脂肪族MBH加合物与N-芳杂环的不对称烯丙基胺化反应

发布时间：2018-05-20 13:10

本文选题：脂肪族MBH加和物 + N-杂芳环化合物　；参考：《河南师范大学》2017年硕士论文

【摘要】：光学活性的α-烷基-N-杂芳基化合物在天然产物、农药和药物中普遍存在,它具有生物活性,因此,寻求有效的方法来构建含有α-烷基的N-杂芳环化合物是非常需要的。MBH加合物的不对称烯丙基化反应,是制备光学活性的α-烷基化合物常用方法之一,芳香族MBH加和物与氮杂环的不对称烯丙基反应已相对成熟了,然而,因为脂肪族MBH加和物的不对称烯丙基胺化很少报道,脂肪族MBH与芳香族MBH加和物相比,活性较低,较小的空间差异、亲电性弱等特点使反应的结果差强人意,除此外,MBH加和物与这些亲核性较弱的N-杂芳环化合物的烯丙基反应很少,例如苯并咪唑、嘌呤、苯并三氮唑等。首先,对过渡金属钯催化的脂肪族MBH加和物与N-杂芳环化合物不对称烯丙基胺化反应进行了一系列的研究和考察,最初,选择苯并咪唑和正己烷衍生的MBH加合物之间的反应作为模型反应。通过使用[Pd(η_3C_3H_5)Cl]2作为Pd盐,(R,R)-DIOP作为配体,N-烯丙基化反应顺利进行,得到相应的胺化产物,产率为92%,77:23的区域选择性,但对映体选择性差(-9%ee)。然后筛选一些优先配体,如(R)-BINAP,(R,R)-Trost配体,(R,R)-BDPP或(R,R,R)-SKP和(R,R,R)-SKP得到较好的结果(92%产率,79:21区域选择性和82%ee)。在P原子处改变具有不同芳基取代基的SKP配体没有得到改善的结果。随后,考察了几种钯盐,Pd2(dba)3得到了优异的结果。然后用Pd2(dba)3-(R,R,R)-SKP作为催化剂,研究了几种溶剂,但得到的结果较差。为了提高反应的对映选择性,研究了不同离去基团的MBH加合物,发现丙酸MBH有更好的选择(92%产率,73:27区域选择性和86%ee)。降低温度可以增强对映体选择性。当催化剂负载量从5mol%降低至2.5mol%时,保持对映体选择性,尽管产率较低。令人高兴的是,当反应在超声波下进行时,反应时间可以从96小时缩短到6小时,同时保持产率和对映体选择。为了进一步提高N-烯丙基化反应的区域选择性和对映选择性,仔细筛选了MBH丙酸盐中的各种酯基。当使用甲酯衍生的MBH加合物时,区域选择性和对映选择性都明显降低,苄基或1-金刚烷基的酯基位阻增加,对映体选择性相同(90-93%ee)。令人惊讶的是,使用2-金刚烷基的丙酸MBH进一步将支链产物的ee值提高到97%ee,同时将区域选择性提高到88:12。因此,最佳反应条件如下:在-20℃下在超声波处理6小时时,将2.5mol%的Pd 2(dba)3,5mol%的SKP,2-金刚烷基衍生的MBH丙酸酯作为反应物。最后,使用~1H NMR、~(13)C NMR、HSQC、HMBC、Noesy、HRMS、HPLC等手段表征手性α-烯丙基-N-杂芳基产物,由于嘌呤、苯并咪唑等N-杂芳环反应的复杂性,使研究存在困难,其中嘌呤反应有N7和N9位的选择性要通过HSQC和HMBC来确定结构,N-杂芳基和MBH的烯丙基胺化反应生成两种互变异构体,分别是手性的支链产物(B)和非手性的支链产物(L),而且反应生成的链产物有Z型和E型,要通过Noesy谱来确定构型,7-甲基苯并咪唑和苯并三氮唑和MBH加合物反应也会有选择位点的不同,可以通过HSQC、HMBC和Noesy来确定结构。由于手性α-烯丙基-N-杂芳基产物的多官能团化,可以对反应产物进行延伸合成需要的目标产物,这为合成光学活性的α-烷基-N-杂芳基化合物提供了一个新思路。
[Abstract]:The optically active alpha alkyl -N- hetero aryl compounds are ubiquitous in natural products, pesticides and drugs, and have biological activity. Therefore, the search for effective methods for the construction of N- heterocyclic compounds containing alpha alkyl is an unsymmetrical allylation reaction of.MBH adducts which are very necessary. It is commonly used for the preparation of optically active alpha alkyl compounds. One of the methods, the asymmetric allyl reaction of aromatic MBH adding and nitrogen heterocyclic is relatively mature. However, because the asymmetric allyl amidation of the aliphatic MBH addition is rarely reported, the aliphatic MBH is lower in activity compared with the aromatic MBH addition, and the smaller spatial difference and weak electrophilic properties make the results less desirable. In addition, the allyl reactions of the MBH addition and the nucleophilic N- heterocyclic compounds are rare, such as benzimidazole, purine, benzo three azoles, etc. first, a series of studies and investigations are conducted on the asymmetric allyl amination of the aliphatic MBH addition catalyzed by the transition metal palladium with the N- heterocyclic compounds. The reaction between the MBH adduct derived from imidazole and n-hexane is used as a model reaction. By using [Pd (ETA _3C_3H_5) Cl]2 as a Pd salt and (R, R) -DIOP as a ligand, the N- allylation reaction is carried out smoothly and the corresponding amination products are obtained, the yield is 92%, the selectivity of 77:23, but the selectivity of enantiomers (-9%ee). Then screening some priority matching. The ligand, such as (R) -BINAP, (R, R) -Trost ligand, (R, R) -BDPP or (R, R, R) -SKP, etc. A) 3- (R, R, R) -SKP was used as a catalyst to study several solvents, but the results were poor. In order to improve the enantioselectivity of the reaction, the MBH adducts of different leaving groups were studied. It was found that propionic acid MBH had a better choice (92% yield, 73:27 regioselectivity and 86%ee). When the 5mol% is reduced to 2.5mol%, the enantioselectivity is maintained, although the yield is low. It is pleasing that the reaction time can be shortened from 96 hours to 6 hours, while the yield and enantiomers are kept at the same time. In order to further improve the regioselectivity and enantioselectivity of the N- allylation reaction, the M is carefully screened. Various ester groups in BH propionate. When the MBH adducts derived from methyl ester are used, the regioselectivity and enantioselectivity are significantly reduced, the steric hindrance of the benzyl or 1- adamantyl ester is increased and the enantiomer selectivity is the same (90-93%ee). It is surprising that the EE value of the branched product is further increased to 97%ee by the 2- MBH adamantal propionate MBH. At the same time, the regioselectivity was raised to 88:12., so the optimum reaction conditions were as follows: at -20 C, the SKP of Pd 2 (DBA) 3,5mol% of 2.5mol% and the MBH propionate derived from 2- adamantyl were used as the reactant at 6 hours at the time of ultrasonic treatment. Finally, the ~1H NMR, ~ (13) C, and other means were used to characterize the chiral alpha allyl The base products, due to the complexity of the N- hetero ring reactions such as purine and benzimidazole, make the study difficult. The selectivity of the purine reaction with N7 and N9 sites is to determine the structure by HSQC and HMBC, and the allyl amine reaction of N- hetero aryl and MBH produces two kinds of hetero amines, which are chiral branched chain products (B) and chiral branched chain products (the chiral branched chain products (B) and chiral branched chain products ( L), and the chain products produced by the reaction are type Z and E type, to determine the configuration by Noesy spectrum. The reaction of 7- methyl benzimidazole and benzo three azoles and MBH adducts will also have different selection sites, which can be determined by HSQC, HMBC and Noesy, and the reaction products can be produced because of the polyfunctionalization of the chiral alpha allyl -N- heteroaryl products. The target products needed to extend the synthesis process provide a new idea for the synthesis of optically active alpha alkyl -N- heteroaryl compounds.
【学位授予单位】：河南师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.25

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