Annulation Reactions Of Aromatic Diazonium Salts For The Construction Of Five-membered N-heteroaromatic Compounds

Aromatic diazonium salts are an important class of intermediates in the field of organic synthesis.The denitrogenation cross-coupling reactions,reduction reactions,and coupling reactions with electron-rich aromatic hydrocarbons of aromatic diazonium salts have been widely used.However,relatively few studies have been carried out to construct nitrogen-containing heterocycles from aromatic diazonium salts,especially in the preparation of functional heterocyclic compounds.In this thesis,a series of tetrazoles,triazoles,and pyrazoles were obtained from easily available aromatic diazonium salts.Furthermore,these synthetic methods have been applied in the preparation of a diverse set of drug-like analogues or key intermediates.A brief overview is as follows:First,a silver catalyzed regioselective[3+2]cycloaddition reaction of Ph SO₂CF₂CHN₂ with aromatic diazonium salts was described.In the presence of silver acetate,and cesium carbonate,[3+2]cycloaddition reaction of Ph SO₂CF₂CHN₂ with aromatic diazonium salts in a cosolvent of tetrahydrofuran and N,N-dimethylformamide at 0 ℃ in 10 hours delivering a wide range of 5-benzenesulfonyl-difluoromethyltetrazoles in 69%–94%yields with high regioselectivities.Meanwhile,a one-pot diazotization/cycloaddition transformation from cheap aromatic amines was realized,which greatly expanded the substrate scope.Further synthetic transformations including dephenylsulfonylation,photoinduced denitrogenation of obtained cycloadducts was also established.The synthetic merit of this method is further demonstrated by the facile preparation of a valuable difluoromethylated analogue of P2X3 receptor antagonist.Secondly,a copper catalyzed three-component reaction of aromatic diazonium salts with fluorinated diazo reagents and nitriles was disclosed.In the presence of Cu Br catalyst,Li₂CO₃,4? molecular sieve,and nitrile compounds,the reaction was stirred at room temperature for 3 hours.A series of 5-benzenesulfonyldifluoromethyl-N¹-aryl-1,2,4-triazoles can be obtained in 50%–94%yields with moderate to excellent regioselectivities.This reaction could also be applied to 2,2,2-trifluorodiazoethane to afford the corresponding trifluoromethylated N¹-aryl-1,2,4-triazoles.This protocol can be extended to the synthesis of several P2X3 receptor antagonist analogues,including5-difluoromethyl-1,2,4-triazole,3-difluoromethyl-1,2,4-triazole,5-trifluoromethyl-1,2,4-triazole,and 3-trifluoromethyl-1,2,4-triazole.Thirdly,a silver catalyzed annulation reaction of aromatic diazonium salts with allenylboronates has been established.In the presence of Ag₂O catalyst and KHCO₃ as base,N¹-aryl pyrazoles can be synthesized by dropping the solution of allenylboronate in tetrahydrofuran,at 40 ℃ for 1–10 hours.This transformation offers unprecedented access to a wide scope of N¹-aryl-1H-pyrazoles with high regioselectivities under mild conditions.In addition,the scalability of this method was investigated.Further transformations of the annulation reaction products involving electrophilic halogenations,rhodium-catalyzed carbene insertion reactions can afford functionalized pyrazoles.Moreover,the obtained cycloadducts could be served as a key intermediate for phosphodiesterase 10A（PDE10A）inhibitor and gout drug Niraxostat.Preliminary experimental and computational studies indicate that this reaction could undergo through a transmetalation/stepwise cycloaddition/pyrazolyl silver hydrolysis sequence.In this process,propargyl silver species could be the key intermediate in controlling reaction regioselectivity.