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

Takafumi Ide,Joshua P Barham,Yuji Kawato,Masashi Fujita,Hiromichi Egami,Yoshitaka Hamashima

doi:10.1039/c8sc02965b

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 N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-methyl group. In contrast, addition of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-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 N-benzyl selectivity was achieved by overriding the inherent N-methyl and/or N-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 N-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.

Highlights

The amino group is found in many kinds of molecules, including naturally occurring bioactive compounds, pharmaceutical drugs, agrochemicals, and functional materials
Considering the importance of such substructures in medicinal chemistry, mild and efficient methods to construct the 1,1-diarylmethylamine framework are of great interest, and benzylic Csp3–H arylation of benzylamines might be a straightforward and expedient approach
The yields were much lower even in the presence of 20 mol% of hydrogen atom transfer (HAT) catalysts. We assume that these less acidic thiols are not deprotonated under the reaction conditions, and single electron transfer (SET) oxidation might not be efficient compared to the case of PhC(O)SK (E1/2 1⁄4 +0.85 V vs. SCE for cysteine in CH3CN,[22] Epox (6/ 5) 1⁄4 +0.65 V vs. SCE in CH3CN; see Electronic supplementary information (ESI)†)

Summary

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All publication charges for this article have been paid for by the Royal Society of Chemistry. Regio- and chemoselective Csp3–H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis†. 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 N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-methyl group. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-methyl and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven a-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 N-benzylic C–H arylation. The reaction is applicable to late-stage functionalization of pharmaceuticals

Findings

Introduction

Conclusions