Transition Metal Copper And Silver Mediated C-N And C-C Coupling Reactions And Mechanistic Investigation

The development of organometallic chemistry provides many highly efficient and selective methods for organic synthesis, which promotes the synthetic technique to a new level. Among them, the transition-metal-catalyzed coupling reaction is one of most effective way to construct the carbon-carbon and carbon-heteroatom bond. Up to now, Pd and Ni are still the major catalysts in the transition-metal-catalyzed coupling reactions. Meanwhile, as a cheap catalyst of low toxicity, the involvement of copper in coupling reactions has recently caught much attention and significant progresses have been achieved in this emerging field. However, there still remain many problems in copper-catalyzed coupling reaction, especially the lack of understanding of the reaction mechanism and active catalyst species. And this is indeed the opportunities and challenges faced by the copper-catalyzed coupling reaction.In this thesis, a brief introduction of the organometallic chemistry and transition-metal-catalyzed coupling reaction was first reviewed. Then the development of copper and silver catalyzed or mediated coupling reaction was surveyed in details. The research work of this thesis was focused on the copper and silver catalyzed or mediated novel C-C and C-N bond forming reactions and the corresponding mechanistic investigation. Details are as followings:1. Based on an umpolung design, an efficient copper catalyzed electrophilic amination of arylboronic acids by using N-chloroamides was successfully developed. The transformation proceeded in high yields at room temperature to form diarylamides and tolerated a wide variety of functional groups, including iodo, bromo, and chloro moieties. Preliminary mechanistic studies by using in situ IR and NMR spectroscopy supported the proposed Cu(Ⅰ)-Cu(Ⅲ) catalytic cycle mechanism.2. An efficient copper catalyzed α-arylation/C-C activation process was developed. Various α-aryl ketones, esters and amides could be efficiently synthesized by this novel method. This method is simple, general, and practical which complemented the classic method for the rapid construction of C-C bonds to a carbonyl moiety. The role of H2O was unprecedented, which assisted the C-C activation. Based on this information, pushed by the crucial alcohol, both selectivity and conversion of the copper-catalyzed deacetylative α-arylation of β-keto esters and amides could be enhanced satisfactorily.3. Based on the copper catalyzed a-arylation, insights toward the Cu-catalyzed C-C coupling reaction were investigated through operando IR, in situ XANES/EXAFS and DFT calculation.(1) The labile complex of Cu(Ⅰ) and C-nucleophile was directly observed and evidenced by operando IR and in situ XANES/EXAFS.(2) Kinetic studies and computational calculations revealed that this labile β-diketone Cu(Ⅰ) species might be the active catalyst for the copper-catalyzed C-C coupling reaction. The labile Cu(Ⅰ) species could rapidly disproportionate to the spectator Cu(Ⅱ) and Cu(0) species in the reaction, which was an off-cycle process.(3) PPh3could stabilize the labile Cu(Ⅰ) β-diketonate species. However, it also inhibited the reactivity of the C-C coupling reaction.(4) In this copper-catalyzed arylation,β-diketone might act both as the substrate and the ligand.4. The unprecedented N-ligands effect on the copper acetylide species which dramatically influences Sonogashira coupling reaction was demonstrated. Meanwhile, by using iPr2NH as the solvent, the transmetalation step of the Pd/Cu synergistically catalyzed Sonogashira coupling reaction was established as the rate-limiting step. It was also the first quantitative measurement of the kinetic over the transmetalation step for Csp-Csp2bond formation from a "live" catalytic reaction. The activation enthalpy is determined as8.5kcal/mol for the transmetalation.5. Based on the a-alkynylation of carbonyl compounds, a novel silver-mediated highly selective oxidative C-H/C-H functionalization of1,3-dicarbonyl compounds with terminal alkynes for the creation of polysubstituted furans and pyrroles in one step was demonstrated. Promoted by the crucial silver species, perfect selectivity and good to excellent yields could be achieved. This protocol represents an extremely simple and atom-economic way to construct polysubstituted furans and pyrroles from basic starting materials under mild conditions. Meanwhile, the concept of "Oxidative Click Reaction" was proposed. Based on this concept, a novel silver-mediated highly selective C-H/N-H oxidative cross-coupling/cyclization between2-aminopyridines and terminal alkynes has been developed. This approach provided a simple way to construct heteroaromatic imidazo[1,2-a]pyridines. By using this protocol, the marketed drug Zolimidine (antiulcer) could be synthesized easily.