Metal-Free Oxidative 2-Trifluoromethylation Of Indoles

Indole compounds are widely found in nature,including natural products,metabolites and alkaloids.Most indole compounds are bioactive.They are widely used in the fields of medicine,dyes,perfume,pesticides and materials.The electronegativit y of fluorine atom is great,the atomic radius is small,and the bond energy of C-F bond is large.As a special functional group,trifluoromethyl is often introduced into drugs to enhance drug metabolism,stabilit y and lipophilicit y.F ro m the perspective of synthetic methodology and application prospect,it is of great significance to study novel,safe,environmentally friendly,highly selective trifluoromethyl indole compounds with potential physio logical activit y.The introduction of trifluoromethyl into the indole framework,especially at the indole C2 site,has only been reported in a few cases,and there are few reports of metal free and highly selective methods of trifluoromethylation at indole C2 site.Among the past synthetic methods,there are many disadvantages,such as expensive reagents,difficult to preserve,poor posit ion selectivit y,difficult to deal with,harsh reaction condit ions,low atom economy,low yield or poor tolerance of functional groups.The synthesis of indole derivatives is an ongoing research project of our research group.Here,we found that TBHP and CF₃SO₂Na,which are easy to handle,low toxic and cheap,can introduce trifluoromethyl to C2 site of indole compounds in high regioselectivit y without the part icipation of transit ion metal catalysts.This method shows a wide range of substrate applications,and can also be applied to 0.7 g scale-up reactions.Through the experiments of free radical capture,it i s verified that the reaction experienced a free rad ical process.The main contents of this thesis are as follows:Firstly,the physical and chemical properties and applications of indole compounds and trifluoromethylated indole compounds are introduced briefly.The synthetic methods of trifluoromethyl indole compounds are summarized from the following three aspects:1)the synthesis of trifluoromethyl indole by the self cyclization of reactants;2)the synthesis of trifluoromethyl indole by the reaction of indole halides,silicides,diazo compounds and the reaction of boric acid wit h trifluoromethyl reagents;3)Direct C-H trifluoromethylation of indoles.Secondly,the background of the preparation of 2-trifluoromethyl indole from indole and sodium trifluoromethyl sulfite was systematically studied,and th e optimum reaction condit ions were optimized:CF₃SO₂Na（2.0 equiv.）,TBHP（3.0equiv.）,CH₃CN 2 m L,140 ^oC air stirring for 18 hours.Thirdly,under the optimal reaction condit ions,1,4-benzoquinone,2,2,6,6-tetramethylpiperidine oxide and 2,6-di-tert-butyl-4-methylphenol（BHT）were added to the reaction system respectively,and t here were no reaction to form the target molecule.However,the intermediate formed by capturing trifluoromethyl radical wit h BHT was detected in the system containing BHT,which verified that the reaction mechanism may be free radical mechanism.