Oxidative Cascade Reaction of N-Aryl-3-alkylideneazetidines and

Letter Cite This: Org. Lett. 2018, 20, 3833−3837

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Oxidative Cascade Reaction of N‑Aryl-3-alkylideneazetidines and Carboxylic Acids: Access to Fused Pyridines Wangshui Cai,†,⊥ Shuang Wang,†,⊥ Hitesh B. Jalani,‡ Junxian Wu,† Hongjian Lu,*,† and Guigen Li†,§

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†

Institute of Chemistry & BioMedical Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China ‡ Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States § Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States S Supporting Information *

ABSTRACT: A versatile silver-promoted oxidative cascade reaction of Naryl-3-alkylideneazetidines with carboxylic acids is reported, providing a very efficient pathway to functionalized fused pyridines. This method allows introduction of fused pyridine ring systems to heterocycles, drugs, and natural products. A mechanistic study revealed that silver salt is essential for the chemo- and regioselective ring expansion, sequential oxidative nucleophilic additions, and oxidative aromatization. This approach represents the first example of the strained N-heterocycles undergoing a cascade reaction with a π bond and a nucleophile together. selectivity is controlled proficiently by fine-tuning of suitable strained N-heterocycle, nucleophiles, and oxidant then the process could provide an efficient cascade strategy7 to construct complex molecules in one step. The carbon−carbon double bond in small strained Nheterocycles can coordinate with transition metals and can participate in stabilizing any cations, anions, or radicals that are formed, which helps this type of compound to exhibit adequate reactivity toward various transformations.8 Among these, 3alkylideneazetidine is known for easy isolation9 and can be stored for several months without decomposition; thus it should be suitable for synthetic transformation. However, its considerably lower ring opening propensity10 can be a challenge in synthetic chemistry.11 Herein, we report a silverpromoted cascade reaction of N-heteroaryl-3-alkylideneazetidines and carboxylic acids (Scheme 1, eq 2). This reaction involves (I) intramolecular ring expansion involving a neighboring phenyl ring followed by (II) intermolecular oxidative nucleophilic addition of carboxylate and finally (III) oxidative aromatization, providing a new strategy to useful functionalized fused pyridines including quinoline, an important scaffold found widely in many natural products and pharmaceuticals.12 Other competitive pathways also exist with different chemo- and regioselectivity (Scheme 1, eq 2). We began our investigation of the chemoselectivity by examining the reaction of 1a with a neighboring N-phenyl group as a 2π component and acetic acid as a nucleophile.

T

he ring opening and rearrangement of small strained Nheterocycles provide powerful strategies for the synthesis of useful N-containing compounds.1,2 The most important and widely used transformations of these rings are intra- or intermolecular nucleophilic addition to form linear or cyclic amines3 and cycloaddition with a π bond to form heterocycles4 (Scheme 1, eq 1). Regardless of many reports for the reaction Scheme 1. Reactions of Small Strained N-Heterocycles

of the strained N-heterocycles with one nucleophile or a single π bond,5 there are no reports on the cascade reaction of strained N-heterocycles with a π bond and a nucleophile together. This could be the result of the chemoselectivity issues governed in strained N-heterocycles due to the competition between a π bond and a nucleophile and the oxidative conditions required in the secondary addition step,6 which makes the reaction system more complicated. If this preferred © 2018 American Chemical Society

Received: May 5, 2018 Published: June 19, 2018 3833

DOI: 10.1021/acs.orglett.8b01427 Org. Lett. 2018, 20, 3833−3837

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Organic Letters

cation intermediate formed under these conditions could be stabilized by the neighboring phenyl group. Use of CF3COOH furnished a 3b and 4b mixture in 81% yield with a 3b/4b ratio of 40:60 (Table 1, entry 15). When less acidic 4-nitrobenzoic acid was used, 3b was obtained in 57% isolated yield in high regio- and chemoselectivity (Table 1, entry 16). When the reaction was performed with AcOH, the ratio of 2b/3b/4b was 94:3:3, and interesting product 2b was isolated in 72% yield (Table 1, entry 17). The yield is slightly decreased (62%) when the reaction is performed on a large scale (Table 1, entry 18). We explored the substrate scope with respect to the N-aryl part of azetidine (Table 2). An N-aryl group with ortho

Selected results of different reaction conditions are summarized in Table 1A (for details, see Table S1). As expected, Table 1. Optimization of the Reaction Conditionsa

Table 2. Scope of Azetidine 1 and Carboxylic Acid

a Yield was calculated based on crude 1H NMR spectra. bHeating in microwave reactor. cIsolated yield. dAcOH (13 μL). eWithout AcOH. f 1.5 equiv of AgOAc. g0.5 equiv of AgOAc. h20 μL of CF3COOH. i10 equiv of acid was used. j2 mmol scale of 1b.

reaction in the absence of Lewis acid furnished exclusively the ring-opening product (2a′) as a result of intermolecular nucleophilic addition (Table 1, entry 1). When a silver salt such as AgSbF6 with Lewis acidity was used, the quinoline heterocycle (2a) was formed in 30% yield along with 2a′ (Table 1, entry 2). This result indicated that the silver salt not only suppressed inherent intermolecular nucleophilic addition of acetate but also promoted oxidation, inducing aromaticity. Upon screening different additives, AgOAc or Cu(OAc)2 was found to increase the yield of 2a with good selectivity (Table 1, entries 2−7). Using Lewis acid BF3·Et2O, Sc(OTf)3, Zn(OTf)2, AlCl3, or InCl3, oxidant 3-chloroperbenzoic acid (mCPBA), tert-butyl hydroperoxide (THBP), or K2S2O8 as the additive, a very small amount of 2a could be observed (Table S1). Finally, we carried out the reaction in a microwave reactor using AgOAc as both a Lewis acid and an oxidizing reagent, providing 2a in 77% isolated yield with a good chemoselectivity ratio (2a/2a′) of 89:11 (Table 1, entry 8). Reducing AcOH or AgOAc diminished the product formation (Table 1, entries 9−12). Next, the regio- and chemoselectivity were studied by using 3-benzylidene-1-phenylazetidine (1b) as a reaction partner with different acids (Table 1B). No major products were formed when CF3SO3H was used (Table 1, entry 13). Use of MeSO3H afforded the quinoline (4b) as a major product (Table 1, entry 14), perhaps because the allylic

a

Standard conditions: 1 (0.1 mmol), RCOOH (0.1 mL), AgOAc (0.25 mmol), DCE (0.5 mL), microwave at 110 °C for 2 h, isolated yield. b95 °C. cUsing CF3COOH (10 equiv) instead of AcOH.

substituents such as methyl, methyl carboxylate, and hydroxyl led to the corresponding quinolines 2b−d. An N-phenyl group without any substituents could be tolerated (2e). p-Phenyl or p-methoxy N-aryl groups worked well (2f, 79%; 2g, 63%). Meta-substituted N-aryl groups were tolerated well (2h,i), and a mixture of two regioisomers for 1i was obtained (p-2i and o2i). Reaction of 9-aminophenanthrene provided a polycyclic ring containing a fused pyridine 2j, thus showcasing the fusion of a heterocycle within aromatic compounds. The method not only can access aryl-fused pyridines, but it is also able to 3834

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Organic Letters provide pyridines by employing enamines. For example, the reaction of (E)-2-phenylethen-1-amine achieved desired product 2k in moderate yield. Heteroaryl-fused pyridines 2l,m can be obtained with high regioselectivity by use of an azetidine-containing pyridine and benzothiazole. The thiazoloquinoline 2m is the key fragment of kuanoniamines D and E, which are structurally unique, highly cytotoxic alkaloids obtained from marine sources.13 Next, we explored the substrate scope with respect to the vinyl part of the azetidine. Various styrene derivatives, such as 4-bromo-, 4-fluoro-, 4-nitro-, and 2-bromostyrene participated well, providing desired products in good yields (2n−r). The structure of 2q was identified by X-ray diffraction analysis (CCDC: 1823285). Alkyl substituents in the terminal position of vinyl group, such as ethyl, isopropyl, and cyclopropyl were all compatible (2s−u). The alkene without any substituent in the terminal position furnished 2a in 77% yield. When the reaction of 1a was performed in the presence of trifluoroacetic acid, the nonfunctionalized quinoline 3a was formed. Substrates with an electron-withdrawing group in the terminal position of the vinyl group provided the quinolines without the acetoxy group (2v,w), possibly due to the difficulty of completing an oxidative nucleophilic addition in the α-position of a carboxylate or nitrile group.6 Then, we investigated the general nature of the carboxylic acids. Alkyl carboxylic acids, such as propionic acid, butyric acid, and chloroacetic acid, were tolerated well (2x, 53%; 2y, 50%; 2z, 61%), but pivalic acid failed to facilitate formation of the desired product, possibly due to the steric hindrance of the tert-butyl group. Since an acetyloxy group can be easily transformed to other functional groups, acetic acid was used as a reactant in most cases. In order to gain a better understanding the mechanism, several experiments were carried out, as described in the Supporting Information (Scheme S1, eqs 1−7). Treatment of byproduct 3,8-dimethylquinoline 3a under the standard conditions failed to produce 2a (Scheme S1, eq 1), indicating the acetoxylation step occurs prior to oxidative aromatization. When the byproduct 2a′ was reacted under the standard conditions, no 2a was produced (Scheme S1, eq 2). This suggested that the ring expansion with the π bond of phenyl ring is the first step in the cascade sequence. When the substrate 1a with two deuteriums in the terminal position of the olefin D2-1a was conducted in absence of silver acetate, only 2a′ with two deuteriums in the terminal position of the olefin (D2-2a′) was formed (Scheme S1, eq 3). The results suggest that inherent intermolecular nucleophilic addition of acetic acid proceeded through an SN2 mechanism. Several competitive experiments suggested the increase of the nucleophilicity of N-aryl group (2e, 23% vs 2g, 29%), the presence of phenyl group instead of p-nitrophenyl (2b, 21% vs 2p, 13%), ethyl (2b, 25% vs 2s, 11%), or carboxylate group (2e, 21% vs 2v, 7%) in the terminal position of the olefin have a positive influence (Scheme S1, eqs 4−7). Plausible reaction mechanisms are described in Scheme 2. When the reaction was performed in the absence of silver salt, acetic acid lead to protonation of nitrogen to give the azetidinium ion intermediate A,14 which is attacked by acetate ion to furnish linear ring opened product 2a′. In the case of a stronger acid such as trifluoroacetic acid (pKa ∼ −0.25), the conjugate base is a very weak nucleophile and fails to attack the azetidinium ion and consequently, the allylic carbocation B is formed which undergoes cationic 6-endotet type ring closure

Scheme 2. Plausible Mechanisms under Different Reaction Conditions

sequence followed by oxidative aromatization, leading to isomers 3b and 4b. When the reaction was performed under less acidic conditions (acetic acid (pKa ∼ 4.76), 4-nitrobenzoic acid (pKa ∼ 3.44)), azetidine 1 with silver acetate forms a silver complex C and then selective intramolecular ring expansion with π bond of phenyl group by suppressing inherent intermolecular nucleophilic addition of acid gives D. Due to the weak nuclephilic ability of 4-nitrobenzoic acid, diarylmethane 3b could be obtained with high selectivity after direct oxidative aromatization. When acetic acid was used, a subsequent oxidative nucleophilic addition reaction of D by acetate ion15 followed by oxidative aromatization with the aid of silver acetate forms the desired product 2b in high selectivity. With utility in diversity-oriented synthesis approaches in mind, and aiming to demonstrate possible applications of this method, we examined the reactions of N-aryl-3-alkylideneazetidine in different scaffolds. Various analogues such as ligands, heterocycles, steroids, and pharmaceutical substances were subjected to this cascade reaction, as depicted in Scheme 3. Scheme 3. Synthetic Applications

Two steps are considered: (i) palladium-catalyzed crosscoupling reactions between the 3-alkylideneazetidine 5 with aryl halides or their analogues16 and (ii) the silver-promoted cascade reaction. Phenanthroline is an important ligand known for its ability to form useful coordination complexes with various metals.17 The unsymmetric phenanthroline 7a could be easily obtained from commercial available 8-bromoquinoline. The pyridine-fused estrone derivative 7b was produced with 63% yield in two steps. Similarly, the reactions of 6-bromo-1tosyl-1H indole and 5 led to the pyrrolo[3,2-h]quinoline 7c, a core structure of biomedically important compounds.18 This protocol also has been used in the modification of the antiallergy drug loratadine, providing its pyridine-fused 3835

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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.

derivative 7d with 73% yield. This late-stage installation of a fused pyridine functional group is a striking application of this method. Postsynthetic functional group transformation is an interesting area of structural modification; therefore, newly synthesized fused pyridines were subjected to various transformations (Scheme 4). For example, Dess−Martin periodinane oxidation

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

Scheme 4. Derivatization of Functionalized Quinolinesa

ORCID

Hitesh B. Jalani: 0000-0002-2442-9798 Hongjian Lu: 0000-0001-7132-3905 Guigen Li: 0000-0002-9312-412X Author Contributions ⊥

W.C. and S.W. contributed equally to this work.

Notes

The authors declare no competing financial interest.

a

See the details of the reaction conditions in the Supporting Information.

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ACKNOWLEDGMENTS We are grateful for financial support by the National Natural Science Foundation of China (21472085, 21332005, and 21672100).

of 2b provided 3-benzoylquinoline 8a. Acid-induced deacetylation of 2b resulted in the quinoline 8b in 94% yield. The palladium-catalyzed cyclization of 2p was achieved by activation of the heteroaryl C−H bond, efficiently providing the acetoxyl-functionalized tetracyclic compound 8c, a structural unit with a fused quinoline and indene framework found in a number of pharmaceuticals and bioactive natural products.19 The nickel-catalyzed Suzuki coupling reaction of 2b with phenylboronic acid furnished the triaryl methane 8d. The reduction of 2b provided 3-benzylquinoline 3b. In summary, we have presented a versatile and highly chemo- and regioselective silver-promoted cascade reaction of N-heteroaryl-3alkylideneazetidines and carboxylic acids, providing a general method for the synthesis of acetyloxyfunctionalized fused pyridines. Mechanistic study reveals the reaction proceeds through intramolecular ring expansion with the π bond of phenyl ring and subsequent intermolecular oxidative nucleophilic addition of acetate and oxidative aromatization under the influence of silver acetate. This protocol allows useful modification of ligands, drugs, and natural product analogues with fused pyridine ring systems. Such compounds are otherwise difficult to produce, and this shows the general applicability of the present protocol to generate diverse structural features. We believe this work will open a new outlook and scientific interest for understanding and exploiting the strained N-heterocycles through ringexpansion and nucleophilic substitution cascade strategies. Investigations toward detailed mechanism and further synthetic applications of this newly established methodology are currently underway in our laboratory.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

TThe Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01427. Experimental details and characterization datas for all new compounds (PDF) Accession Codes

CCDC 1823285 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge 3836

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