Umpolung C(3)–H Functionalization of Indoles via I(III) Intermediates: Synthesis of Indol‐3‐yl Xanthates

A semi-one-pot protocol for the synthesis of previously inaccessible, bench-stable O-alkyl-S-(indol-3-yl)-xanthates has been developed. The transformation involves in situ generation of DMIX(indol-3-yl)iodonium salts, followed by their reaction with potassium O-alkyl-xanthates. The resulting products are of interest due to their potential biological activity and synthetic utility as precursors to C(3)-sulfur-substituted indoles.

Abstract

Herein, we report a transition-metal-free strategy for the synthesis of O-alkyl-S-(indol-3-yl) xanthates, valuable surrogates for indol-3-yl thiols. The method relies on the in situ formation of electrophilic (3,5-dimethylisoxazol-4-yl)(indol-3-yl)iodonium salts via highly chemo- and regioselective C(3)–H functionalization of indoles with (3,5-dimethylisoxazol-4-yl)–I(OH)OTs, a Koser's type reagent. These electrophilic intermediates readily react with potassium O-alkyl xanthates, delivering the corresponding O-alkyl-S-(indol-3-yl) xanthates in good-to-high yields. The protocol exhibits good functional group compatibility and is well-suited for late-stage functionalization of complex bioactive molecules, as demonstrated by the derivatization of the antiviral agent CCG-203926 and estradiol, a steroid hormone. This operationally simple protocol provides an efficient approach to otherwise inaccessible indol-3-yl xanthates that are both a class of compounds of considerable interest due to their potential biological activity and valuable precursors for other indole derivatives containing organosulfur functional groups at the C(3) position.

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