Functionalization of remote C(sp3)-H bonds enabled by copper-catalyzed coupling of O-acyloximes with terminal alkynes

Transition metal catalyzed Sonogashira cross-coupling of terminal alkynes with aryl(vinyl)(pseudo)halides has been successfully extended to alkyl halides for the synthesis of functionalized internal alkynes. The direct alkynylation of remote unfunctionalized sp(3) carbon by terminal alkynes remains difficult to realize. We report herein an approach to this synthetic challenge by developing two catalytic remote sp(3) carbon alkynylation protocols. In the presence of a catalytic amount of Cu(I) salt and a tridentate ligand (tBu(3)-terpyridine), O-acyloximes derived from cycloalkanones and acyclic ketones are efficiently coupled with terminal alkynes to afford a variety of gamma- and delta-alkynyl nitriles and gamma-alkynyl ketones, respectively. These reactions proceed through a domino sequence involving copper-catalyzed reductive generation of iminyl radical followed by radical translocation via either beta-scission or 1,5-hydrogen atom transfer (1,5-HAT) and copper-catalyzed alkynylation of the resulting translocated carbon radicals. The protocols are applicable to complex natural products.