Study On The [3+2] Reaction Of Tetrahydroisoquinolines And Unsaturated Keto Esters

Unsaturated ketone esters have a wide range of applications in organic synthesis,especially β,γ-unsaturated-α-ketone esters,due to their unique conjugated structure,which enables them to participate in reactions as C1,C2,C3,and C4 synthons.They are also widely used in asymmetric synthesis to produce various chiral compounds with excellent enantioselectivity.Pyrroloisoquinoline derivatives are a class of important nitrogen-containing heterocyclic compounds.These alkaloids have strong anti-tumor,anti-virus and antibacterial activities.The synthesis of pyrroloisoquinoline compounds has attracted extensive attention from chemists,and currently two main strategies have been developed to obtain these compounds:one involves building the isoquinoline ring from pyrrole derivatives,and the other involves constructing the pyrrole ring from isoquinoline derivatives.With the potential application prospects of pyrroloisoquinoline compounds in medicine,materials,and other fields receiving more and more attention,the development of convenient and efficient synthetic methods to synthesize multifunctional pyrroloisoquinoline derivatives is important for their applied research.The [3+2] reaction has become one of the most commonly used and effective methods for the synthesis of five-membered nitrogen-containing heterocyclic compounds.In this study,we synthesized pyrroloisoquinoline derivatives using tetrahydroisoquinoline and unsaturated keto ester compounds as raw materials,through a cascade [3+2]/aromatization reaction.This method can construct a pyrrole ring through a one-step operation,and introduce an ester group on the pyrrole ring,which is conducive to the subsequent derivatization of these compounds.In the experiment part,we first attempted the possibility of this cascade[3+2]/aromatization reaction using template substrates and optimized the reaction conditions.The most suitable conditions for this reaction were obtained as follows: catalyst2,4-dichlorobenzoic acid(30 mol %),solvent 1,2-dichloroethane,and reaction temperature of100 ℃.Under these conditions,the reaction was carried out for 6 hours,and the target product was obtained with an 88% yield.Subsequently,we studied the universality of this cascade reaction,discussed the influence of ketone esters with different substituents and tetrahydroisoquinoline derivatives on the reaction,and synthesized 35 new ester-substituted pyrrolodihydroisoquinoline compounds in medium to good yields.Pyrrolodihydroisoquinoline compound can be converted into corresponding pyrroloisoquinoline under DDQ oxidation.In addition,the possible reaction mechanism was speculated.The reaction developed in this paper generates water as the by-product,which has the advantages such as cheap and easily available raw materials,simple operation,high atom economy,and environmental friendliness.The method not only provides a new way for the synthesis of pyrrolodihydroisoquinoline and pyrroloisoquinoline compounds with ester groups,but also enriches the molecular library of these compounds,and lays a certain work foundation for their applied research.