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. 2018 Sep 12;9(44):8453-8460.
doi: 10.1039/c8sc02965b. eCollection 2018 Nov 28.

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

Takafumi Ide  1 , Joshua P Barham  1 , Masashi Fujita  1 , Yuji Kawato  1 , Hiromichi Egami  1 , Yoshitaka Hamashima  1
Affiliations

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

Takafumi Ide et al. Chem Sci. .

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.

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Figures

Fig. 1
Fig. 1. Bioactive compounds containing benzylamines.
Scheme 1
Scheme 1. Previous benzylamine arylation strategies and this work.
Scheme 2
Scheme 2. Csp3–H arylation of N,N-dimethylbenzylamine under photoredox catalysis.
Scheme 3
Scheme 3. Working hypothesis for regioselective arylation at the N-benzylic position.
Fig. 2
Fig. 2. Comparison of oxidation peak potentials measured by cyclic voltammetry.
Scheme 4
Scheme 4. Arylation of 1j under SET conditions.
Scheme 5
Scheme 5. Regio- and chemoselective Csp3–H arylation.
Scheme 6
Scheme 6. Proposed catalytic cycle.
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