Copper-Catalyzed C(sp3 )-H/C(sp3 )-H Cross-Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2-Trifluoromethyl-Substituted Dihydropyrrol-2-ols

Abstract

The first oxidative C(sp³ )-H/C(sp³ )-H cross-dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper-catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2-trifluoromethyldihydropyrrol-2-ol derivatives in a highly diastereoselective manner by cascade C(sp³ )-C(sp³ ) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aβ₄₂ lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.

Keywords: C−H activation; copper catalysis; cross-dehydrogenative coupling; heterocycles; internal oxidants.