The incorporation of fluorine atoms into organic compound may lead to changes in the properties such as lipophilicity, metabolic stability, and bioavailability. Therefore, the fluorine-containing compounds are privileged molecules in the research and development of new medicines. From the synthetic perspective, the selective introduction of fluorine into the drug candidates represents a most straightforward and powerful strategy in drug design and screening. Therefore, the selective difluoromethylation has stood out as an effective tool for the access of fluorine-containing compounds. One of the strategies is using difluorocarbons as an active reaction intermediate for the incorporation of difluoromethyl group and has attracted considerable attention from the organic synthetic community. Recently the reaction of difluorocarbons with hetero-atoms such as alcohols, thiophenols, amines, and phosphine were studied, and provided the difluoromethyl products. However, the reaction of difluorocarbons with C(sp3)−H bond is relatively less developed. To solve this problem, ethyl 2-bromo-2,2-difluoroacetate has come into our sight, as it can generate the ethyl 2,2-difluoroacetate free radical and difluorocarbons. And the difluorocarbons can lead to the direct difluoromethylation reaction without the decarbonylation process, thus has offered a convenient preparation method for the fluorine-containing compounds. On the basis of our recent research in the photocatalyzed reactions and oxidant free difluoroalkylation reactions of alkynes, alkenes and aryl ketones with ethyl difluoroiodoacetate, the selective difluoromethylation of aryl ketones was studied and reported herein. In order to develop an effective direct difluoromethylation reaction with simple reaction conditions, some bases were screened as catalyst. The inorganic bases such as sodium tert-butoxide, lithium tert-butoxide, and potassium tert-butoxide were able to promote the reaction. When the relation was performed in dichloromethane (DCM) under 0°C with three equivalent of sodium tert-butoxide as additive, the desired difluoromethylation product was obtained in 88% yield. Subsequently, the substrate scope of current transformation was studied. It was proved the reaction yields were affected by the steric demanding groups in the ortho -positions of the phenyl rings of the 2-phenyl-3,4-dihydronaphthalen-1(2 H )-one. The reaction yields were not sensitive with electron withdraw and electron donating groups. Substrates with naphthyl and cyclohexyl moieties were also well tolerated to give the difluoromethylation products. The reaction was achieved under mild and simple reaction conditions, using cheap ethyl difluorobromoacetate as the source of difluorocarbene, promoted by sodium tert-butanol, showing high selectivity and good substrate applicability. To gain some insights in the reaction mechanism, some control experiments were conducted. The reaction of ethyl 2,2-difluoro-2-(1-oxo-2-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate under current reaction system failed to give any desired product, which has ruled out the possibility with it as decarbonylation intermediate. And only 46% yield was given by using (bro-modifluoromethyl)trimethylsilane instead of ethyl 2-bromo-2,2-difluoroacetate. According to the control experiment, we believe the present difluoromethylation reaction may initiate with the difluorocarbon, which generates from the BrCF2CO2Et by the debromination and decarbonylation process. And the tert-butyl ethyl carbonate was observed by GC-MS analysis as side-product. Meanwhile, the enol intermediate captures difluorocarbon to realize the selective difluoromethylation of aryl ketone saturated carbon. In this reaction, sodium tert-butanol, as a base, plays a dual catalytic role. In addition to promoting the conversion of ketone to enol, ethyl difluorobromoacetate is also applied to produce difluorocarbons. According to the results of control experiments and related references, sodium tert-butanol was proposed as an effective reagent for the generation of difluorocarbon from ethyl difluorobromoacetate. Therefore, the present study has provided an easy-handling and cost-effective method for the preparation of the valuable difluoromethyl compounds under mild reaction conditions with good functional group tolerance.
Search from 250 M+ research papersSearch from 250 M+ research papers
Open Access
Apr 10, 2021
Shuting Sun + 15
