Precision installation of silyl synthetic handles within arenes by regiocontrolled ruthenium C(sp2)–H functionalization

Docherty, Jamie and Hareram, Mishra Deepak and Nichols, Luke M. and Pérez-Ortega, Ignacio and Vitorica-Yrezabal, Iñigo J. and Larrosa, Igor (2025) Precision installation of silyl synthetic handles within arenes by regiocontrolled ruthenium C(sp2)–H functionalization. Nature Catalysis.

Text (s41929-025-01309-6)
s41929-025-01309-6.pdf - Published Version
Available under License Creative Commons Attribution.
Download (1MB)

Abstract

The site-selective functionalization of C(sp2)–H bonds represents a powerful strategy for the synthesis of structurally diverse compounds with broad applicability. Here we report efcient regioselective catalytic methods for the formation of benzyltrimethylsilanes through ruthenium-catalysed C(sp2)–H silylmethylation. The developed protocols enable selective functionalization at both ortho and meta positions within arenes bearing N-based directing groups. The resulting silylmethyl compounds can undergo diverse transformations, including nucleophilic aromatic substitution, carbonyl addition, olefnation and desilylation. Signifcantly, the regiodivergent installation of silylmethyl synthetic handles allows for the synthesis of the pharmaceutical losmapimod and could further be applied in direct late-stage functionalizations. Mechanistically, an essential role for biscyclometallated ruthenium(II) species has been found, with the formation of intermediate ruthenium(III) species indicated by paramagnetic NMR experiments. These synthetic inventions and mechanistic elucidations signify a transformative step within ruthenium-catalysed C(sp2)–H functionalization, enabling diverse syntheses and providing a framework for future development.