Studies on the Synthesis of Nitrogen-containing Heterocyclic Compounds via the Cascade Reactions of Propargyl Alcohols and the Addition of Oxazolones to Isatin-Derived Ketimines

Author:Tong Pei

Supervisor:li zuo


Degree Year:2019





As key members of the family of heterocyclic compounds,nitrogen-containing heterocyclic compounds are widely found in natural products and drug molecules.These compounds exhibit a wide range of biological and pharmacological activities,and play important roles in many fields such as biology,medicine,and materials.Therefore,this paper focuses on the construction of nitrogen-containing heterocyclic compounds,including the tandem annulation reactions of propargyl alcohols with amino compounds,the addition reaction of isatin-derived ketimine with oxazolone,and the self-condensation of N-sulfinyl aldimine.The main research contents are as follows:Part One:The Tandem Reactions of Propargyl AlcoholsSince propargyl alcohols have both acetylenic and hydroxy functional groups,they can efficiently synthesize a series of structurally rich carbocycles,heterocycles,bridged rings and fused rings.Recently,propargyl alcohols have been widely used as unique synthons in organic synthesis.In this paper,a detailed overview of the tandem reactions of propargyl alcohols has been carried out in recent years.Based on this,two new methods for the synthesis of different nitrogen-containing heterocyclic compounds(chromeno[2,3-b]pyridines and imidazo[1,2-a]pyridines)via the tandem reactions of propargyl alcohols with two amino compounds have been developed.(1)Zn(OTf)2-Catalyzed Formal[3+3]Cascade Annulation of Propargylic Alcohols with 2-Aminochromones:Accessing the Chromeno[2,3-b]pyridines(?)A Zn(OTf)2-catalyzed formal[3+3]cascade annulation strategy for the synthesis of functionalized chromeno[2,3-b]pyridines has been developed using propargylic alcohols and 2-aminochromones as the substrates.The structure of chromeno[2,3-b]pyridine derivative was further identified by the X-ray crystal structure analysis.The method is also effective on the gram scale,which highlights the inherent practicality of this synthetic transformation.Mechanistic studies show that propargyl alcohol forms propargyl carbocation by dehydration upon treatment with Lewis acid,which could afford the allenic carbocation formed in situ through the Meyer-Schuster rearrangement.The allene carbocation is captured by the2-aminochromone to cause a[3+3]cascade annulation.The protocol provides a convenient and atom-economical method of accessing a broad range of chromeno[2,3-b]pyridine derivatives in good yields(70-97%)with good functional-group tolerance.(2)Zn(OTf)2/Bu4NPF6-Catalyzed Formal[2+3]Cascade Annulation of Propargylic Alcohols with 2-Aminopyridines:Accessing the Imidazo[1,2-a]pyridines(?)A Zn(OTf)2/Bu4NPF6-catalyzed formal[2+3]cascade annulation strategy for the synthesis of functionalized imidazo[1,2-a]pyridines has been developed using propargylic alcohols and 2-aminochromones as the substrates.The conversion could be efficiently scaled up to gram quantities,accentuating a potential application of this work.We proposed that the allene carbocation formed in situ through the Meyer-Schuster rearrangement of propargyl alcohol is the key intermediate,which could be captured by the amino nitrogen or the pyridine nitrogen atom of the nucleophilic 2-aminopyridine to cause the 5-exo-dig cyclization.The method has the characteristics of easy availability of materials,simple operation,high atom-economy,broad range of substrates and high yields(up to 90%).This protocol can provide a novel and efficient way to construct biological and pharmacological active imidazo[1,2-a]pyridine skeletons.Part Two:Triphenylphosphine-Catalyzed Diastereoselective Addition of Oxazolones to Isatin-Derived Ketimines:Construction of 3-Amino-2-oxindole(?)3-Substituted 3-amino-2-oxindole skeleton containing a tetrasubstituted centre at the 3-position has emerged as prevalent structure scaffold in a diverse range of biologically active natural products and pharmaceuticals,so the synthesis of these compounds is of great significance.In this chapter,we have developed a method for the diastereoselective synthesis of 3-amino-2-oxindole derivatives via triphenylphosphine-catalyzed addition of oxazolones to isatin-derived ketimine.The reaction is efficiently catalyzed by PPh3 and gives the corresponding aminooxindole-oxazolone adducts containing congested vicinal N-substituted quaternary stereogenic centers with good yields(77-98%)and excellent diastereoselectivity(up to>20:1 dr)under mild reaction conditions.This reaction is applicable not only to oxazolones but also to thiazolones.Moreover,ring opening of aminooxindole-oxazolone adducts under mild acid conditions yielded the correspondingα,α-disubstitutedα-amino acid derivative in good yield.This3-substituted 3-amino-2-oxindoles structure can be further transformed to some biologically or pharmacologically active compounds.We have also studied the asymmetric Mannich reaction of isatin-derived N-Boc ketimines and oxazolones.After screening of a series of chiral catalysts,such as chiral thioureas,quinine-derived amides,chiral phosphoric acids and phosphines,we were delight to find that the quinine-derived amide catalyst could achieve an excellent yield of 97%and good stereoselectivity(4:1 dr and 85%ee and 95%ee),while the chiral phosphoric acid catalyst preferably achieved a high yield of 84%,excellent diastereoselectivity(>20:1 dr)and moderate enantioselectivity(53%ee).Further studies on the catalytic asymmetric version of this reaction are currently underway.Part Three:The Self-Condensation of N-tert-Butanesulfinyl Aldimines:Total Synthesis of Pyrrolidine Alkaloids(?)Nitrogen-containing five-membered heterocycles are important structural motifs that are widely found in natural products and drug molecules.The structure of optically active pyrrolidine is also widely found in alkaloid natural products,and thus has great research value.In this chapter,the construction of core tricyclic skeleton of pyrrolidine alkaloids A and B was selected as synthetic targets.We proposed and designed a strategy established on the basis of self-condensation of N-tert-butanesulfinyl aldimines and cyclization reduction reaction to construct core pyrrole rings.Based on this strategy,we have tried several self-condensation reactions of N-tert-butanesulfinyl aldimines with different substituents,and the success was achieved by using N-tert-butanesulfinyl aldimine with acetal protection.The self-condensation reaction of aldimine gave the expected key precursor compound,which could lay a solid foundation for the total synthesis of pyrrolidine alkaloids A and B,and the subsequent synthetic work is still in progress.