1,3-Dipolar Cycloaddition Reaction Of Diazo Compounds And Development Of Novel PET Tracers Towards The Central Nervous System

This thesis comprises two sections:section I mainly focuses on the 1,3-dipolar cycloaddition reactions of diazo compounds,and Section II describes the development of subtype selective TARP?-8 dependent AMPA receptor?AMPAR?PET tracers.Section I:As a crucial organic synthon,diazo compounds have been involved in diverse types of organic reactions and widely applicated in the fields of pharmaceuticals,material science,polymers,chemical biology and natural products.Recently,the 1,3-dipolar cycloaddition reaction of diazo compounds,which represents one of the most reliable and powerful approach to N-containing heterocycles,has received widespread attention from organic chemists.Based on our previous works,this section focuses on the 1,3-dipolar cycloaddition reaction of 2,2,2-trifluorodiazoethane and diazoacetonitrile with other dipolarophiles or dipoles.A series of N-containing heterocyclic compounds have been successfully synthesized,which falls into four parts as followed:Firstly,we have successfully developed a silver-catalyzed[3+2]cycloaddition reaction of 2,2,2-trifluorodiazoethane with arenediazonium salts.Under mild conditions,a series of 2-aryl substituted 5-trifluoromethyltetrazoles were obtained in moderate to excellent yields with great regioselectivity and wide functional group compatibility.Furthermore,this cycloaddition reaction could be performed in a one-pot diazotization/cycloaddition sequence from commercially available aniline derivatives.Secondly,we have disclosed an efficient one-pot transformation of 2,2,2-trifluorodiazoethane and other perfluorinated homologues with various nitroolefins.This method takes advantage of the nitro group as a traceless activating and directing group?TADG?that is released in the aromatization step to produce 4-substituted 3-perfluoroalkyl pyrazoles with complete regioselectivity.The potential of this method is further demonstrated by the synthesis of penthiopyrad.Thirdly,we have described a transition-metal-free[3+2]cycloaddition reaction between nitroolefins and diazoacetonitrile?N₂CHCN?.This protocol exhibits several merits including simple starting materials,mild reaction conditions,broad substrate scope,good yields and regioselectivities.The one-pot three-component reaction of nitroolefins with N₂CHCN and alkyl halides is also developed,thus delivering a series of multisubstituted cyanopyrazoles in good to high yields.Finally,we disclosed an unprecedented silver-catalyzed[3+3]cycloaddition reaction of 2,2,2-trifluorodiazoethane with glycine imines to afford trifluoromethylated tetrahydrotriazines in moderate to excellent yields as well as excellent regio-and diasteroselectivities.Through isotopic labeling expreiments and real-time monitoring with ¹⁹F NMR,we proposed a tentative reaction mechanism.The potential of this method is further showcased by the facile transformation of the obtained CF₃-containing tetrahydrotriazines into highly functionalized triazines.Section II:Studies have indicated that AMPARs are implicated in the pathology of neurological diseases such as epilepsy and schizophrenia.The quantification of AMPARs by positron emission tomography?PET?would help obtain insights into disease conditions in the living brain and advance the translational development of AMPAR antagonists.As pan antagonists for this target are often accompanied with undesired effects at high doses,we present herein the synthesis and preclinical evaluation of a series of TARP?-8 depedent AMPAR antagonists,amenable for radiolabeling,for the development of subtype-selective AMPAR PET imaging agents.Based on the pharmacology and physiochemical property evaluation as well as molecular docking studies,we identified several promising lead compounds 28,35a-b and 35e for in vivo PET studies.All candidate compounds were labeled with[¹¹C]COCl₂ in high radiochemical yields?13-31%RCY?and high molar activities?35-196 GBq/?mol?.While ragioligands[¹¹C]35a and[¹¹C]35e crossed the blood-brain barrier and showed heterogeneous distribution in PET studies,consistent with expression of TARP?-8,high nonspecific binding hindered further evaluation.To our delight,radioligand[¹¹C]28 showed good in vitro specific binding and characteristic high uptake in the hippocampus in rat brain tissues,which provides the guideline for further development of a new generation of subtype selective TARP?-8 dependent AMPAR PET tracers.