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Photocatalytic N-Heteroarylation of Aldehydes via Formyl C‒ H Activation

preprint
submitted on 06.04.2020 and posted on 07.04.2020 by Hiromu Fuse, Harunobu Mitsunuma, Motomu Kanai
A formal C‒H addition of N-heteroaromatics to aldehydes
was achieved using a binary hybrid catalyst system comprising an acridinium photoredox catalyst and a thiophosphoric acid organocatalyst. The reaction proceeded through the following sequence: 1) photoredox-catalyzed single-electron oxidation of a thiophosphoric acid catalyst to generate a thiyl radical, 2) cleavage of the formyl C‒H bond of the aldehyde substrates by a thiyl radical acting as a hydrogen atom transfer catalyst to generate acyl radicals, 3) Minisci-type addition of the resulting acyl radicals to N-heteroaromatics, and 4) a spin-center shift, photoredox-catalyzed single-electron reduction, and protonation to produce secondary alcohol products. This metal-free hybrid catalysis proceeded under mild conditions for a wide range of substrates, including isoquinolines, quinolines, and pyridines as N-heteroaromatics, as well as both aromatic and aliphatic aldehydes, and tolerated various functional groups. The reaction was applicable to late-stage derivatization of drugs and their leads.

Funding

JP17H06442

Development of catalytic asymmetric nucleophilic addition of sp3 C-H bond to aldehydes

Japan Society for the Promotion of Science

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Development of dehydrogenative Heck reaction by hybrid catalyst aiming at late derivatization of complex drug

Japan Society for the Promotion of Science

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History

Email Address of Submitting Author

h-mitsunuma@mol.f.u-tokyo.ac.jp

Institution

The Universuty of Tokyo

Country

Japan

ORCID For Submitting Author

0000-0001-7609-905X

Declaration of Conflict of Interest

No conflict of interest.

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