Ring opening of donor-acceptor-type cyclopropene unveils electrophilic ketene with vinylogous [4 C + n] periselective cyclization mode
Jianhong Huang, Jiahang Li, Shenli Liu, Wanyao Zhao, Yan Xia, Xiaoyan Liu, Kui‐Zhan Shao, Wenliang Li, Haiyan Yuan, Jinbo Zhao
Abstract
Since its advent 120 years ago, the [2+n] coupling cyclization of ketene has been prevalently used for the synthesis of N- and O-heterocycles. In contrast, its vinylogous version, i.e., use of alkenyl ketene as 4 C synthon, remain elusive. We report herein that in the rare SN1-type ring-opening of electron-deficient cyclopropene, the initially formed sp2-carbocation-containing zwitterionic intermediate undergoes facile 1,4-alkoxy migration to generate a functionalized alkenyl ketene. This electrophilic intermediate not only allows for challenging N-nucleophiles to be engaged in the conventional ketene [2+n] reactions (n = 1 ~ 3), also unveiled the vinylogous [4+n] cyclization mode, as exemplified by the [4 + 1] and formal [4 + 4] cyclization to construct pyrrolidinone and azocine frameworks. The protocol offers a unified entry to a distinct class of lactam scaffolds that exhibit anti-cancer potential, constituent key natural product scaffold and display interesting 1e- and 2e- reactivities. This work reveals a broader synthetic potential of the facile SN1 type ring-opening of cyclopropene as “dehydro”-donor-acceptor cyclopropane (DDAC) substrate, and could have ramifications in ketene chemistry, N-heterocyclic chemistry and related medicinal research, as well as the donor-acceptor system chemistry. The reactivity of ketenes is limited to the conventional [2+n] mode where the ketene is used as a 2 C synthon. Here, the authors present a suite of reactivity of a vinylogous [4+n] cyclization mode of ketenes besides the conventional one, forming a variety of lactam type azacycles.