Base-catalyzed C-Alkylation of potassium enolates with styrenes via a metal-ene reaction : a mechanistic study

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Barham, Joshua P. and Fouquet, Thierry N.J. and Norikane, Yasuo (2020) Base-catalyzed C-Alkylation of potassium enolates with styrenes via a metal-ene reaction : a mechanistic study. Organic and Biomolecular Chemistry, 18 (11). pp. 2063-2075. ISSN 1477-0520 (https://doi.org/10.1039/c9ob02495f)

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Abstract

Base-catalyzed, C-Alkylation of potassium (K) enolates with styrenes (CAKES) has recently emerged as a highly practical and convenient method for elaboration or synthesis of pharmaceutically-relevant cores. K enolate-Type precursors such as alkyl-substituted heterocycles (pyridines, pyrazines and thiophenes), ketones, imines, nitriles and amides undergo C-Alkylation reactions with styrene in the presence of KOtBu or KHMDS. Surprisingly, no studies have probed the reaction mechanism beyond the likely initial formation of a K enolate. Herein, a synergistic approach of computational (DFT), kinetic and deuterium labelling studies rationalizes various experimental observations and supports a metal-ene-Type reaction for amide CAKES. Moreover, our approach explains experimental observations in other reported C-Alkylation reactions of other enolate-Type precursors, thus implicating a general mechanism for CAKES.

ORCID iDs

Barham, Joshua P. ORCID logoORCID: https://orcid.org/0000-0003-1675-9399, Fouquet, Thierry N.J. and Norikane, Yasuo;
CORE (COnnecting REpositories)