Intermolecular Dehydrative [4 + 2] Aza-Annulation of N-Arylamides

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Intermolecular Dehydrative [4 + 2] Aza-Annulation of N‑Arylamides with Alkenes: A Direct and Divergent Entrance to Aza-Heterocycles Ying-Hong Huang, Shu-Ren Wang, Dong-Ping Wu, and Pei-Qiang Huang* Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P.R. China

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S Supporting Information *

ABSTRACT: We disclose that following activation with trifluoromethanesulfonyl anhydride, secondary N-arylamides undergo smooth intermolecular dehydrative [4 + 2] azaannulation with alkenes under mild conditions to give 3,4dihydroquinolines, amenable to further functionalization. Meanwhile, conditions have been established to allow divergent one pot synthesis of tetrahydroquinolines and quinolines as well as tricyclic analogues from N-arylamides.

N

internal alkenyl groups, for the synthesis of analogues of luotonin A and (S)-14-azacamptothecin, respectively. Surprisingly, to the best of our knowledge, intermolecular azaannulation of amides with alkenes has not been reported. Nevertheless, the development of such intermolecular reactions would allow a flexible and versatile construction of nonaromatic heterocycles and thus afford the possibility for further functionalization. Moreover, amides and alkenes are bench-stable and widely used simple chemical feedstocks. This gap might be ascribed to the low reactivity of N-arylimidate generated from classical amide-activing reagents such as Meerwein’s reagent. Moreover, the above-mentioned intramolecular [4+ + 2] reactions have been shown to pass through N-arylimidate intermediates. In one recent work, we have shown that an alkene reacted much less efficiently with an Narylimidate (in situ generated from a secondary amide and Tf2O) than with the corresponding N-arylnitrilium ion (in situ generated from a secondary amide and 1.1 equiv of Tf2O/1.2 equiv of 2-fluoropyridine combination) (yield: 51% versus 95%). Moreover, in our recently reported Tf2O/2-fluoropyridine-mediated N-arylamides with alkynes, we have confirmed that N-arylnitrilium ions instead of N-arylimidate are the reactive intermediates. Herein, we report a divergent strategy for the one-pot synthesis of either 3,4-dihydroquinolines, tetrahydroquinolines, or quinolines and functionalized derivatives starting from secondary N-arylamides and alkenes (Figure 1). Quinoline11 and 1,2,3,4-tetrahydroquinoline12 are two privileged scaffolds13 of many medicinal agents, bioactive alkaloids, coordination ligands, and functional materials. Although many synthetic methods have been developed for their syntheses,11−13 flexible synthesis of 3,4-dihydroquinolines

itrogen-containing heterocycles occupy a central position among pharmaceuticals, agrochemicals, and functional materials. A recent analysis of US FDA-approved drugs revealed that 59% of unique small-molecule drugs contain a nitrogen heterocycle.1 Heterocycloaddition/annulation between two components is the most efficient and versatile strategy to build heterocycles because two C−C bonds or a C−C bond and a C−X bond are formed in one pot. Thus, development of novel heteroannulation reactions is of great value for both medicinal chemistry and the total synthesis of natural products.2 Since the seminal work of Ghosez,3a the direct transformation of amides has emerged as an active area of research in recent years.4−10 Although tremendous progress has been made, the employment of amides as a partner in aza-annulation reactions remains rare.8−10 Only the intramolecular aza-Diels− Alder (IADA) reaction,8 dehydrative [4 + 2] aza-annulation of enamides,9 and of N-arylamides with alkynes10 have been reported. Among them, Fortunak’s synthesis of the indolizino[1,2-b]quinolin-9(11H)-one core of camptothecin was postulated to pass through an intramolecular aza-Diels−Alder (IADA) reaction between an N-arylimidate [in situ generated from arylamide and Meerwein reagent (trimethyloxonium fluoroborate)] and an internal alkynyl group.8a This methodology was improved by Yao by replacing Meerwein’s reagent with Hendrickson’s reagent (hexaphenyloxodiphosphonium triflate, generated in situ from 3 equiv of Ph3PO and 1.5 equiv of Tf2O) as an amide-activating reagent.8b The concerted IADA mechanisms have been confirmed by Yu and co-workers by means of DFT calculations and specified as intramolecular [4+ + 2] reactions.8d The Fortunak−Yao methodology has been extended by Zhang8c and Yao,8e in two examples, to intramolecular azahetero-Diels−Alder reactions between N-arylimidates (in situ generated from arylamides and Hendrickson reagent) and © XXXX American Chemical Society

Received: January 18, 2019

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DOI: 10.1021/acs.orglett.9b00233 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 2. Synthesis of 3,4-Dihydroquinolines via Direct Dehydrative [4 + 2] Aza-Annulation of N-Arylamides with Alkenesa−c

Figure 1. Our plan for the one-pot, divergent synthesis of diverse azaheterocycles by dehydrative aza-annulation of N-arylamides with alkenes.

from simple starting materials is surprisingly limited.14 In particular, there have been few reports of their isolation and full characterization. Moreover, flexible, versatile, and divergent methods for the direct construction of the three related classes of compounds has remained elusive until now. Very recently, we have developed a reductive alkenylation reaction of N-(2,6-dimethylphenyl)amides 1A (Scheme 1) Scheme 1. Our Recently Developed Reductive Alkenylation Reaction of Amide 1A and the Discovery of a Novel Reaction Pathway Yielding 3a from 1a

a

Reaction conditions: amide (1.0 equiv), 2-F-Pyr (1.2 equiv), CH2Cl2 (0.2 M) then −78 °C, Tf2O (1.1 equiv), 5 min, then 0 °C, 10 min. Alkene (1.2 equiv), 40 °C, 2 h. bSee the Supporting Information for the list of amides. cIsolated yield.

noting that the reaction can be run on a gram scale. Indeed, when the aza-annulation reaction of 1a with 2h was run on a 10 mmol scale, 3h was obtained in a high yield of 86%. A secondary amide can serve as an important directing group for C−H functionalization.15a In this regard, Wang’s group recently reported a regioselective iodation of N-(ptolyl)acetamide to give iodoamides such as 1w via Pd-catalyzed sp2 C−H bond activation in a ball mill.15b To demonstrate the potential of our method in the transformation of functionalized amides, the aza-annulation of N-(o-iodo-p-tolyl)acetamide (1w) was undertaken. It proceeded smoothly to afford the iodo compound 3j in 70% yield. To take advantage of the imine functionality in 3,4dihydroquinolines, a demonstration of their synthetic utility by a Ugi-type multicomponent reaction16 of 3k was undertaken. Treatment of 3k with triethylamine (2.0 equiv), acetic acid (3.0 equiv), and cyclohexyl isocyanide (c-hexNC, 9, 2.0 equiv) in trifluoroethanol afforded the desired bisamide 10 in 70% yield (Scheme 3). Furthermore, the two transformations were merged into a one-pot reaction to yield 10 in 56% yield from 1t. Next, we explored the synthesis of 1,2,3,4-tetrahydroquinolines (6) from N-arylamides (1). Given that the dehydrative annulation of amides with alkenes yields 3,4-dihydroquinolines (3) as the primary products, we can expect that an in situ reduction would allow access, in a one-pot manner, to tetrahydroquinolines (6). Indeed, after completion of the aza-annulation reaction, methanol and NaBH4 (1.5 equiv) were added at 0 °C, and the resulting mixture was stirred at rt for 2 h, producing 6a as the only observable diastereomer in 89% yield (Scheme 4). The diastereoselectivity was determined as >20:1 at the limit of 1H NMR. Because both cis- and trans-6a are known compounds,17 a comparison of their 1H NMR data with ours allowed determination of the cis-

with alkenes to yield α,β-unsaturated ketimines 8A or α,βenones after acidic workup.5j We discovered that when Nphenylbenzamide (1a) was used as a substrate, a 3,4dihydroquinoline derivative 3a could be obtained as the major product (Scheme 1). In light of our previous work,5j a quick screening of the key reaction parameter allowed us to define the optimal reaction conditions as successive treatments of a mixture of an N-arylamide and 2-fluoropyridine (1.2 equiv) with Tf2O (−78 °C, 5 min, 0 °C, 10 min) and an alkene at 0 °C (then 40 °C, 2 h). The major difficulty was the isolation of unstable 3,4-dihydroquinolines14a from the enimine byproduct (cf. 8a, R = H). For this purpose, two protocols were established for the isolation of 3,4-dihydroquinolines (cf. Supporting Information). With the optimal reaction conditions and isolation protocols established, the scope of the reaction was examined. Scheme 2 shows that the one-pot dehydrative aza-annulation of styrene worked well with both N-phenyl aromatic amides (1a and 1b) and aliphatic amides, covering primary (1r), secondary (1p), and tertiary alkanoyl (1q, 1s) amides, to give the corresponding 3,4-dihydroquinolines 3a−f in excellent yields. Significantly, the reaction is not limited to styrene and its derivatives. (E)-1-Phenylbuta-1,3-diene (2f), a vinylogous styrene, and methylenecyclohexane (2h) are also effective olefin partners, affording 3,4-dihydroquinolines 3g and 3h in 93% and 88% yield, respectively. Interestingly, the dehydrative annulation of 1a with bicyclo[2.2.1]hept-2-ene (norbornene, 2j) produced the polycyclic product 3i in 73% yield. It is worth B

DOI: 10.1021/acs.orglett.9b00233 Org. Lett. XXXX, XXX, XXX−XXX

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annulation of ester anilide 1v with styrene yielded 6r in 78% yield. The stereochemistries of 6b−r were determined by a comparison of their diagnostic 1H NMR data with those of 6a and confirmed by a single crystal X-ray diffraction analysis of compound 6d (see the Supporting Information). The scope of the alkene partner was next examined. The reductive annulation reactions of p-phenyl- and p-tertbutyldimethylsilyloxy-substituted styrene derivatives 2b and 2c reacted to give the corresponding 6s and 6t in excellent yields (Scheme 5). Styrene bearing a sensitive acetoxy group

Scheme 3. One-Pot Synthesis of Functionalized 3,4Dihydroquinoline Derivative 10 via Tandem Dehydrative Aza-Annulation−Ugi Three-Component Reaction

Scheme 5. Scope of Alkenes Used in the One-Pot Tandem Dehydrative Aza-Annulation−Rduction Yielding Tetrahydroquinolinesa

Scheme 4. Substrate Scope of the One-Pot Tandem Dehydrative Aza-Annulation−Reduction Yielding Tetrahydroquinolines

a

Reaction conditions: cf. Scheme 4. bIsolated yield. cdr >20:1. ddr = 10:1, ratio determined by 1H NMR. a

Reaction conditions: amide (1.0 equiv), 2-F-Pyr. (1.2 equiv), CH2Cl2 (0.2 M), then, −78 °C, Tf2O (1.1 equiv), 5 min, then 0 °C, 10 min; alkene (1.2 equiv), 40 °C, 2 h, then 0 °C, NaBH4 (1.5 equiv), MeOH, rt, 2 h. bSee the Supporting Information for the list of amides. cIsolated yields. ddr >20:1.

2d also reacted smoothly to afford 6u in 83% yield. The lower yield of 76% (6v) obtained from the reaction of pchloromethylstyrene (2e) might reflect the electron-withdrawing inductive effect of the chloromethyl group. The reductive annulations with vinylogous styrene (2f), cyclohexa1,3-diene (2g), methylenecyclohexane (2h), and isobutene (2i) afforded the desired products 6w−z in good yields (80− 84%). The reaction of norbornene (2j) furnished the complex ring system 6aa in 75% yield. More intriguingly, simple alkenes such as hex-1-ene (2k) also reacted to give 6ab in a respectable yield of 61%. In this case, the minor trans-diastereomer became observable in the 1H NMR (dr = 10:1). Next, we envisaged a two-step construction of a bisquinoline ring system. Thus, subjecting 6q to Pd-catalyzed Buchwald−Hartwig reaction18 afforded 7a smoothly in almost quantitative yield (Scheme 6, a). It is remarkable that, starting from simple materials, this pentacyclic compound was built in just two steps and with an overall yield of 82%. Alternatively, upon treatment with sodium hydride, 6r was converted to the tricyclic lactam 7b in 80% yield (Scheme 6, b). Moreover, when 4-chloro-N-phenylbutanamide 1x was employed as a

stereochemistry for the major diastereomer of our reaction. The cis-selectivity implies a trans-attack of a hydride, namely, from the face opposite to the phenyl group in 3,4dihydroquinoline 3a, which avoids steric hindrance. The substrate scope was investigated by examining both the acyl and N-aryl moieties of amides. As can be seen from Scheme 4, N-phenylbenzamide derivatives bearing either an electron-donating or an electron-withdrawing group at the para-position of either the benzoyl moiety or the N-phenyl ring reacted smoothly to yield the corresponding products 6b−l in 78−94% yields. Interestingly, tetrahydroquinolines 6m−p were prepared in excellent yields (91−94%) from aliphatic amides. To take advantage of the good chemoselectivity of the reaction, annulation reactions of functionalized N-arylamides were investigated. Subjecting bromoanilide 1u to reaction with styrene afforded 6q in 82% yield. The one-pot reductive C

DOI: 10.1021/acs.orglett.9b00233 Org. Lett. XXXX, XXX, XXX−XXX

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haloalkyl-substituted quinoline derivative 4e was prepared in good yield. In summary, the first intermolecular dehydrative [4 + 2] azaannulation of secondary N-arylamides with alkenes has been achieved. The methodology displayed wide scope for both amide and alkene partners allowing the efficient one-pot, divergent construction of a broad array of substituted 3,4dihydroquinolines, tetrahydroquinolines, quinolines, and related polycyclic heterocycles. Taking advantage of the mild reaction conditions, good regio- and chemoselectivity, and good functional group tolerance, annulation products were further elaborated into diverse polycyclic heterocycles in onepot reactions (tandem annulation and reductive cyclization) from amides.

Scheme 6. Two-Step (a, b) and One-Pot (c) Construction of Tricyclic Systems from Secondary N-Arylamides

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00233.

substrate, the reductive annulation proceeded in tandem with cyclization to produce the tricyclic system 7c directly in 91% yield (Scheme 6, c). Similarly, the one-pot tandem reaction of 5-chloro-N-phenylpentanamide (1y) afforded the hexahydro1H-pyrido[1,2-a]quinoline 7d in 92% yield. To our delight, electron-deficient p-bromostyrene (2l) also served as an effective nucleophilic partner in the tandem reaction with 1y, producing the tetracyclic compound 7e in 83% yield. Finally, we addressed the synthesis of quinolines. For this purpose, a one-pot aza-annulation reaction of an N-arylamide with an alkene and in situ oxidation of the resulting 3,4dihydroquinoline was envisaged, and 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ) was selected as a mild oxidant. By employing 2 equiv of DDQ, the desired one-pot reaction of 1b with styrene (2a) proceeded smoothly to afford quinoline 4a in 86% yield (Scheme 7). With p-phenylstyrene (2b) as the

Experimental details, including procedures, syntheses, and characterization of new products; 1H and 13C NMR spectra (PDF) Accession Codes

CCDC 1855805 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

Scheme 7. One-Pot Tandem Dehydrative Aza-Annulation− Oxidation Yielding Quinolines

ORCID

Pei-Qiang Huang: 0000-0003-3230-0457 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support provided by the National Natural Science Foundation of China (21332007 and 21472153), the National Key R&D Program of China (grant No. 2017YFA0207302), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education. We thank Dr. JianLiang Ye for assistance in interpreting the NOESY spectrum.

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a

Reaction conditions: amide (1.0 equiv), 2-F-Pyr (1.2 equiv), CH2Cl2 (0.2 M), then, −78 °C, Tf2O (1.1 equiv), 5 min, then 0 °C, 10 min; alkene (1.2 equiv), 40 °C, 2 h, then 0 °C, DDQ, rt, 2 h. bSee the Supporting Information for the list of amides. cIsolated yields.

DEDICATION In honor of the 120th birthday of the late Professor Dr. MingLong Huang.

olefin partner, the reaction afforded 4b in 77% yield. The onepot reaction also displayed good chemoselectivity and functional group tolerance. As can be expected from our previous results, not only halo groups in the amide moiety but also an acetoxy group in the olefin moiety survive the reaction. Ketoamide derivative 1g reacted selectively at the amide group to give keto-quinoline derivative 4d in 62% yield. Similarly, ω-

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DOI: 10.1021/acs.orglett.9b00233 Org. Lett. XXXX, XXX, XXX−XXX