Synthesis of Difluoromethylated Carbinols via a HFIP-Promoted Hydroxydifluoromethylation of Aniline, Indole, and Pyrrole Derivatives with Difluoroacetaldehyde Ethyl Hemiacetal

Abstract

A hexafluoroisopropanol (HFIP)-promoted hydroxydifluoromethylation of aniline, indole, and pyrrole derivatives with difluoroacetaldehyde ethyl hemiacetal has been developed. This protocol provides a facile and straightforward approach to access diverse difluoromethylated carbinols in good to excellent yields under mild conditions. Furthermore, gram-scale and synthetic derivatization experiments have also been demonstrated.

Metal-free synthesis of difluoro/trifluoromethyl carbinol-containing chromones via tandem cyclization of o-hydroxyaryl enaminones

“…Thus, combining the above-mentioned results and previous relevant literature reports on the HFIP catalytic mechanism 6,37,38 and the synthesis of chromones from o -hydroxyaryl enamamines, 34,39–42 a plausible mechanism of the HFIP-promoted tandem cyclization reaction from o -hydroxyaryl enaminones was proposed (Scheme 3). In this conversion, HFIP not only acted as a solvent, but also as a Brønsted acid to promote the reaction.…”

“…1). 5–8 Therefore, it is of considerable academic and application value to explore a facile protocol for the synthesis of difluoro/trifluoromethylated carbinol derivatives. 9–17…”

Divergent synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines

“…14 Recently, Wang and Ren's group reported the elegant work on HFIP-promoted hydroxydifluoromethylation of aniline, indole, and pyrrole derivatives with difluoroacetaldehyde ethyl hemiacetal for the synthesis of difluoromethylated carbinols (Scheme 1e). 15 We reasoned that by taking advantage of the reactivity of difluoroacetaldehyde ethyl hemiacetal, difluoromethylated I3C, BIMs and indole-3-methanamines would be successfully constructed via a Friedel–Crafts reaction of indole with difluoroacetaldehyde ethyl hemiacetal. With this thought in mind and as part of our continuous research on the synthesis of fluoroalkylated molecules, 13,16,17 herein we report a catalyst-controlled approach for accessing difluoromethylated I3C, BIMs and indole-3-methanamines via Friedel–Crafts alkylation.…”

Visible-light-promoted desulfonylative radical difluoroalkylation between difluoroenol silyl ethers and difluoroalkyl sulfones to construct functionalized aryltetrafluoroethane derivatives

“…Taking advantage of the excellent radical reactivity of difluoroalkyl sulfones under visible-light photoredox catalysis, we envision that ArCF 2 CF 2 R moieties can be constructed by radical coupling of difluoroalkyl sulfones with other difluoroalkyl reagents. As part of our ongoing study on the application of silyl difluoroenolates to achieve valuable fluorine-containing compounds, 20 we herein report a novel and efficient visible-light-promoted desulfonylative radical difluoroalkylation between difluoroenol silyl ethers and difluoroalkyl sulfones to construct ArCF 2 CF 2 R moieties (Scheme 1B). This approach provides an alternative way to synthesize aryltetrafluoroethane derivatives bearing diverse functional groups.…”