| Perfluoroalkylation reaction has attracted much attention among organofluorine reactions.Indoles are important motifs present in both physiologically active natural products andpharmaceuticals. The potential bioactivities, stability and other utility values of indoles willbe efficiently improved if a perfluoroalkyl group is selectively introduced into the molecule ofindole. However, methods for perfluoroalkylation of indoles are quite rare. There are twomain types of chemical transformations dedicated to construct this framework:1) indirectsynthesis of the indole ring through cyclization reaction of multi-step synthesis, but thesemethods inherently need two or more steps that increasing consumption of chemicals whichare not green, efficient and economical;2) direct synthesis, although these methods areefficient, they suffer from harsh reaction conditions, stoichiometric oxidants, and narrowsubstrate scope, which hinder their industrial application. Thus, the development of efficient,straightforward and mild methods for the facile introduction of perfluoroalkyl groups toindoles are highly desirable.In this paper, a brief review of recent perfluoroalkylation of arenes was presented, andthe recent synthetic methods for2-trifluoromethyl indoles,2-difluoromethyl indoles and2-perfluoroalkyl indoles were also introduced. On the basis of previous work, we try toachieve direct C–H perfluoroalkylation of C2position of indoles by copper mediation.In this thesis, we choose perfluoroalkyl halides as fluorine sources. After screening theconditions of promoter, solvent, ligand and temperature, we found that in the present of0.2equivalent2,2’-bipyridine, Cu2O or Cu powder as promoter,3-methylindole could react wellwith C4F9I to get the desired product in80%yield at80°C in N,N-dimethyformamide.Studying on the substrate scope of indoles, we found that versatile functional groups weretolerated well in the reactions, such as hydroxy, ester, amide and carboxylic acid. Both freeindole derivatives and N-substituted indole derivatives could react with perfluoroalkyl halidesto give the desired products. We could also achieve difluoromethylation of3-methylindoleunder the same conditions when ICF2COOEt was used as CF2H reagent. The preliminary mechanism study showed that a single electron transfer (SET) process was involved in thereaction. This method is not sensitive to air or moisture, so it may have great potentialapplications for medicinal chemists to synthesize fluorinated bioactive compounds. |
