Studies On Rhodium-catalyzed Synthesis Of 2H-indazoles From ?-Cl Ketones

As an important branch of aza-heterocyclic compounds,indazole has attracted chemists the attention,since it is also an aza-aromatic system with10?electrons similar to indole,and known as bioelectronic isosteres of indole,moreoverthey are not only important intermediates in organic synthesis,but also show good biological and medicinal activity.According to the arrangement of the electron conjugates in the aromatic ring,indazole can be divided into 1H-indazole and 2H-indazole.For the preparation of these two indazoles,study on the synthesis of 2H-indazole is less than 1H-indazole.Traditional procedures to build 2H-indazole required complex substrates,harsh reaction conditions and multi-steps.Therefore,it is highly desired to develop an efficient,convenient and wide substrate range process to construct the 2H-indazole framework due to its broad spectrum bioactivities,such as anti-inflammatory,anti-angiogenesis and anti-cancer.Transition-metal-catalyzed directly intermolecular cyclization via C-H bond activation has been established as a straight forward method to construct aza-heterocycle.In these reactions,sp~2-or sp-carbons,such as aldehydes,alkynes,alkenes,anthranil,organic azide and diazo compounds,were usually used as the key synthons.However,sp~3-carbon synthons have been rarely reported.To solve this limitation,Glorius's group reported a pioneering example of Rhodium(III)-catalyzed[4+2]cyclization to synthesize C3-monosubstituted N-heterocycle based on C(sp~3)electrophiles of?-Cl/MsO/TsO substituted ketones,which complementing the previously reported mode of?-bond reaction.Subsequently,Li and co-workers disclosed the synthesis of C-H/N-H functionalized isoquinolines catalyzed by Rhodium(III)starting from?-Cl/MsO/TsO ketones.In these procedure,alpha halos or pseudohalogens are usually used as C2 synthons.To build versatile heterocycles as well as with our continuing interest in the clean transition-metal-catalyzed C-H bond functionalization,we embark on Rhodium(III)catalyzed[4+1]cyclization of azo compounds with?-Cl ketones for the synthesis of 3-acyl-2H-indazoles(Scheme 1).After examining more than 30 examples,good yields were obtained for most cases(up to 97%).The electronic density affect on the reaction.Generally,azobenzenes containing electro-donating groups on the benzene ring gave better yields than that of electron-poor azobenzenes.For meta-substituted azobenzenes,controlling the C-H activation site relys mainly on the steric hindrances.The eleotron density of?-chloroketone on the benzene ring slightly affect on the the reactivity.Slightly higher yields were afforded for deficient?-chloroketones.In summary,the reaction could proceed smoothly under mild reaction conditions and tolerate broad functional groups.An effective one-step construction of an anti-inflammatory drug was successfully achieved applying this current protocol,which highlights its practicality(Scheme 2).Finally,based on the controlled experiments and literatures,the relevant reaction mechanism was proposed as shown in(Scheme 3).