Reaction of Diaryliodonium Salts with Potassium Alkyl Xanthates as an Entry Point to Accessing Organosulfur Compounds

Abstract

Preparation of S-aryl xanthates via transition-metal-catalyzed or S N Ar reactions is complicated by their further transformations under the utilized conditions. In contrast, S-arylation of potassium O-alkyl xanthates with diaryliodonium salts proceeds under mild conditions, enabling access to substituted S-aryl xanthates. The method exhibits good functional group tolerance and can be applied to the late-stage C−H functionalization of drug molecules. Divergent transformations of the resulting S-aryl xanthates provide rapid access to a range of medicinal chemistry-relevant organosulfur compounds.

A Thiol-Free Route to Alkyl Aryl Thioethers

“…To further demonstrate the utility of the proposed method and considering the importance of deuterium-labeled compounds for medicinal chemistry, we prepared an SCD 3 -modified gemfibrozil and its oxidized derivatives employing the late-stage C–H functionalization strategy for C–S bond formation , (Scheme ). Initially, gemfibrozil methyl ester ( 5 ) reacted with Koser’s reagent 6 derived from 4-iodo-3,5-dimethylisoxazole. , Next, the resulting iodonium salt 7 and the potassium xanthate derived from CD 3 OD were used in the telescoped sequence to afford thioether 8 in 54% overall yield and high purity without column chromatography. Finally, oxidation of 8 under different conditions led to the formation of the corresponding sulfoxide 9 or sulfone 10 in nearly quantitative yields.…”

“…Initially, starting alcohols 3 in 2.5 equiv amounts were successively reacted with t -BuOK and CS 2 in Et 2 O to form potassium O -alkylxanthates. Next, after evaporation of the reaction mixture under a reduced pressure, the resulting O -alkyl xanthates underwent S-arylation with 1 equiv of diaryliodonium salts 4 in CH 2 Cl 2 under previously developed conditions . Finally, when the solvent was changed to DMSO, S -aryl O -alkylxanthates 1 were allowed to react with the remaining amount of potassium O -alkylxanthates to afford alkyl aryl thioethers 2 .…”

“…17 Despite its potential synthetic utility, the conversion of xanthates to thioethers is mostly regarded as an undesired side process and remains a rather underexplored transformation with few precedents limited to nonfunctionalized primary alcohols. 16,17 As a continuation of our recent work on the arylation of O-alkyl xanthates with diaryliodonium salts to obtain S-aryl xanthates, 18 herein, we report on the related cascade transformation of primary and secondary alcohols into the corresponding alkyl aryl thioethers using CS 2 as a sulfur source and diaryliodonium salts as arylating agents. From a synthetic perspective, this operationally simple one-pot protocol affords a shorter synthetic route to alkyl aryl thioethers without a need for the use or preparation of thiols.…”

“…Next, after evaporation of the reaction mixture under a reduced pressure, the resulting O-alkyl xanthates underwent S-arylation with 1 equiv of diaryliodonium salts 4 in CH 2 Cl 2 under previously developed conditions. 18 Finally, when the solvent was changed to DMSO, S-aryl Oalkylxanthates 1 were allowed to react with the remaining amount of potassium O-alkylxanthates to afford alkyl aryl thioethers 2. While the scope of the reaction with respect to diaryliodonium salts and the selectivity of aryl transfer in Sarylation of O-alkyl xanthates were examined in detail in our earlier report, 18 in this study we mainly focused our attention on determining the breadth of alcohols and functional groups that are compatible with the reaction conditions.…”

“…18 Finally, when the solvent was changed to DMSO, S-aryl Oalkylxanthates 1 were allowed to react with the remaining amount of potassium O-alkylxanthates to afford alkyl aryl thioethers 2. While the scope of the reaction with respect to diaryliodonium salts and the selectivity of aryl transfer in Sarylation of O-alkyl xanthates were examined in detail in our earlier report, 18 in this study we mainly focused our attention on determining the breadth of alcohols and functional groups that are compatible with the reaction conditions. A range of primary alcohols with varying carbon chain lengths (C 1 −C 8 ) bearing different functionalities are competent partners in this threestep, one-pot telescoped sequence, delivering the corresponding alkyl aryl thioethers in 43−82% yields.…”