I.Singlet Oxygen Mediated C-H Functionalization of Ethers and Cyclic-Ketones II.Visible-light Initiated Copper (I) Chloride Catalyzed C-C and C-N Cross-Coupling Reactions

I.單重態氧與環酮及醚類之碳-氫官能化 II.可見光initiated氯化銅(I)催化碳-碳及碳-氮交叉偶合反應

戴文(Arunachalam Sagadevan)

指導教授 ： 黃國柱

國立清華大學/理學院/化學系/博士(2013年)

摘要

中文摘要

在化學合成中發展高效率方法製備高價值中間產物和工業原料是值得感興趣的基本議題，以此前提下，本論文將呈獻六個章節來探討之。
前兩章節中我們利用單重態氧分子(1O2)做為一種溫和的氧化劑來官能化醚類化合物。且還可進而以此將環酮氧化為雙酸化合物。後第三
至六章節中，我們將探討以使用氯化銅並以可見光驅使有機官能基的轉換。
章節1-2
具選擇且直接地將C-H官能化，使可取得的起始物轉變為精細化學藥品或複雜的天然物仍是窒礙難行的目標，尤其，選擇性地氧化官能化脂肪醚的α-C-H bond更是在有基合成中最重要的途徑之一。自從此法具合成酯類和環內酯的潛力以來，精密化學藥品、藥物、和合成的天然物中酯類和環內酯即被視為主要的官能基。雖然許多新的氧化方式闡述用較多的添加試劑和過渡金屬來表現選擇性氧化醚類的α-C-H bond。
在第一章裡，我們利用單重態氧分子(1O2)做為一個氧化系統來選擇性地氧化脂肪醚的α-C-H bond，其因單重態氧分子(1O2)是有機反應及生物途徑上一種非常重要的分子。就此性質，我們將之延伸應用於有機官能基團的轉換。更甚者，添加溫合的路易氏酸可增進單重態氧分子(1O2)與醚類上α-C-H bond之氧化反應，且此方法亦可合成多數天然物和複雜分子。

化學製程、藥物、和食品工業中己二酸及雙酸延伸物扮演非常重要的角色，目前的認知中KA Oil(環己酮、環己醇)中依硝酸的加入使其氧化為己二酸是工業製程中一個古典的方法。然而依此工業流程將會產生大量的問題；如一化學劑量的硝酸可被還原成二氧化氮、一氧化氮或氧化亞氮。尤其氧化亞氮是比一氧化碳強三百倍的溫室氣體，更加造成臭氧層損耗。為了克服此問題，之後便發展以過氧化氫做為氧化劑並在金屬的催化下製備己二酸新的工業製程法。在第二章我們將
報導單重態氧分子(1O2)在弱路易氏酸(三乙基硼、氧化鋁)的存在下可直接將環己酮更有效地氧化成己二酸。此外，上述系統將可促進利用溫和條件且無使用過強的氧化劑(硝酸、金屬氧化物、過氧化物)下合成具工業價值的己二酸。

章節3-6
有機合成中最受關注和有效策略莫過於可間光的驅使下轉換有機物官能基。因可見光在自然界中的大量存在且多數的有機物對此光區較無吸收，如此造就其在有機合成中的高度注目，比較逐步驟的傳統合成法，可見光誘導的一步反應法中具有很大的發展潛力，如避免多餘的步驟、高反應效率、節省原子和簡易的操作。但是使用昂貴的釕、銥的光還原試劑在可行性和擴展性受到限制，知此後便利用文獻中以證實具符合經濟效益、光催化性質的有機染料來進行有機反應。近年
來，具可被光活化的銅錯合物出現後即在有機反應中成為新穎、有用的催化劑，例如銅可催化炔-疊氮的環化加成(CuAAC)之點擊化學及耦合反應，但仍方興未艾。章節3-6中即在此方面著重於簡單的氯化銅(I)鹽類，在無使用昂貴的鈀和配位基的前提下，以可見光照射使末端炔、鹵浣或芳香胺等化合物達成直接的碳-碳、碳-氮耦合。詳細的反應圖表將會在每個章節下介紹。

章節3 : 在無任何鈀和配位基的室溫條件下，受光誘導的氯化銅催化Sonogashira交叉耦合反應。

章節4 : 以不添加任何鈀、配位基和鹼，在可間光當媒介下使銅(I)高度選擇性地催化Csp-Csp的單一耦合和交叉耦合反應。

章節5 : 利用可間光誘導銅(I)催化氧化芳香胺和末端炔一步耦合反應合成Alpha-Ketoamides

章節六 : 利用可間光誘導銅(I)催化氧化直接耦合臨位芳香雙胺與末端炔為3-Phenyl-2-Hydroxyl-Quinoxaline.

關鍵字

单线态氧 ； 铜催化剂 ； 可见光 ； C-H键官能

並列摘要

ABSTRACT

The development of new and highly efficient synthetic approaches for the preparation of valuable intermediates and industrially important products are more interesting and remains as a fundamental objective in the synthetic chemistry. In this regard, the present thesis has described six chapters; the first two chapters focused on utilizing singlet oxygen as a mild oxidant system for oxidative functionalization of ethers and direct oxidation of cyclicketones to dicarboxylic acids. In the chapters 3-6, visible light mediated organic functional group transformations using simple copper (I) chloride as catalyst has been described.

Chapter 1 and 2:
Selective and direct C-H functionalization of readily available starting materials for the synthesis of useful fine chemicals and complex natural products remains an elusive goal in synthetic chemistry. Particularly, selective oxidative functionalization α-C-H bond of aliphatic ether is one of the most important reaction pathways in organic synthesis. Since, this direct synthetic potential has easily allowed in synthesizing lactones or esters, which were considered to be as major functional groups found in fine chemicals, pharmaceuticals and synthesis of natural products. Although, several new oxidation methods have been demonstrated typically by using transition metal catalysts along with several additional reagents, have revealed the selective oxidation of α-C-H bond of ethers. In chapter 1, we utilized singlet oxygen (1O2) as an oxidation system to selectively oxidize the α-C-H bond of aliphatic ethers. Since, singlet oxygen (1O2) is a very important molecule in organic reactions as well as in biological pathways; this was extensively studied for organic functional group transformation. Moreover, the reaction of singlet oxygen mediated α-C-H bond oxidation of ethers was enhanced by addition of mild Lewis acid and this strategy has allowed in synthesizing several natural products and complex molecules.

Adipic acid and their family of other dicarboxylic acids are playing important role in chemical process, pharmaceutical and food industries. As known as, nitric acid mediated oxidation of KA oil (cyclohexanone & cyclohexanol) to Adipic acid, is one of the classical approaches used for the industrial production; and still this method has applicability in worldwide. However, in this protocol, a series of problems have been documented during the oxidation of KA-oil to Adipic acid, in which the stoichiometric amount of HNO3 is reduced to NO2, NO, N2O. N2O is a greenhouse gas and ~ 300 times stronger than CO2 which cause the depletion of ozone layer. To overcome these problems, later new routes were developed for the industrial production of adipic acid mainly using H2O2 as oxidant in presence of metal catalyst. In chapter 2, we report an efficient method for direct oxidation of cyclohexanone to industrially important adipic acid in the presence of weak Lewis acid (i.e. Et3B or gamma Al2O3) via singlet oxygen. Moreover, this system has facilitated for the synthesis of industrially valuable adipic acid under mild conditions, without any usage of powerful oxidants (HNO3, metal oxides and peroxides).

Chapter 3-6:
Visible-light mediated organic functional group transformation reactions have emerged as one of the most attractive and powerful strategies in organic synthesis. Visible light is more attractive because most of the organic molecules lack of absorbance in the visible region and hence possess high natural abundance. Compared to traditional stepwise methods, visible light induced one-pot synthetic strategies have more potential towards avoiding extra steps, high reaction efficiency, atom-economical process and simplicity in operation. However, usage of expensive ruthenium and iridium photo-redox catalysts poses severe limitations in terms of feasibility and scalability. Later, organic dyes were utilized as cost-effective photo-catalyst for organic reactions and their achievements have been documented in the literature. Recently, photoactive copper complexes have emerged as a novel and powerful tool for organic reaction in terms of copper catalysed alkyne-azide cycloaddition (CuAAC) click reactions and coupling reactions. In this regard, chapter 3-6 was mainly focused on the simple copper (I) salt catalyzed direct C-C and C-N coupling reactions of terminal alkynes and aryl/alkyl halides or aryl-amines without any usage of expensive palladium and ligands under visible-light irradiation. The detailed reaction schemes for each chapter have described below.

 Chapter 3: Photo-induced copper (I) chlorite catalyzed Sonogashira cross coupling reaction without any palladium and ligands at room temperature.

 Chapter 4: Visible-light-mediated Higly Selective Csp-Csp Homo and Cross-Coupling Reaction using Copper (I) catalyst : Without Palladium, Ligands and Base

 Chapter 5: Visible-light-induced Simple Copper (I) Catalyzed Oxidative Coupling of Aromatic Amines with Terminal Alkynes: One-Pot Synthesis α-Ketoamides.

 Chapter 6: Visible-light-induced Copper(I)-Catalysed Oxidative direct coupling of o-Phenylenediamine and Terminal Alkynes: One-Pot Synthesis 3-phenyl-2-Hydroxy-Quinoxaline.

並列關鍵字

singlet oxygen ； visible light ； copper catalyst ； C-H bond functionalization

參考文獻

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