A General Medium-to-Large Sized Ring Synthesis Enabled by Copper-Catalyzed Difluoroalkylamidation Cyclization of Alkynes

Abstract

This paper describes a novel coordinating activation strategy that enables the synthesis of medium-to-large sized rings (11–17 members) via an unprecedented difluoroalkylamidation cyclization of alkynes. This method provides an efficient platform for accessing skeleton-diverse difluoroalkyl-containing cyclic enamides with complete regio- and stereoselectivity. The protocol features broad substrate compatibility, functional group tolerance, and ease of use at dilution concentrations (50 mM) that are not high. Moreover, the synthetic utility of this difunctional cyclization is underscored by its application in the late-stage modification of complex molecules. Additionally, the click reaction facilitates the derivation of alkynyl-substituted cyclization products, demonstrating the methodology’s potential in biological sciences.