Ruthenium-Catalyzed Regioselective Direct Alkylation of Arenes with Unactivated Alkyl Halides through C-H Bond Cleavage
Ruthenium-Catalyzed Regioselective Direct Alkylation of Arenes with Unactivated Alkyl Halides through C-H Bond Cleavage
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DOI：
10.1002/anie.200902458
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Hofmann, Nora
中科院分区：
文献类型：
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作者：
Ackermann, Lutz;Novak, Petr;Hofmann, Nora
通过 C-H 键断裂对芳烃进行直接芳基化，因其生态和经济上的良性性质而颇具吸引力，是一种日益可行的替代化学计量量有机金属试剂的传统交叉偶联反应的方法。[1, 2] 然而，虽然稳定配体的发展允许在传统交叉偶联化学中使用未活化的卤代烷，[3-5] 普遍适用于分子间 [6] 区域选择性直接芳基化通过 C-H 键断裂将芳烃 [7] 与卤代烷 [8] 进行烷基化已被证明是难以捉摸的。最近，我们报道了羧酸 [9] 作为添加剂在钌催化的与芳基溴、氯化物或甲苯磺酸酯的直接芳基化 [10, 11] 中的有益作用。 [12]鉴于原位生成的催化系统的活性显着提高，我们开始有兴趣探索其在前所未有的钌催化直接烷基化反应中的应用[13]，使用未活化的烷基卤化物[14, 15]作为亲电子试剂。在此，我们报告了此类 C-H 键功能化反应的发展结果，该反应允许伯烷基和仲烷基卤的有效转化，并证明适用于新戊基取代的亲电子试剂。在我们的研究开始时，我们使用 NMP 中的未活化烷基溴 2a 作为溶剂，探讨了钌催化的 2-吡啶基苯 (1a) 直接烷基化反应中的各种添加剂（表 1）。不同的膦并没有显着影响预期反应的结果（表 1，条目 1-4）。相反，当使用催化量的羧酸作为添加剂时，获得了更有希望的结果（表 1，条目 5-9）。烷基取代的位阻酸 1-AdCO2H 得到了最好的结果（表 1，条目 9）。在甲苯 [16] 中作为溶剂进行的反应效率较低（表 1，条目 10），而其他溶剂，如 THF、1, 4-二恶烷、DMSO 或 N,N-二甲基乙酰胺，得到的所需产物 3a 的产率要低得多。作为一种经济上有吸引力的替代方案，RuCl3·nH2O [17] 可用作催化剂前体（表 1，条目 11）。 [18]重要的是，吡啶衍生物 1a 的直接烷基化可以是
Direct arylation of arenes by CÀH bond cleavage, which is attractive because of its ecologically and economically benign nature, is an increasingly viable alternative to conventional cross-coupling reactions with stoichiometric amounts of organometallic reagents.[1, 2] However, while the development of stabilizing ligands allowed for the use of unactivated alkyl halides in traditional cross-coupling chemistry,[3–5] generally applicable methodologies for intermolecular [6] regioselective direct alkylations of arenes [7] with alkyl halides [8] by CÀH bond cleavage have proven elusive. Recently, we reported on the beneficial effect of carboxylic acids [9] as additives in ruthenium-catalyzed direct arylation [10, 11] with aryl bromides, chlorides, or tosylates.[12] Given the significantly improved activity of the in situ generated catalytic system, we became interested in exploring its use for unprecedented ruthenium-catalyzed direct alkylations [13] with unactivated alkyl halides [14, 15] as electrophiles. Herein, we report our findings on the development of such CÀH bond functionalization reactions, which allowed for the efficient conversion of primary and secondary alkyl halides and proved applicable to neopentyl-substituted electrophiles. At the outset of our studies, we probed various additives in the ruthenium-catalyzed direct alkylation of 2-pyridyl benzene (1a), employing unactivated alkyl bromide 2a in NMP as solvent (Table1). Different phosphines did not significantly affect the outcome of the envisioned reaction (Table1, entries1–4). On the contrary, more promising results were obtained when catalytic amounts of carboxylic acids were used as additives (Table 1, entries 5–9). The alkylsubstituted, sterically hindered acid 1-AdCO2H gave the best results (Table 1, entry 9).Reactions performed in toluene [16] as solvent proceeded less efficiently (Table 1, entry 10), and other solvents, such as THF, 1, 4-dioxane, DMSO, or N, N-dimethylacetamide, gave considerably lower yields of desired product 3a. As an economically attractive alternative, RuCl3· nH2O [17] could be employed as catalyst precursor (Table 1, entry 11).[18] Importantly, direct alkylation of pyridine derivative 1a could be