銅催化的DMF作為N雜環的合成良性C1和N1合成子

Copper-Catalyzed Synthesis of N-heterocycles Using DMF as Benign C1 and N1 Synthon

甘柏杰(Balaji Ganesan)

指導教授 ： 林韋佑

高雄醫學大學/生命科學院/醫藥暨應用化學系博士班/博士(2020年)

摘要

我的研究生工作集中於過渡金屬催化的炔基基序的合成，該合成方向是重要的
N 雜環化合物（如吲哚和喹啉）的合成方向。這些雜環由於其特殊的生物活性
而成為藥物和工業領域的潛在候選者。因此，研究人員對各種雜環的合成表現
出了熱情。通常，經修飾的炔基化合物，特別是炔酮是建立各種雜環的重要組
成部分。在這種情況下，我們還選擇了鄰炔基苯胺或炔酮，以通過過渡金屬構
建一些N-雜環。
在第二章中，我們開發了一種在O2 存在下，使用Cu（II）催化2-炔基苯胺與
N，N-二甲基甲酰胺（DMF）的反應，合成多取代的3-甲酰基吲哚支架的方法。
該反應通過級聯的5-內-dig-環化反應進行，然後進行甲酰化反應以製備1,2-
二取代的3-甲酰基吲哚。該方法的關鍵方面是廣泛的底物範圍，並且對各種官
能團的耐受性良好。另外，已經提出了詳細的機理，其中DMF 可以用作獲得的
吲哚衍生物的原位C 3 甲酰化的碳源。
在第三章中，我們公開了一種從易於製備的3-（2-氨基苯基）-1-苯基-2-丙炔
-1-酮起始原料合成4-氨基喹啉衍生物的新合成方案。該方法涉及亞胺離子/氮
雜-邁克爾加成/環化/氧化的產生，並且反應使用Cu（I）/ DMSO / O 2 系統進
行。對照和標記研究表明，DMF 可以充當次甲基和二甲基的雙重合成子。這種
合成方法可用於各種底物，並能生產所需的產品，產率高達82％。

關鍵字

銅 ； DMF ； 合成子 ； 吲哚 ； 喹啉

並列摘要

My graduate work is focused on transition metal-catalyzed of alkynyl motifs in
the direction of the synthesis of important N-heterocycles such as, indole, and quinoline. These heterocycles are the potential candidates in pharmaceuticals and industrial aspects because of its particular bioactive properties. Hence, amongst the researchers are showing enthusiasm toward the synthesis of various heterocycles. Typically, the modified alkynyl compounds, especially the ynones are significant building block to
set up various heterocycles. In this context, we have chosen the o-alkynylanilines or ynones in addition to build some of N-heterocycles by transition metal.
In second chapter, we have developed a method for synthesizing multisubstituted
3-formyl indole scaffolds using a Cu(II)-catalyzed reaction of 2-alkynylanilines with N,N-dimethylformamide (DMF) in the presence of O2. This reaction precedes via a
cascade 5-endo-dig cyclization followed by formylation to make 1,2-disubstituted 3-
formyl indoles. The key aspects of this approach are the broad substrate scope, and well tolerated with various functional groups. In addition, a detailed mechanism has been proposed, where DMF may serve as a carbon source for the in situ C3 formylation of the obtained indole derivatives.
In third chapter, we have disclosed a new synthetic protocol for synthesis of 4-
aminoquinoline derivatives from easily prepared starting material of 3-(2-
aminophenyl)-1-phenyl-2-propyn-1-one. This method involved that generation of
iminium ion/aza-Michael addition/annulation/oxidation and the reaction was
performed using Cu(I)/DMSO/O2 system. The control and labelling studies revealed
that DMF can act a dual synthon of methine, and dimethyl. This synthetic method can
be used for various substrates and can produce the desired products up to 82% yield.

並列關鍵字

Copper ； DMF ； Synthon ； Indoles ； Quinolines

參考文獻

1. Neto, J. S. S.; Zeni, G., Ten years of progress in the synthesis of six-membered Nheterocycles

from alkynes and nitrogen sources. Tetrahedron 2020, 76, 130876.

2. Yu, J.-T.; Pan, C., Radical C–H functionalization to construct heterocyclic compounds.Chem. Commun. 2016, 52, 2220-2236.

3. Li, Y.; Yu, J.; Bi, Y.; Yan, G.; Huang, D., Tandem Reactions of Ynones: via ConjugateAddition of Nitrogen‐, Carbon‐, Oxygen‐, Boron‐, Silicon‐, Phosphorus‐, and Sulfur‐Containing Nucleophiles. Adv. Synth. Catal. 2019, 361, 4839-4881.

4. Aguilar, E.; Sanz, R.; Fernández-Rodríguez, M. A.; García-García, P., 1,3-Dien-5-ynes:Versatile Building Blocks for the Synthesis of Carbo- and Heterocycles. Chem. Rev. 2016, 116,