Catalysis for fluorination and trifluoromethylation

Abstract

Recent advances in catalysis have made the incorporation of fluorine into complex organic molecules easier than ever before, but selective, general and practical fluorination reactions remain sought after. Fluorination of molecules often imparts desirable properties, such as metabolic and thermal stability, and fluorinated molecules are therefore frequently used as pharmaceuticals or materials. But the formation of carbon-fluorine bonds in complex molecules is a significant challenge. Here we discuss reactions to make organofluorides that have emerged within the past few years and which exemplify how to overcome some of the intricate challenges associated with fluorination.

Figure 1. Directed electrophilic palladium-catalyzed Ar–F bond-forming reactions

a, The first palladium-catalyzed fluorination of organic molecules. Phenylpyridine derivatives (1) were fluorinated in the presence of 10 mol% of Pd(OAc)₂ and the electrophilic fluorination reagent N-fluoropyridinium tetrafluoroborate (2) under microwave irradiation. b, A palladium-catalyzed directed electrophilic fluorination of C–H bonds of N-benzyltriflamide derivatives (3) with the catalyst Pd(OTf)₂·2H₂O and the electrophilic fluorination reagent N-fluoro-2,4,6-trimethylpyridinium triflate (4). (Ac: acetyl, Me: methyl, Et: ethyl, Tf: trifluoromethanesulfonyl).

Figure 2. Nucleophilic palladium-catalyzed Ar–F bond-forming reaction

a, The first nucleophilic palladium-catalyzed Ar–F bond-forming reaction of aryl triflates (5) with CsF as the fluorine source, the palladium(0) catalyst precursor [(cinnamyl)PdCl]₂, and the sterically demanding ligand t-BuBrettPhos (6). b, The proposed mechanism for the Pd-catalyzed nucleophilic Ar–F bond-forming reaction is comprised of three elementary steps: oxidative addition, ligand exchange, and C–F reductive elimination. (L: ligand, t-Bu: tert-butyl, i-Pr: iso-propyl, Boc: tert-butoxylcarbonyl, Ph: phenyl).

Figure 3. Electrophilic silver-catalyzed Ar–F bond-forming reaction

a, The first silver-catalyzed Ar–F bond-forming reaction. Aryl stannane derivatives (7) were fluorinated using 5 mol% of Ag₂O as catalyst and the electrophilic fluorination reagent F-TEDA-PF₆ (8). The reaction was applied to late-stage fluorination of complex small molecules, including taxol (9), strychnine (10), and rifamycin (11) derivatives. b, The proposed mechanism of the silver-catalyzed electrophilic fluorination includes three elementary steps: transmetallation, oxidation by an electrophilic fluorination reagent, and C–F reductive elimination. (Bu: butyl).

Figure 4. Transition-metal-catalyzed Ar–CF₃ bond-forming reactions

a, The first copper-catalyzed Ar–CF₃ bond-forming reaction of aryl iodides (12) with 10 mol% of CuI and 1,10-phenanthroline. b, The first palladium-catalyzed nucleophilic Ar–CF₃ bond-forming reaction of aryl chlorides (14) with TESCF₃ as the CF₃ source, 6 mol% of a palladium(0) precursor complex (15 or 16), 9 mol% of the sterically demanding ligand BrettPhos (17), and KF. c, The first palladium-catalyzed directed electrophilic Ar–CF₃ bond-forming reaction with 10 mol% of Pd(OAc)₂ and the electrophilic trifluoromethylation reagent S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate (18). (TES: triethylsilyl, dba:dibenzylideneacetone, Hex: hexyl, Bn, benzyl, TFA: trifluoroacetic acid).

Figure 5. Catalytic enantioselective C_sp3–F and C_sp3–CF₃ bond-forming reactions

a, Metal-catalyzed enantioselective C_sp3–F bond-forming reactions. Branched β-ketoesters were fluorinated using 5 mol% of a Ti-TADDOL catalyst (19) and Selectfluor® (20) or 2.5 mol% of μ-hydroxo-palladium-BINAP complex (21) and N-fluorobenzenesulfonimide (22). b, Examples of organocatalytic enantioselective C_sp3–F bond-forming reactions. Amino acid-derived organocatalysts (23 and 24) and N-fluorobenzenesulfonimide (22) were utilized to fluorinate α-unbranched aldehydes. Due to the potentially facile racemization of α-fluoroaldehydes, the corresponding fluorohydrins (25) were isolated after reduction with NaBH₄ in 54–96% yield and 91–99% ee. c, Enantioselective C_sp3–CF₃ bond-forming reactions. The mechanism of the two presented reactions differ conceptually, but both afford α-trifluoromethylated aldehydes in good yield and high enantioselectivity either using hypervalent iodine 27 as the CF₃ source and amine catalyst 26 or using trifluoroiodomethane as the CF₃ source, 20 mol% amine catalyst 28, 0.5 mol% Ir catalyst 29 and light. (TMS: trimethylsilyl).