Domino N-H/C-H bond activation: Palladium-catalyzed synthesis of annulated heterocycles using dichloro(hetero)arenes
Domino N-H/C-H bond activation: Palladium-catalyzed synthesis of annulated heterocycles using dichloro(hetero)arenes
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DOI：
10.1002/anie.200603833
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Althammer, Andreas
中科院分区：
文献类型：
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作者：
Ackermann, Lutz;Althammer, Andreas
区域选择性地形成C（sp2）-C（sp2）键的方法主要基于过渡金属催化的有机金属试剂和有机（准）卤化物之间的偶联反应。[1，2]有机金属化合物通常不可商购，并且它们的使用导致形成不期望的副产物。因此，焦点已经转移到直接芳基化反应，通过交叉偶联的C2 H4键作为一种经济和生态良性的替代。[3]通过最近开发的方法学，在分子内[5-7]和分子间[8，9]直接芳基化反应中，普遍使用容易获得但反应性较低的芳基氯化物[4]，取得了重大进展。[10]然而，只有一个优雅的，虽然有限的，多米诺骨牌[11，12]的过程被报道，由过渡金属催化的传统偶联的溴化物和C13 H键芳基化与氯化物。[5，7，13]在此，我们报道了一种新的钯催化的多米诺反应[14]，用于合成环状杂环。该方法涉及通过使用容易获得的苯胺和1，2-二卤代-（杂）芳烃进行胺化和直接芳基化[15]，并且重要的是允许将携带氯化物作为唯一离去基团的底物官能化（方案1）。此外，不同于先前报道的基于C2 H4键芳基化的咔唑[16，17]合成，[5，6a，7，12]有效地实现了具有游离NH部分的咔唑的直接合成。为了探索设想的多米诺反应的可行性，在甲苯作为溶剂中，用各种1，2-二卤代芳烃和Ph 2NH筛选衍生自多种配体的钯络合物。优化研究表明，最有效的方法是完成时，使用PCy 3作为配体（Cy=环己基）。重要的是，发现该方法不仅适用于溴化物（表1，条目1 -3），而且适用于反应性较低的氯化物（表1，条目4）。值得注意的是，即使是廉价的1，2-二氯苯也能有效地产生所需的咔唑（表1，条目5）。由于咔啉在生物活性化合物中普遍存在，因此重要的是要注意杂环卤化物[18]可以以相当的功效使用（表1，条目6）。此外，吲哚衍生物可通过与1，2-二卤代烯烃的直接乙烯基化有效地获得（表1，条目7和8）。
Methodologies for the regioselective formation of C (sp2)–C (sp2) linkages are mainly based on transition-metal-catalyzed coupling reactions between organometallic reagents and organic (pseudo) halides.[1, 2] The organometallic compounds are often not commercially available and their use gives rise to the formation of undesired by-products. Accordingly, focus has shifted to direct arylation reactions through cross-coupling of CÀH bonds as an economical and ecologically benign alternative.[3] Significant progress was accomplished by recently developed methodologies for the general use of readily available, but less reactive aryl chlorides [4] in intra-[5–7] and intermolecular [8, 9] direct arylation reactions.[10] However, only one elegant, albeit limited, domino [11, 12] process was reported that consists of a transition-metalcatalyzed traditional coupling of a bromide and a CÀH bond arylation with a chloride.[5, 7, 13] Herein, we report a novel palladium-catalyzed domino reaction [14] for the synthesis of annulated heterocycles. This approach involves an amination and a direct arylation by using readily available anilines and 1, 2-dihalo-(hetero) arenes [15] and importantly allows for the functionalization of substrates bearing chlorides as the only leaving groups (Scheme 1). Furthermore, different from previously reported CÀH bond arylation-based carbazole [16, 17] syntheses,[5, 6a, 7, 12] the direct synthesis of carbazoles with a free NH moiety is efficiently accomplished. To probe the viability of the envisioned domino reaction, palladium complexes derived from numerous ligands were screened with various 1, 2-dihaloarenes and Ph2NH in toluene as solvent. Optimization studies revealed that the most efficient process was accomplished when using PCy3 as the ligand (Cy= cyclohexyl). Importantly, the approach was found to be applicable not only to bromides (Table1, entries1–3) but also to less-reactive chlorides (Table1, entry4). Notably, even inexpensive 1, 2-dichlorobenzene gave rise to the desired carbazole efficiently (Table1, entry 5). As carbolines are ubiquitous in biologically active compounds, it is important to note that heterocyclic halides [18] could be employed with comparable efficacy (Table1, entry 6). Further, an indole derivative was efficiently accessible through a direct vinylation with a 1, 2-dihaloalkene (Table 1, entries 7 and 8).