Issue 11, 2020

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

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.

Graphical abstract: Base-catalyzed C-alkylation of potassium enolates with styrenes via a metal–ene reaction: a mechanistic study

Associated articles

Supplementary files

Article information

Article type
Paper
Submitted
19 Nov 2019
Accepted
26 Jan 2020
First published
25 Feb 2020
This article is Open Access
Creative Commons BY license

Org. Biomol. Chem., 2020,18, 2063-2075

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

J. P. Barham, T. N. J. Fouquet and Y. Norikane, Org. Biomol. Chem., 2020, 18, 2063 DOI: 10.1039/C9OB02495F

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