Studies On The Reaction Of Nickel-catalyzed Oxidative Isocyanide Insertion Into C-H/N-H(S-H)

Substituted pyrrolinone derivatives are important structural motifs of various alkaloids,biologically active compounds and natural products.The transition metal catalyzed reaction of isocyanide insertion was developed for highly atom-economical synthesis of pyrrolinone derivatives.Classical isocyanide insertion usually occurs between nucleophiles and organohalides.The new reaction type of transition metal-catalyzed isocyanide insertion into C-H,N-H,O-H and S-H has become a hot spot.However,this kind of reaction normally involves non-atom-economical and tedious prefunctionalization processes.Therefore,it is necessary to develop an direct oxidative cross-coupling reaction based on isocyanide insertion.An efficient and green synthesis of pyrrolinone derivatives was first developed via nickel-catalyzed oxidative coupling between C_sp3-H/N-H and double isocyanides without any ligand or directed group.This reaction has a low-yield problem at the beginning of the optimization of the reaction conditions.The problem was resolved by changing the loading of catalyst and the type of base.After screening of the reaction conditions,the optimized conditions were established as follows: Ni?acac?2?0.3 equiv?as the catalyst,TEMPO?2.0 equiv?as the oxidant,KHMDS?2.0 equiv?as the base,1,4-dioxane as the solvent at 60 oC.In order to study starting point and the changes in the valence of nickel during the reaction in the process of mechanism research,the control experiment of insertion with the key intermediate 6a has been carried out and different valence of nickel-catalyzed reaction have been achieved.Mechanism was demonstrated in detail on the basis of our control experiments and crystallographic data of 3d.Based on the nickel-catalyzed oxidative isocyanide insertion into C-H/N-H,a nickel-catalyzed oxidative S-H/N-H isocyanide insertion was developed to synthesize 1,3-thiazetidine-2,4-diimine derivatives.After screening of the reaction conditions,the optimized conditions were established as follows: Ni?acac?2?0.1 equiv?as the catalyst,2-Me-THF as the solvent at 60 oC,the yield can achieve 64%.With optimized reaction conditions in hand,the scope of various substrates was tested.A possible reaction mechanism was proposed in detail in this part.The structures of all the 1,3-thiazetidine-2,4-diimine derivatives were confirmed by 1H NMR,13 C NMR and HRMS.