Study On Intramolecular Cyclization Of Propargylamide Based On Dearomatization

Nitrogen-containing heterocycles are the core skeleton of many drug molecules and natural product molecules.It is of great significance to develop simple,economical and efficient synthesis methods of nitrogen-containing heterocycles.Propargylamide is an important precursor of organic chemical synthesis.It is often used as the substrate of cyclization reaction,which can be attributed to the nucleophilic nature of propargylamide α-Carbon and electrophilicity β-Carbon.It is noteworthy that the dearomatization strategy based on N-arylpropargylamide has developed into one of the most direct and effective methods to construct complex molecules.At present,most of the reported work is used to construct spiro rings,while there are few examples of one-pot construction of spiro tricyclic compounds.In addition,the synthetic method of pyrimidine benzothiazolone via de-(hetero)-aromatization has not been reported yet.Therefore,starting with the substrate design,this paper studied the molecular internalization reactions of N-hydroxyethyl-N-arylpropargylamide and N-(2-aminobenzothiazole)propargylamide based on the dearomatization strategy,which were used to construct spiro tricyclic and fused heterocycles efficiently.The details are as follows:1.Study on the dearomatization spirotracylation of N-hydroxyethyl-N-arylpropargylamide initiated by sulfonyl radicalStudy on sulfonyl hydrazide was used as a source of sulfonyl radicals to induce the dearomatization of N-hydroxyethyl-N-arylpropynamides and the ortho-trapping cyclization of phenyl radicals,and a series of sulfonyl radicals Substituted benzo[b]pyrrolo[2,1-c][1,4]oxazin-3-one compounds were successfully constructed.After detailed screening of reaction conditions,the optimal conditions are as follows:sulfonylhydrazine as sulfone source,oxone as oxidant and tetrabutyl ammonium iodide as additive,and react in toluene at 80 °C for 6 hours.Moreover,the reaction process was discussed and the possible reaction mechanism was put forward.Finally,the fluorescence effect of the product was preliminarily detected.After detailed screening of reaction conditions,the optimal conditions are as follows: sulfonylhydrazine as sulfone source,potassium bisulfate composite salt as oxidant and tetrabutyl ammonium iodide as additive,and react in toluene at 80 °C for 6 hours.Moreover,the reaction process was discussed and the possible reaction mechanism was put forward.2.Study on dearomatization spirotracylation of N-hydroxyethyl-N-arylpropargylamide initiated by selenium positive ionA synthetic method of seleno benzo [b] pyrrolo [2,1-c] [1,4] oxazine-3-one based on the dearomatization of N-hydroxyethyl-N-arylpropargylamide was developed.After detailed screening of reaction conditions,the optimal conditions are as follows: selenide as selenium source,oxone as oxidant,acetonitrile as solvent,and reaction at 80 °C for 12 hours under the protection of nitrogen.Through the mechanism study,it is concluded that the reaction may have experienced the effect of selenium free radical on alkyne bond α-Addition,dearomatization of aromatic rings,and ortho capture of spiro intermediates.The reaction does not need transition metal catalysis,has high yield,wide substrate range,and the product can be further derived.3.Intramolecular halogenation of N-(2-aminobenzothiazole)phenylpropargyl amideA new method based on the deheteroaromatization of N-(2-aminobenzothiazole)-3-phenylpropargyl amide and the synthesis of iodo(bromo)pyrimidine benzothiazolone by halocyclization was developed.Through the selection of additive equiv and solvent,the optimum reaction conditions were determined as follows: N-iodo(or brominated)succinimide was used as halogen source,2 equiv peroxytert butanol was used as additive,and reacted at room temperature in acetonitrile solvent for 10 hours.The reaction has high yield and simple operation,and the halogen in the molecule can be further modified to increase the structural diversity of heterocycles.