Transition-Metal-Catalyzed Cross-Coupling Reactions Of Gem-Difluroalkenes With Grignard Reagents

The formation of carbon-carbon bond is an important method to construct the structurally diverse and complex organic molecules in organic synthesis.Transition-metal-catalyzed Kumada cross-coupling reactions of Grignard reagents with organic halides is one of the important and indispensable tools for the construction carbon-carbon bonds.In recent years,the synthesis of fluoroorganic compounds and the cleavage of C-F bond have attracted significant attention from synthetic chemists.gem-Difluoroalkenes and monofluoroalkenes are important fluorine-containing building blocks found in many pharmaceuticals,agrochemicals,and materials.However,there are few reports on the new reaction of gem-difluoroalkenes in organic synthesis.In this dissertation,we successfully developed three mild and facile methods for the synthesis of three series of novel multi-alkylsubstituted alkenes by the palladium-,nickel-and Cu-catalyzed or metal-free cross-coupling of gem-difluoro-and gem-dibromoalkenes with tertiary,secondary,primary alkyl Grignard reagents or di-Grignard reagents,respectively.1.The C-F bond cleavage of aryl fluorides have attracted much attention.However,the cleavage of C-F bond alkenyl fluorides have been rarely reported.In the second chapter,we have developed two new and efficient palladium and nickle-based catalytic systems for the coupling of gem-difluoroalkenes or monofluoroalkenes with Grignard reagents under simple and mild reaction conditions without any additional ligands.The catalytic system involving Pd(PPh3)4 was found to be exceptionally effective for the coupling reaction of fluoroalkenes with Grignard reagents without ?-hydrogens to exclusively afford the corresponding di-coupled product in high yield,whereas NiCl2(dppe)exhibited superior reactivity in the cross-coupling of fluoroalkenes with Grignard reagents bearing?-hydrogens.The two catalytic systems can afford the corresponding decoupled product in good to high yields.The reaction exhibited broad functional group tolerance.The mechanisms of Pd-or Ni-catalyzed cross-coupling reactions of gem-difluroalkenes with Grignard reagents were also discussed.In this chapter,eighteen novel dialkyl-substituted alkenes have been synthesized.2.Exocyclic alkenes are important structural motifs found in many natural products and drugs.In the third chapter,we have developed an efficient Ni-catalyzed Kumada-type double cross-coupling reaction of gem-difluoroalkenes with 1,4-or 1,5-di-Grignard reagents.The reaction proceeded efficiently at room temperature in the presence of 4 mol%NiCl2(dppe).Twenty-seven novel arylmethylenecyclopentanes and arylmethylenecyclohexanes were obtained in high to excellent yields.This method provides a new alternative approach to exocyclic trisubstituted alkenes.3.The modification of organic molecules by the incorporation of a teat-butyl group is a great challenge in organic syntheses owing to the large steric hindrance of the tertiary alkyl group,the isomerization of metal tertiary alkyl species,and the facile elimination of?-hydrogen.In the fourth chapter,we have developed new strategies for the cross-coupling of gem-difluoroalkenes and gem-dibromoalkenes with tertiary,secondary,and primary alkyl Grignard reagents in the presence of CuCN or under transition-metal-free conditions.Seventy-three mono-or dialkylated multisubstituted alkenes have been be synthesized.The structures of the target compounds are depended on the structure of the alkyl moiety in the Grignard reagents and reaction conditions.The results show that the steric effect played a key role in the formation of products.Remarkably,the tertiary and secondary alkylation of gem-difluoroalkenes in the presence of 25 mol%CuCN or under transition-metal-free conditions could afford the tertiary and secondary alkyl-substituted fluoroalkenes in high to excellent yields with excellent Z-stereoselectivity.Meanwhile,simple reaction operation,good functional groups tolerance and avoiding the use of expensive metal catalysts are advantages of these reactions.They provide a general access to multisubstituted alkenes containing bulky tertiary alkyl group.