The trifluoromethyl (CF3) group is an important structural motif in many pharmaceutically relevant molecules because of its unique chemical and metabolic stability, lipophilicity, and binding selectivity. Consequently, much effort has been directed toward the development of efficient methods for the introduction of the trifluoromethyl group into small molecules. While a variety of processes have been reported to generate aromatic C(sp) CF3 bonds, the analogous direct trifluoromethylation of alkenes and their derivatives has received less attention. In 2011, the groups of Buchwald, Liu, and Wang independently reported efficient allylic trifluoromethylation of unactivated alkenes with copper catalysts under mild conditions. The trifluoromethylation of allylsilanes, vinyltrifluoroborates, and enamides has since been disclosed by several groups, allowing the effective formation of compounds with a CF3 group in an allylic or vinylic position. Furthermore, oxytrifluoromethylation, carbotrifluoromethylation, and hydrotrifluoromethylation of alkenes have been achieved with and without transition-metal catalysis. These reactions provide a valuable array of highly regioselective C CF3 bond-forming methods under mild conditions. However, the mechanism of these copper-catalyzed trifluoromethylation reactions is not fully understood. Addition of both the trifluoromethyl cation or radical have been suggested as routes to the observed products. Buchwald reported the efficient formation of CF3-containing epoxides from secondary allylic alcohols, possibly via intermediate A [Eq. (1)]. Thus, we envisioned that the trifluoromethylation of a,a-diaryl allylic alcohols 2 with the Togni reagent (1) would lead to the analogous intermediates B, which could undergo 1,2-aryl migration to provide btrifluoromethyl ketones 3 [Eq. (2)]. Importantly, electronrich aryl groups migrate preferentially in cationic (semipinacol) rearrangements, whereas electron-poor aryl groups migrate preferentially in radical (“neophyl”) rearrangements. Therefore, the structures of the products from unsymmetrical substrates would provide important insight into the reaction mechanism. b-Trifluoromethyl ketones such as 3 are difficult to prepare. Nucleophilic trifluoromethylating reagents typically undergo 1,2-addition to enones, affording trifluoromethyl allylic alcohols rather than b-trifluoromethyl ketones by 1,4addition. Only a few cyclic b-trifluoromethyl ketones have been prepared by 1,4-addition of a nucleophilic CF3 group to cyclic enones. The use of radical or electrophilic CF3 reagents for this challenging task has been rarely described. Consequently, we wanted to develop new C(sp) CF3 bond-forming reactions to prepare b-trifluoromethyl ketones, and to probe the mechanism of the copper-catalyzed trifluoromethylation of alkenes as discussed above. We report herein an unprecedented trifluoromethylation-initiated radical 1,2-aryl migration(“neophyl rearrangement”) in a,adiaryl allylic alcohols utilizing 1, leading to a wide variety of acyclic b-trifluoromethyl a-aryl ketones 3. We commenced our study with the reaction of 2a with the Togni reagent (1) and [(MeCN)4Cu]PF6 as catalyst (Table 1). To our delight, the reaction in methanol at 50 8C for 14 h afforded the desired rearranged product 3a in 27% yield (entry 1). It also provided 48% of compound 4a, which was probably derived by trapping of the allylic cation of 2a by MeOH. Complex product mixtures were obtained when the reaction was performed in the less nucleophilic alcohols trifluoroethanol or hexafluoroisopropanol (HFIP; entries 2 and 3, respectively). In acetonitrile and dichloromethane, mixtures of the desired ketone 3a (22% and 9%, respectively) and substitution product 4b (23% and 76%, respectively, entries 4 and 5) were formed. In DMSO, the yield of 3a increased to 51%, but the conversion was not complete (entry 6). In DMF, the yield of 3a increased further to 69% [*] X. Liu, F. Xiong, X. Huang, Prof. Dr. X. Wu Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences 190 Kaiyuan Avenue, Guangzhou 510530 (China) E-mail: wu_xiaoxing@gibh.ac.cn
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Jan 1, 2023
Fei Li + 2
Open Access
