Synthesis Of Indazole And Cyclic Sulfonamide Compounds

Indazoles,a kind of unsaturated heterocyclic compounds,have good pharmacological activity,such as anti-inflammatory activity,anti-tumor activity,anti-virus activity,etc.Therefore,such kind of compounds play a significant role in medicinal chemistry.At present,some drugs containing an indazole structural framework,such as Lonidamine,Axitinib and Benzydamine,are already booming in the market.In addition,indazoles also play important parts in industry and agriculture.Due to the good pharmacological activity and versatile application,numerious methods have been established to synthesize indazoles.These methods mainly include cross-coupling reactions,1,3-dipolar cycloaddition reactions,C-H amination reactions and some other reactions.Although each approach has its own advantages,some limitations and shortcoming still exist,including use of heavy metal catalysts,ungreen synthetic approaches,harsh reaction conditions and difficult preparation of starting materials.In this study,we have developed an atom-efficient approach to constructing indazoles from arylhydrazones via intramolecular C-H amination under neutral and mild DDQ-oxidative conditions.The main contents of this study include four parts.1)The conditions for the synthesis of indoles were first explored,and the optimal reaction conditions were carried out the use of DDQ(1.2 equiv)in DCE at 40? under N2 atmosphere.2)11 symmetric diaryl hydrazone substrates and 16 asymmetric diaryl hydrazone substrates were examined under the optimal reaction conditions,and the desired indazole products were obtained in moderate to good yield with high regioselectivity.3)The reaction could be conducted on a gram scale,and the target compound was still attained in high yields.4)With the assistant of control experements,the mechanism of the reaction,which undergoes a radical pathway,was also proposed.Cyclic sulfonamides are a class of heterocyclic compounds containing three heteroatoms of S,N and 0.This class of compounds exhibit excellent pharmacological activity in many aspects,such as anti-thyroid activity,anti-tumor activity,etc,and thus they are often treated as candidates in drug discovery.Sulfonamides are also widely used as pesticides,herbicides and fungicides because of their low toxicity,high efficiency and environmental friendliness.The synthetic methods for such compounds mainly include F-C reactions,olefin aziridine reactions,reductive amination reactions,Diels-Alder reactions,and some other reactions.Despite significant progress,these approaches still have some drawbacks.For instance,some reactions have low regioselectivity,some use heavy metal catalysts,and some are not environmentally friendly.Therefore,facile and efficient access to cyclic sulfonamides is still in great demand.Starting from substituted 2-benzyl benzenesulfonic amides and nitromethane,a novel protocol for the construction of eight-membered cyclic sulfonamides has been developed via a cascade C-N and C-C bond formation under the catalysis of FeCh at 80 oC under visible light irradiation.This method is simple and does not require strict anhydrous and anaerobic conditions.The detailed research work includes four parts:1)Exploration of the reaction conditions for the synthesis of cyclic sulfonamides,and the optimal conditions were determined with 0.2 equiv FeC13 as catalyst in nitromethane at 80? under the visible irradiation.2)16 substituted 2-benzyl benzenesulfonic amides were investigated as substrate under the optimal conditions,and all of them could afford the expected cyclic sulfonamides in moderate yields regiospecifically.3)A mechanism study was carried out on the reaction.It proved that nitromethane is both a reactant and a solvent for this reaction.4)The sulfonamide products were further derivatized,and several N-modified cyclic sulfonamide dericatives were obtained in high yields.