Organocatalyzed Trifluoromethylation of Ketones and Sulfonyl Fluorides by Fluoroform under a Superbase System

Abstract

Fluoroform (HCF3, HFC-23) is a side product in the manufacture of polytetrafluoroethylene (Teflon). Despite its attractive properties, taming HCF3 for trifluoromethylation is quite problematic owing to its low acidity and the lability of the naked trifluoromethyl carbanion generated from HCF3. Herein we report the organic-superbase-catalyzed trifluoromethylation of ketones and arylsulfonyl fluorides by HCF3. The reactions were carried out by using a newly developed “superbase organocatalyst system” consisting of catalytic amounts of P4-tBu and N(SiMe3)3. A series of aryl and alkyl ketones were converted into the corresponding α-trifluoromethyl carbinols in good yields under the organocatalysis conditions in THF. The superbase organocatalytic system can also be applied to the trifluoromethylation of arylsulfonyl fluorides for biologically important aryl triflones in THF or DMF in good yields. Protonated P4-tBu, H[P4-tBu]+, is suggested to be crucial for the catalytic process. This new catalytic methodology using HCF3 is expected to expand the range of synthetic applications of trifluoromethylation.

Application of fluoroform in trifluoromethylation and difluoromethylation reactions

“…26,[31][32][33][34] A series of aldehydes and ketones were tested for trifluoromethylation, and gave moderate to good yields of the target products 2 in most cases. 24,[35][36][37] In these studies, various carbonyl compounds were scrutinized, giving moderate to good yields of products 2, 4 or 5 in most cases. Prakash et al showed that all the trifluoromethylation reactions, performed in THF or ether instead of DMF as solvent in the presence of fluoroform as a CF3 source and KHMDS or t-BuOK as a base, afforded the desired products 2 in 0-81% yields (Scheme 2).…”

“…35 The other two research groups, such as Shibata and Mikami, both reported that in the effect of [(Me2N)3PN]3PNCMe3 as base, fluoroform was used for difluoromethylation reaction at lower temperature (-30 o C or -40 o C) or room temperature, and produced the compounds 2 in moderate to excellent yields (Shibata: 52-92% and 64-99%, Mikami: 48-99%, respectively). 24,36,37 In addition, the carboxylic acid esters and halides 3 were also employed for trifluoromethylation by Mikami and co-workers (Scheme 3). 36 It is very interesting that when benzoyl chloride and 1.2 equiv [(Me2N)3PN]3PNCMe3 were used for this transformation, the reaction time had no effect on the yield of the product 4 (72% yield).…”

“…37 A series of sulfonyl fluorides 10a-g bearing an electron-withdrawing or electron-donating group located on the aromatic ring, underwent the desired transformations, and afforded the aryl triflones 11 in good to high yields (11a-g: 50-84%). Beyond that, the naphthyl-substituted sulfonyl fluorides 10h,i were also employed for the synthesis of aryl triflones, and give 60-78% yields of the the desired products 11h, i.…”

“…51,52 They showed that the phenols and thiophenols 33 containing either electron withdrawing or electron donating groups, performed well under the conditions of synthetic methods A and B, and afforded the products 34 in moderate to excellent yields. 51 Dolbier and co-workers found that, under the conditions of method B, difluoromethylation of heterocyclic compounds, such as imidazoles, benzimidazoles, indazoles and benzotriazoles (35) and hydroxypyridines (37) …”

Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

“…This transformation, and related ones, [14] have been reported with moderate success using TMSCF 3 and TBAF,a lthough owing to the inevitable presence of water in the reagent mixture,the nature of the fluoride is uncertain because TBAF samples are almost always hydrated. This transformation, and related ones, [14] have been reported with moderate success using TMSCF 3 and TBAF,a lthough owing to the inevitable presence of water in the reagent mixture,the nature of the fluoride is uncertain because TBAF samples are almost always hydrated.…”