Theoretical Investigations On The Mechanism Of The Dearomatization Reaction Of Pyrazines With Bis(pinacolato)diboron

The dearomatization reactions of six-membered N-heteroaromatic compounds,such as 1,4-dihydropyrazine and piperazine,playing an important role in the area of medicine and natural product synthesis,have attracted researchers’attention for a long time.Traditional methods such as hydrogenation reduction of N-heteroaromatic compounds rely on the participation of precious transition metal catalysts or sensitive metal hydrogen compounds.The reactions usually require harsh conditions,and also suffer from limited selectivity and poor functional group compatibility.Recently,Suginome and co-workers found that bis（pinacolato）diboron（B₂pin₂）can participate in the dearomatization diboration reaction of pyrazine compounds.This reaction can be used to synthesize some high-value 1,4-dihydropyrazine products,without the participation of transition metals or sensitive reagents,which provides a feasible solution to the above problems.However,the mechanism of this reaction is still unclear.In addition,for pyrazine with greater steric hindrance（such as 2,3-dimethylpyrazine）,the reaction with B₂pin₂ was found to take place only in the presence of 4,4′-bipyridine as the catalyst.The catalytic mechanism of this process is still unclear.In view of the important value of this reaction,it is of great significance to clarify the microscopic mechanism of the dearomatization reaction of pyrazine compounds,which would be valuable to design and develop better high-efficiency catalysts for related reactions.In this thesis,we will investigate the mechanism of the dearomatization reaction of pyrazine compounds by combining density functional theory calculations and experimental studies.We not only studied the dearomatization reaction of the unsubstituted pyrazine,but also the dearomatization reaction of the sterically hindered pyrazine under the condition of 4,4′-bipyridine as a catalyst.The relevant research contents are summarized as follows:Part I.We investigate the reaction mechanism on the dearomatization reaction of pyrazine with B₂pin₂ by density functional theory calculations.Our results indicate that the dearomatization reaction of pyrazine with B₂pin₂ undergoes two synergistic[3,3]-σ-rearrangement processes;pyrazine plays a role as an autocatalyst.Due to the steric hindrance,2,3-dimethylpyrazine cannot directly react with B₂pin₂.The energy barrier for this reaction is as high as 39.2 kcal/mol.It is difficult to obtain the corresponding dearomatized products under the experimental conditions.The calculated results are in good agreement with the experimental results reported in the literature.Part II.We perform density functional theory calculations on the reaction between sterically hindered pyrazine and B₂pin₂ catalyzed by 4,4′-bipyridine to explore the reaction mechanism.Our calculations show that the mechanism of this reaction is quite different from that of the above-mentioned reaction of pyrazine and B₂pin₂.First,the4,4′-bipyridine catalyst will react with bis（pinacolato）diboron（B₂pin₂）to activate the B-B bond of B₂pin₂,generating the 4,4′-bipyridine-boryl radical as the active intermediate.Then two sequential boryl radical transfer processes occur from the 4,4′-bipyridine-boryl radical to the sterically hindered pyrazine substrate,yielding the corresponding dearomatization product.From the theoretical results,we could clarify the reactivity difference for the reaction between B₂pin₂and pyrazine or sterically hindered pyrazine.The dearomatization reaction of pyrazine undergoes two synergistic[3,3]-σ-rearrangement processes,and no pyrazine-boryl radicals are generated in the reaction.The reaction between sterically hindered pyrazine and B₂pin₂needs to be catalyzed by 4,4′-bipyridine.The reaction is likely to undergo two sequential 4,4′-bipyridine-boryl radical transfer processes to give the N,N′-diboryl-1,4-dihydropyrazine product.Some important reactive intermediates have been confirmed by the experimental collaborator of this work.The elucidated reaction mechanism on the dearomatization reaction of pyrazine compounds with B₂pin₂is expected to provide helpful guidance for designing more efficient catalysts.