Ayuso-Carrillo Josue, Fina Federica, Galleposo El Czar, Ferreira Rúben R, Mondal Pradip Kumar, Ward Benjamin D, Bonifazi Davide
Institute of Organic Chemistry, University of Vienna, Währinger Strasse 38, Vienna A-1090, Austria.
Elettra Sincrotrone Trieste S.C.p.A., Strada Statale 14-km 163, 5 in Area Science Park, Basovizza, Trieste 34149, Italy.
J Am Chem Soc. 2024 Jun 7;146(24):16440-57. doi: 10.1021/jacs.4c02319.
In this paper, we report on a one-step catalyst-transfer macrocyclization (CTM) reaction, based on the Pd-catalyzed Buchwald-Hartwig cross-coupling reaction, selectively affording only cyclic structures. This route offers a versatile and efficient approach to synthesize aza[1]paracyclophanes (APCs) featuring diverse functionalities and lumens. The method operates at mild reaction temperatures (40 °C) and short reaction times (∼2 h), delivering excellent isolated yields (>75% macrocycles) and up to 30% of a 6-membered cyclophane, all under nonhigh-dilution concentrations (35-350 mM). Structural insights into APCs reveal variations in product distribution based on different endocyclic substituents, with steric properties of exocyclic substituents having minimal influence on the macrocyclization. Aryl-type endocyclic substituents predominantly yield 6-membered macrocycles, while polycyclic aromatic units such as fluorene and carbazole favor 4-membered species. Experimental and computational studies support a proposed mechanism of ring-walking catalyst transfer that promotes the macrocycle formation. It has been found that the macrocyclization is driven by the formation of cyclic conformers during the oligomerization step favoring an intramolecular C-N bond formation that, depending on the cycle size, hinges on either preorganization effect or kinetic increase of the reductive elimination step or a combination of the two. The CTM process exhibits a "living" behavior, facilitating sequential synthesis of other macrocycles by introducing relevant monomers, thus providing a practical synthetic platform for chemical libraries. Notably, CTM operates both under diluted and concentrated regimes, offering scalability potential, unlike typical macrocyclization reactions usually operating in the 0.1-1 mM range.
在本文中，我们报道了一种基于钯催化的布赫瓦尔德-哈特维希交叉偶联反应的一步法催化剂转移大环化（CTM）反应，该反应仅选择性地生成环状结构。此路线为合成具有多种功能和内腔的氮杂[1]对环芳烷（APCs）提供了一种通用且高效的方法。该方法在温和的反应温度（40°C）和较短的反应时间（约2小时）下进行，在非高稀释浓度（35 - 350 mM）的条件下，能提供优异的分离产率（>75%的大环）以及高达30%的六元环芳烷。对APCs的结构研究表明，基于不同的内环取代基，产物分布存在差异，而外环取代基的空间性质对大环化的影响最小。芳基型内环取代基主要生成六元大环，而芴和咔唑等多环芳烃单元则有利于生成四元物种。实验和计算研究支持了一种促进大环形成的环迁移催化剂转移的拟议机制。已发现大环化是由低聚步骤中环状构象体的形成驱动的，有利于分子内C - N键的形成，这取决于环的大小，要么取决于预组织效应，要么取决于还原消除步骤的动力学增加，或者是两者的结合。CTM过程表现出“活性”行为，通过引入相关单体促进其他大环的顺序合成，从而为化学文库提供了一个实用的合成平台。值得注意的是，与通常在0.1 - 1 mM范围内进行的典型大环化反应不同，CTM在稀释和浓缩条件下均可操作，具有扩大规模的潜力。
