2-苯并氮杂卓和1-苯并硫杂卓类化合物的合成新方法研究

【作者】 李良喜；

【导师】 王全瑞；

【作者基本信息】 复旦大学 ， 有机化学， 2009， 博士

【摘要】 苯并氮杂卓是一类很重要的化合物,具有很强的生理活性和药用价值。目前市场上很多销售较好的治疗精神疾病的药物都属于苯并氮杂卓类化合物。很多2-苯并氮杂卓在自然界中以生物碱的形式存在,具有极强的生理活性。但是它们在自然界存在的数量不能满足人们的需要,因此需要通过有机合成来制备这类化合物。人们发现了很多合成方法如Pictet-Spengler环化,Schmidt反应,烯烃环化复分解反应制备2-苯并氮杂卓。1-苯并硫杂卓在自然界中存在数量很少,但是它们都具有很好的生理活性,目前主要由人工合成得到这类化合物。但是报道过的合成方法大都步骤较长或使用到极昂贵的试剂。因此我们希望通过新颖的步骤较短且经济适用的方法来制备这两类化合物。本论文第一章主要介绍了2-苯并氮杂卓和1-苯并硫杂卓的研究意义和现状,还对他们的合成方法做了简单的综述。论文第二章中首先制备了一系列N-甲基苄胺（23）,然后又由它们制备了N-甲基-N-苄基乙氧甲基胺（21）。以N-甲基-N-乙氧甲基-3,4-二甲氧基苯甲胺（21a）为底物,摸索出了一个新的串联反应,也就是它与2,3-二氢呋喃在TiCl₄催化下发生苄基亚胺正离子与烯醚的Mannich反应（形成C-N键）和Friedel-Crafts烷基化（形成C-C键）的Mannich/Aromatic electrophilic substitution串联反应得到2-苯并氮杂卓类化合物。利用这个反应,我们用N-甲基-N-苄基乙氧甲基胺（21）与2,3-二氢呋喃,3,4-二氢吡喃得到了一系列的2-苯并氮杂卓类化合物,其中有些是含有三环结构的2-苯并氮杂卓。N-甲基-N-苄基乙氧甲基胺（21）和乙烯基乙基醚反应得到了2,3-二氢-1H-苯并[c]氮杂卓27。但是只有N-甲基-N-苄基乙氧甲基胺的苯环上有强供电子基团甲氧基存在下才会发生这类反应,当苯环上没有甲氧基取代时,反应只得到Mannich反应产物,也就是在2,3-二氢呋喃和3,4-二氢吡喃上亲电取代的产物。当N-甲基-N-苄基乙氧甲基胺（21）在TiCl₄催化下生成的亚胺正离子与异氰酸酯反应时,反应没有得到设想的产物苯并二氮杂卓,而得到无意义的脲。当用苯乙酰氯和异氰酸酯在TiCl₄催化下发生了串联反应得到了isoquinoline-1,3（2H,4H）-dione 35。论文第三章中首先由肉桂酸乙酯出发经Corey-Chavkovsky反应合成了一系列环丙烷甲醛类化合物41,然后通过筛选条件,得到在（S）-脯氨酸催化下使用苯硫酚45作为亲核试剂对环丙烷甲醛41的亲核开环条件。然后以一系列苯硫酚45作为亲核试剂对一系列环丙烷甲醛41的亲核开环反应做了研究,反应都以中等收率得到了γ-苯硫基丁醛类化合物44。我们使用其他的一些亲核试剂如I^-,NHR₂,ROH,ArOH在有机催化下对环丙烷甲醛41的亲核开环反应进行了尝试,但是没有得到结果。论文第四章中介绍了在（S）-脯氨酸催化下,环丙烷甲醛41与2-巯基苯甲醛65发生了homo-Michael/Aldol串联反应,一步反应得到了1-苯并硫杂卓66,但是得到的产物却是消旋的,有可能是因为底物使用的是消旋的2-苯基环丙烷甲醛,而反应没有对映选择性,得到产物的ee值为0。产物的构型进一步由化合物66e的单晶衍射得到确证。我们设想串联反应中的关键反应亲核开环有可能在反应中手性被传导到产物中,如果我们使用手性的2-苯基环丙烷甲醛,反应可能得到手性产物1-苯并硫杂卓。因此我们从肉桂醛出发以不对称Simmons-Smith反应制备了手性底物（1R,2R）-2-苯基环丙烷甲醛41f,它与2-巯基苯甲醛65在（S）-脯氨酸催化下以较高的ee值得到了手性产物1-苯并硫杂卓66。这样就验证了我们的设想。论文第五章实验部分介绍了所有化合物合成的实验步骤,记录了化合物的IR,¹H NMR,¹³C NMR,GC-MS及HRMS。更多还原

【Abstract】 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.更多还原