Transition Metal Copper-catalyzed A~3 Coupling/Cyclization Reaction Of Dinucleophilic Reagents

Propargylamine is a widely used class of compounds,especially in the fields of pharmacology and medicinal chemistry.The traditional synthesis method of propargylamine is to use terminal alkynes to form metal alkynes with organometallic reagents(such as butyllithium)and then interact with imines to form propargylamine compounds.However,the organometallic reagent used in this strategy requires stoichiometry and is highly sensitive to water and air,which affects its application range.Inspired by the formation of imine or imide ions in situ by aldehydes and amines,the coupling reactions of aldehydes,acetylene and amines(A~3 coupling)catalyzed by transition metals have made great progress.Different types of catalysts have been developed successively,including gold(Au),silver(Ag),zinc(Zn),nickel(Ni),iron(Fe)and copper(Cu).Copper is widely used to catalyze A~3 coupling reactions due to a high affinity forπbonds,especially the activation of alkynes.In this paper,a series of new N-propargyl nitrogen-containing heterocyclic derivatives,including imidazolane,hexahydropyrimidine and oxazolane analogues with various potential biological properties and pharmacological effects,were constructed based on the copper-catalyzed A~3coupling/cyclization strategy.The details are as follows:The second chapter of this paper specifically introduces the cyclization and double A~3coupling cascade reaction of primary diamine,formaldehyde solution and alkyne under the catalysis of copper,which the reaction only needs to be carried out at 70°C for 30 minutes with the microwave assist and then the unique nitrogen-containing heterocyclic substituted compound can be produced.Based on this,a total of 34 new compounds were obtained with up to 96%yield.This novel and efficient method not only can withstand a wide range of substrates,but also produces highly chemically selective symmetric and asymmetric dialkynylimidazolidine and dialkynylhexahydropyrimidine derivatives.Next,with copper as the catalyst and 1,2-amino alcohol as the chiral precursor,A~3coupling/cyclization reaction with aldehydes and alkynyl was conducted to efficiently synthesize a series of monocyclic N-propargyloxazolidine derivatives with three stereocentric centers,and a total of 36 target compounds were obtained.This method has extensive universality and excellent diastereomeric selectivity control for aldehydes and alkynyl substrates.In addition,this reaction can also change the alkyne into propargylic acid and also be extended to the formation of terminal propargyloxazolidines,which are then transformed into 1,4-diamino-2-butyne through a two-step continuous process in a pot(corresponding to chapter III of this paper).On this basis,the above strategies used to expand into formaldehyde and aromatic aldehyde,two different aldehydes,achieving domino reaction with chiral amino alcohol and alkynes under the catalysis of copper,which was got 42 new N-propargyloxazolidine derivatives containing two chiral center with good yield and stereoselectivity,most of them with the excellent diastereoselectivity.This novel synthesis method has not only tolerated the double chanllege of chemical selectivity and stereoselectivity,but also has a wide range of substrate applications.By evaluating the volume of o-substituents on aromatic aldehydes,it is shown that steric hindrance(i.e.,atomic radius)has a significant adverse effect on diastereotopic selectivity(corresponding to chapter IV of this paper).