Synthesis Of Heterocyclic Compounds From Acetylene Ketones Catalyzed By Titanocene/zirconium Metal Catalyst

The catalytic conversion of 1,3-ynones is an important method for the synthesis of heterocyclic compounds,and the development of green synthetic routes based on cheap metal catalysts has become an important research topic in this field.Titanium/zirconium is a group IVB metal with high abundance and low toxicity.It can activate substrates containing carbon-carbon triple bonds,but these high-activity titanium/zirconium-containing catalysts have poor stability and require strict experimental conditions.How to take into account the activity while improving its stability is a challenging task.The titanocene/zirconocene complex has good stability due to the existence of the Cp ring,and has made great progress in the fields of catalyzing olefin polymerization and heterocyclic synthesis,but there are few reports in the field of catalytic conversion of 1,3-ynones.Based on the theory of coordination chemistry and the research foundation of our group,the development of coordination environmental regulation strategies is expected to balance the activity and stability of titanium/zirconium metal catalysts,and achieve high-efficiency catalytic conversion of 1,3-ynones.In this thesis,inert Cp₂TiCl₂/Cp₂Zr Cl₂ was used as the catalyst precursor,and the catalytic activity of the titanium/zirconium metal center was enhanced by changing the number of Cp ring,adjusting the type of solvent/ligand,and changing the type of center metal,etc.Meanwhile,the balance of catalyst activity and stability has been successfully adjusted,and the selective synthesis of five-membered ring,six-membered ring,and seven-membered ring nitrogen-containing heterocyclic compounds with 1,3-ynones as substrates have been realized,through which Titanium/zirconium catalytic system and coordination chemistry theory have been substantially advanced.The main research contents and innovation contents are as follows:（1）Through the dual adjustment of ligand and solvent for the activity and stability of the inert Cp₂TiCl₂,a new type of ligand activation strategy for mono-Cp titanocene has been developed.By using 2 mol%Cp₂TiCl₂ as the catalytic precursor,isophthalic acid as the ligand,the substrates of 1,3-ynones and o-phenylenediamine were successfully catalyzed in an alcohol solvent at room temperature leading to 25cases of 1,5-benzodiazepine derivative,with the yield up to 96%.Mechanism research experiments inluding ¹H NMR and ESI-MS show that the catalytic species is Cp Ti（OMe）₂（η¹-C₈H₅O₄）,and the alcohol solvent and o-phenylenediamine as the substrate together promote the formation of the catalytic species.The catalytic system is stable and resistant to water and oxygen.It can still maintain a high catalytic efficiency after five cycles of catalyzing the reaction in an air atmosphere,and can efficiently catalyze the reaction in a 70%alcohol-water system.In the in situ synthesized half-titaocene complex,the Cp ring and the alcohol ligand promote the stability of the titanium metal center,while a dissociable carboxylic acid ligand provides a catalytically active site.Therefore,the balance of the stability and activity of the titanocene catalyst has been successfully adjusted.（2）Aiming at the synthesis of 1,5-benzothiazine by 1,3-ynone and o-aminothiophenol,through the activation of by natural amino acid ligands for the inert Cp₂Zr Cl₂,a highly efficient Lewis acid/Br?nsted base bifunctional catalysis system has been developed.In the novel developed reaction,5 mol%of Cp₂Zr Cl₂ was used as the catalyst precursor,L-phenylalanine was used as the ligand,and the substrates of 1,3-ynone and o-aminothiophenol was successfully catalyzed,leading to 22 cases of 1,5-benzothiazine derivatives,with the yield up to 97%,among which 13 products were reported for the first time.¹H NMR and ESI-MS studies show that the catalytic species was Cp₂Zr[OCOCH（NH₂）CH₂C₆H₅]₂.Through MS analysis,the adducts of the catalyst and the reaction substrate or reaction intermediates was characterized,indicating the Lewis acidic role of zirconocene center.At the same time,through the control experiment and NMR titration analysis,the amino group of the ligand acting as a Br?nsted base catalytic site was proposed.Furthermore,the coordination mode of the zirconocene complex in the catalytic reaction was studied through theoretical calculations.In this work,a bifunctional catalyst was obtained by activating the zirconocene complex with an amino acid ligand for the first time,and established an efficient catalytic mode as Lewis acid-Br?nsted base combination,viewed as the reason for the improved activity and selectivity of the reaction.（3）The effects of different solvents on the catalysts and reactions were investigated by using 1,3-ynone and o-aminothiophenol as raw materials.The one-pot synthesis of quinolines was conducted in an alcohol solution containing 1-naphthol with a selectivity of 9:1.Mechanistic studies demonstrated that the reaction was a free radical process,in which the free radicals probably generated by the cleavage of the Zr-OR bond.With the addition of alcohol,the selective synthesis of1,5-benzothiazine with quinoline in a non-alcoholic solvent was convert to a selective synthesis of quinoline with benzothiazole,demonstrating that the alcohol solvent plays an important role in modulating the activity and selectivity of the zirconocene complexes.The benzothiazole compounds could be obtained with high selectivity when tert-butanol was used as the solvent and potassium tert-butoxide was worked as the catalyst.Furthermore,a method for the synthesis of quinolines by desulfurization with iodine was developed based on the free radical desulfurization process.23 kinds of quinolines were obtained under above conditions in yields of50-99%.（4）A pre-transition metal Zr and post-transition metal Pd bimetallic catalytic system was developed for the one-pot synthesis of quinolines.The one-pot method includes the preparation of 1,3-ynones in situ and the subsequent addition of o-aminothiophenol,which provides a green reaction path.A ppm-level carbene-palladium complex was used as catalyst for the insertion of carbonyl couplings from iodobenzene,phenylethynyl and CO to form 1,3-ynones.Then,the continue addition of o-aminothiophenol and zirconocene Lewis acid catalyst into the pot lead to the successful synthesis of quinolines.Controlled reaction studies show that the reaction undergo a four-step process,in which involving Sonogashira coupling,Michael addition,cyclization condensation and desulfurization,without the isolation of intermediate 1,3-ynone.This work provides a new method for the synthesis of quinoline derivatives with simple raw materials and easy operation,and a successful case for the combination of the former transition metal Zr and the latter transition metal Pd catalytic system.