Synthesis Of Various Heterocyclic Compounds With Gem-difluoroalkenes And Their Bioactivities

Aromatic heterocyclic compounds are widely used in medicines,pesticides,materials,dyes and industry of fine chemicals.Thus,a novel method for the synthesis of bioactive heterocyclic compounds is highly desirable.In recent years,gem-difluoroalkenes have aroused wide interest of chemists as significant fluorine-containing building blocks.Particularly,gem-difluoroalkenes have found their application in the construction of heterocycles via intramolecular cyclization.In this dissertation,we have synthesized 132 aromatic heterocyclic compounds,including fluorovinyl-substituted aromatic heterocycles,2,3,5-trisubstituted furans,2,3,5-trisubstituted thiophenes and 2,5-disubstituted oxadiazoles via reaction of gem-difluoroalkenes with heterocycles with unactivated C-H bonds,activited methylene carbonyl compounds,?-ketothioamides and hydrazines,respectively.The bioactivities of some target compounds were tested,and the results indicated that these compounds showed different inhibitory effects on K562 cells.1.We have developed a mild and efficient method for KHMDS or NaH-mediated coupling of a,a-diaryl-?,?-difluoroalkenes with azole heterocycles in the absence of metal catalyst.Sixteen fluorovinyl-substituted aromatic heterocycles were synthesized without prefunctionalization of the Csp2-H bonds of heterocycles.This procedure provides a simple and convenient method for the construction of fluorovinyl heterocycles.2.A novel and efficient CuI-catalyzed synthesis of 2,3,5-trisubstituted furans was developed via coupling cyclization of ?-aryl-?,?-difluoroalkenes with active methylene carbonyl compounds such as 1,3-dicarbonyl compounds,acetoacetonitrile,and phenylsulfonylacetone with the assistance of Cs2CO3.The methodology displays broad substrate scope and excellent functional group compatibility,affording furan derivatives substituted with acyl,ester,amide,nitrile and benzenesulfonyl.A plausible mechanism involving the allenyl ketone is suggested.We anticipate that this method opens up a new avenue for the synthesis of various valuable furans.3.We have developed a facile and practical method for the synthesis of N,N-disubstituted 2-aminothiophenes via the cyclization of ?-aryl-?,?-difluoroalkenes with ?-keto tertiary thioamides.The cyclization reactions proceed smoothly in the presence of K2CO3 without the addition of a metal catalyst,affording a variety of valuable N,N-disubstituted 2-aminothiophenes via addition-elimination,cyclization,and 1,2-hydrogen migration procedures.4.Based on our previous work,in this chapter,we studied the reaction of ?-ketothioamides with ?-aryl-?,?-dibromoalkenes or ?-aryl-?,?-dichloroalkenes instead of?-aryl-?,?-difluoroalkenes.Unexpectly,the reaction did not generate thiophene derivatives rather than polysubstituted furans.The active methylene and carbonyl group of?-ketothioamide were involved in the formation of furan ring.Sixteen thiocarbonyl-substituted furans were firstly synthesized,contributing to the structural diversity of furan derivatives.5.Efficient annulation of gem-difluoroalkenes and hydrazines with the assistance of Cs2CO3 was realized.This method provides 2,5-disubstituted oxadiazoles efficiently via intermolecular addition and aromatization reaction,avoiding the application of catalyst,oxidant,and dehydrating agent.Substitution on the benzene ring of?-aryl-?,?-difluoroalkenes has no significant effect on the yield.Aryl or alkyl hydrazine can produce the target products with good yield.This protocol provides a novel and new method for the synthesis of 2,5-disubstituted oxadiazoles.