Studies on Heterocylic Synthesis Initiated by Metal Carbenes or Tert-Butyl Nitrite

Author:Mai Shao Zuo

Supervisor:song qiu ling


Degree Year:2019





Heterocyclic compounds,including cyclic systems,are the largest number in organic compounds.Besides carbon atoms,heterocyclic compounds also contain one or more heteroatom such as nitrogen,sulfur and oxygen.Heterocyclic compounds are ubiquitous in many natural products,drugs,bioactive molecules and organic functional materials.So far,a plethora of efficient methods for the synthesis of heterocyclic compounds have been established,while novel methods are still continuously emerging.It is well known that metal carbenes usually possess versatile reactivities,especially in heterocyclic synthesis.Diazo compounds are commonly used for the generation of such species.However,they are often unstable,explosive,and toxic,which limits their applications in large-scale syntheses.Thus,identifying sustainable and safe surrogates for the generation of metal carbenes has attracted great attention.This paper is divided into five parts.The first four parts are based on the development and utilization of metal carbene precursors to realize the efficient synthesis of various valuable compounds.The last part is about the application of tert-butyl nitrite in heterocyclic synthesis.Details follow:(1)We report unprecedented Suzuki-Miyaura coupling reaction of the in situ generated Pd-carbene complexes via desulfuration of thioureas or thioamides.In our method,a series of substituted amidinium salts and valuable diarylketones can be prepared in moderate to excellent yields.According to the mechanism studies,we identified that the diamino-palladium carbene is an important intermediate and unambiguously confirmed by X-ray crystallographic analysis.(2)Disulfide compounds are widely found in natural products and bioactive molecules,and one of the most important ones is disulfide compounds containing 2-aminofuran skeleton.The N-Tosylhydrazone containing thiocarbamate in the ortho-position was synthesized by using cheap and readily available salicylaldehyde as the raw material and cheap carbamyl chloride as the source of S,O,N and C in a two-step reaction.The whole process did not require column chromatography separation,and it could be prepared on a gram scale.A series of series reactions,such as[1+2]cycloaddition/ring opening/[1,2]-H migration between metal carbene and thiocarbonyl,were carried out using cheap copper salts as the reaction substrate,and important compounds containing 2-aminofuran disulfide skeletons were efficiently constructed.(3)Compounds containing adjacent sulfur and nitrogen atoms in aromatic rings are widely found in bioactive molecules.The rapid construction of such structural units is one of the challenges in organic synthesis.N-Tosylhydrazone containing thiocarbamate was used as the reaction substrate,and cheap copper salt was used as the catalyst to achieve a series of series reactions followed by the combination of aryne chemistry,and2-amino-3-thioaryl benzofurans were selectively constructed.(4)Most imidazole[2,1-a]isoquinoline compounds have good biological activity,and the structure and substitution diversity of their 5 and 6 positions often determine the level of their biological activity.We report an efficient,practical and diversity-oriented strategy for the synthesis of five types of imidazo[2,1-a]isoquinolines via Cp*RhIII-catalyzed[4+2]annulation of2-arylimidazoles and a-diazoketoesters,whose structural and substituted diversity at 5-or 6-position can be precisely controlled by the a-diazoketoester coupling partners.Moreover,the synthetic efficacies of these methods were demonstrated by the concise synthesis of several bioactive compounds.(5)For the first time,a new C-N bond was constructed in a one-pot process by the combination of gold catalysis and tert-butyl nitrite.We used the novel the three components of the catalytic system:gold catalysis,NHPI and transition metal catalysts.We use propargyl amides as reaction substrate,tert-butyl nitrite as sources of NO radical for the for chemodivergent synthesis of 5-functionalized oxazoles through the synergetic gold catalytic cyclization,addition reaction Initiated by NO radical,oxidation reaction promoted by NHPI and condensation or rearrangement catalyzed by transition metal copper salts or nickel salts.