Regio- and chemoselective Csp³–H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis

Abstract

We present a highly regio- and chemoselective Csp³-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis. Under well precedented SET catalysis alone, the arylation reaction of <i>N</i>,<i>N</i>-dimethylbenzylamine proceeded <i>via</i> aminium radical cation formation and selectively targeted the <i>N</i>-methyl group. In contrast, addition of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp³-H arylation at the <i>N</i>-benzylic position. Measurement of oxidation potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the <i>N</i>-benzyl selectivity was achieved by overriding the inherent <i>N</i>-methyl and/or <i>N</i>-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivatives and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient <i>N</i>-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.