para-Selective C–H alkylation of aroyl chlorides through organic photoredox-catalyzed radical tele-substitution

Abstract

The site-selective C(sp²)–H alkylation of arenes has provided ubiquitous fragments found in pharmaceutical drugs and agrochemicals. Although ortho- and meta-selective alkylation reactions have been achieved well, para-selective examples are scarce. The currently available methods have been designed on the unique behaviors and characteristics of metals to achieve high para-selectivity. Herein, we demonstrate the para-selective C(sp²)–H alkylation of aroyl chlorides with alkyltrifluoroborates and trialkylphosphine through an organic photoredox-catalyzed radical tele-substitution. The reaction proceeds through the para-selective addition of alkyl radicals to in-situ-generated aroyl trialkylphosphonium intermediates followed by a hydrogen shift. Notably, the para-alkylation is associated with the conversion of the carbonyl trialkylphosphonium group to the formyl group, producing para-alkylated benzaldehyde derivatives. This metal-free site-selective C(sp²)–C(sp³) bond formation allows for streamlined synthesis of siponimod and SR-31747.