Synthesis Of Dialkyl-Substituted Monofluoroalkenes Via Palladium-Catalyzed Cross-Coupling Of Alkyl Carbagermatranes

The incorporation of fluorine atom or fluorine-containing groups into drug molecules could bring about unique biological and physical properties,including better lipid solubility,metabolic stability and binding properties to biological targets.One idea about developing new drugs is developing fluorine-containing analogues of biologically active small molecules.Among these fluorine-containing compounds,monofluoroalkenes which are isosteres of amides,cuold be used as the mimics of corresponding amide molecules.Not only commom advantages mentioned above,monofluoroalkenes also have better conformation stability than corresponding amides and tolerate to natural amide hydrolase.Therefore,monofluoroalkenes have been very important structural motifs in pharmaceutical chemistry,and attracted wide attention of organic synthesis field.Defluorinative cross-coupling of gem-difluoroalkenes has emerged as a powerful strategy to construct monofluoroalkenes.Rhodium-catalyzed tandem C-H/C-F activation procedure of arenes with gem-difluoroalkenes could directly incorporate fluoroalkenyl into arenes;Palladium-catalyzed defluorinative cross-coupling of gem-difluoroalkenes with aryl boric acid provided an simple way to obtain diaryl-substituted monofluoroalkenes;With nickel-catalyzed reductive cross-coupling of gemdifluoroalkenes with alkyl halide and zinc-mediated cross-coupling of gem-difluoroalkenes with carboxylic acid derivatives,the unilateral substituents of monofluoroolefin effectively extended to alkyls.However,it seems difficult for synthesis of dialkyl-substituted monofluoroalkenes.In this paper,we developed a general strategy for the synthesis of dialkyl-substituted monofluoroolefins by palladium-catalyzed cross-coupling of alkyl carbagermatranes with bromofluoroolefins according to the cross-coupling of alkyl carbagermatranes with aryl electrophiles.This reaction is compatible with various functional groups.Besides,this paper proposed a new strategy for the synthesis of amide compounds mimics:cross-coupling of bromofluoroolefins which are corresponding to aminos with alkyl carbagermatranes through decarboxylation carbagermatranation from corresponding alkyl carboxylic acids.The novel reaction and strategy developed in this paper not only provide a synthesis method of dialkyl-substituted monofluoroolefins,but also expand the bioisosterics of dialkyl-substituted amides.