JACS: palladium catalyzed asymmetric allylic trifluoromethylation reported by Trost et al

Trifluoromethyl can regulate the pH and lipophilicity of drug molecules and increase the stability of metabolites, which is widely existed in drug molecules At present, most of the reports on the introduction of trifluoromethyl into molecules are focused on the transition metal catalyzed aromatic trifluoromethylation, while the direct trifluoromethylation of aliphatic group is less concerned, especially the asymmetric form (scheme 1a) Early researchers reported that addition of nucleophilic trifluoromethyl to carbonyl compounds induced the asymmetry of addition reaction by chiral quaternary ammonium salt Macmillan's team has developed a novel α - trifluoromethylation of aldehydes based on asymmetric groups by combining organic catalysis with photo oxidation-reduction catalysis In addition to these groundbreaking reports, it is extremely rare to introduce the nucleophilic trifluoromethyl asymmetrically into the electrophilic carbon center Baylis Hillman type reaction is the only example of this (scheme 1b) (source: J am Chem SOC.) recently, Barry M Trost et al Of Stanford University reported the first palladium catalyzed asymmetric allylic trifluoromethylation This method leads to a basic principle by which the synergistic interaction of the leaving group and the subsequent activation of the nucleophilic trifluoromethyl make the reaction possible This study emphasizes the unique role of bidentamine phosphite ligands in palladium catalyzed reactions Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b06231) Firstly, the reaction conditions were optimized with 1-A as the substrate (Table 1) The results show that at 50 ℃, with l-9 as the ligand and MTBE as the solvent, the yield of 2 can be obtained with the ratio of > 90% NMR and 79% separation yield, and the ER value is 96:4 (source: J am Chem SOC.) then, the author examined the universality of the reaction (scheme 2) The reaction showed good tolerance to the substituents directly linked to π - allyl group The electron rich and electron deficient aromatic rings with different substitution modes have good tolerance, and the product 2 of trifluoromethylation is produced with good yield and high enantioselectivity The reaction is not limited to trifluoromethyl Perfluoroalkyl groups such as pentafluoroethyl, heptafluoropropyl and pentafluorophenyl are also suitable for this allyl functionalization, showing good yield and excellent enantioselectivity The absolute configuration of the product was determined by obtaining the crystal structure of 2-j (source: J am Chem SOC.) it is worth noting that the reaction can be carried out on a gram scale (scheme 3), and the palladium loading can be further reduced to 2 mol%, the ligand loading can be reduced to 2.5 mol%, and the yield and enantioselectivity are slightly improved The double bond in the product can be used to expand the molecular diversity As shown in scheme 3, the double bond in 2-J can be easily dihydroxylated and hydrogenated, and the C-F bond in 2-x can be converted into thioether (source: J am Chem SOC.) further studied the mechanism of the reaction (scheme 4) First, they sought to establish the overall stereochemical results of the reaction Allyl fluoride 6 was used to detect the process of trifluoromethylation, and noe was used to determine the relative stereochemistry of the stereocenter in the product The results show that no noe can be observed between the hydrogen atoms in the center of 7, suggesting that the two kinds of hydrogen have trans configuration The ester group was further reduced to primary alcohol There is a positive noe between the hydrogen atom on the hydroxy carbon and the hydrogen atom on the carbon with trifluoromethyl, which confirms the configuration of the trans substituent The analysis showed that the stereochemistry was retained in the process of trifluoromethylation (source: J am Chem SOC.) conclusion: Barry M Trost et al Of Stanford University reported the first palladium catalyzed asymmetric allylic trifluoromethylation reaction involving unique ligands for the first time Allylic fluoride, as an excellent precursor of π - allylic complex, shows the synergistic interaction between fluoride leaving group and tmscf 3 in ionization and nucleophilic activation All kinds of perfluoroalkylation products with high functional group tolerance and excellent enantioselectivity can be obtained by this method.