【作者】 李先纬；

【导师】 江焕峰；

【作者基本信息】 华南理工大学 ， 应用化学， 2014， 博士

【摘要】 过渡金属催化的交叉偶联反应来构建碳-碳键及碳-杂原子键作为金属有机化学的一个重要板块，在过去的三十年里得到了迅猛的发展。2010年的诺贝尔化学奖颁给了Richard Heck, Ei-ichi Negishi和Akira Suzuki，以奖励他们在钯催化的基于碳-卤键的交叉偶联反应的贡献。而目前这个领域的发展则把交叉偶联作为串联反应的一个重要步骤，并且C-H键活化则扮演着重要的角色。最近，人们开始把以前认为相对惰性的而又广泛存在于有机分子中的C-H键作为一种官能团来实现交叉偶联反应，并且将C-H键的官能化推向一个与C-X (X=卤原子)一样的高度和热度。基于C-H键的交叉偶联反应具有缩短合成步骤、提高原子经济性,可以省去前活化程序，可望发展高效、经济的合成策略,为化学反应合成路线的设计，特别是天然产物的全合成的逆合成分析提供新的思路等优点。尽管如此，目前发展的基于C-H键的交叉偶联反应使用的催化剂仍大多为金、铂、铑、铱等贵金属，而实现催化循环常用的氧化剂常常是当量的金属盐（如醋酸铜、氧化银等），以及醋酸碘苯、苯醌、过硫酸钾等环境不友好的试剂。因此发展由廉价金属（如铜、铁等）催化剂，并且使用氧气作为当量的绿色氧化剂实现有机分子的选择性官能化来构建碳-碳键及碳-杂原子键是实验室以及工业上非常吸引人的课题。沿着这样的思路，我们也意识到使用铜催化剂，氧气为最终氧化剂对有机分子的选择性氧化官能化还面临着以下的挑战：（1）活性：铜配合物对于有机分子的催化活性，以及氧气作为一种相对较弱的氧化剂来实现催化循环的能力；（2）选择性：相对惰性的C-H键与C-X键的化学选择性，对于同一个分子中多个活性的C-H键的区域选择性以及立体选择性。在此背景下，本文研究了铜催化氧气氧化官能化来构建碳-碳键以及碳-杂原子键，并且提供了合成多取代噁二唑、噁唑、吡唑、吲唑等含氮杂环衍生物以及炔烃的合成方法学：(1)铜催化氧化亚胺C-H键的官能化/Csp2-O键的偶联反应，产物为在农药、医药、材料（特别是发光材料）中广泛使用的噁二唑的衍生物。该反应代表着较少的使用铜催化氧气氧化Csp2-O键形成的例子。另外特别吸引人之处是使用了常压的氧气作为最终的氧化剂。（2）铜催化氧化分子内Csp2-H键官能化/C-N键的形成来构建在医药、材料领域有广泛应用的吡唑、吲唑类衍生物。该反应具有较好的区域选择性，从而解决了以往此类吡唑化合物的合成过程中产生的异构体，同时该反应条件温和，底物使用范围广，并且通过简单的添加剂的调控就可以实现芳环Csp2-H的胺化反应。(3)一种新颖的合成炔烃的方式，即用腙作为炔烃的前体，以铜作为催化剂，氧气氧化，实现了氧气的选择性氧化Csp3-H键为Csp-H键。同时，本文具有以下特点：（a）解决了铜催化氧气氧化的活性，即Csp3-H键的氧化；以及选择性的问题，该反应具有很好的区域选择性；（b）为长期困扰炔烃合成的难题提供了一条新思路，即使用腙作为炔烃的替代物，可以在炔烃参与的交叉偶联反应中，避免使用大大过量的末端炔，或很麻烦的操作，并且可以实现很高的催化效率。(4)铜催化氧气氧化烯烃、芳烃的Csp2-H键官能化/C-S键的偶联反应，分别得到烯基砜以及芳基硫醚的衍生物。该反应使用的硫源是磺酰肼，一价铜催化，通过简单地调节不同的碱添加剂，即可以实现N-S键、S-O键以及C-S键的断裂，使得磺酰肼可以在铜/氧气体系下分别作为砜源、硫源以及芳基源来实现交叉偶联反应。值得一提的是，该反应具有较好的区域、化学和立体选择性。（5）铜催化氧化内炔、腈、水的Cascade反应得到多官能化的噁唑衍生物。该反应有非常好区域选择性，对于内炔两端的取代基的电性有很好的敏感性，从而对不对称地内炔底物有单一构型的噁唑产物；同时该反应应用一个大气压的氧气作为该反应的最终氧化剂，绿色环保；一个COX-2抑制剂的衍生物应用该反应可以很简便的合成，从而说明该反应潜在的实用性。更多还原

【Abstract】 Transition-metal-catalyzed carbon–carbon as well as carbon–heteroatom bond-formingreactions constitutes a major fraction of the area of Organometallic Chemistry. Nobel Prize inChemistry was awarded to Richard Heck, Ei-ichi Negishi, and Akira Suzuki in2010for theirseminal work on such cross-coupling reactions. Recent development brings forward more andmore sequential reactions incorporating cross-couplings as one of the steps and that C–Hbond activation has started to play a major role. Chemists also begin to performcross-coupling reactions using widely existed but relatively inert C-H bond as a functionalgroup, what’s more, C-H bond functionalization is emerging as a hot topic as well as C-Xbond functionalization. Cross-coupling reactions of C-H bonds offer advantages such asshorten the synthetic steps, improve the atom-economy, eliminate the pre-activation steps, andare also expected to develop efficient and economic synthetic strategies, more importantly, toprovide fresh ideas on the design of synthetic routes for organic synthesis, especiallyretrosynthetic analysis for the totle synthesis of natural products. Despite these merits, recentadvancement in this field still face some challenges, such as using noble metals Au, Pt, Rh, Iret. al. as the catalysts, what’s more, the frequently-used oxidant to achieve the high turn-overnumber in the catalytic cycle is metal salts (such as Cu(OAc)2and Ag2O), PhI(OAc)2, BQ,K2S2O8, which is not environment friendly oxidant and bring tremendous pressure on theenvironment. Thus, the development of utilizing cheap and abundant metal catalyst (such ascopper or iron)，and using molecular oxygen as the green oxidant to achieve the selectivelyoxidative functionalization of organic molecules is a highly promising and desirable topic inlab research and industry.Along such mentality, we also realize that there are some formidable challenges layahead:(1) the catalytic reactivity of copper complex towards organic molecules, as well as theability of molecular oxygen as a relative weak oxidant to operate the catalytic cycle;(2)chemoselectivity of relative inert C-H bonds versus C-X bonds, regioselectivity towards morethan one C-H bond available to participate the corresponding reactions. In this context, westudies copper-catalyzed aerobic oxidative functionalization of organic molecules for the C-Cand C-heteroatom bond formation, what’s more, we also provide the synthetic methodology on the synthesis of nitro-containing heterocycles such as oxadiazoles, oxazoles, pyrazoles,indazoles etc. as well as fucntionlized alkynes using this strategy.(1) In chapter2, we developed a copper-catalyzed aerobic oxidative imine C-H bondfunctionalization/Csp2-O bond formation to deliver1,3,4-oxadiazoles, which were widelyused as key fragments in pesticides, medicines, functionalized materials (especially opticalmaterials). This reaction represents a relative rare example in the field of copper-catalyzedaerobic Csp2-O bond formation. An attractive feature of this transformation is the use ofmolecular oxygen as the terminal oxidant.(2) In chapter3, we developed a copper-catalyzed intramolecular Csp2-H bondfunctionalization/C-N bond formation, affording pyrazoles and indazoles which were widelyapplied in medicines and materials. This reaction features good regioselectivity, which wasthe often encountered challenge in the traditional pyrazoles synthesis. The reaction behavesmild condition, great functional-group tolerance, more significantly, aromatic Csp2-H bondamination could be also realized with slight modification of the additive.(3) In chapter4, we developed a novel strategy for the alkyne synthesis, that is, utilizingketone-derived hydrazones as the precursors of the alkynes. With the aid of copper catalyst,molecular oxygen as the oxidant, we realized herein aerobic oxidative transformation ofCsp3-H bond into C-C triple bond;(a) As to the selectivity issue, this reaction features goodregioselectivity towards more than one C-H bond available to oxidation for the C-C triplebond formation;(b) This discovery also provides a new opportunity for dealing with the issuepeople puzzled always, that is, using N-Tosyl hydrazones as the alternatives for alkynes couldeliminate the use of highly excess terminal alkynes or troublesome operations, instead, highturn-over number was also achieved.(5) In chapter5, a regio-, chemo-, stereoselective synthesis of sulfones and thioethers viaCu(I)-catalyzed aerobic oxidative N-S bond cleavage of sulfonyl hydrazides andcross-coupling with alkenes and aromatic compounds for the Csp2-S bond formation isdeveloped. N2and H2O are the byproducts of this transformation, thus offering anenvironmentally benign process with wide potential applications in organic synthesis andmedicinal chemistry.(5) In chapter6, we developed a copper-catalyzed oxidative cascade reaction of internal alkynes, nitriles and water leading to highly fuctionalized oxazoles. This reaction featuresgreat regioselectivity, and showed a good sensitivity towards the substituents on the internalalkynes, thus the exclusive formation of the oxazoles with single configuration when usingunsymmetric internal alkynes as substrates. Molecular oxygen was used in this reaction as theoxidant. Further synthetic potential was also investigated by synthesizing a core structure ofCOX-2inhibitor derivative.更多还原