Rearrangement-driven divergent synthesis: a metal-free tandem annulation for CF3-functionalized 1-(aminomethyl)naphthalen-2-ols and 1-(2-naphthyl)azetidines

Abstract

This study successfully developed a novel metal- and base-free controllable tandem cyclization/rearrangement strategy using 2-[3-(trifluoromethyl)but-3-en-1-yn-1-yl]benzaldehydes for the divergent synthesis of CF₃-containing 1-(aminomethyl)naphthalen-2-ols and CF₃-containing 1-(2-naphthyl)azetidines. This method was successfully applied to the late-stage modification of various approved drug molecules, facilitating the efficient synthesis of complex CF₃-containing 1-(aminomethyl)naphthalen-2-ols. Millimole-scale reactions and post-transformation functionalizations further demonstrate the utility of this methodology for constructing diverse CF₃-containing 1-(aminomethyl)naphthalen-2-ols and 1-(2-naphthyl)azetidines.