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

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.

Photochemical Wolff Rearrangement Initiated Generation and Subsequent α-Chlorination of C1 Ammonium Enolates

“…Other O -nucleophiles were also tolerated (Scheme B), but the use of more bulky alcohols led to somewhat lower yields, as outlined for 2o . The somewhat lower er with those alcohols may be explained by a slower addition to the intermediate chlorinated-catalyst-bound species A , which we recently identified being prone to epimerization . It is of note that even the use of 2 equiv of H 2 O worked satisfyingly (giving the free carboxylic acid 2p ).…”

“…We, of course, also tested different concentrations, stoichiometric ratios of reagents, and reaction times but, overall, we found the conditions outlined in entry 6 to be the best-suited (also on 1 mmol scale). In addition, the long reaction times and cryogenic conditions that were necessary when using our previous aryl ester strategy (Scheme B) could be successfully avoided. With respect to the observed sense of induction, we rationalize that the reaction proceeds via a well-organized O–S σ-hole-stabilized C1 ammonium enolate , where the Si-face is blocked by the Ph ring when using ( R )-BTM ( ITU3 ).…”

“…Very recently, Zheng and co-workers reported an enantioselective ITU-catalyzed α-fluorination strategy, 20 and our group introduced a conceptually similar ITU-catalyzed α-chlorination protocol ( Scheme 1 B). 21 While Zheng et al started from free carboxylic acids, which were activated in situ with TsCl, 20 we utilized aryl esters as pronucleophiles. 21 Although reliant on different starting materials, both approaches proceed via in situ formation of a chiral C1 ammonium enolate.…”

Advances in Chemical Crystallography: A Themed Issue Honoring Professor Alexandra M. Z. Slawin on the Occasion of Her 60th Birthday

“…We have expanded the scope of electrophiles applicable within this catalyst turnover strategy to include iminium ions generated under either photoredox conditions or Brønsted acid catalysis, as well as bis-sulfone Michael acceptors, and pyridinium salts (Scheme 1e) [76][77][78][79]. Recently, Waser also reported an elegant example of this turnover strategy for the enantioselective α-chlorination of pentafluorophenyl esters [80], while Zheng and co-workers reported a related approach using diphenyl methanol as an external turnover reagent for the fluorination of carboxylic acids [81,82]. A significant challenge within this area is the identification of electrophilic reaction partners that react with the catalytically-generated C(1)-ammonium enolate, but are compatible with the nucleophilic tertiary amine catalyst and aryloxide, which is essential for catalyst turnover.…”

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides

“…We have expanded the scope of electrophiles applicable within this catalyst turnover strategy to include iminium ions generated under either photoredox conditions or Brønsted acid catalysis, as well as bis-sulfone Michael acceptors, and pyridinium salts (Scheme 1e) [76][77][78][79]. Recently, Waser also reported an elegant example of this turnover strategy for the enantioselective α-chlorination of pentafluorophenyl esters [80], while Zheng and co-workers reported a related approach using diphenyl methanol as an external turnover reagent for the fluorination of carboxylic acids [81,82]. A significant challenge within this area is the identification of electrophilic reaction partners that react with the catalytically-generated C(1)-ammonium enolate, but are compatible with the nucleophilic tertiary amine catalyst and aryloxide, which is essential for catalyst turnover.…”