Preparation Of 2-Substituted-2H-Inzadole By Copper-Catalyzed Regioselective Cross-Coupling

Indazole,a bioisostere of indole,is widely existed in many molecules with good biological activity.It has very important applications in medicine,pesticides and other fields.As we all know,indazole is divided into two structures:1H indazole and 2H indazole.According to recent reports,we find that the research on the preparation of 1H indazole compounds is more in-depth.In contrast,the preparation of 2H-indazole compounds is rarely reported.At present,the methods for preparing 2H-indazole require relatively severe conditions and the selectivity of reaction is not high,so it is very necessary to develop a new method for the preparation of 2H-indazole compounds.By using the more available 1H indozale as a substrate,the occurrence of a cross-coupling reaction at the N-2 position of indazole is the most direct method for the synthesis of 2-substituted-2H indazole.However,due to the nucleophilicity of N1 and N2 positions of indazole,the selectivity of the reaction is the biggest difficulty of this method.In this paper,diaryl iodonium salts are used as an ideal electrophilic reagent for the cross-coupling at N2 position of the indazole.After investigating a large number of solvents,catalysts,reaction temperature and reaction time,the optimal conditions for the reaction were determined.The 5.0 mol%of CuCl is used as a catalyst,the reaction solvent is DCM and reacts at 50 ~oC for 12 h.The method is applicable to 1H indazole substituted with active groups at different positions,diaryliodonium salts substituted at different positions of the benzene ring,heterocyclic iodide salts,and alkene iodide salts.After extending the substrate,we find that different substituted indazole derivatives and different iodide salts have similar results.In terms of electronic effects,electron-donating substrates such as-MeO are more reactive than electron-withdrawing groups such as-NO2 and CF3.In terms of steric effects,the indazole substrates substituted at C4-C6 are more reactive than the C3 substitutions,and meta-substituted and para-substituted diaryl iodonium salt substrates are more reactive than the ortho-substitution.Moreover,some substrates with lower reaction activity can also obtain high yields by increasing the amount of catalyst and increasing the reaction temperature and other methods.To prove the practicability of this method,the estrogen receptor ligand has been successfully synthesized by this method.