论文总字数：48715字

摘 要

噁唑-2-酮是有机合成中的一种重要中间体，同时也是天然产物和具有生物活性物质中反复出现的结构^[1]。因此，科研人员在构建这一优越结构方面做出了巨大的努力^[2]，在这些工作中，金属（金，钯，铜等）催化的N-alkynyl tert-butyloxycarbamates环合反应被认为是合成噁唑-2-酮最为高效的策略（Scheme 1,a）^[3]。例如，Gagosz^[3a]报道了一种利用金催化的环异构化反应，高效快速合成3,5-二取代噁唑-2-酮的方法。尽管取得了这些成果，但是高效快速合成3,4,5-三取代噁唑-2-酮以及4-取代噁唑-2-酮依旧是很具有挑战性的课题^[4]。本文以炔酰胺为底物，通过卤钯反应，以良好的产率得到3，4，5-全取代噁唑-2-酮。并通过多种手段表征了他们的结构。

合成了用于N-炔酰胺环合反应研究的12个N-炔酰胺底物（1a-1l）。通过末端炔烃与NBS在硝酸银的催化下反应生成炔基修，再与酰胺发生C-N键偶联反应得到N-炔酰胺。采用张严实开发的在CuSO₄·5H₂O和1，10-邻菲罗琳催化下炔基修与酰胺的偶联方法，以33%到67%的产率得到系列N-炔酰胺（1a-1l）。

首先以N-苯基-N-苯乙炔基氨基甲酸叔丁酯(1a)作为底物，对不同的催化剂，碱，溶剂，以及铜盐进行了筛选反应。我们最终发现以Pd(PPh₃)₄做催化剂，K₂CO₃做碱，DMF做溶剂与4.0当量的铜盐反应，以91%的产率得到相应的4-溴代噁唑-2-酮，且催化剂用量对反应影响不大。

接着对该反应的普适性进行了研究，结果表明无论芳基上连有吸电子基团还是供电子集团的N-芳基炔酰胺都能以良好到优秀得到相应的噁唑-2-酮，但是N-烷基炔酰胺的产率稍低。

最后，对所合成得到的4-溴代噁唑-2-酮与芳基硼酸的Suzuki-Miyaura偶联反应进行了研究，结果表明在Pd(PPh₃)₄，Na₂CO₃以及甲苯/乙醇/水条件下，以65%到98%的产率在噁唑-2-酮四号位引入芳基（3a-3d）。

上述目标产物和中间体结构都经熔点、核磁共振氢谱、核磁共振碳谱、质谱、元素分析/高分辨质谱表征，对化合物2a进行了单晶培养与X-单晶衍射分析，证明合成产物为预期结构。

上述Pd(Ⅱ)催化的N-炔酰胺环合反应，可高效快速合成4-卤代噁唑-2-酮，可与芳基硼酸进行Suzuki-Miyaura偶联反应继而合成新型生物活性物质，丰富了有机合成方法学。

关键词：炔酰胺，噁唑-2-酮，卤钯反应，Suzuki-Miyaura偶联

Pd-Catalyzed Intramolecular Cyclization of Ynamides: An effictive

and quick way to synthesis 4-Halo-Oxazolones

Abstract

Oxazolones are not only valuable building blocks in organic synthesis, but also a recurring functional group in a large number of natural products and bioactive compounds. Therefore, great efforts had been directed toward developing synthetic approaches for the construction of this privileged structure, among which the metal catalyzed (e.g., Au, Pd, and Cu) cyclization of the N-alkynyl tert-butyloxycarbamates is considered to be one of the most effective strategies (Scheme 1, a). For instance, Gagosz reported the Au-catalyzed cycloisomerization which provided the efficient and rapid process for the synthesis of 3,5-disubstituted oxazolones. Despite these advances, the effective synthesis of 3,4,5-multisubstituted oxazolones and modification of the 4-position of oxazolones still remain to be a highly challenging area.^[4] Hence, in the dissertation, a novel strategy to synthesize 4-halo-oxazolones via the halopalladation of alkynes was discovered.

The first chapter is about the synthesis of N-alkynamides which were used as the substrates of the cyclization of ynamides. A series of alkynamides (1a-1l) can be obtain with the yields of 33%-67% through the C-N coupling reaction of alkynyl btomide with N-nucleophiles at 80 ^oC according to Hsung’s protocol (using copper sulfate pentahydrate as catalyst, 1,10-phenanthroline as ligand, potassium carbonate or potassium phosphate as base).

In the following chapter, the optimized cyclization conditions using tert-butyl N-phenyl-N-(phenyl-ethynyl) carbamate (1a) as model substrate were explored by screening catalysts, bases, solvents and copper salt. The experimental results indicated that the 4-bromo-3,5-diphenyl-3H-oxazol-2-one (2a) can be obtained in 91 % isolated yield using Pd(PPh₃)₄ as catalyst, CuBr₂ as copper salt, K₂CO₃ as base, DMF as solvent.

Consequently, with the optimized conditions in hand, the scope and limitation of the Pd-catalyzed intramolecular cyclization of ynamides were investigated. Notably, electronic effects did not alter the yield obviously. But N-alkylalkynylated amide show a lower yield than N-arylalkynylated amide.

Finally, the Suzuki-Miyaura coupling was performed on 2a and 2f with arylboronic acids in toluene/EtOH/H₂O by using Pd(PPh₃)₄ as catalyst, Na₂CO₃ as base, which demonstrate the synthetic potential of this strategy.

The structures of all target products and substrates had been characterized by m.p., IR, ¹H NMR, ¹³C NMR, MS and EA.

In conclusion, we have developed a novel Pd-catalyzed cyclization of N-alkynyl alkyloxycarbamates affording the corresponding 4-halo-oxazolones in good yields under mild conditions. Furthermore, this method affords oxazolones with a halogen (Br) at 4-position, which provides an attractive and useful route to introduce new groups for the synthesis of new bioactive products.

Keywords: Ynamides Oxazolones Halopalladation Suzuki-Miyaura coupling

目 录

摘要--------------------------------------------------------------Ⅰ

Abstract-----------------------------------------------------------Ⅲ

第一章 文献综述-------------------------------------------------1

1.1 引言---------------------------------------------------------1

1.2 噁唑-2-酮的研究进展------------------------------------------1

1.2.1 噁唑-2-酮的应用------------------------------------------1

1.2.2 噁唑-2-酮的合成研究--------------------------------------3

1.3 炔酰胺的合成及反应研究---------------------------------------5

1.3.1 炔酰胺的合成---------------------------------------------5

1.3.2 炔酰胺的反应研究-----------------------------------------7

1.4 卤钯反应的研究进展-------------------------------------------8

1.5 本课题研究内容----------------------------------------------10

第二章 N-炔基氨基甲酸酯的合成--------------------------------11

2.1 前言--------------------------------------------------------11

2.2 N-炔基氨基甲酸酯化合物及其合成路线的设计------------------13

2.2.1 N-炔基氨基甲酸酯化合物的设计----------------------------13

2.2.2 N-炔基氨基甲酸酯的合成路线------------------------------14

2.3 实验部分----------------------------------------------------15

2.3.1 主要试剂与仪器------------------------------------------15

2.3.2 实验步骤和表征分析--------------------------------------17

2.4 结果与讨论--------------------------------------------------19

2.4.1 合成总体结果与讨论--------------------------------------19

2.4.2 实验条件讨论--------------------------------------------20

2.5 小结--------------------------------------------------------20

第三章 N-炔基氨基甲酸酯环合反应条件筛选--------------------22

3.1 前言--------------------------------------------------------22

3.2 实验部分----------------------------------------------------22

3.2.1 主要试剂与仪器------------------------------------------22

3.2.2 实验步骤------------------------------------------------22

3.3 结果与讨论--------------------------------------------------23

3.4 小结--------------------------------------------------------24

第四章 N-炔基氨基甲酸酯环合反应的普适性研究-----------------25

4.1 引言--------------------------------------------------------25

请支付后下载全文，论文总字数：48715字