Reactions of TFDA with Ketones. Synthesis of Difluoromethyl 2,2-Difluorocyclopropyl Ethers

Abstract

The sequential reaction of 2 equiv of difluorocarbene (generated from trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) by treatment with catalytic fluoride ion) with a series of electron-rich aromatic ketones and alpha,beta-unsaturated ketones leads to the formation of difluoromethyl 2,2-difluorocyclopropyl ethers in good yield.

Introduction of Fluorine and Fluorine‐Containing Functional Groups

“…Treatment of enolates with chlorodifluoromethane gives rise to α‐difluoromethylated carbonyl products,232 while diasteroselective α‐difluoromethylation of N ‐acyloxazolidinones is achieved with bromodifluoromethane 233. Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA), which also acts as a source of difluorocarbene, reacts with alkenes,234 alkynes,234d and ketones235 to form geminal difluorocyclopropanes, difluorocyclopropenes, and difluoropropane ethers, respectively. Less commonly, this reagent is used for difluoromethylation reactions at heteroatoms 234a.…”

A new synthesis of 2-fluoro-1-naphthols

“…Recently, we reported the sequential reaction of aryl alkyl ketones with two equivalents of difluorocarbene, generated thermally (under fluoride catalysis) from acid free trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) [10], to form difluoromethyl 2,2-difluorocyclopropyl ethers, via the intermediate formation of difluoromethyl enol ethers (Scheme 3) [11].…”

Synthesis of gem‐Difluorocyclopropa(e)nes and O‐, S‐, N‐, and P‐Difluoromethylated Compounds with TMSCF2Br

“…However, a major limitation of most of the difluorocarbene sources is that they focus on only one type of reaction, either [2+1] cycloaddition with alkenes/alkynes under non‐basic conditions (Category A)12–18 or α‐addition with Nu‐H under basic conditions (Category C) 6–11. Although difluorocarbene generated from FSO 2 CF 2 CO 2 H19 and FSO 2 CF 2 CO 2 TMS (TFDA; Category B)20 under nonbasic conditions is reactive towards both alkenes/alkynes and Nu‐H, the synthesis of difluoromethyl compounds with these reagents is subject to low yields19 or narrow substrate scope 20b–d. As the most commonly used reagent for heteroatom difluoromethylation, HCF 2 Cl (Category B) itself is an ozone‐depleting substance (ODS) and its [2+1] cycloaddition only works with electron‐rich alkenes 21.…”