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Deoxygenative Suzuki–Miyaura arylation of tertiary alcohols through silyl ethers

Nature Synthesis volume 2, pages 663–669 (2023)Cite this article

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Abstract

Conventional Suzuki–Miyaura arylations use halogenated compounds as electrophilic coupling partners. Although the catalytic activation of organohalides is well established, these substrates are seldom naturally abundant and questions exist as to their metabolic and environmental friendliness. Owing to their existence as readily available chemical feedstocks, alcohols are highly desirable cross-coupling partners, although pathways to activate the strong C–O bond are rarer. Here the coupling of tertiary alcohols with boronic esters through in situ alcohol silylation is described, providing access to quaternary carbon scaffolds without needing to proceed by an activated alkyl halide or pseudohalide intermediate. A dual catalyst system is used with both Ni(0) and Bi(III) components playing a critical role, along with a mild chlorosilane reactant. This method was found to tolerate diverse functional groups including chloro, nitro, olefin, ketone, ester and phenol moieties, while also being applicable to the derivatization of heterocyclic scaffolds. Mechanistic studies suggest the combination of a Lewis acid catalyst and organosilane promote the heterolytic cleavage of the substrate C–O bond to generate an electrophilic intermediate, providing a powerful strategy for derivatizing readily available alcohols.

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Fig. 1: Contemporary strategies for cross-coupling of unprotected alcohols.
Fig. 2: Mechanistic experiments to examine potential reaction intermediates.

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Data availability

The data supporting the findings of the study are available in the paper and its Supplementary Information.

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Acknowledgements

Financial support for this work was provided by the National Science and Engineering Research Council of Canada (grant no. RGPIN-2020-05065) and the Canada Research Chair Program (grant no. 950-232650). The Canadian Foundation for Innovation and the Ontario Ministry of Research, Innovation, & Science are thanked for essential infrastructure. A.C. thanks the National Science and Engineering Research Council of Canada for a Canada Graduate Scholarship–Doctoral fellowship.

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Authors and Affiliations

  1. Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada

    Adam Cook, Piers St. Onge & Stephen G. Newman

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Contributions

A.C. and S.G.N. designed the project. A.C. discovered and developed the reaction. A.C. and P.S.O. carried out all experimental work. A.C. wrote the draft of the paper and Supplementary Information. All authors participated in revising the paper.

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Correspondence to Stephen G. Newman.

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Nature Synthesis thanks Martins Oderinde, Xing-Zhong Shu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary Figs. 1–31, Tables 1–16, Discussion, Experimental details and NMR spectra.

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Cook, A., St. Onge, P. & Newman, S.G. Deoxygenative Suzuki–Miyaura arylation of tertiary alcohols through silyl ethers. Nat. Synth 2, 663–669 (2023). https://doi.org/10.1038/s44160-023-00275-w

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