叔丁醇钠促进酮的选择性二氟甲基化反应

Selective difluoromethylation of ketones promoted by sodium tert-butoxide

有机氟化合物广泛应用于医药、农药、新型功能材料、生命科学等领域.由于其独特的化学、物理和生物性能,近年来,发展与之相关的高效引氟方法和手段,受到了合成化学家的高度关注.相对来说,三氟甲基化反应研究较多,二氟甲基化反应发展滞后.二氟甲基作为醇羟基和硫羟基的生物电子等排体,可提高生物活性分子代谢稳定性和生物利用度,发展经济高效的选择性二氟甲基化方法对相关含氟药物的合成具有重要的意义.本研究以廉价的二氟溴乙酸乙酯为二氟卡宾来源,采用叔丁醇钠促进,在温和简单的反应条件下,实现了芳基酮的选择性二氟甲基化,表现出较高的选择性和良好的底物适用性.在该反应中,叔丁醇钠作为碱发挥了双重促进作用,在促使酮向烯醇式转变的同时,还促进二氟溴乙酸乙酯产生二氟卡宾,烯醇式中间体捕获二氟卡宾从而实现了芳基酮α位的选择性二氟甲基化.该反应底物适用性广,且方法绿色经济.

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(sp^(3))-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℃ 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(2H)-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 BrCF_(2)CO_(2)Et by the debromination and decarbonylation process. And the tert-butyl ethyl carbonate was observed by GC-MS analysis as sideproduct. 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.