论文总字数：25752字

摘 要

吡咯是最重要的五元含氮杂环化合物之一，广泛存在于天然产物、生物活性分子、治疗剂、农用化学品、合成中间体和功能材料中。由于吡咯在各方面的意义，人们为获得吡咯化合物，开发出了许多合成吡咯的方法，包括经典的吡咯合成方法，hantzsch、knorr和paal−knorr合成法。然而，这些合成路线可能受底物不容易获得、反应条件苛刻、多步合成的影响导致副产物的生成和原子经济性差。因此，人们开发了新的催化方法来有效地合成吡咯化合物，特别是由廉价金属催化的合成方法。值得注意的是，在许多最近的廉价金属催化方法中，催化剂在线性中间体如α-烯胺酮、γ-酮亚胺(或其互变异构体)和1，4-二亚胺的形成中起着关键作用，这些中间体经历脱水或脱氨基的环缩合以提供吡咯产物。

随着绿色化学的发展和可持续性经济发展的需要，现在必须开发环境友好、低成本的合成方法。在含量丰富、环境友好的金属衍生的催化剂催化下，由容易获得且廉价的原料合成复杂的分子一直是化学家的长期目标。为了实现这一目标，人们设计了各种巧妙的方法，其中突出的有多组分、环异构化、级联或连续一锅反应等几种方法。

硝酸铈铵（CAN）是一种多功能氧化剂，用于有机合成和过渡金属化学中许多官能团的氧化,例如，醇、羰基化合物、羧酸衍生物、有机氮和有机硫化合物或碳氢化合物的氧化。烯胺酮是活泼的有机合成中间体，是合成各种杂环和天然产物的常用原料。本课题以烯胺酮和酮肟为原料，在CAN催化下合成多取代吡咯。该方法的催化剂为廉价金属催化剂并且含量丰富，原料容易获得，反应条件温和，从而降低了成本。

关键词：吡咯 烯胺酮 硝酸铈铵 廉价金属

Synthesis of polysubstituted pyrrole drug skeleton based on enaminone

Abstract

Pyrrole is one of the most important five-membered N-containing heterocyclic compounds and exists in natural products, bioactive molecules, therapeutic agents, agrochemicals, synthetic intermediates, and functional materials. Due to the significance of pyrrole in various aspects, people have developed many methods for synthesizing pyrrole, including classic pyrrole synthesis methods, hantzsch, knorr and paal-knorr synthesis methods. However, these synthetic routes may be affected by the difficulty of obtaining substrates, harsh reaction conditions, and multi-step synthesis leading to the formation of by-products and low atomic economy. Therefore, people have developed new catalytic methods to effectively synthesize pyrrole compounds, especially those catalyzed by inexpensive metals. It is worth noting that in many recent inexpensive metal catalysis methods, Catalysts play a key role in the formation of linear intermediates such as α-enaminones, γ-ketimines (or their tautomers) and 1,4-diimines, these intermediates undergo dehydration or deamination Ring condensation to provide the pyrrole product.

With the development of green chemistry and the need for sustainable economic development, it is now necessary to develop environmentally friendly, low-cost synthetic methods. Under the catalysis of rich and environmentally friendly metal-derived catalysts, the synthesis of complex molecules from readily available and inexpensive raw materials has been the long-term goal of chemists. In order to achieve this goal, people have designed a variety of ingenious methods, among which there are several methods such as multi-component, ring isomerization, cascade or continuous one-pot reaction.

Cerium ammonium nitrate (CAN) is a multifunctional oxidant used in the organic synthesis and oxidation of many functional groups in transition metal chemistry, for example, alcohols, carbonyl compounds, carboxylic acid derivatives, organic nitrogen and organic sulfur compounds or hydrocarbon Oxidation. Enamione is an active organic synthesis intermediate and a common raw material for the synthesis of various heterocycles and natural products. In this project, enolone and ketoxime were used as raw materials to synthesize polysubstituted pyrrole under the catalysis of cerium ammonium nitrate. The catalyst of the method is an inexpensive metal catalyst and is rich in content, the raw materials are easily obtained, and the reaction conditions are mild, thereby reducing the cost.

Key Words: pyrrole; enaminone; cerium ammonium nitrate; inexpensive metal

目录

摘要 I

Abstract II

第一章 文献综述 1

1.1吡咯类药物骨架的研究背景 1

1.2烯胺酮的研究背景 2

1.3硝酸铈铵的研究背景 3

1.4基于烯胺酮合成多取代吡咯的研究背景 3

1.5 结语 9

第二章 实验内容 10

2.1 实验思路 10

2.2 实验材料 10

2.2.1 实验仪器 10

2.2.2 实验试剂 11

2.3 实验方法 11

2.3.1 烯胺酮的制备 11

2.3.2 烯胺酮与酮肟反应生成多取代吡咯 12

2.4 实验结果与讨论 15

2.4.1基于烯胺酮合成多取代吡咯类药物骨架的反应结果 15

第三章 结论与展望 20

参考文献 21

致谢 26

第一章 文献综述

1.1吡咯类药物骨架的研究背景

吡咯核是多种功能材料的重要化学支架，在生物活性化合物、药物、电导体等领域具有广泛的应用^[1a-g]。例如，用于治疗血脂异常的阿托伐他汀^[2b-c]，抗精神病药物伊洛哌唑^[2e]，Bcl-2/Bcl-xl抑制剂^[2a]和CB₁拮抗剂^[2d]（图1）。

由于它的药学意义，已经开发了许多制备取代吡咯的方法，包括著名的hantzsch^[3]、knorr^[4]和paal−knorr^[5]合成法，如图式1所示。这些方法存在反应条件激烈、成本高、产率低、工作繁琐和反应时间较长等局限性。因此，人们开发了新的催化方法来有效地合成吡咯化合物。例如，2013年，Beller小组报道了钌催化三组分合成吡咯，类似于经典的Hantzsch合成方法。Michlik和Kempe实现了醇和氨基醇的直接铱催化偶联，得到吡咯。在这些反应过程中，醇底物经脱氢反应生成相应的羰基化合物，该羰基化合物进一步与胺反应形成所需的吡咯产物^[6-11]。

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