Highly Enantioselective Synthesis of 3 a-Fluorofuro[3,2- b]indolines via Organocatalytic Aza-Friedel-Crafts Reaction/Selective C-F Bond Activation

Org Lett. 2023 Dec 8;25(48):8666-8671. doi: 10.1021/acs.orglett.3c03445. Epub 2023 Nov 28.

Abstract

Fluoroalkylated compounds are of high interest in drug discovery and have inspired the evolution of diverse C-F bond activation methodologies. However, the selective activation of polyfluorinated compounds remains challenging. Herein, we describe an unprecedented strategy for synthesizing enantioenriched fluorofuro[3,2-b]indolines through the organocatalytic aza-Friedel-Crafts reaction coupled with selective C-F bond activation. These reactions feature excellent enantioselectivities (≤96% ee) and yields (≤96%) as well as good functional group compatibility. Mechanistic investigations by means of 19F nuclear magnetic resonance experiments provided sufficient support for silica gel as the key medium in this transformation.