Studies On The Synthesis Of Novel Sulfonyl Fluorides Compounds Based On Vinyl Sulfonyl Fluorides

With the rapid development of Sulfur Fluoride Exchange（Su FEx）click chemistry,sulfonyl fluorides have been widely used in drug discovery,material sciences and chemical transformations due to their unique chemical and physical properties.However,nowadays most of the methods for the synthesis of sulfonyl fluorides are centred on the transformation of ethenesulfonyl fluoride（ESF）and sulfuryl difluoride（SO₂F₂）,which have largely limited the scopes of sulfonyl fluoride compounds.In the present dissertation,we focus on the design and synthesis of novel sulfonyl fluoride reagents with multiple reaction sites and functional groups based on the structure of ESF.The main contents are briefly summarized as follows:（1）Design and synthesis of 1-bromoethene-1-sulfonyl fluoride（BESF）and the construction of 5-sulfonylfluoro isoxazoles by 1,3-dipolar cycloaddition reaction with N-hydroxybenzimidoyl chlorides.Firstly,1,2-dibromoethane-1-sulfonyl fluoride（DESF）is obtained by free radical addition of bromine to ESF at room temperature under the irradiation of 50 W white light;then BESF is generated by the elimination of hydrogen bromide at-50 ^oC.Finally,twenty-one 5-sulfonylfluoro isoxazoles are achieved under the optimal conditions of[3+2]cycloaddition,which are obtained by screening the bases,starting material ratio,solvents,temperature and so on.The structures of these compounds are characterized by testing instruments and the reaction mechanism is clearly clarified.Further reactivity of BESF as a Michael acceptor is also investigated.（2）BESF is developed as a Suzuki coupling partner.Twenty-seven 1-substituted ethenesulfonyl fluorides are prepared through the reaction with（hetero）arylboronic acids after the screening of metal catalysts,ligands,reaction temperature,solvents and starting material ratio.The structures of these compounds are characterized thoroughly.The construction of these 1-substituted ethenesulfonyl fluorides is an effective complement for the family of ESF and its derivatives,and these bifunctional electrophiles with terminal alkene motif and sulfonyl fluoride functionality can firstly react with nucleophiles chemoselectively to form sulfonamides and sulfonates by Su FEx reactions of sulfonyl fluoride group followed by the Michael addition occurred on the terminal alkene motif.This character provides significant references for the discovery of covalent small molecule kinase inhibitors.（3）Design and synthesis of 2-azido-1-bromoethane-1-sulfonyl fluoride（ABESF）and the formation of 1-bromo-2-（4-substituted-1H-1,2,3-triazol-1-yl）ethane-1-sulfonyl fluoride（BTESF）by copper（I）catalyzed cycloaddition reaction with terminal alkynes.Firstly,ABESF is generated by the sodium azide participated Michael addition of BESF or nucleophilic substitution of DESF.Secondly,by the screening of reaction conditions of classic click reactions,twenty-six diverse BTESFs are obtained,which demonstrates the potential application of ABESF in click chemistry.Finally,in order to explore the reactivity of BTESFs,twenty-two NH-1,2,3-triazoles are facilely generated through the cleavage of carbon-nitrogen bond under basic conditions.In addition,triazole substituted ethenesulfonyl fluoride can also be generated by the elimination of hydrogen bromide.（4）BTESF is developed as a fluorosulfonylvinylation reagent for amines and forty-three 2-amine ethenesulfonyl fluorides（N-ESF）are synthesized with high efficiency,including the modification of eleven commercial available drugs.The E configuration of alkene skeleton is confirmed by XRD analysis.Then the potential of N-ESF in the discovery of covalent inhibitors is evaluated for their chemoselective superiority in Su FEx area compared with 2-arylethene sulfonyl fluorides.Antibacterial results of seven fluoroquinolones and their fluorosulfonylvinylated derivatives reveal that fluorosulfonylvinylation does not alter the antimicrobial spectrum of quinolones,but the level of antibacterial activity can be improved in some extent,which furnishes a novel approach to result in effective antibacterial therapies to sustainably combat antibacterial resistance.