Base Catalysis Enables Access to α,α-Difluoroalkylthioethers

Abstract

A nucleophilic addition reaction of aryl thiols to readily available β,β-difluorostyrenes provides α,α-difluoroalkylthioethers. The reaction proceeds through an unstable anionic intermediate, prone to eliminate fluoride and generate α-fluorovinylthioethers. However, the use of base-catalysis overcomes the facile β-fluoride elimination, generating α,α-difluoroalkylthioethers in excellent yields and selectivities.

Solvent‐Switched Oxidation Selectivities with O2: Controlled Synthesis of α‐Difluoro(thio)methylated Alcohols and Ketones

“…Proposed Mechanism . Based on these results and previous works, [12–14] a mechanism for this reaction was proposed in Scheme 12. Firstly, Deprotonation of thiol 2 will give thiol‐based nucleophile A , which subsequently converts to α‐difluoro(thio)methylated carbanion B by nucleophilic addition to gem ‐difluoroalkene 1 .…”

Organic Superbases in Recent Synthetic Methodology Research

“…Altman recently disclosed methods for the catalytic addition of thiophenols [27a] and phenols [27b] to β,β‐gemdifluoroaryl alkenes, substrates that are prone to competing fluoride elimination after nucleophilic addition (Figure 4 a). [28] In fact, inorganic base catalysts (e.g.…”

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

“…47 In a first example, 1,1,3,3-tetramethylguanidine (TMG) served as a catalytic base for hydrothiolation reactions of gem-difluoroalkenes with thiophenols to deliver -difluorothioethers (Scheme 20A). 49 Generally, the reaction performed well for electron-rich and -neutral gemdifluorostyrenes, but did not perform as well for electron-deficient substrates. Additionally, this method only coupled thiophenol derived nucleophiles, and did not function for alkyl thiols.…”

“…A complementary reaction to access ,-difluoro thioethers was developed using an acid-derived catalyst system that added thiol nucleophiles across gem-difluoroalkenes to generate hydrothiolated products with high regio-and chemoselectivity (Scheme 22A). 51 Moreover, this method expanded the scope of the prior base-catalyzed strategy 49 to include alkyl thiols and improved both the yield and selectivity of previously challenging substrate combinations, 49 notably reactions of thiophenols with electron-deficient gem-difluororalkenes. Although this system exploited LiOTf and pyridine as catalytic additives, the reaction actually proceeded through an acid-catalyzed process.…”