Synthesis And Catalytic C-H Activation Of Methylene-bridged N-heterocyclic Carbene Palladium Complexes

N-heterocyclic carbenes（NHCs）have strongσ-donor and relatively weakπ-receptor abilities,and a pair of lone pair electrons on carbene can coordinate with transition metals to form NHC metal complexes.Compared with the traditional phosphine ligands,the NHCs have more flexible spatial structure and electronic effects,and can form more stable C-M bonds with the metal centers.The resulting NHC metal complexes have good thermal,air and water stability.After more than 30 years of development,NHC metal complexes have been widely used in many fields,including drugs,materials,organic,medical science and so on.NHC metal complexes with different structures can be designed by introducing coordinating hetero-atoms（such as S,P,O,N）into the side chain or another NHC.In recent years,NHC metal complexes have been widely used as multi-dentate ligands to coordinate with metal centers to form chelated NHC metal complexes with different spatial structures and electronic properties.The resulting chelated NHC metal complexeshave higher structural stability and reactivity than the classical monodentate NHC metal complexes.It shows excellent catalytic performance in C-C and C-X cross-coupling reactions.In this paper,a series of NHC palladium complexes functionalized by methylene-bridged amides and alkyl hydroxyl groups were designed and synthesized,and were applied to the direct arylation of 2-acetylthiophene and the direct arylation of imidazole derivatives to test the catalytic performance of the synthesized complexes.The main contents were presented as following:1)Using L-phenylalanine as raw material,the imidazole carboxylic acid derivatives were synthesized by condensation reaction,and then the side-chain were functionalized to form imidazole amides by acylation and amidation reaction,and the imidazole amides were ionized with diiodomethane to form methylene-bridged amides functionalized imidozolium salts 3a-b.The target compounds and intermediates were characterized by ¹H NMR and ¹³C NMR.2)Using L-phenylalanine and L-leucinol as raw materials,the corresponding imidazole derivatives were prepared by one-step condensation reaction,and the resulting imidazole derivatives were ionized with diiodomethane to form methylene-bridged alkylhydroxyl-functionalized imidozolium salts 5a-b.The target compounds and intermediates were characterized by ¹H NMR and ¹³C NMR.3)The methylene-bridged imidozolium salts 3a-b and 5a-b reacted with palladium acetate at 85℃to form corresponding new methylene-bridged amides or alkylhydroxyl-functionalized NHC palladium complexes 6a-b and 7a-b.Target products were characterized by ¹H NMR,¹³C NMR,HR-MS.The structure of complex 7a was characterized by X-ray single crystal diffraction.4)The direct arylation of imidazole derivatives catalyzed by the NHC palladium complexes was investigated.Using the coupling reaction of 1,2-dimethylimidazole and p-bromoacetophenone as template reaction,the reaction conditions were optimized different reaction conditions were tested,including catalyst NHC-Pd（6a-b,7a-b）,the kind of bases（t-Bu OK,Na H,Na OAc,KOAC,K₂CO₃,CS₂CO₃,K₃PO₄）,the kinds of solvents（Tol,THF,1,4-dioxane,DMF,DMAC,DMSO）,and the loading of catalysts（2 mol%,1 mol%）.The optimized conditions were:the base was potassium acetate（2.0 eq）,the solvent was DMAC,and the amount of catalyst is 1 mol%.The results proved that the methylene-bridged NHC palladium complexes have good substrate universality.Based on the catalytic reaction,the electronic effect and steric hindrance effect of functional groups on the coupling reaction were analyzed and summarized.5)The direct arylation of 2-acetylthiophene catalyzed by the NHC palladium complexes was investigated.Using the coupling reaction of 2-acetylthiophene with p-bromoacetophenone as template reaction,the reaction conditions were optimized different reaction conditions were tested,including catalyst NHC（6a-b,7a-b）,the kinds of bases（Na H,Li₂CO₃,Na OAc,KOAC,K₂CO₃,CS₂CO₃,K₃PO₄）,the kinds of solvents（Tol,THF,1,4-dioxane,DMF,DMAC,DMSO）and the loading of catalyst（2 mol%,1 mol%,0.5 mol%）.The optimized conditions were:the base was potassium acetate（3.0 eq）,the solvent was DMAC,and the amount of catalyst was 2 mol%.The results proved that the methylene-bridged NHC palladium complexes have good substrate universality.Based on the catalytic reaction,the electronic effect and steric hindrance effect of functional groups on the coupling reaction were analyzed and summarized.