Mechanistic insights and improvement on the synthesis of oxazine N-Fused imidazole-2-thiones:roles of additives and solvent
Density functional theory(DFT)calculations are employed to disclose the detailed reaction mechanism of the synthesis of 3-phenyl-2,5-dihydro-1H-benzo[d]imidazo[5,1-b][1,3]oxazine-1-thione under unassisted,water-assisted,and trifluoroacetic acid(TFA)assisted conditions by 2,2-dihydroxy-1-phenylethanone(1),(2-aminophenyl)methanol(2),and KSCN(3).The computational results show that the title mechanism can be altered and accelerated by TFA,water,and substrate 2.Three types of mecha-nisms are reported by DFT calculations differing in the reaction sequence of substrates,such as M1:1+2 then 3;M2:1+3 then 2;M3:2+3 then 1.It is found that the nucleophilicity of substrate 2 is stron-ger than 3.The DFT calculations suggest that the TFA-water co-assisted pathway of M1 is the most fa-vorable case,which proceeds the nucleophilic addition and H-shift,intramolecular cyclization and water elimination,second nucleophilic addition and H-shift,intramolecular cyclization[3+2]cyclo-addition,and C—C bond formation and water elimination.The rate-determining step is the process of[3+2]cy-cloaddition.More importantly,we found that TFA and water molecules play critical roles in the whole re-action,by acting as efficient catalysts,proton shuttle,and stabilizer to stabilize the structures of transition states and intermediates via O…H—N,O…H—O,and O…H—C interactions.And they also act as hy-drogen bonds(HBs)donor and acceptor to improve the reactive activity of the substrates by changing the reaction form of glyoxal monohydrates and KSCN.Substrate 2 as HBs acceptor promotes the enol-ketone tautomerization and favors the proton transfer process.The origin of the different reactivity of M1,M2,and M3 is ascribed to the pivotal non-covalent interactions that exist between catalyst(water and TFA)and reactants.Interestingly,our computations revealed that the title reaction can be performed in water instead of CH3CN,which paves the way to design a greener synthetic strategy for oxazine N-fused imidaz-ole-2-thiones and their derivatives.
density functional theoryreaction mechanismadditives and solventmulticomponent reaction
MOHAMED Hend、袁海艳、张景萍
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东北师范大学化学学院,吉林长春 130024
密度泛函理论 反应机理 添加剂和溶剂 多组分反应
National Natural science Foundation of ChinaNational Natural science Foundation of ChinaNational Natural science Foundation of ChinaFundamental Research Funds for the Central Universitiesopen project of the Jilin Province Key Laboratory of Organic Functional Molecular Design and Synthesis
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