 418).637 If the C-6 position is substituted, formylation takes place at C-8. Meshram and co-workers developed a regioselective method to functionalize the C-6 position of N-unprotected THQs 1554 with chromene hemiacetals 1555 for the synthesis of 6substituted THQ derivatives 1556 (Schemes 419).638 This reaction proceeded well with various chromene hemiacetals bearing chloro, bromo, or nitro groups in the presence of PTSA as catalyst in water at 100 °C to afford 6-substituted THQ derivatives 1556 in good to excellent yields. The same authors studied a related reaction of 1,2,3,4-THQ 1557 with βDG


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the presence of CO and hexafluoroisopropyl alcohol afforded benzoate ester 1563, which could be readily functionalized both at C-6 and C-7 to yield THQ derivatives 1564 (Scheme 421).641

Scheme 418. Vilsmeier−Haack Formylation of Tetrahydroquinolines

Scheme 421. Pd-Catalyzed Functionalization of the Tetrahydroquinoline C-7 Position by Use of a C-6 Directing Group

Scheme 419. Reaction of the C-6 Position of Tetrahydroquinolines with Oxonium Cations Derived from Chromene Hemiacetals

nitrostyrenes 1558 as electrophiles in water, using InCl3 as catalyst, that gave C-6-substituted products 1559 (Scheme 420). Yu and co-workers also achieved C-7 functionalization of the tetrahydroquinoline core by a Pd-catalyzed remote C−H olefination in substrates 1565 with compound 1566, assisted by the presence of a recyclable directing group at the tetrahydroquinoline nitrogen.642 This template bears a directing nitrile group that was designed in order to selectively activate the meta carbon relative to nitrogen in compounds 1565via the generation of a highly strained, cyclophane-like palladated intermediate to deliver compounds 1567. The meta orientation was most efficient for the case of the F-containing directing group, which was explained by the conformational bias induced by the fluorine substituent (Scheme 422). Fan and co-workers developed a Pd-catalyzed ortho-arylation of tetrahydroquinoline derivatives 1568 that allowed the

Scheme 420. Henry Reaction at the C-6 Position of Tetrahydroquinolines

Regarding carbon−heteroatom bond-forming reactions, Cordeiro and co-workers studied the action of several nitrating mixtures on THQs bearing various N-protecting groups (COMe, COi-Pr, COCF3, Fmoc). They obtained 6- or 8nitro-THQs, together with small amounts of the 6,8-dinitro derivative.639 The reaction of THQs with Br2 and NBS under various reaction conditions allowed the transformation of 1,2,3,4-tetrahydroquinolines into the corresponding 6,8-dibromoquinoline and 3,6,8-tribromoquinolines in good yield through dehydrogenative bromination processes.640 The activation of other positions can be achieved using Pdbased functionalization that exploits suitable directing effects. As part of their work on C−H carbonylation reactions, Wang and Gevorgyan explored THQ substrates. Thus, the gold-catalyzed iodination of the N-protected compound 1560 with Niodosuccinimide (NIS) afforded 1561. The presence of the iodo substituent allowed the installation of the (2-pyridyldiisopropyl)silyl (PyrDipSi) group, which allows o-C−H functionalization reactions, via Rh-catalyzed cross-coupling of the aryl iodide with PyrDipSiH to yield 1562. The subsequent Pd(II)-catalyzed o-C−H alkoxycarbonylation of silane 1562 in

Scheme 422. Pd-Catalyzed Remote Functionalization of the Tetrahydroquinoline C-7 Position

DH


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synthesis of the corresponding 8-aryl derivatives 1570 (Scheme 423).643 Thus, the aryl iodides 1569 underwent ready ortho-

Scheme 425. Friedel−Crafts Acylation of the Tetrahydroquinoline C-6 Position

Scheme 423. Pd-Catalyzed Arylation of the Tetrahydroquinoline C-8 Position

arylation with aryl ureas 1568 in water, in the presence of Pd(OTs)2(MeCN)2 as catalyst and under ligand-free conditions, to yield compounds 1570 in high yields, with remarkable functional group tolerance. Similarly, Sun and co-workers demonstrated a synthesis of 8arylcarbonyl-1,2,3,4-tetrahydroquinolines 1573 via the palladium-catalyzed decarboxylative ortho-aroylation of N-acetyl1,2,3,4-tetrahydroquinolines 1571 with α-oxoarylacetic acids 1572 involving C−H bond activation (Scheme 424).644

Scheme 426. Synthesis of 7-([1,2,4]Triazolo[1,5a]pyrimidin-2-yl)tetrahydroquinoline Derivatives

Scheme 424. Pd-Catalyzed Acylation of the Tetrahydroquinoline C-8 Position

Scheme 427. Synthesis of Medium-Ring-Sized Fused Nitrogen Heterocycles from Tetrahydroquinolines

The selective Friedel−Crafts acylation of tetrahydroquinoline derivatives is problematic due to the presence of several reaction centers and normally requires prior N-deactivation. The reaction of N- acetyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline 1574 with acetyl chloride in the presence of AlCl3 yields a mixture of the C-6 and C-8 monoacylated products. The Ndeacetylation of the 6-substituted derivative afforded compound 1575, which was condensed with dimethylformamide dimethylacetal in the presence of NaOMe in refluxing DMF to provide enaminones 1576. These intermediates were converted into pyrimidine derivatives 1578 by treatment with arylguanidines 1577 in 2-propanol under reflux conditions (Scheme 425).645 Similarly, compound 1579 was treated with 1,2,4-triazol-5amines 1580 in DMF under reflux to give tetrahydroquinolines 1581 in good yields (Scheme 426).646

Scheme 428. Synthesis of Diazabicyclo[7.4.0]tetradecane Derivatives from Tetrahydroquinolines

13.4. Synthesis of Complex Heterocycles from Tetrahydroquinolines

Clayden and co-workers found that benzylic urea derivatives of some benzo-fused nitrogen heterocycles 1582, including tetrahydroquinolines, undergo ring expansion through benzylic deprotonation with LDA in the presence of N,N′-dimethylpropylideneurea (DMPU) to yield medium ring-sized fused heterocycles 1583 (Scheme 427).647 The same chemistry allowed the preparation of fused systems such as diazabicyclo[7.4.0]tetradecane derivatives 1585 starting from THQs 1584 (Scheme 428). Zhang and co-workers demonstrated the hydrogen-transfermediated α-functionalization of 1,8-naphthyridines 1587 with

tetrahydroquinolines 1586 in the presence of an iridium catalyst (Scheme 429).648 The observed product 1588 is obtained through C8−Ir insertion of this unit onto a C-2 imino group formed from the starting 1,8-naphthyridines 1587 via hydrogen transfer followed by protodemetalation. Compounds 1588 were then employed as starting materials for the synthesis of DI


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Scheme 429. Ir-Catalyzed α-Functionalization of 1,8Naphthyridines with Tetrahydroquinolines

Scheme 431. Synthesis of Fused Tetrahydroquinolines by Visible-Light-Induced Decarboxylative Coupling/ Cyclization from a 1-Acyltetrahydroquinoline

assisted ortho-benzoylation of the N-acetyltetrahydroquinoline 1596, directed by N-acetyl group, to afford intermediate C. Its intramolecular aldol condensation in the presence of DBU as base provides the target molecule 1598 in one pot (Scheme 432). Scheme 432. Mechanism Proposed for the Photochemical Decarboxylative Coupling/Cyclization Process

pentacyclic compounds 1589 by treatment with both alkyl and aryl aldehydes in acetic acid at 70 °C, in moderate to good yields. Tricyclic isatin derivatives 1590 underwent Knoevenagel condensation with aryl cyanomethyl ketones 1591 in the presence of TsOH in refluxing EtOH to yield 3-(aroyl(cyano)methylidene)oxindoles 1592 (Scheme 430).649 These highly Scheme 430. Synthesis of Spirocyclic Hemiacetals from a Fused Tetrahydroquinoline

The aza-Prins reaction of 3-vinyltetrahydroquinolines 1599 with aldehydes 1600 proceeded smoothly in hydrogen chloride, and the tricyclic benzazocine derivatives 1601 and 1602 thus generated were isolated in good to excellent yields (Scheme 433).651 In the presence of hydrogen chloride, an iminium ion was generated from the secondary amine in 1599 and the Scheme 433. Aza-Prins Reaction of 3Vinyltetrahydroquinolines with Aldehydes

electrophilic alkenes undergo cyclization with the anion of cyclic 1,3-diketones, generated by treatment with DMAP at room temperature, to produce spirocyclic hemiacetals 1593−1595 in good yields. Chu and co-workers reported the construction of fused THQs 1598 by a visible-light-induced one-pot domino sequence comprising decarboxylative coupling and intramolecular cyclization steps (Scheme 431).650 The benzoyl radical, obtained by visible light-promoted decarboxylation of 1597, allows the PdDJ


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aldehyde in 1600. This intermediate was intercepted intramolecularly by the C3-pendant olefin to give a tricyclic benzazocine-derived carbocation, which finally reacts with the chloride ion to form derivatives 1601 and 1602. The scope of the reaction was extended by using other hydrogen halides such as HBr and HI. The bromo derivatives were further functionalized by cross coupling with PhMgBr in the presence of a Co catalyst. Zhang and co-workers reported a gold-catalyzed 1,2-alkyl migration of 2-alkynyl carbonyl compounds containing a cyclopentane ring or a heterocycle. For instance, the THQ derivatives 1603 underwent a 1,2′-alkyl migration involving a C−C bond cleavage/cyclization sequence to provide tetrahydroazepine derivatives 1604 in good to excellent yields (Scheme 434).652

Scheme 435. Dehydrogenation of Tetrahydroquinolines to Quinolines

Scheme 434. 1,2′-Alkyl Migration from a Fused Tetrahydroquinoline

13.5. Dehydrogenation of Tetrahydroquinolines

1,2,3,4-THQs have been aromatized into the corresponding quinoline derivatives using a large number of catalysts, including metal catalysts and organocatalysts (Scheme 435). Some catalysts employed for this purpose include photoredox Ru catalyst 1607 and cobalt catalyst 1609 in the presence of visiblelight,653 [Ru(phd)3](PF6)2 1608 and Co(salophen) 1610,654 Ru(II)-NHC complexes 1611,655 palladium nanoparticles/ TBHP,656,657 Pt/C,535 cobalt oxide supported on nitrogendoped carbon,658 cobalt porphyrin,659 FeCl2/DMSO,660 iron− nitrogen-doped graphene,661 CuI and di-tert-butyl azodicarboxylate (DABD),662 Rose Bengal/visible light,663 graphite particles and DC high voltage (HV) in air,664 and TEMPO as an organoelectrocatalyst.665 Zhang and co-workers developed a copper-catalyzed dehydrogenative α-C(sp3)−H amination of tetrahydroquinolines 1612 at their C-2 position with O-benzoyl hydroxylamines1613 in the presence of butylated hydroxytoluene (BHT), Cu(I) iodide, and a 1:1 KOH/K2CO3 mixture, and that afforded the C-2 amino-functionalized quinoline derivatives 1614 (Scheme 436).666 The authors proposed the mechanism summarized in Scheme 437, where the secondary amine function in the starting tetrahydroquinoline 1612 is oxidized to an imine A by the BHT/Cu+/O2 system, which is in tautomeric equilibrium with B and C. Tautomer C then undergoes a single-electron oxidation followed by basepromoted deprotonation to furnish radical D, which gives intermediate E after reaction with the Cu+ catalyst. Finally, this intermediate reacts with the benzoylhydroxylamine starting material 1613 to furnish F, which is transformed into the final product 1614 in an oxidative aromatization step catalyzed by the Cu+/O2 system. The same group described a protocol for the oxidative benzylation of the tetrahydroquinoline C-3 position by

Scheme 436. Cu-Catalyzed Dehydrogenative α-C(sp3)−H Amination of Tetrahydroquinolines at C-2

treatment of compounds 1615 with aldehydes in the presence of [RuCl2(p-cymene)]2 and O2 as the only oxidant to access 3benzylquinolines 1616 (Scheme 438).667 In this case, the reactive species was the B tautomer of the dihydroquinoline framework. We have observed that heating 4,4-disubstituted 1,2,3,4tetrahydroquinoline derivatives 1617, bearing electron-withdrawing groups at the vinyl substituent, in refluxing dichlorobenzene in an air-open system leads to dehydrogenative C-4 to C-3 rearrangement of the vinyl substituent to afford polysubstituted quinolines 1618 in good to excellent yields.668 The mechanism proposed to explain this transformation involves an initial dehydrogenation, followed by migration of a fragment of the molecule from C-4 to C-3 via the generation and subsequent opening of an unstable cyclopropane intermediate, followed by a second dehydrogenation (Scheme 439). DK


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that the present contribution will assist interested readers in acquiring a systematic view of the field and inspire researchers to contribute new discoveries to it.

Scheme 437. Mechanism Proposed for the Cu-Catalyzed Dehydrogenative α-C(sp3)−H Amination of Tetrahydroquinolines

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected] or [email protected]. in. *E-mail: [email protected]. ORCID

Vellaisamy Sridharan: 0000-0002-3099-4734 J. Carlos Menéndez: 0000-0002-0560-8416 Notes

The authors declare no competing financial interest. Biographies Isravel Muthukrishnan was born in K. Meenakshipuram, Tamil Nadu, India. He obtained his B.Sc. and M.Sc. degrees in chemistry from Madurai Kamaraj University, Madurai. Subsequently, he worked as a Senior Research Associate at Syngene International Ltd., a Biocon Company, in Bangalore. Later, he joined Dr. Vellaisamy Sridharan’s group at Shanmugha Arts, Science, Technology & Research Academy (SASTRA) Deemed University, Thanjavur, Tamil Nadu, in 2015 as a Ph.D. student, working on the development of multicomponent and domino reactions for the synthesis of biologically significant heterocyclic compounds. He is the recipient of a Senior Research Fellowship (SRF) awarded by Council of Scientific and Industrial Research (CSIR), New Delhi. He has qualified the national level exams including CSIR-NET and GATE.

Scheme 438. Oxidative Benzylation of the Tetrahydroquinoline C-3 Position

Vellaisamy Sridharan was born in Kumarapalayam, Tamil Nadu, India. He received his M.Sc. degree in chemistry with a Gold Medal for university first rank and Ph.D. degree in synthetic organic chemistry (advisors: Prof. S. Sivasubramanian and Prof. S. Muthusubramanian) from Madurai Kamaraj University, Madurai, India. After postdoctoral research with Prof. J. Carlos Menéndez at Complutense University, Madrid, Spain (2005−2008, 2009-2010), with Prof. Jean Rodriguez at Paul Cezanne University, Marseille, France (2008−2009), and with Prof. Hiroaki Sasai at Osaka University, Osaka, Japan (2010−2012, JSPS Fellow), he joined SASTRA Deemed University, Thanjavur, India, as Associate Professor in 2012. After five years of service, he moved to the Central University of Jammu, where he currently heads the Department of Chemistry and Chemical Sciences. His research interests include the development of novel multi-bond-forming reactions for the synthesis of biologically relevant compounds and nucleopalladation-initiated cascade reactions. He has co-authored around 75 international publications, including two previous papers in Chemical Reviews.

Scheme 439. Thermal Dehydrogenative C-4 to C-3 Rearrangement of the Vinyl Substituent in 4-Vinyl-1,2,3,4tetrahydroquinolines

José Carlos Menéndez was born in Madrid and obtained degrees in Pharmacy from Universidad Complutense at Madrid (UCM) and chemistry from Universidad Nacional de Educación a Distancia (UNED), followed by a Ph.D. in pharmacy from UCM, under the supervision of Dr. Mónica M. Söllhuber. After a postdoctoral stay in the group of Prof. Steven V. Ley at Imperial College, London, he returned in September 1989 to the Organic and Medicinal Chemistry Department at UCM, where he is now a Full Professor. He has varied research interests in synthetic and medicinal chemistry, including the development of new multicomponent and domino reactions for diversity-oriented synthesis and the design, synthesis, and study of new multitarget compounds for the diagnosis and treatment of neurodegenerative diseases, such as new theranostic compounds and new chemotherapeutic compounds (antitubercular, antileishmanial, anti-

14. CONCLUDING REMARKS The chemistry of tetrahydroquinoline derivatives continues to be a very active research topic, which comprises three main areas, namely their isolation from natural sources and studies on their biosynthesis, their use as a privileged structure in drug discovery, and the development of methods for their synthesis. Regarding the latter topic, the main areas of current interest are the study of new step- and atom-economic methods based on the use of multicomponent and domino strategies and the development of new catalytic reactions leading to chiral tetrahydroquinolines in enantiomerically pure form. We hope DL


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cancer). This work has been documented in about 260 research papers, reviews, and book chapters and 11 patents. He also has long-standing collaborations with several chemical and pharmaceutical companies in Spain. Additionally, he has co-authored several textbooks in medicinal chemistry, including Medicinal Chemistry of Anticancer Drugs (Elsevier, 2008 and 2015). He has been the head of the Organic Microanalysis service at UCM since its creation in 1991. He has been a Visiting Professor at Paul Cézanne (Aix-Marseille III) University in 2007 and Bologna University in 2014. In 2017, he was elected as a Full Member of the Spanish Royal Academy of Pharmacy.

ACKNOWLEDGMENTS We gratefully acknowledge financial support of the work from our groups cited in this Review from the Department of Science and Technology (DST) (No. SB/FT/CS-006/2013 and No. EMR/2016/001619); the Council of Scientific and Industrial Research (CSIR), New Delhi (No. 02(0219)/14/EMR-II); Ministerio de Economı ́a y Competitividad (MINECO) (grants CTQ2012-33272-BQU and CTQ2015-68380-R); and Comunidad Autónoma de Madrid (CAM) (grant B2017/BMD3813). REFERENCES (1) Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A. Some aspects of reduced quinoline chemistry. J. Heterocycl. Chem. 1998, 35, 761−785. (2) Mitchinson, A.; Nadin, A. Saturated nitrogen heterocycles. J. Chem. Soc., Perkin Trans. 1 1999, 2553−2582. (3) Mitchenson, A.; Nadin, A. Saturated nitrogen heterocycles. J. Chem. Soc., Perkin Trans. 1 2000, 2862−2892. (4) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Recent progress in the synthesis of 1,2,3,4,-tetrahydroquinolines. Tetrahedron 1996, 52, 15031−15070. (5) Nammalwar, B.; Bunce, R. A. Recent syntheses of 1,2,3,4tetrahydroquinolines, 2,3-dihydro-4(1H)-quinolinones and 4(1H)quinolinones using domino reactions. Molecules 2014, 19, 204−232. (6) Sridharan, V.; Suryavanshi, P.; Menéndez, J. C. Advances in the chemistry of tetrahydroquinolines. Chem. Rev. 2011, 111, 7157−7259. (7) Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.; Fourasté, I.; Moulis, C. Two tetrahydroquinoline alkaloids from Galipea of f icinalis. Phytochemistry 1999, 51, 1167−1169. (8) Houghton, P. J.; Woldemariam, T. Z.; Watanabe, T.; Yates, M. Activity against Mycobacterium tuberculosis of alkaloid constituents of Angostura bark, Galipea of f icinalis. Planta Med. 1999, 65, 250−254. (9) Jacquemond-Collet, I.; Benoit-Vical, F.; Valentin, M. A.; Stanislas, E.; Mallié, M.; Fourasté, I. Antiplasmodial and cytotoxic activity of galipinine and other tetrahydroquinolines from Galipea of f icinalis. Planta Med. 2002, 68, 68−69. (10) Davies, S. G.; Fletcher, A. M.; Houlsby, I. T. T.; Roberts, P. M.; Thomson, J. E. Structural revision of the hancock alkaloid (−)-galipeine. J. Org. Chem. 2017, 82, 10673−10679. (11) Motohashi, K.; Nagai, A.; Takagi, M.; Shin-Ya, K. Two novel benzastatin derivatives, JBIR-67 and JBIR-73, isolated from Streptomyces sp. RI18. J. Antibiot. 2011, 64, 281−283. (12) Tsutsumi, H.; Katsuyama, Y.; Izumikawa, M.; Takagi, M.; Fujie, M.; Satoh, N.; Shin-Ya, K.; Ohnishi, Y. Unprecedented cyclization catalyzed by a cytochrome P450 in benzastatin biosynthesis. J. Am. Chem. Soc. 2018, 140, 6631−6639. (13) Sugiyama, R.; Nishimura, S.; Ozaki, T.; Asamizu, S.; Onaka, H.; Kakeya, H. 5-Alkyl-1,2,3,4-tetrahydroquinolines, new membraneinteracting lipophilic metabolites produced by combined culture of Streptomyces nigrescens and Tsukamurella pulmonis. Org. Lett. 2015, 17, 1918−1921. (14) Simonetti, S. O.; Larghi, E. L.; Kaufman, T. S. The 3,4dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one alkaloids. Results of 20 years of research, uncovering a new family of natural products. Nat. Prod. Rep. 2016, 33, 1425−1446. DM


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