Studies On The Construction Of Several Fused-azaheterocycles Via Nucleophilic Heterocyclization Of Functionalized Isocyanides

Heterocycles are an important class of organic compounds.Heterocyclic compounds are widely applied in medicine,pesticides,functional materials,and other fields.The development of simple and efficient methods for the synthesis of heterocyclic compounds has always been one of the hot research fields in synthetic chemistry.Due to their unique reactivies such as α-addition and insertion reation,isocyanides have become versatile building blocks and been found widely applications in the synthesis of nitrogen-containing heterocycles.In this thesis,the related literatures on the synthesis and bioactivities of several nitrogen-containing compounds such as rutaecarpine,polylcyclic spiroindolines,4-azafluorenones were firstly summaried.The isocyanide-based multi-component reactions and the synthesis of heterocycles from isocyanides were also briefly reviewed.The synthetic protocols for these heterocycles often suffered from the drawbacks such as multi-step synthetic route,complicated operation as well as sustainability and green chemistry issues.Therefore,the devepment of concise and efficient synthetic route to these fused azaheterocycles is still highly desirable.The specific research content of this thesis is divided into the following three parts:In the first part,solvent-dependent regioselective tandem heterocyclization reactions of tryptamine derived isocyanides and 2-azidobenzoate were developed for the direct and efficient synthesis of alkaloid rutaecarpine and spiroindoline derivatives.Using ethylene glycol as solvent,the reaction gave rutaecarpine in moderate yield through indoyl C2-cyclization;while using tetrahydrogen furan as solvent,a series of spiroindoline derivatives were obtained in high yields via indoyl C3-cyclization.Additionally,ring-opening of the indoline moiety of the obtained spiroindoline by the cleveage of C-C bond occurs smoothly to deliver 3-(2-aminophenyl)quinazolinone,which is the key precursor of natural alkaloid vasicoline 291.The results of control experiments reveal that the spiroindoline could not convert to rutaecarpine under the standard conditions.Finally,a reasonable mechanism is proposed on the basis of the experimental results and related literature precedents.In the second part,a dearomative spirocyclization of tryptamine derived isocyanides with quinone esters is developed for the convenient and efficient synthesis of structurally complex chromeno[2,3-b]indole and spiroindoline derivatives.Using 1,4-dioxane as solvent,the reaction of tryptamine derived isocyanides with quinone esters occurs smoothly at 120 ~oC under acid-/base-/catalyst-free conditions,affording a wide range of chromeno[2,3-b]indole derivatives in high to excellent yields.Furthermore,a reduction-triggered lactonization/ring-opening cascade of the resulting chromeno[2,3-b]indoles allows to furnish the polycyclic spiroindolines.A one-pot transformation of these isocyanides with quinones to the polycyclic spiroindolines is also developed,demonstrating the efficiency and diversity of this domino reaction.This domino transformation features simple operation,acid-/base/catalyst-free conditions,a broad scope,readily available substrates,and high diastereoselectivity.In the third part,a novel domino reaction of isocyanoacetates with enynones has been successfully developed for the efficient and practical synthesis of azafluorene and azafluorenone derivatives.In the presence of 0.3 equivalent of t-Bu OK,the reaction of isocyanoacetates with enynones produces various 4-azafluorenes in good to high yields.The resulting azafluorenes could be readily oxidized to 4-azafluorenones by BHT in excellent yield.A one-pot transformation of isocyanoacetates and enynones to 4-azafluorenone derivatives is also explored.In this transformation,a new reactivity profile of isocyanoacetate is found in which the active methylene and isocyano groups act as nucleophiles.The bisnucleophilic additions accordingly generate an allenyl ketone and a six-membered cyclic nitrilium ion intermediate,which play key roles in the multistep process.This new domino reaction features many advantages such as a high efficiency,readily available starting materials,metal-free conditions,good yields,and good functional group tolerance.