Mechanochemical Difluoromethylations of Alcohols

Abstract

Difluoromethyl ethers are formed through mechanochemical reactions of alcohols with difluorocarbene in a mixer mill. The protocol could be applied to primary, secondary, and tertiary alcohols, yielding the corresponding products in excellent yields (up to 99%) after 1 h reaction time at room temperature. The transformations proceeded under solvent-free reaction conditions, followed by product purification by filtration, which drastically reduced the amount of waste generated during the process.

Mechanochemical difluoromethylation of (thio)phenols and N‐heterocycles

“…Applying the conditions for the difluoromethylation of aliphatic alcohols recently reported by Bolm and co-workers, who propose TMSCF 2 Br as a DFC reagent in combination with CsCl and KHF 2 activators, also gave only traces of the difluoromethylated phenol (Table 1, entry 12). [28] Meanwhile, application of reagent 1 with a KOH activator on a model primary benzylic alcohol (biphenyl-4-methanol) gave the difluoromethylated product in 29 % yield, as determined by quantitative 19 F NMR (Figure S2). [31] Hu and co-workers proposed that installing electron-withdrawing groups at the para position of the aromatic ring (i. e. nitro (4) and chloro ( 5)) improved reagent efficacy of chlorodifluoromethyl aryl sulfone derivatives by increasing the electrophilicity of the sulfone sulfur, resulting in an increased rate of DFC release.…”

“…Applying the conditions for the difluoromethylation of aliphatic alcohols recently reported by Bolm and co‐workers, who propose TMSCF 2 Br as a DFC reagent in combination with CsCl and KHF 2 activators, also gave only traces of the difluoromethylated phenol (Table 1, entry 12) [28] . Meanwhile, application of reagent 1 with a KOH activator on a model primary benzylic alcohol (biphenyl‐4‐methanol) gave the difluoromethylated product in 29 % yield, as determined by quantitative 19 F NMR (Figure S2) [31]…”

“…Interestingly, despite these efforts, a solvent‐free mechanochemical difluoromethylation reaction was not reported until very recently. During the preparation of this manuscript, Bolm and co‐workers disclosed the first mechanochemical difluoromethylation of aliphatic alcohols using the difluorocarbene (DFC) precursor TMSCF 2 Br [28,29] . While their optimised conditions performed very efficiently for the difluoromethylation of aliphatic alcohols, as well as a single example of an N ‐heterocycle, (thio)phenols were suggested not to be accessible substrates.…”

“…During the preparation of this manuscript, Bolm and co-workers disclosed the first mechanochemical difluoromethylation of aliphatic alcohols using the difluorocarbene (DFC) precursor TMSCF 2 Br. [28,29] While their optimised conditions performed very efficiently for the difluoromethylation of aliphatic alcohols, as well as a single example of an N-heterocycle, (thio)phenols were suggested not to be accessible substrates. In this report, we disclose an orthogonal set of conditions for the solid-phase generation of DFC and study its reactivity towards (thio)phenolic OÀ H and SÀ H insertions, as well as the difluoromethylation of N-heterocycles (Figure 1).…”

Mechanochemical Deoxyfluorination of Carboxylic Acids to Acyl Fluorides and Successive Mechanochemical Amide Bond Formation

“…25−32 A ball mill is a mechanochemical apparatus that employs the controlled movement of a ball at a specified frequency to exert mechanical force on a mixture of reagents, thereby expediting the reaction process. Although many mechanochemical reactions, including fluorination 33,34 and difluoromethylation, 35,36 have recently been reported, there is an absence of mechanochemical synthesis methods for acyl fluorides.…”