Synthesis of (4-Trifluoromethyl)isoxazoles through a Tandem Trifluoromethyloximation/Cyclization/Elimination Reaction of α,β-Unsaturated Carbonyls

Abstract

We disclose a metal-free, cascade regio- and stereoselective trifluormethyloximation, cyclization, and elimination strategy with readily available α,β-unsaturated carbonyl compounds to access a wide variety of pharmaceutically potential heteroaromatics, i.e., 4-(trifluoromethyl)isoxazoles including a trifluoromethyl analogue of an anticancer agent. The transformation requires only a couple of commercially available and cheap reagents i.e., CF3SO2Na as the trifluoromethyl source, and tBuONO as an oxidant as well as a source of N and O. Notably, 5-alkenyl-4-(trifluoromethyl)isoxazoles were further synthetically diversified to a new class of biheteroaryls, i.e., 5-(3-pyrrolyl)-4-(trifluoromethyl)isoxazoles. Mechanistic studies revealed a radical pathway for the reaction.