Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes

• Published in: Angewandte Chemie International Edition Vol. 62; no. 48
• Main Authors: Tang, Lei, Xiao, Yuanjiu, Wu, Feng, Zhou, Jin‐Lan, Xu, Tong‐Tong, Feng, Jian‐Jun
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 27.11.2023
• Subjects: Bicyclic Compounds; Bioisosteres; Chemistry; Chemistry, Multidisciplinary; Cycloaddition; Heterocycles; Physical Sciences; Science & Technology; Strained Molecules; Heterocycles; ASYMMETRIC DEAROMATIZATION; CYCLOPENTANNULATION; STRAIN-RELEASE; ANNULATION; REARRANGEMENTS; STRATEGIES; Cycloaddition; 3-ALKYLINDOLES; Bioisosteres; Strained Molecules; CONSTRUCTION; COMPLEXITY; CHEMISTRY; Bicyclic Compounds
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202310066

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver‐catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N‐unprotected indoles and bicyclobutane precursors is described. The strain‐release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale‐up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility. A silver Lewis acid catalyzes dearomative [2π+2σ] cycloadditions of N‐unprotected indoles and bicyclobutanes to afford indoline fused bicyclo[2.1.1]hexanes (BCHs) bearing up to four contiguous quaternary carbon centers in high yields and with an opposite regioselectivity compared to the classical pathway.