JACS: selective defluorination and allylation of trifluoromethylarene

α α - difluorobenzyl structure exists widely in the active molecules of drugs, and it is a very valuable fragment In drug design, it can increase the molecular fat solubility, improve the metabolic stability, and increase the bioavailability of drug molecules At the same time, it can also be used as the bioelectrophore of aryl ether Therefore, the efficient synthesis of these compounds has attracted great attention In this respect, there are defects in carbonyl defluorination or in the use of aryldifluoromethyl or difluoroalkyl coupling agents to construct difluorobenzyl structures, such as the use of equivalent chemical reagents α - difluorobenzyl structure is a fast and modular way to synthesize α through the C-F bond single substitution reaction of trifluoromethyl aromatics However, with the substitution reaction going on, the remaining C-F bond energy will be reduced, so it is a difficult process to selectively generate the single substitution reaction of trifluoromethyl aromatics Among them, there are three strategies to initiate the mono substitution of trifluoromethyl aromatic hydrocarbons: 1) metal catalysis or electrochemical reduction, 2) photocatalysis reduction of CF 3, 3) the reaction of aryl difluoromethyl cations with nucleophiles, but only the substituent of ortho silicon group (Figure 1) Recently, Jeffrey S Bandar group of Colorado State University reported a method to construct α, α - difluorobenzyl structure through coupling reaction initiated by fluoride anion The reaction is highly efficient and selective The mechanism study shows that the reaction is carried out through the single electron transfer process initiated by alkali Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b07766) (source: J am Chem SOC.) on the basis of previous accidental discovery, the author took 1,3-di (trifluoromethyl) benzene as template substrate to optimize the conditions Through the investigation of reaction factors such as solvent, temperature and fluorine source, the optimal conditions were determined as: CSF (10 mol%), 18-crown-6 (30 mol%), The reaction of trifluoromethyl aromatic hydrocarbon and allylsilicon in DME at 80 ℃ for 15 h was carried out, and the target product was obtained in 90% yield Subsequently, the range of substrates for the defluoroallylation reaction was investigated (Table 1) Among them, the electron absorbing trifluoromethyl aromatic hydrocarbons with sulfonamides, cyanogens and phosphates can be obtained in high yield, and heterocycles such as benzo [C] - 1,2,5-thiadiazole and pyridine can be compatible with the reaction conditions It is worth mentioning that 2-chloro-5-trifluoromethylpyridine can also carry out this process smoothly without the formation of dechlorinated products The drug aripitan can also be obtained in 72% yield When the asymmetric allylsilicon reagent is used, a mixture of regional isomers will be produced in the reaction, and the regional selectivity still needs to be improved (source: J am Chem SOC.) in order to illustrate the practicability of this reaction, the author first tried to prepare a 30 mmol reaction (formula 1), and obtained the target product in 81% yield (source: J am Chem SOC.) then the author carried out a continuous allylation / functionalization attempt (scheme 2), and carried out subsequent transformation of the product The product can be converted into alkyl alcohol, alkyl iodine and other structures, and the subsequent C-C bonding process is realized (source: J am Chem SOC.) finally, the author proposed the reaction mechanism of single electron transfer by comparing the mechanism of related literature and the corresponding free radical capture experiment Summary: Jeffrey S Bandar group has developed a strategy of trifluoromethyl aromatics de fluorination and allylation via fluoride anion initiation The reaction conditions are mild, which provides an attractive method for the synthesis of α, α - difluorobenzyl compounds The mechanism of alkali promoted single electron transfer is proposed through mechanism experiments, which provides the possibility for the development of other new coupling reactions.