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C=O Methylenation mediated by organo-alkali metal reagents: metal identity and ligand effects

Lookup NU author(s): Matthew Lowe, Dr Paul Waddell, Dr Roly ArmstrongORCiD, Dr Matt HopkinsonORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

C=O Methylenation mediated by α-silyl organo-alkali metal reagents, namely Peterson methylenation, is a textbook organic reaction that has been widely employed in synthetic chemistry for over 50 years. The process is performed over two-steps, by isolating the β-silyl alcohol intermediate generated via nucleophilic addition and then subjecting it to elimination. The choices of alkali metal and external Lewis Base ligand play a critical role in the elimination step, but the reasons remain poorly understood. In this work, we have systematically investigated the metal identity and ligand effects in C=O methylenation reactions mediated by MCH2SiMe3 (M = Li; Na; K). We observed pronounced alkali metal cation and ligand effects on the methylenation performance, with K+ and tetrahydrofuran (THF) being optimal. Based upon these learnings, a straightforward new methylenation method has been designed involving carbonyl addition with LiCH2SiMe3, followed by in situ addition of KOtBu in THF, facilitating facile transmetallation-enabled elimination. This strategy enables the methylenation to be achieved in one pot, whilst circumventing the use of KCH2SiMe3. Excellent yields have been achieved for a range of ketones (including enolizable examples) and aldehydes. The method uses commercial solvents and reagents, and can be performed without any requirement for stringent drying or deoxygenation.

Publication metadata

Author(s): Yang X, Davison N, Lowe ME, Waddell PG, Armstrong RJ, McMullin CL, Hopkinson MN, Lu E

Publication type: Article

Publication status: Published

Journal: Chemical Science

Year: 2025

Volume: 16

Issue: 24

Pages: 11151-11160

Online publication date: 19/05/2025

Acceptance date: 17/05/2025

Date deposited: 19/05/2025

ISSN (electronic): 2041-6539

Publisher: Royal Society of Chemistry

URL: https://doi.org/10.1039/D5SC02313K

DOI: 10.1039/D5SC02313K

Data Access Statement: CCDC 2374573 ([KOSiMe3]4) and 2374574 (3 K) contain the supplementary crystallographic data for the corresponding complexes, respectively. This data can be obtained free of charge via https://www.ccdc.cam.ac.uk/data_request/cif, orby emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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