N-Heterocyclic Carbene-Catalysed Synthesis Of Organofluorine Compounds Through Reaction Of Aldehydes And Ketones With Silylated Reagents

Organofluorine compounds have found widespread applications in pharmaceuticals,agrochemicals and medicinal chemistry.The introduction of fluorine atoms or fluorinated moieties into organic molecules has become a powerful strategy in new drug discovery.As a result,the development of highly efficient methodologies for the synthesis of fluoroorganics is of great importance.As an important type of organocatalyst,N-heterocyclic carbenes(NHCs)have been utilized widely in organic synthesis.In particular,NHCs exhibit extremely high reactivity toward the activation of silylated reagents.In this dissertation,NHCs-catalysed difluoroesterification reaction,direct difluoromethylation reaction,Peterson fluoroolefination and multifluorophenylation reaction of carbonyl compounds have been successfully developed.In the first part,NHCs-catalysed difluoroesterification reaction between carbonyl compounds and ?–silyldifluoroacetate was discovered.NHCs derived from imidazolium salts can catalyse the addition efficiently under very mild reaction conditions to afford the desired products in 52-99% yields.The reaction can be scaled-up easily and high yield maintained.NMR experiments indicated that NHCs can catalyse the reaction via the activation of ?–silyldifluoroacetate or aldehydes.In the second part,NHCs and the Schwesinger's superbase-catalysed direct difluoromethylation reaction between carbonyl compounds and Me3SiCF2 H was studied.NHCs exhibited very low efficiency for the reaction and the desired product was obtained in about 28% yield after optimization of reaction conditions.The Schwesinger's superbase can efficiently activate the Si–CF2H bond and initiate this difluoromethylation reaction under very mild conditions.Aromatic aldehydes,heteroaromatic aldehydes,aliphatic aldehydes as well as biaryl ketones underwent the addition smoothly to produce the corresponding difluoromethylated adducts in 42–99% yields.The reaction can also be conducted on gram-scale without sacrifcing reaction yield.In the third part,NHCs-catalysed Peterson fluoroolefination reaction of aldehydes,2,2,2-trifluoroacetophenone and fluorinated silyl ketene acetal was developed.NHCs generated from imidazolium precursors can promote this olefination reaction efficiently to produce the corresponding ?-fluoroolefines in 32-88% yields with > 25:1 Z/E selectivities.In the final part,NHCs-catalysed pentafluorophenylation reaction between aldehydes and pentafluorophenyltrimethylsilane was developed.NHCs can promote the reaction efficiently under mild conditions.Both aromatic and aliphatic aldehydes are suitable reactants,producing the desired adducts in 49-99% yields.Under similar reaction conditions,NHCs can also facilitate tetrafluorophenylation of aldehydes and bis(trimethylsilyl)tetrafluorobenzene efficiently,affording tetrafluorophenylated diols in good yields.