A general approach to chemo- and regioselective cyclotrimerization reactions
A general approach to chemo- and regioselective cyclotrimerization reactions
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DOI：
10.1002/anie.200700802
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Deiters, Alexander
中科院分区：
文献类型：
--
作者：
Young, Douglas D.;Deiters, Alexander
过渡金属催化反应的传统优化涉及底物、金属和配体的定制，以高效实现所需的转化。在这里，我们通过结合基板的空间分离和微波辐射，报告了一种更普遍适用和更实用的方法来解决这个问题。我们以[2+ 2+ 2]环三聚反应为例，从而解决了该反应持续存在的反应性和选择性问题。 [2+ 2+ 2] 环三聚反应是构建碳环和杂环结构的有效工具。[1, 2] 传统上，最常用的催化剂体系基于钴和铑。这些催化剂与使用束缚炔烃的部分分子内反应相结合，导致了 [2+ 2+ 2] 环三聚在稠合吡啶和苯分子构建中的一些实际应用，包括一些全合成。 [3]然而，用于合成杂环的经典钴催化[2+ 2+ 2]环三聚反应仍然存在各种问题。这些包括长反应时间、高稀释条件、高反应温度以及需要通过光或添加剂照射来活化催化剂。[1]此外，还观察到与某些底物的低反应性以及导致复杂产物混合物的副反应。[1] Co、Ni、Rh 和 Ru 催化剂的最新发展导致了更温和的反应条件和更短的反应时间，但通常需要专门设计的配体。 [4, 5] 此外，化学选择性（起始材料的二聚和三聚）和区域选择性问题仍然存在于许多催化剂中，除非使用专门设计的底物（例如三炔或内二炔）。因此，迄今为止尚未开发出多种底物的[2+ 2+ 2]环三聚化的高产率通用方法。在此，我们报告了一种开发高效[2+ 2+ 2]环三聚反应的不同方法，该方法也有可能为其他过渡金属催化的环加成反应提供统一条件。微波[6-8]辐射和聚合物固体载体的协同应用也使得[2+ 2+ 2]环三聚反应高度适用于各种底物。使用三苯甲基保护的二炔丙胺和苯甲腈作为起始原料，进行初始溶液相研究以得到稠合吡啶 3（方案 1）。环三聚反应以非极性甲苯为溶剂，在1108℃、10mol%[CpCo(CO)2]、微波照射(300W)下进行10分钟。用TFA去除保护基后，得到3，收率46%（最近其他人也观察到类似的结果[9, 10]）。当在没有微波辐射的情况下进行相同的环三聚反应时，即使在1108℃下延长反应时间24小时后，也仅观察到9％的产物形成。此前，这一问题已通过光照射、提高反应温度（例如 1448°C）、添加催化剂活化剂和延长反应时间（最多 5 天）来补偿。[11, 12] 溶液相环三聚中 3 的适度产率 (46%) 是由于二炔起始材料的二聚和三聚形成苯副产物，这是反应性二炔环三聚反应中常见的问题（特别是末端二炔）。[5, 13] 这个问题通过固定在聚苯乙烯树脂上的二炔底物的空间分离得到解决。[14]我们之前在化学选择性固体支持中采用了这种策略……
Traditional optimization of transition-metal-catalyzed reactions involves the tailoring of substrates, metals, and ligands to achieve the desired transformation with high efficiency. Here we report a more generally applicable and more practical approach to this problem through the combination of spatial separation of the substrates and microwave irradiation. We employed the [2+ 2+ 2] cyclotrimerization as an example, and thereby solved persisting reactivity and selectivity issues of this reaction. The [2+ 2+ 2] cyclotrimerization reaction is an efficient tool for the construction of carbo-and heterocyclic structures.[1, 2] Traditionally, the most commonly used catalyst systems are based on cobalt and rhodium. These catalysts, in conjunction with a partially intramolecular reaction using tethered alkynes, have led to several practical applications of the [2+ 2+ 2] cyclotrimerization in the construction of fused pyridine and benzene molecules, including several total syntheses.[3] However, a variety of problems regarding classical cobalt-catalyzed [2+ 2+ 2] cyclotrimerizations for the synthesis of heterocycles still persist. These include long reaction times, high-dilution conditions, high reaction temperatures, and the necessity to activate the catalyst through irradiation with light or additives.[1] Moreover, low reactivity with certain substrates, as well as side reactions leading to complex product mixtures have been observed.[1] The recent development of Co, Ni, Rh, and Ru catalysts have led to milder reaction conditions and shorter reaction times, but often require specifically designed ligands.[4, 5] Furthermore, chemoselectivity (di-and trimerization of starting materials) and regioselectivity issues are still persistent with many of the catalysts, unless specifically designed substrates are used (for example, triynes or internal diynes). As a result, no highyielding universal approach to the [2+ 2+ 2] cyclotrimerization of a wide range of substrates has been developed to date. Herein we report a different approach to the development of highly efficient [2+ 2+ 2] cyclotrimerizations which has the potential to provide unifying conditions for other transitionmetal-catalyzed cycloadditions as well. The synergistic application of microwave [6–8] irradiation and a polymeric solid support also makes the [2+ 2+ 2] cyclotrimerization highly applicable to a variety of substrates. An initial solution-phase investigation to give the fused pyridine 3 (Scheme 1) was conducted using trityl-protected dipropargylamine and benzonitrile as the starting materials. The cyclotrimerization was performed in nonpolar toluene as the solvent at 1108C with 10mol%[CpCo (CO) 2] under microwave irradiation (300 W) for 10 min. After removal of the protecting group with TFA, 3 was obtained in 46% yield (similar results have recently been observed by others [9, 10]). When the same cyclotrimerization was conducted without microwave irradiation, only 9% product formation was observed, even after a prolonged reaction time of 24 h at 1108C. Previously this has been compensated by irradiation with light, increased reaction temperatures (for example, 1448C), addition of catalyst activating agents, and extended reaction times (up to 5 days).[11, 12] The modest yield of 3 (46%) in the solution-phase cyclotrimerization is a result of the formation of benzene by-products through di-and trimerization of the diyne starting material, a problem commonly seen in cyclotrimerization reactions of reactive diynes (especially of terminal diynes).[5, 13] This problem was solved through spatial separation of the diyne substrates by immobilization on a polystyrene resin.[14] We employed this strategy previously in chemoselective solid-supported …