[毕业论文] 铜催化异喹啉酮衍生物的合成 [复制链接]

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毕业论文-铜催化异喹啉酮衍生物的合成，共106页，18135字

中文摘要

含氮杂环化合物广泛存在于自然界，作为活性分子，它们在制药工业与临床研

究上发挥不可替代的作用。异喹啉酮、咪唑酮和喹唑啉酮是重要的含氮杂环化合

物，各自具有重要的生理和药理活性，其化学合成备受关注。本论文设计了两类

新型的异喹啉酮衍生物，并围绕其化学合成展开研究，取得如下研究结果：

一、设计了含异喹啉酮、咪唑酮结构的新型含氮杂环分子，建立了铜催化的以

氨基酸为基础的一锅反应制备异喹啉酮咪唑酮的两种新方法。

方法 1 以 N-(2-溴代芳香基)氨基酸酯和 2-取代乙腈为原料，使用 CuI 为催化剂，

K2CO3 或 Cs2CO3 为碱，DMSO 为溶剂，高产率地得到了一系列具有异喹啉酮、

咪唑酮、氨基酸侧链结构的含氮杂环化合物。该方法有较高的官能团容忍性，具

有无需添加配体、操作简单、产率高等优点。

方法 2 以 N-(2-氯代芳香基)氨基酸和取代苯乙腈为原料，高产率地得到了一系

列具有异喹啉酮、咪唑酮、氨基酸侧链结构的含氮杂环化合物。该方法在简单和

温和的条件下实现了 C-Cl 键的活化，以廉价易得的原料实现目标产物的合成。

合成的含氮杂化化合物有较好的产物多样性，新的母核结构具有较大药物应用

潜在价值。反应机理研究证明，该一锅反应是通过 C-芳基化、环加成、重排和脱

去小分子四步反应的串联来实现目标产物的合成的。

二、设计了含异喹啉酮、喹唑啉酮结构的新型含氮杂环分子，建立了铜催化的

以邻氨基苯甲酸酯为基础的一锅反应制备异喹啉酮喹唑啉酮的新方法。该方法以

N-(2’-甲氧羰基芳香基)-2-卤代芳香甲酰胺与取代乙腈为原料，使用 CuI 为催化剂，

K2CO3 或 Cs2CO3 为碱，DMF 为溶剂，部分底物在脯氨酸配体的参与下，高产率

地得到了一系列具有异喹啉酮、喹唑啉酮结构的含氮杂环化合物，产物具有很高

的结构多样性。

本论文建立的方法为合成复杂含氮杂环化合物提供了一种全新的策略。

关键词：铜催化；异喹啉酮；咪唑酮；喹唑啉酮；氨基酸；乌尔曼反应

ABSTRACT

Nitrogen-containing heterocycles widely exist in nature. Many N-heterocycles play

unique

roles

in

pharmacy

industry

and

clinical

research.

Isoquinolinones,

imidazolidinones and quinazolinones are important N-heterocyclic compounds and

show irreplaceable biological and pharmaceutical activities. The chemical syntheses of

such compounds have drawn much attention recently. In this thesis, two kinds of noval

and inspiring poly-N-heterocycles containing isoquinolinone frameworks are designed

and synthesized. Some important results were obtained as followsbr />
Firstly, a kind of novel N-heterocycles containing isoquinolinone and imidazolidinone

frameworks is designed, and two efficient copper-catalyzed methods based on amino

acids for its syntheses have been developed.

For Method A, coupling of 2-bromobenzamides containing amino acid methyl esters

with substituted phenylacetonitriles or malononitrile provided the target products. The

protocol uses CuI as the catalyst, K2CO3 or Cs2CO3 as the base, and DMSO as the

solvent. The corresponding poly-N-heterocycles were obtained in good yields under

mild conditions without the addition of ligands or additive. The cascade reactions could

tolerate various functional groups. For Method B, 2-chlorobenzamides containing

amino acid and substituted phenylacetonitriles were used as the substrates, and the

desired poly-N-heterocycles were synthesized in good yields. This method achieved

C-Cl bond activation under mild conditions.

The synthesized poly-N-heterocycles containing isoquinolinone and imidazolidinone

frameworks have a wide range of structural diversity. The noval core has great practical

value in drug development. Mechanism research shows that the reaction undergoes the

following process: C-arylation, cycloaddition, rearrangement and the elimination of

small molecules.

IV

Secondly, a kind of novel poly-N-heterocycles containing isoquinolinone and

quinazolinone frameworks is designed, and a convenient and efficient copper-catalyzed

synthetic method has been developed via cascade reactions of substituted methyl

2-(2-halobenzamido)benzoates with substituted acetonitriles. The protocol uses CuI as

the catalyst, K2CO3 or Cs2CO3 as the base, and DMF as the solvent, ligand L-proline is

needed for particular substrates. A wide range of substitution groups are tested in this

method and proved tolerable, the desired poly-N-heterocycles with high structural

diversities were prepared in good yields.

The methods developed in this dissertation should provide a novel and useful strategy

for synthesis of N-heterocyclic compounds.

Keywords： Copper; Isoquinolinone; Imidazolidinone; Quinazolinone; Amino Acid;

Ullmann-type reaction

目录

第1章

引言.... 1

1.1 研究背景与选题意义 ....... 1

1.2 铜催化乌尔曼型反应：含氮杂环合成 ...... 2

1.2.1 咪唑酮环的构建 ......... 2

1.2.2 异喹啉酮环的构建 ..... 4

1.2.3 喹唑啉酮环的构建 ..... 4

1.3 铜催化乌尔曼型反应的可能机理 .......... 4

1.4 论文的主要目的、意义及内容 ............ 5

第2章

铜催化 N-(2-溴代芳香基)氨基酸与 2-取代乙腈的反应 7

2.1 条件探索与结构鉴定 ....... 7

2.2 底物适用性 .. 9

2.3 反应机理探讨 ............ 11

2.4 本章小结 ... 12

2.5 实验部分 ... 13

2.5.1 通用实验过程 ........... 13

2.5.2 产物结构鉴定数据 ... 13

第3章

铜催化 N-(2-氯代芳香基)氨基酸与取代苯乙腈的反应 ............ 19

3.1 结果与讨论 . 19

3.2 反应机理探讨 ............ 21

3.3 本章小结 ... 22

3.4 实验部分 ... 23

3.4.1 通用实验过程 ........... 23

3.4.2 产物结构鉴定数据 ... 23

第4章

铜催化异喹啉酮喹唑啉酮的合成..... 25

4.1 条件探索 ... 25

4.2 底物适用性 . 26

4.3 本章小结 ... 29

4.4 实验部分 ... 29

4.4.1 通用实验过程 ........... 29

4.4.2 产物结构鉴定数据 ... 29

第5章

结论... 30

附图索引 ....... 32

附表索引 ....... 33

参考文献 ....... 34

致谢 ........... 37

声明 ........... 39

附录 A

附录 B

外文资料的调研阅读报告 ........... 41

核磁谱图 ............ 47

在学期间参加课题的研究成果 .. 95

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