A novel three-component coupling reaction of aryne, C=N derivatives, and acrylonitrile

Abstract

A literature-unprecedented three-component aryne coupling reaction with pyrroline, imine, dihydroisoquinoline, imidazoline or oxazoline as a nucleophile, and acrylonitrile as a third component, acting as both a proton donor and a nucleophile, has been developed. With imidazoline or oxazoline as the substrate, the initially formed three-component reaction product could react further to provide tetrahydro-1,4-diazepine or tetrahydro-1,4-oxazepine, respectively.

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The aza-Baylis–Hillman reaction^1,2 is an atom economical and operationally simple carbon–carbon bond forming reaction between a Michael acceptor and an imine in the presence of a Lewis base, affording α-methylene-β-aminocarbonyl derivatives. It has found wide application in the synthesis of natural products³ and biologically active molecules.^1b,c,4 Unfortunately, the reaction rates are sluggish, and the substrate scope is limited to activated aldimines (N-sulfonylimines, N-sulfinylimines, N-phosphinylimines) only. Thus, the development of an efficient strategy with a broad substrate scope is still desirable.

Over the last few decades, arynes⁵ have emerged as useful synthetic intermediates in organic synthesis.⁶ Because of their low-lying LUMO, arynes are readily attacked by neutral nucleophiles including isocyanides, imines, and amides to form zwitterionic species. In 2004, Yoshida et al. developed a novel three-component coupling reaction for the synthesis of iminoisobenzofurans by trapping with aldehydes the zwitterion generated from the nucleophilic attack of isocyanides on arynes (Scheme 1a).⁷ With a judicious choice of nucleophile and electrophile combinations, various benzoannulated heterocycles and multisubstituted arenes could be constructed via the three-component aryne coupling reactions.^8–10 In 2015, Hwu and co-workers demonstrated a three-component reaction of benzyne, glycine Schiff base, and an electron-deficient alkene for the synthesis of pyrrolidines, which proceeded via a [3 + 2] cycloaddition pathway between the electron-deficient alkene and the azomethine ylide generated in situ from the aryne and glycine Schiff base (Scheme 1b).¹¹ The presence of the electron-withdrawing ester group was key for the transformation of the initially formed zwitterionic species to the azomethine ylide for the [3 + 2] cycloaddition reaction. It is against this background we wonder that without such an electron-withdrawing group, will the zwitterion from the nucleophilic attack of an imine on an aryne react with an electron-deficient alkene by [4 + 2] cycloaddition to provide tetrahydroquinoline species. However, our studies indicate that the three-component coupling reactions of benzyne, acrylonitrile, and C=N derivatives result in the formation of aza-Baylis–Hillman type reaction products instead (Scheme 1c). In these transformations, acrylonitrile acts as both a proton donor and a nucleophile (vide infra). Herein, we report the details of these novel three-component aryne coupling reactions. With imidazolines or oxazolines as nucleophiles, the initially formed three-component coupling products could react further to yield 1,4-diazepines or 1,4-oxazepines, respectively. These structural motifs are found in nature,¹² and many synthetic analogues have shown a broad spectrum of biological activities as anticonvulsants,¹³ dopamine D4 receptor ligands,¹⁴ immunosuppressants,¹⁵ glycosidase inhibitors,¹⁶ nitric oxide synthase inhibitors,¹⁷ and antifungal, antibacterial, and anticancer agents.¹⁸ Our work provides a new method toward the synthesis of these pharmaceutically important heterocyclic systems.

Scheme 1 Three-component benzyne coupling reactions.

Our initial attempt of the three-component coupling reaction of 2-phenyl-1-pyrroline¹⁹1a (0.2 mmol), 2-(trimethylsilyl)phenyl triflate 2a (0.4 mmol), and acrylonitrile 3 (0.5 mL) in the presence of CsF (0.8 mmol) in THF (0.5 mL) at 70 °C afforded compound 4a in 77% isolated yield (Scheme 2). The optimization of reaction conditions has been described in detail in the ESI.† The key to the success of the reaction was the use of a large excess of acrylonitrile. Otherwise, the product 4a′ resulting from benzyne-triggered hydrolysis of 1a was dominant (ESI).† With acrylonitrile-2-d3 as the substrate, the corresponding 4a-D was obtained in 69% isolated yield (Scheme 3). Based on this result, a plausible mechanism was proposed (Scheme 4). The nucleophilic attack on benzyne 5 (generated from 2a) by pyrroline 1a afforded zwitterion 6. Subsequent deprotonation of acrylonitrile 3 with 6 provided cation 7 and anion 8, which reacted to furnish 4a. Intrigued by this novel three-component coupling reaction, we examined the substrate scope. 2-Aryl-1-pyrrolines with either an electron-withdrawing group or electron-donating group substituted benzene ring could tolerate the reaction conditions, and resulted in the formation of the three-component coupling products 4b–4g in moderate to good isolated yields. Compound 4h with a thiophenyl moiety and 4i with an alkyl side-chain could be obtained. The aryne precursors were examined. While 4j from methylenedioxybenzyne was obtained in a comparable yield to 4a, compound 4k from difluorobenzyne was isolated in a much lower yield. Under the conditions, simple imines as well as dihydroisoquinolines performed as expected to provide compounds 4l–4p in moderate to good isolated yields. Finally, we tested the three-component reaction of crotonitrile 9 with imine 1q and benzyne (Scheme 5). The reaction gave a mixture of products, from which the [3 + 2] cycloaddition product 11 was isolated.¹¹ However, it was contaminated with a minor inseparable impurity and a clean NMR spectrum could not be obtained. Fortunately, with methyl crotonate 10 as a component, pyrrolidine-3-carboxylate 12 was isolated in 40% yield as a single diastereoisomer, the relative stereochemistry of which was confirmed by X-ray single crystal diffraction.²⁰

Scheme 2 Three-component coupling reaction of imine, aryne, and acrylonitrile.

Scheme 3 Three-component coupling reaction of pyrroline 1a, 2-(trimethylsilyl)phenyl triflate 2a, and acrylonitrile-2-d3.

Scheme 4 Proposed mechanism for the three-component reaction to form 4a.

Scheme 5 [3 + 2] cycloaddition reaction of imine, benzyne and a Michael acceptor.

Next, we tested the three-component coupling reaction of imidazoline, benzyne, and acrylonitrile. The reaction of 1,2-diphenylimidazoline 13a with benzyne and acrylonitrile 3 generated tetrahydro-1,4-diazepine 14a, rather than the corresponding formal aza-Baylis–Hillman reaction product as shown in Scheme 2 (Scheme 6). We postulated that 14a was yielded from the initially formed formal aza-Baylis–Hillman reaction product 15via a ring-opening/closing process (Scheme 7). The reaction of representative 2-aryl-1-phenylimidazolines and 2-alkyl-1-phenylimidazolines proceeded smoothly to provide tetrahydro-1,4-diazepines 14b–14f in good isolated yields. Next, 1-benzyl-2-phenylimidazoline was evaluated. Of the two possible tetrahydro-1,4-diazepines, only 14g was obtained, and no trace of the alternative product was evident on the TLC plate. Similarly, with 1-(4-methoxybenzyl)-2-phenylimidazoline as the substrate, the sole product isolated was 14h, the structure of which was unambiguously confirmed by X-ray single crystal diffraction.²¹ With 1-(4-methoxybenzyl)-2-phenylimidazoline as a nucleophile, aryne precursors were examined. It was observed that electron-donating groups favored product formation (14ivs.14j).

Scheme 6 Three-component coupling reaction of imidazoline, aryne, and acrylonitrile.

Scheme 7 Proposed mechanism for the formation of tetrahydro-1,4-diazepine 14a.

Finally, we explored the three-component coupling reaction of oxazoline, benzyne, and acrylonitrile. The reaction of 2-phenyloxazoline 17a with benzyne and acrylonitrile provided oxazolidine 18 as a stable compound, which could be isolated and fully characterized (Scheme 8). On standing, 18 gradually transformed into tetrahydro-1,4-oxazepine 19a. This process could complete in 10 min by treatment of the former with TFA at ambient temperature. Therefore, we applied the two-step procedure for the rest of our study of the three-component reaction to obtain tetrahydro-1,4-oxazepine directly. As shown in Scheme 9, while the reaction of 2-(4-methoxyphenyl)oxazoline and 2-(thiophen-2-yl)oxazoline proceeded smoothly to provide 19b and 19d in good isolated yields, the reaction of the substrate bearing an electron-deficient chlorophenyl moiety was less satisfactory, giving 19c in 33% isolated yield. The structure of 19d was unambiguously confirmed by X-ray single crystal diffraction.²² Chiral oxazolines could tolerate the reaction conditions to afford 19e and 19f in good isolated yields without racemization of the stereogenic center as determined with chiral HPLC.

Scheme 8 Synthesis of tetrahydro-1,4-oxazepine 19a.

Scheme 9 Two-step synthesis of tetrahydro-1,4-oxazepine 19.

Conclusions

In summary, we have developed a novel three-component coupling reaction of benzyne, acrylonitrile, and various nucleophiles including pyrroline, imine, dihydroisoquinoline, imidazoline, and oxazoline. Interestingly, the imidazolidine and oxazolidine intermediates could react further to provide tetrahydro-1,4-diazepine and tetrahydro-1,4-oxazepine, respectively. Biological studies of the compounds synthesized are currently underway in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the NSFC (82130103, 82373724) for financial support.

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20. Crystallographic data for structural analysis have been deposited with the Cambridge Crystallographic Data Center, CCDC 2189779.†.
21. Crystallographic data for structural analysis have been deposited with the Cambridge Crystallographic Data Center, CCDC 2190017.†.
22. Crystallographic data for structural analysis have been deposited with the Cambridge Crystallographic Data Center, CCDC 2190240.†.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data and NMR spectra. CCDC 2189779; 2190017; 2190240. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo01454a

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