The Difluoromethyl Group as a Masked Nucleophile: A Lewis Acid/Base Approach

Abstract

The difluoromethyl group (R-CFH) imparts desirable pharmacokinetic properties to drug molecules and is commonly targeted as a terminal functional group that is not amenable to further modification. Deprotonation of widely available Ar-CFH starting materials to expose nucleophilic Ar-CF synthons represents an unexplored, yet promising route to construct benzylic Ar-CF-R linkages. Here we show that the combination of a Brønsted superbase with a weak Lewis acid enables deprotonation of Ar-CFH groups and capture of reactive Ar-CF fragments. This route provides access to isolable and reactive Ar-CF synthons that react with a broad array of electrophiles at room temperature. The methodology is highly general in both electrophile and difluoromethyl (hetero)arene and can be applied directly to the synthesis of benzylic difluoromethylene (Ar-CF-R) linkages, which are useful lipophilic and metabolically resistant replacements for benzylic linkages in medicinal chemistry.

Selective C–F Functionalization of Unactivated Trifluoromethylarenes

“…The use of benzotrifluoride as a precursor to difluoroalkyl benzene derivatives is attractive, because it is abundantly available at low cost (~$7/mol) when compared to conventional reagents that accomplish deoxyfluorination of aryl ketones (e.g., diethylaminosulfur trifluoride (DAST) or Fluolead). 40 While the standard conditions (5 equiv of olefin with limiting Ar–CF 3 substrate) were effective here (see Table 1 and Supporting Information for examples), we found that using a cosolvent quantity (50 equiv) of benzotrifluoride could be conveniently employed for coupling of simple olefins with acetate, acetal, or Weinreb amide groups (Table 2: 23 – 25 , 64–78% yield). Other nucleophilic olefins including the vinyl ether, acetate, amides, and vinyl carbazole were also effective coupling partners under this protocol ( 26 – 30 , 55–95%).…”

(Het)aryl Difluoromethyl‐Substituted β‐Alkoxyenones: Synthesis and Heterocyclizations

“…Introducing gem-difluoromethylene unit into organic compounds is an important design approach in medicinal, [1][2][3][4][5] agricultural, [6,7] and synthetic, [8][9][10][11][12][13][14][15][16][17] chemistry in view of improving physico-chemical properties of derivatives. [18][19][20][21][22] The CF 2 moiety was considered as a bioisosteric replacement of methylene, carbonyl, or ether groups with improved metabolic stability. [23][24][25] Incorporation of the difluoromethylene linker between (hetero)aromatic rings improved activity and/or pharmacokinetic properties of the compounds as compared to their non-fluorinated counterparts.…”

“…Introducing gem ‐difluoromethylene unit into organic compounds is an important design approach in medicinal, agricultural,, and synthetic, chemistry in view of improving physico‐chemical properties of derivatives . The CF 2 moiety was considered as a bioisosteric replacement of methylene, carbonyl, or ether groups with improved metabolic stability .…”

Modular synthesis of α-fluorinated arylmethanes via desulfonylative cross-coupling

“…However, despite these recent advances, α-fluorinated diarylmethanes are still prepared by classical methods including deoxyfluorination of diarylmethanols or diarylketone derivatives 12–16 . Important advances from the Zhang 17,18 and Szymczak 19 groups have begun to address these issues, but still require difluoromethylarenes as starting materials, which can be of limited availability (Fig. 1b, c).…”