A radical approach for the selective C–H borylation of azines - Nature.com

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Abstract

Boron functional groups are often introduced in place of aromatic carbon–hydrogen bonds to expedite small-molecule diversification through coupling of molecular fragments^1–3. Current approaches based on transition metal-catalysed C–H activation are effective for the borylation of many (hetero)aromatic derivatives^4,5 but show narrow applicability to azines, N-containing aromatic heterocycles and key components of many pharmaceutical and agrochemical products.⁶ Here, we report an azine borylation strategy using stable and inexpensive amine-borane⁷ reagents. Photocatalysis converts these low molecular weight materials into highly reactive boryl radicals⁸ that undergo efficient addition to azine building blocks. This reactivity provides a mechanistically alternative tactic for sp² carbon–boron bond assembly where the elementary steps of transition-metal mediated C–H activation and reductive elimination from azine-organometallic intermediates are replaced with a direct, Minisci⁹-style, radical addition. The strong nucleophilic character of the amine-boryl radicals is the key feature enabling predictable and site-selective carbon–boron bond formation by targeting the azine’s most activated position, including the challenging sites adjacent to the basic N-atom. This approach enables access to aromatic sites currently elusive to C–H activation strategies and has led to borylated materials that would otherwise be difficult to prepare. The process has been applied to the introduction of amine-borane functionalities onto complex and industrially-relevant products. The diversification of the borylated azine products by mainstream cross-coupling technologies establishes aromatic amino-boranes as a powerful class of building blocks for chemical synthesis.

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Affiliations

Department of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

Ji Hye Kim, T. Constantin, M. Simonetti & D. Leonori
Discovery Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75A, 45007, Toledo, Spain

J. Llaveria
Department of Chemistry, College of Science, King Faisal University, P.O. Box 380, Al-Ahsa, 31982, Saudi Arabia

N. S. Sheikh

Authors

Ji Hye Kim

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T. Constantin

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M. Simonetti

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J. Llaveria

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N. S. Sheikh

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D. Leonori

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Corresponding author

Correspondence to D. Leonori.

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Kim, J.H., Constantin, T., Simonetti, M. et al. A radical approach for the selective C–H borylation of azines. Nature (2021). https://ift.tt/3bHuIcK

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Received: 02 January 2021
Accepted: 12 May 2021
Published: 20 May 2021
DOI: https://doi.org/10.1038/s41586-021-03637-6

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