Mechanistic Insights On Organocatalytic Tandem Reactions For The Synthesis Of Imidazopyridine And Chromenopyridine

The development of new atomic economic reactions has become a hot research field of green chemistry,and catalysts are crucial to the sustainable chemical development.Theoretical studies can achieve the screening and design of catalysts for experimental chemistry,thus reducing labor and material consumption.The mechanism makes a connection between theory and experiment,which provides valuable theoretical basis with visual image for experimental phenomena that are difficult to explain experimentally.In this paper,we performed quantum chemical calculation to inverstigate the mechanisms of two typical green catalytic reactions,revealing the origin of the effects of catalysts,substrates and solvents on the mechanism,and providing further development of more efficient catalysts and new types of chemical reaction.The results are shown as follows:1.The mechanism of N-Bromosuccinimide?NBS?promoted synthesis of imidazo[1,2-a]pyridine in water as well as the effective activation modes of NBS was investigated by Density Functional Theory?DFT?calculations.Two main mechanisms that differ in the reaction sequence of substrate were explored:styrene with NBS then followed by2-aminopyridine?M1?or simultaneously with NBS and 2-aminopyridine?M2?,and water-assisted M2 is the more favored one.We found that the adding sequence of2-aminopyridine affects profoundly on the title reaction.Moreover,upon the assistance of water and NBS,the preferential mechanistic scenario involves three major processes:nucleophilic addition,stepwise H-shift and intramolecular cyclization,three step deprotonation,rather than a classical bromonium ion species.Specifically,the cooperative interaction of NBS and water plays a critical role in the title reaction.Water acts as solvent,reactant,anchoring,stabilizer,and catalyst.NBS promotes the reaction by the effective forms of Br⁺/Br^-,succinimide,and its ethanol isomer.Furthermore,noncovalent interactions between catalysts and substrates are responsible for the different reactive activities of M1 and M2.Our results indicate that simultaneous adding of all reactants is recommended toward economical synthesis.2.Themechanismof4-fluoroanilinecatalyzedthesynthesisof5-hydroxy-chromeno[2,3-b]pyridineshasbeentheoreticallyinvestigatedat M06-2X/6-31+G**level.Three mechanisms that differ in the reaction sequence of substrates were explored:3-formylchromone attacks firstly to malononitrile?M1?or to 4-fluoroaniline?M2?,and then with 4-fluoroaniline,or malononitrile with 4-fluoroaniline and then followed by 3-formyl ketone?M3?.Our calculations indicated that 4-fluoroaniline self-catalytic M1 is the most advantageous.It undergoes three processes:stepwise nucleophilic addition and deprotonation,nucleophilic addition,stepwise cyclization and proton transfer.Additionally,we found that 4-fluoroaniline acts not only as a reactant but also as a catalyst to effectively promotes the proton transfer process with water,forming–NH₃⁺group as effective catalyst form in the above process.Our results can help to further develop primary amine catalysts to achieve efficient green chemical reactions.