Studies On Annulation And Rearrangement Reactions Of Diazo Compounds

Diazo compounds are highly reactive and versatile organic building blocks,which have been extensively studied in the fields of organic synthesis,medicinal chemistry,and natural products.Furthermore,diazo compounds have also been applied in the post-modification of protein and nucleic acid molecules in the living systems.Therefore,the development of new diazo reagents from readily available bioactive small molecules and their applications in the construction of functional molecular structures via new chemical transformations is of high importance and desirable.In this thesis,we have focused on the synthesis and transformation of coumarin-diazo reagents,α-amino acid-derived diazoketones,andα-aryl-α-diazoacetates.Several annulation reactions and a tandem cyclization-rearrangement reaction of these diazo compounds have been successfully developed for the facile construction of tetrazoles,triazines,andα,α-bisaryl-α-hydroxyacetates.This thesis includes the following three sections:Section 1:A series of coumarin diazo reagents has been easily obtained from the corresponding 4-methylcoumarin.[3+2]and[3+3]cycloaddition reactions of these diazo compounds have been developed for the efficient construction of structurely diverse coumarin-derived tetrazoles and 1,2,4-triazines.In the presence of KOAc and10 mol%Ag OTf,a[3+2]cycloaddition reaction of coumarin diazo reagents with aryl diazonium salts was realized for the facile synthesis of coumarin-decorated tetrazoles in good yields with excellent regioselectivities.Subsequently,a Cs₂CO₃-catalyzed[3+3]cycloaddition reaction of coumarin-diazo reagents with glycine imino esters was established to produce tetrahydro-1,2,4-triazines in good yields with excellent regioselectivity.One-pot cycloaddition/oxidation protocol could further furnish a series of new coumarin-decorated 1,2,4-triazines.These two reactions could provide a new synthetic plarform for the development of coumarin-based biorthogonal reagents.Section 2:A silver-catalyzed[3+2]cycloaddition reaction ofα-amino acid-derived diazoketones with aryldiazonium salts was developed to produce the tetrazole-modified amino acids in good yields with excellent regioselectivities.The utility of this method is demonstrated for the synthesis of optically pureα-amino alcohols,dipeptide molecules,and a drug-like intermediate of leukocyte-associated antigen-1（LFA-1）antagonists Lifitegrast with tetrazole moieties.Moreover,the obtained tetrazoles could also undergo subsequent photo-induced denitrogenation/cycloaddition reactions with alkenes or alkynes.Preliminary experimental and density functional theory studies indicate that aryldiazonium salts could act as highly reactive dipolarophiles to react with diazoketones in a facile concerted cycloaddition manner,while the classic Wolff rearrangement process of diazoketones to generate ketene intermediates could be fully inhibited.Section 3:A one-pot tandem cyclization-rearrangement-aromatization transformation ofα-aryl-α-diazoacetates with para-quinamines was developed.The Rh-carbene complex generated fromα-aryl-α-diazoacetates reacts with the para-quinamines to form epoxide intermediate.In the presence of citric acid,this intermediate can undergo the opening/rearrangement/aromatization sequence to give tetra-substitutedα,α-bisaryl-α-hydroxyacetates.This one-pot protocol is applicable to a wide variety of easily accessibleα-aryl-α-diazoacetates and para-quinamines to affordα,α-bisaryl-α-hydroxyacetates in good yields with high chemoselectivities.