Highly Selective Transfer Hydrogenation And Hydrogenolysis Reaction Based On Acid-resistant Iridium Catalysis

Metal-catalyzed transfer hydrogenation as well as hydrogenolysis reactions of unsaturated and carbon-heteroatom bonds are effective methods for constructing a variety of high value-added saturated systems,which are widely used in the fields of scientific research,chemical industry and medicine.Therefore,the development of novel metal catalysts and more efficient and environmentally friendly catalytic strategies is of great practical significance and application value.In this thesis,we constructed a variety of high-added-value products via transfer hydrogenation or hydrogenolysis reactions catalyzed by iridium complexes with pyridine-imidazoline coordination using cheap and easily available 2-arylbenzoic acid,cis-2-acylcycloalkyl-1-acids,McGeachin-type bisaminals,and 11-aryldibenzoxazepines as synthetic building blocks.The diastereoselectivity of the reductive lactonation reaction,the chemoselectivity of the hydrogenolysis reaction,the enantioselectivity of the transfer hydrogenation were explored in depth.The following achievements have been made.(1)Based on acid-resistant iridium catalysts,an efficient and practical strategy was developed for the synthesis of 3-substituted phthalides from 2-acylbenzoic acid via reductive γ-lactonization reaction.The method,using water as solvent and formic acid as reducing agent,has the advantages of high yield,good functional group compatibility,high catalyst efficiency(substratecatalyst molar ratio as high as 5000),environmental friendliness,easy operation,easy product purification(by filtration or extraction)and easy largescale preparation.Mechanistic studies have shown that hydrogen bonding between the carboxyl and carbonyl groups on the substrate activates the carbonyl group and then accelerates the hydride reduction.Kinetic isotope effect(KIE)studies reveal that the formation of iridium hydride is likely to be the rate-determining step in the reaction.The products were derivatized to give3-substituted phthalide derivatives with potential biological activities and applications.The decagram-scale preparation of the drug molecule(±)-3-butylphthalide proves the utility and application prospects of the reaction.(2)Based on the above iridium-catalyzed reductive lactonization strategy,a high yield and high diastereoselective synthesis of diastereoselective pure bicyclic and polycyclic syn-γ-lactones using cis-2-acyl-cycloalkyl-1-acids as substrates has been developed.For the first time,the highly diastereoselective reductive lactonization of cis-2-acyl-cycloalkyl-1-acids under acidic conditions has been achieved.The method is characterized by good diastereoselectivity,wide substrate range,and high catalytic efficiency.Mechanistic studies indicate that the formation of iridium hydride is the ratedetermining step of the reaction,while the hydride transfer step is the diastereoselective determining step.The huge steric hindrance of iridium hydride and intramolecular hydrogen bonding are the key factors for the control of diastereoselectivity.Conformational analysis and the Bürgi-Dunitz angle of attack indicate the plausibility of high diastereoselectivity.In addition,a more general rule of thumb based on facet-selectivity analysis is proposed to inform future interpretations and predictions of related stereochemistry.(3)In a selective transfer hydrogenolysis reactivity study of McGeachintype bisaminals,two new methods for the synthesis of chiral or racemic McGeachin-type bisaminals catalyzed by p-toluenesulfonic acid hydrate and trifluoroacetic acid,respectively,have been developed.Two molecules of omethylaminobenzaldehyde were condensed with one molecule of chiral or achiral amine to obtain optically pure or racemic bisaminals,respectively.These two methods,with a wide range of substrates,high yields,and easy operation of gram-scale synthesis,provide a basis for further investigation of the reactivity of McGeachin-type bisaminals.Based on an iridium-catalyzed transfer hydrogenation system,a selective transfer hydrogenolysis reaction of McGeachin-type bisaminals under neutral conditions was developed.Using silane as the hydrogen donor,two carbon-nitrogen bonds of bisaminals were selectively severed for 13-alkyl bisaminals to give N-alkyldibenzylamine products,and one carbon-nitrogen bond of bisaminals was selectively severed for 13-aryl bisaminals to give tetrahydropyrimidinium derivatives.The special structure of the N-alkyldibenzylamine products has the potential to be used as amine catalysts and as polydentate nitrogen ligands.The reactivity of the McGeachin type bisaminals and their product applications need to be further investigated.(4)A novel chiral bis-iridium complex containing both an iridacycle and an iridium chelate has been developed for the highly enantioselective transfer hydrogenation of 11-aryldibenzo [b,f][1,4] oxazepines under acidic conditions.Using formic acid as the hydride donor and a mixture of water and hexafluoroisopropanol as the solvent,chiral 11-aryl-10,11-dihydrodibenzo[b,f][1,4] oxazepines was obtained in 96% yields and 99:1 er values.Comparative experiments showed that the catalytic reaction site under acidic conditions was the iridium chelate portion rather than the iridacycle portion.KIE demonstrated that the β-H elimination of iridium formate to produce iridium hydride is likely to be the rate-determining step of the reaction,whereas the hydride transfer of iridium hydride to the protonated imine is the key step in determining enantioselectivity.Based on the fact that the methodology is selectively effective for 11-aryl substrates and the presence of multiple aromatic ring structures in the chiral catalysts,it is hypothesized thatπ-π stacking interactions between the catalysts and the substrates,as well as hydrogen bonding interactions involving the participation of formic acid,have an important influence in the control of enantioselectivity.A library of Cp*Irbased chiral catalysts was established,which is important for the future development of practical asymmetric synthesis methodologies.In summary,hydrogenation or hydrolysis reactions in the aqueous phase or in alcohols are explored using bis-nitrogen chelated Cp*Ir catalysts as the main line of research in this thesis.A series of studies were carried out from the perspectives of chemoselectivity,stereoselectivity and enantioselectivity.It enriches the variety of Cp*Ir catalysts,broadens their application scope,makes up for some shortcomings of the current research,and promotes the further development of Cp*Ir catalysts.