A Route to α-Fluoroalkyl Sulfides from α-Fluorodiaroylmethanes

Abstract

α,α-Difluorodiaroylmethane can be used as a nucleophilic difluoromethylation reagent for generating α-thioaryl-α,α-difluoroacetophenones (Ar(1)COCF2SAr) and difluoromethylthiolated arenes (ArSCF2H) under transition-metal-free conditions. The reaction selectivity is mainly dependent on temperature. The method has also been extended to the synthesis of α-thioaryl-α-monofluoroacetophenones using α-monofluorodibenzoylmethane. Moreover, the benzoyl cation derived from α,α-difluorodibenzoylmethane can react with nucleophiles to afford the desired products in a one-pot process.

Switching Chemoselectivity: Using Mechanochemistry to Alter Reaction Kinetics

“…The unreacted disulfide could also be isolated quantitatively from this reaction mixture. This product/observation is in contrast to the result reported for the same reagents in solution by Yi, Lu, and co‐workers, who report the formation of the difluorothioether compounds 3 a and 3 b 7. Encouraged by the significantly different reactivity observed under mechanochemical conditions, this reaction was investigated further.…”

“…The reaction with the disulfide, observed under LAG conditions with the more polar solvents, and also in solution, yields difluorinated thioether 3 a . Under longer reaction times, or at higher temperatures, this can fragment further to difluoromethylthioether 3 b 7. In order to probe the validity of the proposed mechanism, we designed several control experiments to test the various aspects.…”

Methods for the Synthesis of α,α‐Difluoroketones

“…The combination of LiBr and Selectfluor gives an electrophilic brominating agent suitable for the synthesis of CF 2 Br ketones 108 . Trapping with disulfides (which can also be generated by the oxidation of a thiol with DMSO) allows the synthesis of CF 2 SPh ketones 109 from symmetrical difluorinated 1,3‐diketones …”

An Electrophilic Reagent for the Direct Introduction of the SCF2PO(OEt)2 Group to Molecules

“…Taking into consideration the myriad of available fluorinated groups (CF 3 ,C F 2 H, CF 2 PO-(OR) 2 ,C F 2 SO 2 Ph, C n F 2n+1 …), the synthesis of their sulfurcontaining analogues would provide an ew generation of fluorinated residues.T his strategy has been recently illustrated by the contributions of the groups of Hu, [6] Gooßen, [7] Billard, [8] and others. [9] Indeed, various SCF 2 FG-containing molecules (FG = SO 2 Ph, R f ,S Ar and COAr) were successfully synthesized using two main synthetic pathways:1 )the construction of aS ÀCF 2 FG bond by reaction of aC F 2 FG reagent with either thiols or disulfides,a nd 2) the direct introduction of aSCF 2 FG group to molecules thanks to newly designed reagents.W ith these considerations in mind, we turned our attention to the SCF 2 PO(OR) 2 group.W e imagined that the original combination of at hioether with the CF 2 PO(OR) 2 residue will be highly beneficial considering the intrinsic properties of both functional groups. [10] To date,o nly ah andful of reports have dealt with the synthesis of SCF 2 PO(OR) 2 -containing molecules.They relied on the difluorination of PhSCH 2 PO(OEt) 2 by either an electrochemical pathway (Scheme 1a) [11a] or by means of ahalogen-exchange using 3HF·NEt 3 and ZnBr 2 starting from the corresponding chlorinated analogue (Scheme 1b).…”