Study On Microdroplet Accelerated Tri-component Betti Reaction And Petasis Reaction,and Tetra-component Synthesis Of 3,4-dihydropyrans

As a typical format of confined-volume microreactor,microdroplets are characterized by astonishingly accelerating rates of many chemical reactions and even driving extraordinary reaction pathways in comparison with its bulk counterpart.Therefore,microdroplet chemistry has attracted extensive interest in analytical,organic and biological communities in the past two decades.Multicomponent reactions（MCRs）refer to participating in at least three different reactants to afford only one product in a reaction vessel.MCRs offer several advantages including energy economy,high atomic efficiency and good sustainability,and have drawn continuou attention from the synthetic community.In this dissertation,multicomponent reactions were accomplished in microdroplets to take full advantages of both technologies,leading to green,efficient and sustainable methodologies.This dissertation was initiated from a brief introduction of typical formats,acceleration mechanisms and current applications of microdroplet reactions in chemical synthesis,material science and biochemistry.In the following,the definition,classification,characteristics and applications of multicomponent reactions are summarized.On this basis,a microdroplet multicomponent reaction device was designed to study the three-component reactions such as Betti reaction and Petasis reaction in microdroplets and the four-component synthesis of 3,4-dihydropyrans.Reaction conditions,substrate scope,scaling-up and acceleration factors were explored,and rapid and catalyst-free mild gram-scale multicomponent reactions in microdroplets was realized as detailed as follows:（1）A microdroplet method for the synthesis of Betti bases by three-component Betti reaction without the use of any catalyst was developed.Under mild conditions（30°C reaction temperature and 40°C collection temperature）,microdroplets of reactant mixtures were sprayed at a flow rate of 100μL min^-1 to allow Betti reactions within 20 min for affording Betti bases with high yields（68-98%）.In contrast,no Betti bases were produced in bulk phase under the same conditions with only low yields（0.1-11%）in 48 h.By comparing the rate constants measured in both reactors,the Betti reaction in microdroplets was accelerated by 6.53×10³.This method has the advantages of high yield,short reaction time,catalyst freedom,mild reaction conditions and wide range of substrates as well as gram-scale synthesis(1.9 g h^-1).（2）A microdroplet method for the synthesis of aryl amines by three-component Petasis reaction was developed.Under catalyst-free and mild conditions（reaction temperature of 30°C）,good yields（54%-92%）can be obtained within 20 minutes of the microdroplet reactions,whereas almost no products were afforded in 20 minutes in bulk.The Petasis reaction in microdroplets was accelerated by 1.35×10⁴（second order kinetics）or 2.12×10⁴（third order kinetic）relative to the bulk phase.Advantages of this method include no catalyst,short reaction time,mild reaction conditions,wide substrate range,and gram-scale synthesis(0.8 g h^-1).（3）A microdroplet method for four-component synthesis of 3,4-dihydropyrans was developed.Reaction conditions including solvent,temperature and flow rate were explored,leading to methanol,35°C reaction temperature,45°C collection temperature,and 150μL min^-1 spray rate as the optimal.Yields of the microdroplet reactions were up to 87%by using a variety of aryl aldehydes.In addition,the micrdroplet synthesis of 3,4-dihydropyrans can be gram scaled(5.2 g h^-1).This method has the advantages of high yield,short reaction time,no catalyst,mild reaction conditions and wide range of substrates.In this paper,three component reactions,such as Betti reaction and Petasis reaction,as well as the four component synthesis of 3,4-dihydropyran in micro droplets were studied,and a rapid catalytic free gram synthesis of multi-component reactions in microdroplets was achieved.Microdroplet reaction conditions are mild,no use of any catalyst,high yield,short reaction time,and wide substrate range,making it an excellent method for preparing various organic substances.