Metal-mediated Carbon Dioxide Activation

Being an important part in carbon cycle on earth, carbon dioxide itself is considered as one of the most ideal C1 synthon in constructing C-C bond especially carboxylic acid derivatives due to its non-toxic and abundant feature. However, owing to its high thermodynamic and kinetic stability, the activation of CO2 is still remaining a big challenge. We have been focusing our attention on the synthesis of bioactive and synthetically useful molecules via CO2 activation reactions under mild conditions. The whole dissertation may be divided into the following five parts: Part I:Metal-mediated allylation of carbon dioxide1. We firstly developed an indium-mediated allylation reaction of CO2 with allylic halides. Allylic bromides, iodides and even chlorides could be converted to the corresponding 3-alkenoic acids under a CO2 atmosphere of 2.0 MPa with a wide substrate scope and an excellent functional group tolerance. The branch-type product was afforded regiospecifically starting either from a linear or a branch-type allylic halide.2. A zinc-mediated allylation reaction of CO2 under room temperature with a CO2 balloon was developed in order to solve the scale-up and pressure problem in the In-mediated process. The reaction could easily be scaled-up to 70 mmol with an outstanding substrates scope and regioselectivity. A dramatic LiOAc effect on the activation of CO2 was observed.Part Ⅱ:The steric effect-controlled zinc-mediated carboxylation of 2-alkynylic bromidesA steric effect-controlled zinc-mediated carboxylation of 2-alkynylic bromides under an atmospheric pressure of CO2 provided by a balloon has been developed after very careful screening on the reaction conditions:2-substituted 2,3-butadienoic acids were afforded from primary 2-alkynylic bromides while the carboxylation of secondary 2-alkynylic bromides yielded 3-alkynoic acids in decent yields and a nice substrate scope. The reaction may be conducted on 100 mmol scale to afford 10 g of 2,3-butadienoic acid. A base-mediated rearrangement of 3-alkynoic acids to tri-substituted 2,3-butadienoic acids was also realized in high yields.Part Ⅲ:Pd(0)-catalyzed ligand controlled synthesis of multi-substituted allenesA Pd(0)-catalyzed ligand controlled synthesis of multi-substituted allenes starting from propargylic carbonates and ZnR2 has been reported. Tri-substituted allenes were afforded via a reductive elimination process using SPhos as a ligand while a direct P-H elimination type product,1,3-disubstituted allenes, were yielded using Gorlos-Phos as a ligand. Commonly encountered reactive functional groups were tolerated. We surprisingly found that the reaction might be accelerated by a CO2 atmosphere as compared with the results under an Ar atmosphere. In some cases, the reaction proceeded smoothly with a CO2 balloon while an Ar atmosphere led to a complicated result.Part IV:Ni(cod)2-catalyzed hydrocarboxylation of 2-alkynylanilines and homopropargyl aminesBased on our previous studies, the substrate scope and functional group tolerance on Ni(cod)2-catalyzed hydrocarboxylation of 2-alkynylanilines and homopropargyl amines under very mild conditions (room temperature and 1 atm CO2) were carefully studied affording hydrocarboxylation products with exclusive regio-and (E)-stereoselectivities. Functionalities such as ester, cyano and hydroxyl group were well tolerated.Part V:ZnEt2-mediated cyclic anti-azacarboxylation of 2-alkynylanilineIn the absence of a nickel catalyst, a direct anti-azacarboxylation of 2-alkynylaniline mediated by ZnEt2 was achieved affording indole-3-carboxylate acids in high yields at room temperature with a CO2 balloon. Various functional groups were tolerated and the method has been applied to the gram-scale synthesis of LotronexTM-aa drug molecule used for the treatment of IBS (irritable bowel syndrome) developed by GlaxoSmithKline company.