【作者】 孙浩；

【导师】 潘毅；

【作者基本信息】 南京大学 ， 有机化学， 2013， 博士

【摘要】 有机胺类化合物是一类非常重要的化合物,它们在有机合成和有机材料中具有重要的应用。有机胺是生命体重要的组成部分,比如蛋白质、核酸等。同时绝大多数药物中都含有有机胺。因此,对于有机胺的合成方法研究对有机化学,生命科学和人类健康都有着重要的意义。烯烃和亚胺的功能胺化反应都是合成有机胺的有效方法,而且近几年这关于这两种方法的研究报道也越来越多。但如何寻找简单有效的方法,可以高选择性的合成有机胺,一直是化学家们所面临的的挑战。本文研究了烯烃的胺卤化反应和亚胺的加成反应,简单有效的合成了各种多功能化的有机胺。1.查尔酮与N-烃基对甲苯磺酰胺的胺卤化反应以N-烃基对甲苯磺酰胺作为新型氮源,研究其与查尔酮进行胺卤化反应,氮原子上烃基的引入既可以增加立体位阻,也可以改变电性,从而影响胺卤化反应的立体选择性,研究表明,在氮原子上导入烃基可以提高反应的立体选择性,得到区域和立体选择性单一的胺卤化产物,反应以简单的无机盐醋酸镍作为催化剂,反应操作简单,底物适用性广,产率较高,最高达到85%。对得到的产物,通过1H NMR、13C NMR、MS、IR和元素分析进行了结构鉴定和确认。对其中的一个化合物进行了X-射线单晶结构分析。2.硝基芳乙烯与N,N---溴代氨基甲酸叔丁酯加成反应的GAP化学我们发现了一种高效率的胺卤化反应,只需要使用1.0mo1%的K3PO4-3H2O催化剂就能催化硝基苯乙烯和N,N---溴代氨基甲酸酯的反应,生成β，β-二溴代产物,反应区域选择性好,产率高(82～99%),反应不需要惰性气体保护,室温下1小时内就能完成。该反应产物的分离,符合GAP化学的要求,通过直接淋洗就可以得到比较纯的产物,不需要使用色谱分离,推测反应的机理可能是自由基的反应。反应可以进行放大化,放大后,反应效率不降低,而且同样很容易通过GAP方法进行产物分离。对得到的产物,通过1H NMR、13C NMR、HRMS和IR进行了结构鉴定和确认。对其中的一个化合物进行了X-射线单晶结构分析。3.查尔酮的胺卤化取代反应在以对甲氧基查尔酮为底物,N-甲基对甲苯磺酰胺为氮源,进行的胺卤化反应研究中,我们发现,没有得到常规的胺卤化产物,而是得到了取代的胺卤化反应产物,反应产率比较好,最高可达81%,顺反产物的比例在4：1->20：1之间。使用容易得到的NBS/TsNHR来代替N-烷基-N-溴代对甲苯磺酰胺,反应同样可以很好的进行。但是,如果查尔酮的苯环上4-位没有甲氧基取代,得到的不是取代产物,而是常规的饱和的邻卤化胺化合物。进一步研究发现,如果中途停止反应,可以得到常规的胺卤化产物,证实取代反应经历加成-消去的过程。所有产物都经过了1H NMR、13C NMR、MS、IR和元素分析的鉴定和确认,对其中的顺反产物和中间体都进行了X-射线单晶结构分析。4.(S)-联萘酚亚胺和1,3-环己二酮的加成反应我们基于(S)-联荼酚设计并合成了一系列的联萘酚磷酰亚胺,这种新型的亚胺可以跟1,3-环已二酮直接发生加成反应,得到非对映体选择性较好的加成产物,最高到99：1,反应在室温下进行,不需要碱作为催化剂,反应产率也比较好,从62%到几乎定量。在弱碱碳酸钾的作用下,(S)-联萘酚磷酰亚胺也可以与丙二酸二乙酯反应,产品经过脱保护,与文献中的化合物旋光度经行比对,确认产物的构型为R构型。所有产物都经过了1H NMR、13C NMR、31PNMP和比旋光度鉴定和确认。5.手性磷酰亚胺和Ni配合物的不对称加成反应以N-磷酰亚胺作为亲电底物,以结合有甘氨酸单元的镍(Ⅱ)配合物作为亲核试剂,在叔丁醇钾的存在下,发生反应,生成α,β-顺式二氨基酯,为单一构型的非对映选择性产物(>99%de),产率也很高(91%-97%)。该反应产物的分离,符合GAP化学分离条件,不需要使用色谱柱。得到的产物都通过1HNMR、13CNMR、31P NMR、HRMS、IR和比旋光度进行了结构鉴定和确认。产物的绝对构型通过X-射线单晶结构分析进行了确认。更多还原

【Abstract】 Organic amines are very important compounds, which have important applications in organic synthesis and organic materials. Organic amine is an important part of life, such as proteins, nucleic acids, etc. At the same time most medicines contain organic amine. Therefore, to find methods for organic amine synthesis are great significance in chemistry, life science and human health.In the past years, the amino functionalization of olefins and imines has been studied for several decades and become the most useful synthetic methods for this functionality. But to develop simple and high selective synthetic approaches to the amino functionality still remain lot of difficulties and challenges.The dissertation focuses on the aminohalogenation and addition to imines, simply gives effective synthesis of varieties of functional organic amines.1. Aminobromination of chalcons with N-alkyl-p-toluenesulfonamideA new nitrogen source--N-alkyl-p-toluenesulfonamide, was used as nitrogen source of aminoholgentation with α,β-unsaturated ketones. The introduction of alkyl halide can increase the steric hindrance of the reaction and change the electrical property, so as to improve the stereoselectivity of aminoholgentation. Through the research, we found that the introduction of N-alkyl group to the nitrogen improved stereoselectivity and gave single regio-and steroselectivited vicinal haloamines. The reaction with simple inorganic salt nickel acetate as the catalyst proceeded smoothly, and was simply operated. The suapplicability was wide and the yield was up to85%. All these products have been characterized by1H NMR,13C NMR, MS, IR and elemental analysis. The stereochemistry was unambiguously confirmed by X-ray analysis.2. Aminobromination of Nitrostyrenes with N,N-dibromo-tert-butylcarbamate via GAP work-up1.0%mol of K3PO4·3H2O was found to catalyze aminohalogenation reaction of nitrostyrenes with N,N-dibromo-tert-butylcarbamate (t-Boc-NBr2). This reaction proceeded smoothly and environmentally friendly to give the β,β-dibromo Boc-protected amines in complete regioselectivity and good to excellent yields (82～99%). The reaction can occur to completion within one hour at room temperature without using protection of inert gases. The GAP chemistry was found to be suitable for simply purifying the products without using traditional purification techniques of column chromatography. A free-radical chain mechanism was suggested for experimental observations. Finally, this reaction showed promising result for practical scale up synthesis. All these products have been characterized by1H NMR,13C NMR, HRMS, and IR. The structure of one product was unambiguously confirmed by X-ray analysis.3. Aminohalogenation and substitution reaction of chalconsIn the study of the amonihalogenation reaction with p-methoxy-chalcon as substrate and N-alkyl-p-toluenesulfonamide as nitrogen sourse, we didn’t find normal aminobromination product, but the substitution product. The yield is up to81%, and E/Z is from4:1to>20:1. If the simple starting material like NBS/TsNHR was used instead of N-methyl-N-bromo-p-toluenesulfonamide, the reaction also proceeded very well. If the methoxy group is not on the para-position of the benzene ring in chalcon, only regular aminobromination product was obtained. When the reaction was stopped before finished, we got the regular amionbromination product. This isolated intermediate discloses that the current system proceeded through the aminobromination process. All these products have been characterized by H NMR,13C NMR, MS, IR and elemental analysis. The stereochemistries of two different configuration and intermediate were unambiguously confirmed by X-ray analysis.4. Asymmetric addition reaction of (S)-BINOL based phosphoryl imine with1,3-cyclohexanedioneChiral N-phosphoryl imines derived from (S)-BINOL which have been designed and synthesized, was used to react with diketones smoothly and gave good diastereoselectivities (up to99:1dr). The reaction proceeded in room temperature and gave good yields (62%-92%). They can also serve as electrophiles for the reaction with diethyl malonate in the presence of potassium carbonate. The R configuration was confirmed by comparing the optical rotation of its deprotected product as reported in literature. All these products have been characterized by1H NMR,13C NMR,31P NMR and polarimetry.5. Asymmetric C-C Bond Formation between Chiral N-Phosphonyl Imines and Ni(Ⅱ)-Complex of Glycine SchiffBaseUnder the base potassium tert-butoxide, the glycine-derived Ni(Ⅱ) complexed was used to reacted with N-phosphonyl imines, and lead to formation of α,β-syn-diamino ester analogs. The reaction gave complete diastereoselectivity (>99%de) products and very high yields (91%-97%). This synthesis was achieved through the GAP chemistry process without using chromatography. All these products have been characterized by1H NMR,13C NMR,31P NMR, HRMS, IR and polarimetry. The configuration of the product was unambiguously confirmed by X-ray analysis.更多还原