Complex molecules can be rapidly modified by molecular clipping such as insertions, deletions, and single-atom exchanges, and thus have received considerable attention. Aryltrifluoromethyl structures are widely distributed in drug and material molecules due to their unique fluorine atom characteristics. If the carbon-fluorine bond of the trifluoromethyl group can be inserted, the diversity of the molecular structure can be rapidly increased and aryl difluoromethyl and monofluorine fragments can be obtained, which will be used in synthetic chemistry, especially in the development of new drugs. However, this method is difficult to realize due to the high bond energy and uncontrollable defluorination of trifluoromethyl groups and the weak bond energy of carbon-fluorine single bonds.
Recently, it was reported that the insertion of electron-deficient trifluorotoluene into alkenes was achieved through a radical-polar crossover strategy, and the trifluoromethyl group was successfully converted into structural units with high-value difluoromethyl groups and carbon-nitrogen single bonds in one step.
First, the researchers used p-cyanotrifluorotoluene and p-methoxystyrene as standard substrates, screened photocatalysts, solvents, and fluorine sources, and determined the optimal conditions for the reaction: 5 mol% of Miyake Phenoxazine is used as the catalyst, ethylene glycol dimethyl ether is used as the solvent, and 3 equivalents of triethylamine trihydrogen fluoride is used as the external fluorine source. The target product can be obtained with an isolated yield of 68% under blue light. Free radical capture experiments showed that the reaction proceeded by a free radical process. Fluorescence quenching experiments showed that the electron-deficient trifluorotoluene quenched the excited photocatalyst and initiated the reaction. In addition to fluorine, the researchers also tried phenol, pyrazole, s-trimethoxybenzene and unprotected indole as nucleophiles, and successfully constructed carbon-carbon bonds and carbon-heterobonds, demonstrating the wide application of this reaction prospect.
Under optimal conditions, the substrate universality of the reaction was also investigated. Moderate to excellent yields were obtained using monosubstituted styrenes on the benzene ring, polysubstituted styrenes on the benzene ring, and 1,1-disubstituted styrenes and 1,2-disubstituted styrenes. Some heterocyclic alkenes and heteroatom alkenes are also suitable for this reaction. When the aryltrifluoromethyl group was used as the substrate, moderate yields could be obtained regardless of whether the cyano group was in the para-position or the ortho-position. It is worth mentioning that when there are three trifluoromethyl groups attached to the benzene ring, only one of the trifluoromethyl groups will react selectively. In addition to simple trifluorotoluene, some more complex aryl perfluoro substrates can also achieve carbon-fluorine bond insertion through this reaction, showing excellent chemoselectivity and functional group tolerance.
To further demonstrate the great value of this reaction in drug discovery, the researchers directly applied the reaction to the later modification of some drug molecules. Some commercially available drugs, such as Enzalutamide and Bicalutamide for the treatment of prostate cancer, can achieve carbon-fluorine bond insertion with moderate to good yields, and some sensitive functional groups such as hydroxyl and amide groups are not affected, and are rich in electrons The trifluoromethyl group on the aromatic ring was also preserved. In addition, some drugs with alkyl trifluoromethyl and active hydrogen can also be inserted into carbon-fluorine bonds through this reaction, showing the excellent regioselectivity and functional group tolerance of this reaction. Some complex alkenes can also be intercalated through carbon-fluorine bonds, and their fluorinated products can be obtained rapidly and in moderate to excellent yields. (Figure 1)
Figure 1. Late-Stage Modification of Drugs
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Reference
- Late-Stage Modification of Drugs via Alkene Formal Insertion into Benzylic C-F Bond.
Jing Wang,Yahui Wang,Yan Liang,Liejin Zhou,Lijuan Liu,Zuxiao Zhang
Angew. Chem. Int. Ed., 2022, DOI: 10.1002/anie.202215062
