鎳金屬錯合物在苯炔、異氰酸酯及1,2-二碘苯衍生物的耦合與合環反應上之應用

Application of Nickel Complexes on the Coupling Reactions and Annulations involving Benzyne, Isocyanate and 1,2-Diiodobenzene Derivatives

謝仁傑(Jen-Chieh Hsieh)

指導教授 ： 鄭建鴻

國立清華大學/理學院/化學系/博士(2006年)

摘要

摘要

本論文旨在描述利用有機鎳金屬催化以及的有機雙極(Dipolar)反應來完成合環以及耦合反應。本論文主要共分為四個章節，並且在每一個章節內包含兩個同類型反應；利用相似的反應條件在不同的反應物下合成出不同的產物。首先在第一章我們描述利用苯炔(Benzyne)在有機鎳金屬催化下分別與一二雙希化合物(allene)和雙炔化合物(diyne)進行合環反應而形成九、十-二氫化菲(9，10－dihydrophenanthrene)與萘(naphthalene)衍生物。而在第二章中我們則要探討苯炔前驅物與疊氮化合物(Azide)及異氰酸酯化合物(Isocyanate)在一三雙極環化加成反應(1,3-dipolar cycloaddition)下的環化與耦合反應。第三章將針對異氰酸酯化合物(Isocyanate)與鄰碘苯甲酸酯化合物(β-Iodobenzoate)和芳香環鹵化物(Halobenzene)的環化及耦合反應形成亞胺(Imide)和醯胺(Amide)來做研究。最後在第四章的部分我們則要討論一、二雙鹵芳香環(1,2-Dihalidearene)與炔化合物(Alkyne)以及雙炔化合物的合環反應形成一二三四－四取代的萘衍生物(1,2,3,4-Tetrasubstituted naphthalene)。
第一章我們描述利用一二雙稀和雙炔化合物在有機鎳金屬催化下與苯炔進行環化加成反應。苯炔前驅物在有機鎳金屬錯合物NiBr2(dppe)以及鋅粉(Zn)的催化系統中，加入過量的銫氟化物(CsF)並利用乙晴(Acetonitrile)作為溶劑在80 oC的條件下可以得到二氫化菲以及萘衍生物。其中在二氫化菲衍生物的合環反應方面具有非常高度的立體選擇性與化學選擇性；然而在萘衍生物的合環反應中則具有絕佳官能基容忍性，同時也對合環時環的大小有非著常高度的相容性。 在反應機構的研究方面我們推論這兩個合環反應同樣都是利用零價的有機鎳金屬錯合物與苯炔及另一不飽和三鍵或雙鍵進行還原偶合反應(Reductive coupling)[或是氧化合環反應(Oxidative cyclization)]形成二價的五環雙稀有機鎳金屬錯合物(Nickelacyclopentadiene)的中間體(Intermediate)，隨後另一分子的三鍵化合物對此中間體進行插入反應，最後在經由還原減位(Reductive elimination)而形成相對應的二氫化菲與萘化合物。
第二章則旨在探討苯炔化合物與疊氮化合物的環化反應以及和異氰酸酯化合物間的耦合反應。 其中，苯炔前驅物在過量的銫氟化物和乙晴溶劑中會進行一三雙極環化加成反應而形成一氫苯並三唑化合物。此環化反應不但具有相當高的產率，且對於官能基有著絕佳的容忍性。此外，苯炔前驅物在過量的銫氟化物和乙晴溶劑的條件下也可以對異氰酸酯化合物進行耦合反應，此耦合反應經由相當獨特的反應機構來形成雙取代芳香環胺類的衍生物。
第三章是研究在有機鎳金屬錯合物的催化下異氰酸酯與鄰碘苯甲酸酯化合物和芳香環鹵化物的環化及耦合反應。 以有機鎳金屬錯合物NiBr2(dppe)和鋅粉作為催化系統的情況下， 在80 oC的乙晴溶劑裡額外加入配位基dppe及三乙胺。異氰酸酯與鄰碘苯甲酸酯化合物和芳香環鹵化物可以進行環化加成反應與耦合反應而形成相對應的亞胺和醯胺衍生物。其中，亞胺的合環反應具有高度的官能基容忍性，並且有別於傳統有機反應可以合成出高度非對稱的亞胺衍生物。然而在醯胺的耦合反應中則具有較低的反應性。
第四章鄰碘芳香環在有機鎳金屬催化下對炔類以及雙炔化合物的合環反應中，主要分為兩個部份來提供討論。首先，我們將探討在有機鎳金屬錯合物NiBr2(dppe)以及鋅粉(Zn)的催化系統中，加入過量的配位基DPPE並利用乙晴作為溶劑在80 oC的條件下可以得到四取代萘衍生物。其次，我們將此催化反應延伸至雙炔的系統下則可以更進一步地在萘衍生物上增加環數。此型態的合環反應不但具有相當好的官能基容忍性以及產率，更重要的是它提供了相當方便的多苯環衍生物合成的方法。

關鍵字

苯炔 ； 異氰酸酯 ； 二鹵芳香環

並列摘要

The thesis describes dipolar and nickel-catalyzed organic synthesis leading to coupling and cyclization of heterocyclic compounds. It is subdivided into four topics in four chapters. The first chapter describes nickel-catalyzed cyclization of aryne precursors with allene and diyne derivatives resulting in the formation of 9,10-dihydrophenanthrene and naphthalene derivatives in moderate to excellent yields. The second chapter extends the aryne precursors to precede 1,3-dipolar cycloaddition and coupling reaction with azide and isocyanate derivatives to form benzotriazole and diphenylamine derivatives in good to excellent yields. The third chapter deals with reaction of isocyanates with β-iodobenzoate and halobenzene derivatives to form imides and amides. The fourth chapter consists of cycloaddition of 1,2-dihalidearenes with alkynes and diynes to form 1,2,3,4-tetrasubstituted naphthalene derivatives.
The first chapter describes the nickel-catalyzed cycloaddition of arynes with allenes and diynes. The arynes could be proceeded cycloaddition with allenes and diynes in the presence of Ni(dppe)Br2, zinc powder and cesium fluoride in acetonitrile at 80 oC to afford the corresponding phenanthrene and naphthalene derivatives in moderate to excellent yields. The phenanthrene derivatives give high regio-, stereo- and chemo selectivity; in contract the naphthalene derivatives afford excellent functional group and fused ring size tolerance. The mechanism of these two reactions is through the intermediate of nickelacyclopentadiene by Ni(0) complex with two molecules of triple bonds, followed by insertion of another one and reductive elimination to form the corresponding products.
The second chapter describes the coupling reaction of arynes with azides and isocyanates. The arynes undergo the 1,3-dipolar cycloaddition with azides to form the 1H-benzo[d][1,2,3]triazole derivatives in good to excellent yields with high functional groups tolerance. The arynes could also precede the very unique fluoride promoted coupling reaction with isocyanates in moderate to good yields.
The third chapter describes the nickel-catalyzed cycloaddition and coupling reaction of isocyanates with β-iodiesters and arylhalide. In the presence of NiBr2(dppe), additional dppe and zinc powder in acetonitrile at 80 oC, the coupling reaction of isocyanates with β-iodiesters and arylhalide could be succeed to proceed and afford the corresponding imide and amide derivatives in moderate to excellent yields. The reaction of forming imides shows the excellent functional group tolerance, however, the reaction of forming amides reveals the lower yields with limited cases.
The fourth chapter describes the nickel-catalyzed cycloaddition of 1,2-dihaloarenes with alkynes and diynes. The 1,2-dihaloarenes undergo cycloaddition with alkynes and diynes in the presence of Ni(dppe)Br2, additional dppe and zinc powder in acetonitrile at 100 oC to afford the corresponding 1,2,3,4-tetra substituted naphthalene products in moderate to excellent yields. Variou alkynes and diynes react with 1,2-dihaloarene derivatives to give good functional group tolerance. The mechanism is proposed by the oxidative addition first, then insertion of a triple bond and coupling with another carbon-halide bond to form the intermediate of nickelacyclobenzopentene. Finally, another triple inserts to the nickel complex and proceeds reductive elimination to afford the corresponding naphthalene products.

並列關鍵字

Benzyne ； Isocyanate ； Dihaloarene ； Allene ； Diyen ； Triazole

參考文獻

Chapter 1

3.Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett, 1983, 1211.

8.T. T. Jayanth, M. Jeganmohan and C.-H. Cheng, J. Org. Chem. 2004, 69, 8445.

11.Z. Liu and R. Larock, Org. Lett., 2004, 6, 3739.

12.X. Zhang and R. Larock, Org. Lett., 2005, 7, 3973-3976.