Construction of Azepino[2,3-b]indole Core via Sulfur Ylide Mediated Annulations

Abstract

A novel [4 + 3] annulation of indoline-based aza-dienes and crotonate-derived sulfur ylides is described. This method could be further expanded by using more efficient synthetic strategies, including three-component [3 + 1 + 3] cascade and the direct sulfide-catalyzed [4 + 3] cyclization. These protocols enable the rapid construction of azepino­[2,3-b]­indole cores, and a broad spectrum of the desired products with diverse substituents was facilely accessed in generally high yield.

Construction of Oxepino[3,2‐b]indoles via [4+3] Annulation of 2‐Ylideneoxindoles with Crotonate‐Derived Sulfur Ylides

“…Because of its importance in structure and biological activity, these indole‐fused seven‐membered ring skeletons has drawn tremendous interest from both synthetic and medicinal chemists [1,2] . So far, although various synthetic methods have been developed for the construction of these indole‐fused seven‐membered ring skeletons, [1a,g,2,3] most of these established methods mainly focus on cyclohepta[ b ]indole skeletons [1a,2a–b] and indole‐fused seven‐membered nitrogen‐heterocycle skeletons, [1g,2c–k] but the research on oxepino[3,2‐ b ] indoles are generally lacking (Scheme 1). [3] In recently years, a few synthetic methods like NHC‐catalyzed annulation reaction of indolin‐3‐ones with α,β‐unsaturated aldehydes (Scheme 1a), [3d] visible light catalyzed diastereoselective oxidative C−N/C−O bond formation tandems (Scheme 1b) [3f] and gold‐catalyzed bicyclization of diaryl alkyne (Scheme 1c) [3e] have been developed to construct oxepino[3,2‐ b ] indole skeletons, however, these reported strategies usually require complex reaction system and have limited applications.…”

“…Over the past decades, crotonate‐derived sulfur ylides have been widely used as C1, C2 and C3 synthons in various cascade annulation reactions and has shown great potential in the synthesis of structurally diverse carbo‐ and heterocyclic skeletons [2c,4] . In particular, the formal [4+3] annulation involving crotonate‐derived sulfur ylides has provided a powerful tool to construct highly functionalized seven‐membered heterocycles [4c,f,j] .…”

“…Over the past decades, crotonate‐derived sulfur ylides have been widely used as C1, C2 and C3 synthons in various cascade annulation reactions and has shown great potential in the synthesis of structurally diverse carbo‐ and heterocyclic skeletons [2c,4] . In particular, the formal [4+3] annulation involving crotonate‐derived sulfur ylides has provided a powerful tool to construct highly functionalized seven‐membered heterocycles [4c,f,j] . For example, by using above similar [4+3] cascade annulation strategies, the synthesis of thieno[3,2‐ b ]oxepines, [4f] benzofuro[3,2‐ b ]azepine [4c] and azepino[2,3‐ b ]indole [4j] skeletons have been realized in recent years by Meng's, Huang's and Li's group, respectively.…”

“…In particular, the formal [4+3] annulation involving crotonate‐derived sulfur ylides has provided a powerful tool to construct highly functionalized seven‐membered heterocycles [4c,f,j] . For example, by using above similar [4+3] cascade annulation strategies, the synthesis of thieno[3,2‐ b ]oxepines, [4f] benzofuro[3,2‐ b ]azepine [4c] and azepino[2,3‐ b ]indole [4j] skeletons have been realized in recent years by Meng's, Huang's and Li's group, respectively. Despite these significant advances, it should be noted that the development of new cyclization domino reactions of crotonate‐derived sulfur ylides with new substrates and its applications in the synthesis of important polycyclic skeletons remains to be developed.…”

Recent Advances in Transition-Metal-Free (4+3)-Annulations

“…The first example utilizing crotonate-derived sulfonium salts 2.16a as C 3 synthons was developed by Yu, Wei and Meng in 2017 (Scheme 2.16, a). 38 The authors coupled 2.16a to thioaurones 2.16b to deliver 2,5-dihydrobenzo [4,5] 39 In some cases, a novel sulfide-catalyzed (4+3)-cyclization was also reported (Scheme 2.16, b). The products were generated in good to excellent yields with many different (hetero)aryl and aliphatic groups at R 3 .…”