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. 2020 Dec 16;142(50):20979-20986.
doi: 10.1021/jacs.0c11214. Epub 2020 Dec 1.

Electroreductive Olefin-Ketone Coupling

Pengfei Hu  1   2 , Byron K Peters  1   2 , Christian A Malapit  3   2 , Julien C Vantourout  1   2 , Pan Wang  4 , Jinjun Li  4 , Lucas Mele  5 , Pierre-Georges Echeverria  5 , Shelley D Minteer  3   2 , Phil S Baran  1   2
Affiliations

Electroreductive Olefin-Ketone Coupling

Pengfei Hu et al. J Am Chem Soc. .

Abstract

A user-friendly approach is presented to sidestep the venerable Grignard addition to unactivated ketones to access tertiary alcohols by reversing the polarity of the disconnection. In this work a ketone instead acts as a nucleophile when adding to simple unactivated olefins to accomplish the same overall transformation. The scope of this coupling is broad as enabled using an electrochemical approach, and the reaction is scalable, chemoselective, and requires no precaution to exclude air or water. Multiple applications demonstrate the simplifying nature of the reaction on multistep synthesis, and mechanistic studies point to an intuitive mechanism reminiscent of other chemical reductants such as SmI2 (which cannot accomplish the same reaction).

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Figures

FIGURE 1.
FIGURE 1.
Tertiary alcohols from simple ketones remain a challenge for modern synthesis (A). Synthesis of 2 is emblematic of the problems with Grignard (B). Recent approaches so far do not address the problem (C). Electrochemical precedent on activated olefins (D) and a summary of this work (E).
SCHEME 1.
SCHEME 1.
(A) Electrochemical ketone-olefin coupling facilitates rapid access to medicinally relevant structures such as a vitamin D sidechain (1), a DNA-binding metabolite (2), and a hedgehog signaling modulator (3). (B) Batch and flow scale-up. aIsolated yield
SCHEME 2.
SCHEME 2.
Mechanistic insights from byproducts (A), deuterium labeling (B), proposed reaction mechanism (C), and voltammetry studies (D & E). See SI for details. affording a comparable yield to the batch reaction(Scheme 1B, see SI for details).
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