Synthesis of aryl α,α-difluoroethyl thioethers a novel structure motif in organic chemistry, and extending to aryl α,α-difluoro oxyethers

Abstract

A method for the preparation of aryl α,α-difluoroethyl thioethers (ArSCFCH) is reported and the synthesis approach is extended to aryl α,α-difluoroethyl oxygen ethers. Selected building blocks are further elaborated in cross-coupling reactions and are incorporated into analogues of established trifluoromethyl ether drugs. Conformations are explored and log P studies of these motifs indicate that they are significantly more polar than their trifluoromethyl ether analogues rendering them attractive for bioactives discovery.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…[232] Recent years have witnessedt he publication of numerouss ynthetic works on novel advanced buildingb locks for drug discovery,f ocusingm ainly on unusual bicyclic, spirocyclic, heteroaliphatic,o rh eteroaromatic compounds, especially those with fluorine atoms; selected examples are given in Figure 44. [233][234][235][236][237][238][239][240]…”

“…Among the bifunctional reagents, (monoprotected) amino acids and diamines are most popular . Recent years have witnessed the publication of numerous synthetic works on novel advanced building blocks for drug discovery, focusing mainly on unusual bicyclic, spirocyclic, heteroaliphatic, or heteroaromatic compounds, especially those with fluorine atoms; selected examples are given in Figure …”

Metabolism and hydrophilicity of the polarised ‘Janus face’ all-cis tetrafluorocyclohexyl ring, a candidate motif for drug discovery

“…log P's were measured by reverse phase HPLC (AcCN 60%: water 40%, with TFA 0.05%), as previously described. 20 The measured log P's of a series of phenyl fluorocyclohexane derivatives are summarised in Fig. 2 and against a series of compounds, of known log P values, which were re-measured for comparison, including biphenyl 16 and phenylcyclohexane 17.…”

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

“…In this regard, partially fluorinated alkyl substituents become an interesting alternative, as the fluorines polarise the adjacent hydrogens and lipophilicity reduces relative to the perfluoro substituents [13–15]. In this context we recently introduced aryl α,α-difluoroethyl thioethers such as 1 as a motif of this class [16–18]. Log P assessments of PhSCF 2 CH 3 ( 1 ) indicate that it is more polar than the PhSCF 3 ( 2 ) and also the aliphatic PhSCH 2 CH 3 ether 3 as shown in Fig.…”