Copper-catalyzed enantioselective Sonogashira-type oxidative cross-coupling of unactivated C(sp³)-H bonds with alkynes.

Abstract

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp³)-C(sp) coupling of unactivated C(sp³)-H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C(sp³)-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(sp³)-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(sp³)-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(sp³)-C(sp), C(sp³)-C(sp²), and C(sp³)-C(sp³) bonds when allied with follow-up transformations.