Synthesis Of Sulfur-Containing Heterocyclic Compounds From Reactions Of Pyridine And Dialkyl But-2-Ynedioates

Dialkyl but-2-ynedioates have strong electrophilic property due to its two electron-deficient ester groups,the nitrogen atom of pyridines has strong nucleophilicity.Therefore,dialkyl but-2-ynedioates and pyridines were used together to build various heterocyclic compounds in organic synthesis.From early Huisgen 1,4-dipoles to pyridine N-ylides and pyridinium 1,4-zwitterionic thiolates were developed as nucleophiles to react with C=C,C=O,C=N and other dipole reagents,giving annulation products and showed the strong reactivities of dialkyl but-2-ynedioates and pyridines.However,the annulation reaction modes of dialkyl but-2-ynedioates and pyridines still needs to be studied deeply.In this dissertation,the synthesis sulfur-containing heterocyclic compounds involved reactions of pyridines and dialkyl but-2-ynedioates,including the reactions with sulfonyl chlorides,phosphoryl diazo compounds,and potassium bromodifluoroacetates,in which S,P and F were introduced into heterocyclic organic compounds,respectively.The main contents and conclusions are as following:（1）Based on the[2+2]annulation reactions of sulfonyl chlorides with electron-deficient imines and electron-deficient aldehydes,the annulation reaction of sulfonyl chlorides with dialkyl but-2-ynedioates was developed.The annulation of sulfenes and nonpolar electron-deficient alkynes,dialkyl but-2-ynedioates,is achieved for the first time in the presence of pyridine as both base and nucleophilic catalyst,generating highly strained binfunctionalized four-membered thiaheterocyclic derivatives,dialkyl 2H-thiete-2,3-dicarboxylate 1,1-dioxides.The annulation mechanism is proposed as the pyridine-promoted HCl elimination of sulfonyl chlorides to generate sulfenes,pyridine nucleophilic attacking the sulfenes to generate zwitterionic intermediates,and the zwitterionic intermediates further nucleophilic attacking dialkyl but-2-ynedioates followed by intramolecular nucleophilic addition-elimination and isomerization to produce final dialkyl 2H-thiete-2,3-dicarboxylate 1,1-dioxides.Pyridine served first as a base and then as a nucleophilic catalyst in the annulation.The current reaction provides a direct and convenient method to prepare highly strained bifunctionalized 2H-thiete derivatives from readily available starting materials and inexpensive base and catalyst.The steric hindrance of dialkyl but-2-ynedioates is one of key factors to controlling reactivity,and dialkyl but-2-ynedioates with the more steric hindrance showed stronger reactivity.Gram-scaled synthesis and a variety of derivatization experiments were carried out,and a variety of sulfone-containing compounds were obtained,showing the practicality and importance of the reaction.（2）The visible light-induced[1+5]annulation of phosphoryl diazo compounds and pyridinium 1,4-zwitterionic thiolates is achieved for the first time,generating phosphoryl-1,9a-dihydropyrido[2,1-c][1,4]thiazine derivatives in high yields with excellent diastereoselectivities（up to>99:1）.The singlet carbene intermediates first generate from diazo compounds under blue light irradiation,then undergo the[1+5]annulation with pyridinium 1,4-zwitterionic thiolates through thiolates nucleophilic addition to the carbenes followed by intramolecular nucleophilic addition.The reaction is affected obviously by both steric hindrance and electronic effect.Phosphoryl diazo compounds show the following reactive order,（diazo（aryl）methyl）diarylphosphineoxides>alkyl（diazo（phenyl）methyl）（phenyl）phosphinates>dialkyl diazo（phenyl）methyl)phosphonates,and arylmethyls with electron-donating groups are more active than those with strong electron-withdrawing groups.The visible-light-induced annulation features the advantages of catalyst-free,highly environmental benign and atomic economy,wide range of substrates,and mild reaction conditions.（3）Functionalized 1-diarylphosphoryl-1H-benzo[c]thiopyran and indolizine derivatives,espectially 5-alkylindolizines,are prepared chemoselectively from diazo（aryl）methyl（diaryl）phosphine oxides and pyridinium 1,4-zwitterionic thiolates via stereo-controlled[3+3]and（[1+5]-1）annulations.Less steric pyridinium thiolates favor the[3+3]annulation with pyridines as leaving groups,while more steric pyridinium thiolates prefered to the（[1+5]-1）annulation through tandem[1+5]annulation,the P-Cope elimination,and sulfur extrusion.Through derivatization experiments,it was found that dimethyl 1-（diphenylphosphoryl）-1H-isothiochromene-3,4-dicarboxylate developed via the Baeyer-Villiger reaction and the P-Cope elimination reaction could be directly converted to dimethyl 1-oxo-1H-isothiochromene-3,4-dicarboxylate.（4）A novel and easy way to prepare dialkyl 1,1-difluoro-1,9a-dihydropyrido[2,1-c][1,4]thiazine-3,4-dicarboxylate derivatives was developed by using potassium bromodifluoroacetates as the difluorocarbene precursor to react with pyridinium 1,4-zwitterionic thiolates under heating,directly introducing difluoromethylene into bifunctionalized 1,9a-dihydropyrido[2,1-c][1,4]thiazine derivatives in moderated to high yields.The single difluorocarbene generated from BrCF₂CO₂K and was attacked by pyridinium 1,4-zwitterionic thiolates followed by an intramolecular nucleophilic addition to afford the desired geminal difluoro products.The annulation features the advantages of wide substrate range,catalyst-free,environmentally friendly,and mild conditions.The gram-scaled reaction can be successfully carried out,and the drug molecules could be modified through the annulation,providing the practicality of the annulation.The products can aromatize to obtain pyridine derivatives by simple heat treatment,the method can also be used for pyridine modification.