Domino Synthesis Of Fused 1,5-benzoazepines Catalyzed By Magnetic Dual-acid Nanocatalyst

1,5-Benzoazepines are a class of heterocyclic compounds with physiological and pharmacological activities.They are multifunctional molecular skeletons with privileged structures which have a very wide range of applications in the fields of medicinal chemistry and organic synthesis.They are often used as anti-anxiety,antibacterial and anti-inflammatory drugs.Traditional methods for the synthesis of 1,5-benzoazepines mostly use a single acid as a catalyst,which possess the weakness of step-by-step synthesis and cumbersome steps,poor selectivity,low yield.Therefore,it is of great significance to develop a green and efficient catalytic domino reaction for one-pot synthesis of novel 1,5-benzoazepines.Magnetic nano-supported catalyst is a new type of heterogeneous catalyst with high catalytic activity,reusability,easy separation and strong stability.It shows excellent catalytic performance in organic chemical reactions.Multicomponent domino reaction is a simple and efficient synthesis method in organic reactions.It is usually possible to synthesize organic compounds with high yield in an organic reaction system,which is in line with the synthesis concept of green sustainable development.Therefore,in this paper,a magnetic dual-acid nanocatalyst loaded with Lewis acid and Br（?）nsted acid was designed and prepared,and its structure and properties were characterized and analyzed.Two types of the three-component domino reactions catalyzed magnetic dual-acid nanocatalysts were developed to synthesize fused 1,5-benzoazepines.47 polycyclic fused 1,5-benzodiazepines and 4 indanedione fused1,5-benzothiazepines were synthesized.The specific research work is as follows:1、A magnetic dual-acid nanocatalyst loaded with both Br（?）nsted acid and Lewis acid was designed and prepared.The magnetic nanoparticle Co Fe₂O₄ was used as the magnetic core,and the surface was coated with Si O₂.The silane coupling agent（APTES）was chemically bonded to achieve the immobilization of the amino group.The 2-aminoterephthalic acid was immobilized in the form of amide bond and the coordination of copper chloride was achieved.A new type of magnetic dual-acid nanocatalyst（Co Fe₂O₄@Si O₂@APTES@ATA@Cu Cl₂）with both Br（?）nsted acid sites（-COOH）and Lewis acid sites（Cu Cl₂）was successfully prepared.The structure,composition and morphology of the catalysts were characterized by infrared spectroscopy（FT-IR）,X-ray diffraction（XRD）,scanning electron microscopy（SEM）,energy dispersive spectroscopy（EDS）,transmission electron microscopy（TEM）,nitrogen absorption-desorption experiment（BET）,X-ray photoelectron spectroscopy（XPS）and vibrating sample magnetometer（VSM）.2、A magnetic dual-acid nanocatalyst（Co Fe₂O₄@Si O₂@APTES@ATA@Cu Cl₂）catalyzed three-component domino reaction for the synthesis of polycyclic fused1,5-benzodiazepines was developed.Using substituted 1,2-phenylenediamine,1,3-dicarbonyl compounds（1,3-cyclopentanedione,1,3-cyclohexanedione,5,5-dimethyl-1,3-cyclohexanedione,1,3-indandione）and ethyl acetylpyruvate as raw materials,Co Fe₂O₄@Si O₂@APTES@ATA@Cu Cl₂ as catalyst,ethanol as solvent,23polycyclic fused 1,5-benzodiazepines were synthesized in one pot.The reaction achieves intramolecular cyclization by constructing an active intermediate of the enamine-enamine structure in the molecule for the first time,followed by a coupling reaction.The products were characterized by ¹H NMR,¹³C NMR,IR,MS and elemental analysis.The single crystal structure of the target compound 4c2 was combined to prove the correctness of the structure of such compounds.A possible reaction mechanism was proposed.This method doesn’t apply the traditional synthesis method of constructing enamine-imine structural intermediates but utilize intramolecular construction of enamine-enamine structural active intermediates to synthesize polycyclic fused 1,5-benzodiazepine compounds,and the magnetic dual-acid nanocatalyst is green and recyclable.It is of great significance for the green synthesis of structurally diverse 1,5-benzodiazepines.3、A new method for the synthesis of 24 novel indandione fused 1,5-benzodiazepines and4 indandione fused 1,5-benzothiazepines catalyzed by magnetic dual-acid nanoparticles was developed.Firstly,substituted 1,2-phenylenediamine,1,3-indanedione and aldehydes（benzaldehyde,phenylacetaldehyde,phenylpropanal）or dicarbonyl compounds（isatin,1-phenyl-1,2-propanedione,ethyl acetoacetate）were used as reaction raw materials,anhydrous ethanol was used as the green reaction solvent,Co Fe₂O₄@Si O₂@APTES@ATA@Cu Cl₂ was used as the catalyst of the reaction,and 24multi-functional substituted indanedione-fused 1,5-benzodiazepine compounds were synthesized in series.Using Co Fe₂O₄@Si O₂@APTES@ATA@Cu Cl₂ as the catalyst,aldehydes（phenylacetaldehyde,phenylpropanal）and 1,3-indanedione as raw materials,the Knoevenagel reaction was carried out at room temperature to synthesize intermediateα,β-unsaturated carbonyl compounds.Without separating the intermediates,the reaction was continued with substituted 2-aminothiophenol in anhydrous ethanol,and 4 unreported indanedione-fused 1,5-benzothiazepine compounds were synthesized in one pot by domino reaction.The 28 target compounds were characterized by ¹H NMR,¹³C NMR,IR,MS and elemental analysis.The target compound 6b4 was analyzed by X-ray single crystal diffraction to prove the correctness of the structure.The effects of reaction conditions on the yield of target compounds were investigated,the optimal reaction conditions were screened,and the possible reaction mechanism was proposed.The advantages of this method are atomic economy,high yield of target compounds,and good selectivity.The catalyst is green and recyclable.The one-pot synthesis of 1,5-benzoazepines by three-component domino reaction provides a new green and efficient method for the synthesis of such compounds.