2 - Benzazepine 1 - Synthesis Of Benzo-thia-zhuo New Method

The benzazepine motif occurs as a core structure which has found to exhibit wide biological activities.Now many drugs on market which are used as therapy of mental diseases contain a benzazepine skeleton.As a member of benzazepines,2-benzaepines occur as alkaloid in nature,and also exhibit good biological activities too.However,their amount in nature is so deficient that the people's demand can't be satisfied,therefore,it's necessary to prepare them by organic synthesis.Till now,many methods such as Pictet-Spengler cyclization,Schimdt reaction,and ring-closing metathesis have been found to prepare 2-benzazepines.Some compounds containing 1-benzothiepine skeleton are reported to exhibit good biological activities,but their occurrence in nature is even more deficient,and are obtained mainly by organic synthesis.However,the reported methods to prepare 2-benzazepines and 1-benzothiepines either required expensive reagents or suffered from lengthy steps.Here,we want to investigate on preparing these compounds by novel methods which are short-steps and economically convenient.The first chapter is a brief review on the research of 2-benzazepines and 1-benzothiepines,and also introduces some typical synthetic methods for them.In chapter 2,a series of N-benzylmethylamines(23) were prepared from benzaldehydes by reductive amination,and then converted to aminol ethers(21).A novel tandem Mannich reaction of electron-rich benzyl iminium ions generated from 21 with alkyl enol ethers(C-N bond formation) and Friedel-Crafts-type alkylation(C-C bond formation) mediated by TiCl₄ was developed.The protocol was amenable to provide the tricyclic furo[3,2-c][2]benzazepine and respectively pyrano[3,2-c][2]benzazepine derivatives with 2,3-dihydrofuran or 3,4-dihydro-2H-pyran as reagents,and provide 2,3-dihydro-1H-benzazepines with ethyl vinyl ether.When benzyl iminium ions reacted with isocyanate under the catalysis of TiCl₄,the reaction didn't give the expected benzodiazepines 32,but the trivial products urea 33.When phenyl acetyl chloride was used to react with isocyante under the catalysis of TiCl₄,a tandem reaction proceeded to give isoquinoline-1,3(2H,4H)-dione 35.In chapter 3,firstly a series of cyclopropanecarbaldehydes 41 were prepared from ethyl cinnamate by Corey-Chavkovsky reaction.After screening for the reaction reagents and conditions,cycloparopanecarbaldehydes' ring-opening by benzenethiols' nucleophilic attack(homo-Michael reaction) catalyzed by(S)-proline was developed,and the reaction gave moderate yields ofγ-phenylthio-substituted butyraldchydes.When other nucleophilic regents such as I,NHR₂,ROH,ArOH were used to attack cyclopropanecarbaldehydes under the catalysis of several organocatalysts,the reaction either didn't occur or gave no expected product.In chapter 4,we further investigated the reaction of cyclopropanecarbaldehydes with o-thiosalicylaldehydes under the catalysis of(S)-proline.A tandem homoconjugate addition/aldol reaction proceeded to offer 1-benzothiepines.The structure of them was unambiguously confirmed by an X-ray crystal diffraction analysis for 2-(4-methoxyphenyl)-7-methyl-2,3-dihydrobenzo[b]thiepine-4-carbaldehyde(66e). However the reaction occurs with no enantioselectivity.This can be attributed to the racemic starting materials and the low stereoselectivity of the reaction.When we used the chiral starting material(1R,2R)-2-benzylcyclopropanecarbaldehyde(prepared from cinnamaldehyde by asymmetric Simmons-Smith reaction) as substrate,the reaction gave the chiral products with high ee%.The chapter 5 is the experimental section,which record the synthesis of the compounds and the corresponding spectra data.