Aqueous Base Promoted O-Difluoromethylation of Carboxylic Acids with TMSCF₂Br: Bench-Top Access to Difluoromethyl Esters

Abstract

A method for the O-difluoromethylation of carboxylic acids using commercially available TMSCF 2 Br is disclosed. The devised benchtop reaction system is air-stable and offers mild reaction conditions while using readily available reagents and solvents. The method is applicable to both aliphatic and aromatic carboxylic acids while demonstrating compatibility with a range of commonly encountered functional groups. The difluoromethyl esters of FDA approved drugs and pharmaceutically relevant molecules are also presented, demonstrating the potential for late-stage functionalization.

Recent synthetic methods towards the –OCHF2 moiety

“…Since then TMSCF2Br 9 also proved to be an efficient source of carbene for the difluoromethylation of carboxylic acids by Prakash et al [28].…”

“…More recently, in 2019, Prakash reported the use of TMSCF2Br 9 as difluorocarbene source for the direct transformation of carboxylic acids into the corresponding difluoromethyl esters. [28] As for phenols, KOH is required to activate the substrates. The reaction thus takes places in CH3CN but required the presence of water in order to dissolve the aqueous base.…”

Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers

“…Moreover, this might provide a new reference for the breaking of carbon-oxygen bonds in alkyl ethers [35][36][37][38][43][44][45][46][47] . However, there are several challenges on our hypothesis: 1) difluorocarbene is not a highly electron-deficient carbene species compared with well-known normal carbenes, because the lone pair electrons of fluorine atom can conjugate with the carbene empty orbital to make it more stable and relatively "electron-rich", thus the interaction between difluorocarbene and the neutral O atom in alkyl ethers will not be very strong; 2) because of the weak interaction, it will not significantly weaken C-O bond thus make the cleavage of C-O bond difficult and challenging; 3) there are competitions between the third component which serves as a nucleophile to break C-O bond and the alkyl ether, and the reaction between the third part with difluorocarbene might be the dominant one [58][59][60] ; 4) the choice of the third component will be critical for the success of this hypothesis.…”

Chemoselective N- and O-Difluoromethylation of 2-Pyridones, Isoquinolinones, and Quinolinones with TMSCF2Br

“…Difluorocarbene can also be efficiently generated from (per)­fluoroalkylsilanes like TMSCF 3 or TMSCF 2 Br . The latter compound, first synthesized by our group, is defining a new trend in difluoromethylation methodology due in part to its versatility and ease of activation. ,, …”

“…31 The latter compound, first synthesized by our group, 32 is defining a new trend in difluoromethylation methodology due in part to its versatility and ease of activation. 20,21,33 2-Pyridones are important structures prevalent in pharmaceuticals and biomolecules. 34−36 For example, leporin A is known to possess antifungal properties.…”