Density functional theory(DFT)calculations are employed to disclose the detailed reaction mechanism of the synthesis of 3-phenyl-2,5-dihydro-lH-benzo[d]imidazo[5,1-b][1,3]oxazine-l-thione under unassisted,water-assist...Density functional theory(DFT)calculations are employed to disclose the detailed reaction mechanism of the synthesis of 3-phenyl-2,5-dihydro-lH-benzo[d]imidazo[5,1-b][1,3]oxazine-l-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 mechanisms 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 stronger than 3.The DFT calculations suggest that the TFA-water co-assisted pathway of M1 is the most favorable 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]cycloaddition.More importantly,we found that TFA and water molecules play critical roles in the whole reaction,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 hydrogen 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 CH_(3)CN,which paves the way to design a greener synthetic strategy for oxazine N-fused imidazole-2-thiones and their derivatives.展开更多
基金Financial support by the National Natural Science Foundation of China(21873018,21573036,and 21603028)the Fundamental Research Funds for the Central Universities(2412019FZ010)the open project of the Jilin Province Key Laboratory of Organic Functional Molecular Design and Synthesis(130028655)are greatly acknowledged
文摘Density functional theory(DFT)calculations are employed to disclose the detailed reaction mechanism of the synthesis of 3-phenyl-2,5-dihydro-lH-benzo[d]imidazo[5,1-b][1,3]oxazine-l-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 mechanisms 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 stronger than 3.The DFT calculations suggest that the TFA-water co-assisted pathway of M1 is the most favorable 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]cycloaddition.More importantly,we found that TFA and water molecules play critical roles in the whole reaction,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 hydrogen 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 CH_(3)CN,which paves the way to design a greener synthetic strategy for oxazine N-fused imidazole-2-thiones and their derivatives.
