The synthesis of highly substituted cyclooctatetraene scaffolds by metal-catalyzed [2+2+2+2] cycloadditions: studies on regioselectivity, dynamic properties, and metal chelation.
The synthesis of highly substituted cyclooctatetraene scaffolds by metal-catalyzed [2+2+2+2] cycloadditions: studies on regioselectivity, dynamic properties, and metal chelation.
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金属催化[2 2 2 2]环加成合成高度取代的环辛四烯支架：区域选择性、动力学性质和金属螯合的研究。
DOI：
10.1002/anie.200903859
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发表时间：
2009
影响因子：
--
通讯作者：
M. T. Gieseler
中科院分区：
文献类型：
--
作者：
P. Wender;J. Christy;Adam B. Lesser;M. T. Gieseler
环辛四烯（COTs）是一类迷人的分子，具有巨大的潜在用途，可作为合成的构建块，[1]药物发现的支架，设计的碳水化合物模拟物，[2] d-和f-区金属的配体[3]包括不对称催化[4]和分子检测设备的组件（例如动态分子镊子）[5]和新型材料。[6]对于许多应用，包括在流动材料中使用COT，[7]导电聚合物，[8]和发光器件，[9] COT取代的类型和程度在控制系统的氧化还原和电子性质方面起着关键作用。对于其他应用，取代决定COT拓扑手性和通过桶到桶环反转的COT外消旋化速率。[10]尽管它们具有相当大的潜力，高度取代和官能化的COTs受到了有限的关注，部分原因是它们的通用和有效合成方法相对缺乏。[11]虽然Reppe的Ni 0催化的乙炔四聚反应提供了环辛四烯本身，[12]相关的末端炔的环四聚反应会导致复杂的混合物，而内部炔的环四聚反应会遇到反应性问题。[13]已经开发了两类用于合成六取代和八取代的COT的替代方法，这些方法基于两个二烯的金属介导的偶联[14]和semibullvalenes，[15] barrelenes，[16]或环丁二烯二聚体的高温重排。[17]然而，这些方法主要限于简单的烷基和/或芳基取代的COT的构建。最近，我们报道了金属催化的二炔的[2+ 2+ 2]环加成反应可以用某些镍催化剂完全逆转，生成[2+ 2+ 2+ 2]环加成产物。[18]然而，与COTs应用相关的关键问题，如六取代和八取代COTs的形成，反应区域选择性和杂原子取代的耐受性尚未探索。我们现在报道，通过混合的分子内/分子间镍（0）-催化的[2+ 2+ 2+ 2]环加成，可以克服内部炔的反应性的缺乏，提供具有多种官能度的六取代和八取代的COT。我们还报告了该过程的区域选择性的第一次研究，一个完全的分子内[2+ 2+ 2+ 2]环加成的第一个例子，以及这些新的配体在金属络合中的使用的初步研究。我们的研究最初集中在结合内部和末端炔的二炔，其以良好的产率提供六取代的COT（表1）。仅观察到痕量的[2+ 2+ 2]产物。值得注意的是，该方法的区域选择性范围为4.6：1（当取代基为CH 2 OCH 3时）（条目2）至> 20：1（当其为芳族或杂芳族时）（条目3-6）。值得注意的是，在合成和机械上，丙炔和炔丙醇的相应的完全分子间反应以最小的区域选择性进行，以提供复杂且难以分离的区域异构体和其他异构体的混合物。[19]在该方法中容许各种各样的官能团，包括醚（条目2）、酯（条目5）、Boc保护的氮杂环（条目6）和甚至游离酚基（条目4）。这种四组分环加成过程中分子复杂性的快速增加是值得注意的，并且是罕见的，因为在一次操作中形成了四个碳键和三个环。接下来研究含有两个内炔的二炔（表2）。烷基-（条目4），官能化的烷基-（条目2和3），和芳基取代的炔，最后与...
Cyclooctatetraenes (COTs) are a fascinating class of molecules with great potential utility as building blocks for synthesis,[1] scaffolds for drug discovery, designed carbohydrate mimics,[2] ligands for d-and f-block metals [3] including those for asymmetric catalysis,[4] and components for molecular detection devices (eg dynamic molecular tweezers)[5] and novel materials.[6] For many applications including the use of COTs in fluxional materials,[7] conducting polymers,[8] and light emitting devices,[9] the type and degree of COT substitution play a critical role in controlling the redox and electronic properties of the system. For other applications, substitution determines COT topological chirality and the rate of COT racemization by tub-to-tub ring inversion.[10] Notwithstanding their considerable potential, highly substituted and functionalized COTs have received limited attention partly due to the relative paucity of methods for their general and efficient synthesis.[11] While Reppe s Ni0-catalyzed tetramerization of acetylene provides cyclooctatetraene itself,[12] related cyclo-tetramerizations of terminal alkynes lead to complex mixtures and those of internal alkynes encounter reactivity problems.[13] Two classes of alternative methods for the synthesis of hexaand octa-substituted COTs have been developed, those based on the metal-mediated coupling of two dienes,[14] and hightemperature rearrangement of semibullvalenes,[15] barrelenes,[16] or cyclobutadiene dimers.[17] However, these approaches have been limited mainly to the construction of simple alkyl and/or aryl substituted COTs. Recently, we reported that the favored metal-catalyzed [2+ 2+ 2] cycloaddition of diynes can be completely reversed with certain nickel catalysts to produce [2+ 2+ 2+ 2] cycloaddition products.[18] However, key issues related to the applications of COTs such as the formation of hexa-and octa-substitutedCOTs, reaction regioselectivity, and tolerance of heteroatom substitution are unexplored. We now report that the lack of reactivity of internal alkynes can be overcome through a mixed inter/intramolecular nickel (0)-catalyzed [2+ 2+ 2+ 2] cycloaddition of commercially or readily available 1, 6-diynes, providing access to hexa-and octa-substituted COTs with a variety of functionalities. We also report the first study of the regioselectivity of this process, the first example of a fully intramolecular [2+ 2+ 2+ 2] cycloaddition, and the initial study of the use of these novel ligands in metal complexation. Our studies initially focused on diynes which incorporate both an internal and a terminal alkyne, which provide hexasubstituted COTs in good yields (Table 1). Only trace amounts of [2+ 2+ 2] products were observed. Significantly, the regioselectivities of the process range from 4.6: 1 when the substituent is CH2OCH3(entry 2) to> 20: 1 when it is aromatic or heteroaromatic (entries 3–6). It is noteworthy, both synthetically and mechanistically, that the corresponding fully intermolecular reactions of propyne and propargyl alcohol proceed with minimal regioselectivity to provide complex and difficult to separate mixtures of regio-and other isomers.[19] A wide variety of functional groups are tolerated in this process including an ether (entry 2), an ester (entry 5), a Boc-protected nitrogen heterocycle (entry 6) and even a free phenolic group (entry 4). The rapid increase in molecular complexity attending this four-component cycloaddition process is noteworthy and rare as four carbonÀcarbon bonds and three rings are formed in a single operation. Diynes containing two internal alkynes were next studied (Table2). Alkyl-(entry4), functionalized alkyl-(entries2 and 3), and aryl substituted alkynes, the last with …