Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions.

Lotte Stockhammer,Mario Waser,Thomas Bögl,David Weinzierl

doi:10.1021/acs.orglett.1c02256

Lotte Stockhammer, Mario Waser + Show 2 more

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https://doi.org/10.1021/acs.orglett.1c02256

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Journal: Organic letters	Publication Date: Jul 28, 2021
Citations: 18	License type: CC BY 4.0

Affiliation: Johannes Kepler University of Linz

Abstract

The asymmetric α-chlorination of activated aryl acetic acid esters can be carried out with high levels of enantioselectivities utilizing commercially available isothiourea catalysts under base-free conditions. The reaction, which proceeds via the in situ formation of chiral C1 ammonium enolates, is best carried out under cryogenic conditions combined with a direct trapping of the activated α-chlorinated ester derivative to prevent epimerization, thus allowing for enantioselectivities of up to e.r. 99:1.

Highlights

Asymmetric α-heterofunctionalization reactions, especially α-halogenations, of prochiral enolate precursors and analogues represent important transformations to access valuable chiral building blocks suited for further manipulations as well as potentially biologically active target molecules.[1]
(Turnover was achieved by the choice of the proper electrophilic halide-transfer reagent or the addition of an external nucleophile.)[10,11] In addition, Smith’s and Fu’s groups reported α-halogenations of ketene precursors using either chiral N-heterocyclic carbenes (NHCs)[12] or planar chiral pyridine catalysts,[13] underscoring the potential of this concept to access valuable enantioenriched α-halogenated acyclic carboxylic acid derivatives
Our group recently became interested in asymmetric αchlorination reactions,[14] and considering the value of αchlorinated carbonyl compounds[15] and the unique potential of C1 ammonium enolate chemistry to facilitate asymmetric αfunctionalizations of simple carboxylic acid derivatives, we thought about developing the, to the best of our knowledge, unprecedented α-chlorination of simple activated esters 1 (Scheme 1C)

Summary

Introduction

Asymmetric α-heterofunctionalization reactions, especially α-halogenations, of prochiral enolate precursors and analogues represent important transformations to access valuable chiral building blocks suited for further manipulations as well as potentially biologically active target molecules.[1]. Our group recently became interested in asymmetric αchlorination reactions,[14] and considering the value of αchlorinated carbonyl compounds[15] and the unique potential of C1 ammonium enolate chemistry to facilitate asymmetric αfunctionalizations of simple carboxylic acid derivatives, we thought about developing the, to the best of our knowledge, unprecedented α-chlorination of simple activated esters 1 (Scheme 1C).

Results

Conclusion