Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments

Abstract

Methods for introducing fluorine into organic molecules are reviewed, with an emphasis on preparation of compounds designed for biomedicinal applications. Electrophilic fluorination, nucleophilic fluorination, and enantioselective monofluorination procedures are discussed. This is followed by a review of the development of nucleophilic and electrophilic trifluoromethylation procedures. The final sections highlight recent applications of fluorine chemistry in drug development with selected examples.

Direct ortho‐Trifluoroethylation of Aromatic Ureas by Palladium Catalyzed C‐H activation: A Missing Piece of Aromatic Substitutions

“…6 In fact, a large number of robust trifluoromethylation methods have been developed. 7 In contrast the introduction of trifluoroethyl group into aromatic systems is less investigated. In the literature only limited number of examples can be found for the installation of trifluoroethyl group into the aromatic systems with the aid of transition metal catalysis via cross-coupling 8 and C-H activation 9 under relatively harsh reaction conditions, and via radical functionalization.…”

Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl)trimethylsilane

“…In this context, fluorinated heterocycles have gained attention as new drug candidates over the past few decades in medicine and agro-chemistry [21][22][23][24][25][26][27][28]. Fluorinated and trifluoromethylated compounds have been well targeted in this research area [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], and difluoromethylated compounds are next [16,[21][22][23][24][25][26][27][28]. The difluoromethyl (CF 2 H) group is known to be isosteric and isopolar to a hydroxy (OH) and thiol (SH) unit.…”

“…Manmade fluorinated organic compounds have become a remarkable success in the pharmaceutical industry, despite their relatively young history [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In this context, fluorinated heterocycles have gained attention as new drug candidates over the past few decades in medicine and agro-chemistry [21][22][23][24][25][26][27][28].…”

“…No effect on product yield (52%) was observed with a catalytic amount of cetyltrimethylammonium bromide (entry 12). Solvent screening did not improve the reaction (entries [13][14][15][16][17], and the best condition was determined to be entry 8, by treating 3a with Me 3 CF 2 H (2.0 equiv) in N,N-dimethylformide (DMF) in the presence of Me 4 NF at room temperature for 4 h, and desired product 2a was obtained in 53% yield (entry 8). The stereochemistry of 2a was tentatively assigned according to comparisons with previous results [39,40,41].…”

New N-difluoromethylindoles: features of N-difluoromethylation of indoles with electron-donor or electron-withdrawing substituents

“…Recently, difluoromethyl group has become one of the most popular substituents in medicinal and agricultural chemistry. Introduction of CF2H group can affect membrane permeability, binding affinity and lipophilicity [5]. However, N-difluoromethylation of indoles has been studied insufficiently till now.…”