Theoretical Study On The Cyclization Mechanism Of Haloheteroaryl Ynones With Nitromethanes

Ynones are a kind of compound with C≡C triple bond connected with carbonyl group,which has high reactivity.In organic synthesis,ynones can react with nucleophile or electrophilic reagent in different cyclization reactions to give multifunctional aromatic compounds.Ynones can participate in various cyclization reactions as 2C,3C or 4C synthons,and generate four-membered,five-membered,six-membered ring compounds,or various cocyclization compounds.Therefore,the study of cyclization reactions of ynones catalyzed by transition metals or non-transition metal has always been a hot spot in chemical synthesis.A deep understanding of the relevant reaction mechanism is of great significance for developing new reactions of ynones.In this paper,the reaction mechanisms of nitromethane anion with two kinds of halogen substituted nitrogen heterocyclic aryl ynones without transition metal catalyst were studied theoretically:1)The reaction mechanism of nitromethane anion with 2-halopyridyl-3-yl-ynones/3-halopyridyl-4-yl-ynones was studied at the SMD（CH₃OH）-B3LYP/def2tzvp level.The results showed that the reaction mechanism included Michael addition,1,3-H migration,cyclization dehalogenation and deprotonation of cyclization intermediate.Among them,in the two stages of 1,3-H migration and deprotonation of cyclization intermediate,the mechanism of H-migration and deprotonation assisted by CH₃O^-/CH₃OH greatly reduced the energy barrier of the reaction.The barriers of the addition reaction stage and 1,3-H migration reaction stage are low,so the addition products can be formed at room temperature,and the cyclization dehalogenation reaction has a high barrier,which suggests the cyclization product can only be formed at elevated temperature.In alkaline solution,the final product is phenol anion,which will transform to quinoline product after workup.3-halopyridyl-4-yl-ynones are less reactive than 2-halopyridyl-3-yl-ynones,due to the lesser positive charge on the Cl-substituted C atom in 3-halopyridyl-4-yl-ynones than that in 2-halopyridyl-3-yl-ynones.2)At the SMD（DMF）-B3LYP/6-311G（d,p）level,the reaction mechanism of nitromethane anion/acyl substituted nitromethane anion with o-chloropyrazolyl ynone was studied.The results show that the reaction mechanism mainly includes Michael addition,1,3-H migration,cyclization dehalogenation and deprotonation of cyclization intermediate.Among them,cyclization dehalogenationin step is the rate control step,and the two stages of1,3-H migration and deprotonation of cyclization intermediate,the mechanism of H-migration and deprotonation assisted by CO₃^2-/HCO₃^-greatly reduced the reaction barriers.For the reaction of acyl-substituted nitromethane anion with o-chloropyrazolyl ynone,the addition intermediate will transfer acyl to the C atom of protoalkyne which is not involved in the addition reaction through the four-membered ring transition state,and the progress of acyl transfer reaction will reduce the steric hindrance of the subsequent cyclization dechlorination reaction step,which is beneficial to obtain indazole products with functional groups on four consecutive C atoms of aromatic rings.Weaker nucleophilicity of acyl-substituted nitromethane than nitromethane can be attributed to the delocalization of negative charge,and greater steric effect of the acyl group.