Chemoselective N-Difluoromethylation of Functionalized Tertiary Amines

Abstract

A practical, convenient, and general method for the difluoromethylation of tertiary amines, using diethyl bromodifluoromethylphosphonate and fluoride, is described. This commercially available phosphonate smoothly reacts with a fluoride ion to liberate a difluorocarbene intermediate that in the presence of a proton source and a tertiary amine generates the corresponding α-difluoromethylammonium compound in good to excellent yields. Despite the involvement of a difluorocarbene intermediate, this difluoromethylation occurs almost exclusively on the nitrogen atom with diverse molecular structures, including drugs, surfactants, chiral phase transfer catalysts, polymers, ionic liquids, and other fine chemicals. A preliminary assessment of the effects that an α-difluoromethyl groupT has on hydrogen bonding and logP of quaternary ammonium salts is also described.

A simple method for the synthesis of N-difluoromethylated pyridines and 4-pyridones/quinolones by using BrCF2COOEt as the difluoromethylation reagent

“…Although halodiuoromethyl compounds have been extensively used as diuorocarbene synthons in diuoromethylation reactions, 17 the presence of 2a and 2b supports a direct nucleophilic attack of the pyridine nitrogen on the electrophilic carbon of 1 rather than the generation of a diuorocarbene intermediate. In order to conrm this mechanism, compound 2b was isolated by reversed-phase HPLC and fully characterized by 1 H, 13 C and 19 F-NMR, IR and HR ESI-MS (see ESI †). It is worth noting that the ester intermediate 2acould not be isolated since it was completely transformed into 2b during the purication by silica column chromatography.…”

“…More recently, Zafrani, Gershonov and collaborators have described the diuorocarbene-mediated N-diuoromethylation of trialkyl amines using diethyl bromodi-uoromethylphosphonate and a uoride source. 13 Although the reaction was optimized for the synthesis of N-diuoromethyltrialkylammonium salts, the method proved to be adequate for the N-diuoromethylation of DMAP. On the other hand, the two examples reported in the literature for the synthesis of N-diuoromethylated 4-quinolones are based on the use of CHBrF 2 as uorinating reagent of a quinolin-4-ol derivative, 14 and on the photogeneration of diuorocarbene by deiodination and deacetylation of ethyl diuoroiodoacetate under basic conditions.…”

Functionalization of polyesters with multiple B vitamins

“…S7) and normalized with surface area . LogP oct values provide an accurate assessment of polarity and indicate hydrophobic (positive LogP oct ) or hydrophilic (negative LogP oct ) molecules and polymers . Given the negative LogP oct values (Supporting Information Table S4), B vitamins were hypothesized to dissolve in polar monomers, such as diglycerol (DG) and glycerol (Gly), which have negative LogP oct values.…”

Difluoromethylation Reactions of Organic Compounds

“…Difluoromethylation of tertiary amines [111] Zafrani, Gershonov and colleagues [112] have recently reported a transition metal-fee difluoromethylation strategy of functionalized tertiary amines.T he reactione mploys (OEt) 2 P(O)CF 2 Br as difluoromethylating reagent, CsF,M eOH as Hs ource,i nD CM as solvent. The scope of the transformation is illustrated in Scheme45.…”

“…It is observed that alkyl-substituted tertiary amines such as triethyla nd trimethyl amines, render products 268 and The product 275 revealed again that difluoromethylation took place exclusively on the nitrogen atom even with am ultifunctional amine containing thiophene, hydroxyl, ester,a nd epoxide groups are present.T he authors [112] proposeareaction mechanism such as that shown in Scheme 46.…”