Catalysis for fluorination and trifluoromethylation
(26 May 2011)
15 December 2010
07 April 2011
25 May 2011
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.
Figures at a glance
Figure 1: Directed electrophilic palladium-catalysed Ar−F bond-forming reactions.
a, Palladium-catalysed 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-catalysed directed electrophilic fluorination of C–H bonds of N-benzyltriflamide derivatives ( 3) with the catalyst Pd(OTf) 2·2H 2O and the electrophilic fluorination reagent N-fluoro-2,4,6-trimethylpyridinium triflate ( 4). Ac, acetyl; Me, methyl; Et, ethyl; Tf, trifluoromethanesulphonyl.
Figure 2: Nucleophilic palladium-catalysed Ar−F bond-forming reaction.
a, The nucleophilic palladium-catalysed 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 a comprises 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-catalysed Ar−F bond-forming reaction.
a, The silver-catalysed Ar−F bond-forming reaction. Aryl stannane derivatives ( 7) were fluorinated using 5 mol% of Ag 2O as catalyst and the electrophilic fluorination reagent F-TEDA-PF 6 ( 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 for a includes three elementary steps: transmetallation, oxidation by an electrophilic fluorination reagent, and C−F reductive elimination. Bu, butyl.
Figure 4: Transition-metal-catalysed Ar−CF 3 bond-forming reactions.
a, The copper-catalysed Ar−CF 3 bond-forming reaction of aryl iodides ( 12) with 10 mol% of CuI and 1,10-phenanthroline. b, The palladium-catalysed nucleophilic Ar−CF 3 bond-forming reaction of aryl chlorides ( 14), with TESCF 3 as the CF 3 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 palladium-catalysed directed electrophilic Ar−CF 3 bond-forming reaction with 10 mol% of Pd(OAc) 2 and the electrophilic trifluoromethylation reagent S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate ( 18). TES, triethylsilyl; dba, dibenzylideneacetone; Cy, cyclohexyl; Hex, hexyl; Bn, benzyl; TFA, trifluoroacetic acid.
Figure 5: Catalytic enantioselective C sp 3−F and C sp 3−CF 3 bond-forming reactions.
a, Metal-catalysed 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-fluorobenzenesulphonimide ( 22). b, Examples of organocatalytic enantioselective C sp 3−F bond-forming reactions. Amino acid-derived organocatalysts ( 23 and 24) and N-fluorobenzenesulphonimide ( 22) were used to fluorinate α-unbranched aldehydes. Owing to the potentially facile racemization of α-fluoroaldehydes, the corresponding fluorohydrins ( 25) were isolated after reduction with NaBH 4 in 54−96% yield and 91−99% enantiomeric excess (e.e.). c, Enantioselective C sp 3−CF 3 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 CF 3 source and amine catalyst 26, or using trifluoroiodomethane as the CF 3 source, 20 mol% amine catalyst 28, 0.5 mol% Ir catalyst 29 and light (from a fluorescent household light bulb). TMS, trimethylsilyl.