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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Precision installation of silyl synthetic handles within arenes by regiocontrolled ruthenium C(sp2)–H functionalization
AU - Docherty, Jamie
AU - Hareram, Mishra Deepak
AU - Nichols, Luke M.
AU - Pérez-Ortega, Ignacio
AU - Vitorica-Yrezabal, Iñigo J.
AU - Larrosa, Igor
PY - 2025/4/30
Y1 - 2025/4/30
N2 - The site-selective functionalization of C(sp2)–H bonds represents a powerfulstrategy for the synthesis of structurally diverse compounds with broadapplicability. Here we report efcient regioselective catalytic methods for theformation of benzyltrimethylsilanes through ruthenium-catalysed C(sp2)–Hsilylmethylation. The developed protocols enable selective functionalizationat both ortho and meta positions within arenes bearing N-based directinggroups. The resulting silylmethyl compounds can undergo diverse transformations, including nucleophilic aromatic substitution, carbonyladdition, olefnation and desilylation. Signifcantly, the regiodivergentinstallation of silylmethyl synthetic handles allows for the synthesis of thepharmaceutical losmapimod and could further be applied in direct late-stagefunctionalizations. Mechanistically, an essential role for biscyclometallatedruthenium(II) species has been found, with the formation of intermediateruthenium(III) species indicated by paramagnetic NMR experiments. Thesesynthetic inventions and mechanistic elucidations signify a transformativestep within ruthenium-catalysed C(sp2)–H functionalization, enabling diverse syntheses and providing a framework for future development.
AB - The site-selective functionalization of C(sp2)–H bonds represents a powerfulstrategy for the synthesis of structurally diverse compounds with broadapplicability. Here we report efcient regioselective catalytic methods for theformation of benzyltrimethylsilanes through ruthenium-catalysed C(sp2)–Hsilylmethylation. The developed protocols enable selective functionalizationat both ortho and meta positions within arenes bearing N-based directinggroups. The resulting silylmethyl compounds can undergo diverse transformations, including nucleophilic aromatic substitution, carbonyladdition, olefnation and desilylation. Signifcantly, the regiodivergentinstallation of silylmethyl synthetic handles allows for the synthesis of thepharmaceutical losmapimod and could further be applied in direct late-stagefunctionalizations. Mechanistically, an essential role for biscyclometallatedruthenium(II) species has been found, with the formation of intermediateruthenium(III) species indicated by paramagnetic NMR experiments. Thesesynthetic inventions and mechanistic elucidations signify a transformativestep within ruthenium-catalysed C(sp2)–H functionalization, enabling diverse syntheses and providing a framework for future development.
U2 - 10.1038/s41929-025-01309-6
DO - 10.1038/s41929-025-01309-6
M3 - Journal article
VL - 8
SP - 301
EP - 314
JO - Nature Catalysis
JF - Nature Catalysis
IS - 4
ER -