Copper-catalyzed enantioselective Sonogashira-type oxidative cross-coupling of unactivated C( sp ³)−H bonds with alkynes

Abstract

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C( sp ³)—C( sp) coupling of unactivated C( sp ³)−H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C( sp ³)—H bond functionalization and the inhibition of readily occurring Glaser homocoupling of terminal alkynes. Here, we report a copper/chiral cinchona alkaloid-based N,N,P-ligand catalyst for asymmetric oxidative cross-coupling of unactivated C( sp ³)—H bonds with terminal alkynes in a highly regio-, chemo-, and enantioselective manner. The use of N-fluoroamide as a mild oxidant is essential to site-selectively generate alkyl radical species while efficiently avoiding Glaser homocoupling. This reaction accommodates a range of (hetero)aryl and alkyl alkynes; (hetero)benzylic and propargylic C( sp ³)−H bonds are all applicable. This process allows expedient access to chiral alkynyl amides/aldehydes. More importantly, it also provides a versatile tool for the construction of chiral C( sp ³)—C( sp), C( sp ³)—C( sp ²), and C( sp ³)—C( sp ³) bonds when allied with follow-up transformations.

Abstract

Enantioselective oxidative cross-coupling of unactivated C( sp ³)−H bonds and terminal alkynes is challenging. Here, the authors developed a copper/cinchona alkaloid catalyst for the asymmetric Sonogashira-type alkynylation of C( sp ³)-H bonds via radical intermediates.