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    Home > JACS: selective C-F functionalization of non activated trifluoromethyl aromatic hydrocarbons

    JACS: selective C-F functionalization of non activated trifluoromethyl aromatic hydrocarbons

    • Last Update: 2019-08-11
    • Source: Internet
    • Author: User
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    In the past few decades, due to the wide application of trifluoromethyl (CF 3) group in the field of drug design, people have developed many effective methods to construct arcf 3 compounds Therefore, the synthesis of fluorinated organic molecules with arcf3 as the precursor has some advantages over the traditional methods At present, although a series of methods (such as electrochemical reduction) can be used to realize the reduction and activation of the inert C-F bond of trifluoromethyl aromatic hydrocarbons, it is still an important challenge to prevent the complete defluorination of CF 3 group in the synthesis Part of the reason is that with the defluorination process, the strength of C-F bond decreases, so many by-products of excessive defluorination are produced In addition, troupel, lalic and other research groups have developed different systems to functionalize arcf3, but these systems can only achieve the defluorination of specific substrates, and there is still a lack of a general method to achieve such processes Recently, on the basis of previous work, the Nathan T Jui research group of Emory University has realized the defluoroalkylation and hydrofluorination of non activated three fluoromethylaromatics by activating the corresponding three fluoromethylaromatics precursor and the free radical anion of aromatics, and synthesized a series of Ar-CF 2 R and Ar-CF 2 H compounds Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b06004) (source: J am Chem SOC.) at first, the author optimized the conditions by using trifluoromethyl (ph-cf3) and 3-butene-1-ol as template substrates On the basis of the early optimization of conditions in the laboratory, through the screening of photocatalyst and temperature, the author determined that the best conditions for the reaction were: at 100 ℃, P3 was used as the catalyst, under blue light irradiation for 24 hours, and the product (scheme 1) was obtained in 89% yield (source: J am Chem SOC.) after obtaining the best conditions, the author investigated the substrate range of the inactive trifluoromethyl aromatic hydrocarbons (Table 1) Carbon, oxygen and nitrogen substituted substrates can participate in the reaction well The heterocycles such as benzyl methanol and pyridine can also be well compatible with the reaction In order to further demonstrate the practicability of this scheme, the author has functionalized the bioactive molecules containing various trifluoromethyl groups, and the alkylation products can be obtained in medium yield In addition, thioether, sulfoxide, sulfone and other groups can be compatible without the change of valence state (source: J am Chem SOC.) then, the authors evaluated the range of application of various olefins (Table 2) The reaction has good functional group tolerance, such as ester group, acetal, Weinreb amide and so on Alkenyl ether and alkenylamine can participate in the reaction well In addition, β - substituted aliphatic olefins are also compatible with reaction conditions Finally, good yield can be obtained by the reaction of olefins in the form of gas under high pressure (source: J am Chem SOC.) later, in order to illustrate the important value of this method in pharmaceutical chemistry, the author applied this method to realize the apparent synthesis of drug active molecules with difluoroalkyl groups Then, the author proposed the possible reaction mechanism (scheme 3) First of all, under visible light irradiation, the catalyst P3 reaches the excited state from the ground state Then, the catalyst P3 and the trifluoromethyl arene substrate undergo a single electron transfer process to produce the corresponding intermediate of difluorophenyl radical At the same time, the catalyst P3 recovers to the ground state The intermediate of difluorophenyl radical is selectively added to olefin to produce alkyl radical, and finally the product is formed by hydrogen transfer reaction with Thiophenol At the same time, the regeneration of photocatalyst and thiophenol can be realized under the action of formate (source: J am Chem SOC.) finally, the range of substrates for hydrodefluorination was simply extended Although the yield is only moderate, the system is compatible with acid protons, heterocycles and other reducible groups Summary: the author developed a practical method to realize the de fluorination and hydrofluorination of non activated trifluoromethyl aromatic hydrocarbons In this paper, the organic catalyst and cheap formate were used under the condition of light, avoiding the use of metal catalyst Among them, the development and application of Miyake's phenoxazine catalyst P3 is the key to the success of the reaction This method opens up a new way for the synthesis of ar-cf2r and ar-cf2h compounds.
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