Cross-Coupling Reactions through the Intramolecular Activation of Alkyl(triorgano)silanes
Cross-Coupling Reactions through the Intramolecular Activation of Alkyl(triorgano)silanes
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DOI：
10.1002/anie.201000816
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Hiyama, Tamejiro
中科院分区：
文献类型：
--
作者：
Nakao, Yoshiaki;Takeda, Masahide;Hiyama, Tamejiro
硅基交叉偶联反应因其化学选择性、试剂稳定性和有机硅试剂的无毒性而受到广泛关注，并且在过去十年中，许多努力导致了烯基和芳基硅烷化合物的交叉偶联反应的广泛发展。 [1]尽管这些烷基交叉偶联策略在有机合成中得到广泛使用，[2]但基于硅的方法仍然依赖于使用多氟化烷基硅烷试剂，这些试剂对水分、酸和碱敏感，并且需要使用高度亲核且昂贵的氟化物活化剂。[3]在此，我们报道了使用 2-(2-羟基丙-2-基)苯基取代的烷基硅烷进行的钯/铜催化的烷基交叉偶联反应，该反应是高度稳定的四有机硅试剂，可借助 K3PO4 作为弱碱来转移伯烷基和仲烷基。我们之前曾报道过 2-（羟甲基）-苯基取代的烯基硅烷和芳基硅烷与一系列亲电试剂交叉偶联。 [4]因此，我们首先使用结构改性的烷基硅烷试剂三甲基[2-(2-羟基丙-2-基)苯基]硅烷检查钯催化的芳基卤化物甲基化（1；方案1）。 1 (1.5 mmol) 与 4-氯苯甲腈 (2a, 1.0 mmol) 在 Pd (OAc) 2 (1 mol%)、Qphos (2.1 mol%),[5] 和 K3PO4 (2.5 mmol) 存在下，在四氢呋喃中于 1008℃ 反应 2 小时，得到 4-甲基苯甲腈 (3a)，产率 88%，估算如下： 1H 核磁共振波谱。值得注意的是，在金属催化剂和弱碱的帮助下，四有机硅试剂中非常强的 Si-Me 键仅比 Si-Ar 键被活化。 [6, 7] 事实上，在这些反应条件下没有观察到芳基的偶联。基于 1 的转化率 (95%) 计算环状甲硅烷基醚 4a 的形成，产率 93%，两者均通过 GC 分析估算。随后使用环状甲硅烷基醚4a作为起始材料，通过与烷基锂试剂的开环反应合成烷基硅烷。 1 中苄基甲基的存在至关重要：三甲基[2-（羟甲基）苯基]硅烷 (1') 在相同条件下的反应导致 1' 氧化和 2a 还原，分别几乎完全生成 5 和 6。这些结果促使我们研究一系列芳基亲电子试剂的甲基化（表 1）。 [8]该反应可耐受多种官能团，包括硝基、甲酰基、酮基和酯基（表 1，条目 1-5）。对于某些芳基卤化物的甲基化，1, 1’-双（二苯基膦）二茂铁 (DPPF)[9] 具有更好的产率（表 1，条目 2 和 4）。使用六氟乙酰丙酮铜 (II) 水合物 [Cu (hfacac) 2] 作为助催化剂对于 2’d 的甲基化是有效的，而在不存在时观察到乙酰基 [10] 的竞争性 a-芳基化。通过氟化物以外的碱活化硅试剂，使甲硅烷基醚参与偶联反应，同时保护基团被完全保留（表 1，条目 6）。在大多数情况下，观察到硅残留物4a具有良好的收率。空间要求高的 2-氯间二甲苯 (2j) 成功甲基化（表 1，条目 10）。以 10 mmol 规模进行反应，可以通过蒸馏分离出 4a，收率 64%；所得残余物通过硅胶快速色谱纯化，得到甲基化芳烃3k，产率89%（表1，条目11）。回收的 4a 用甲基锂处理得到 1，产率 88%，[8] 这证明了这种甲基硅烷试剂的容易合成。杂芳基亲电子试剂也在适度的情况下经历了甲基化……
Silicon-based cross-coupling reactions have received much attention in terms of their chemoselectivity, reagent stability, and the nontoxicity associated with organosilicon reagents, and many efforts have resulted in the extensive development of cross-coupling reactions with alkenyl-and arylsilane compounds in the last decade.[1] Despite the widespread use of these alkyl cross-coupling strategies in organic synthesis,[2] the silicon-based methods have relied on the use of polyfluorinated alkylsilane reagents, which are moisture-, acid-, and base-sensitive, and require the use of a highly nucleophilic and expensive fluoride activator.[3] Herein, we report a palladium/copper-catalyzed alkyl-cross-coupling reaction using 2-(2-hydroxyprop-2-yl) phenyl-substituted alkylsilanes, which are highly stable tetraorganosilicon reagents that transfer both primary and secondary alkyl groups with the aid of K3PO4 as a mild base. We have previously reported that 2-(hydroxymethyl)-phenyl-substituted alkenyl-and arylsilanes cross-couple with a range of electrophiles.[4] Therefore, we began by examining the palladium-catalyzed methylation of aryl halides using a structurally modified alkylsilane reagent, trimethyl [2-(2-hydroxyprop-2-yl) phenyl] silane (1; Scheme 1). The reaction of 1 (1.5 mmol) with 4-chlorobenzonitrile (2a, 1.0 mmol) in the presence of Pd (OAc) 2 (1 mol%), Qphos (2.1 mol%),[5] and K3PO4(2.5 mmol) in tetrahydrofuran at 1008C for 2hours gave 4-methylbenzonitrile (3a) in 88% yield, as estimated by 1H NMR spectroscopy. It is worth noting that the very strong SiÀMe bond of the tetraorganosilicon reagent is activated exclusively over the SiÀAr bond with the aid of the metal catalysts and the mild base.[6, 7] Indeed, no coupling of the aryl group was observed under these reaction conditions. Formation of cyclic silyl ether 4a in 93% yield was calculated based on the conversion of 1 (95%), both estimated by GC analysis. Cyclic silyl ether 4a was subsequently used as a starting material for synthesizing alkylsilanes through ring-opening reactions with alkyl lithium reagents. The presence of the benzylic methyl groups in 1 is essential: the reaction of trimethyl [2-(hydroxymethyl) phenyl] silane (1’) under identical conditions resulted in the oxidation of 1’and reduction of 2a to almost-exclusively afford 5 and 6, respectively.These results prompted us to examine the methylation of a range of aryl electrophiles (Table 1).[8] A variety of functional groups were tolerated in the reaction, including nitro, formyl, keto, and ester groups (Table 1, entries 1–5). For the methylation of some aryl halides, 1, 1’-bis (diphenylphosphino) ferrocene (DPPF)[9] gave better yields (Table 1, entries 2 and 4). Use of copper (II) hexafluoroacetylacetonate hydrate [Cu (hfacac) 2] as a co-catalyst was effective for the methylation of 2’d, whilst competitive a-arylation of the acetyl group [10] was observed in its absence. Activation of the silicon reagents by a base other than fluoride allowed silyl ethers to participate in the coupling reaction, with the protecting group being completely retained (Table 1, entry 6). In most cases, silicon residue 4a was observed in good yields. The highly sterically demanding 2-chloro-meta-xylene (2j) was methylated successfully (Table 1, entry 10). Performing the reaction on a 10 mmol scale allowed isolation of 4a by distillation in 64% yield; the resultant residue was purified by flash chromatography on silica gel to give methylated arene 3k in 89% yield (Table 1, entry 11). Recovered 4a was treated with methyllithium to give 1 in 88% yield,[8] which demonstrates the facile synthesis of this methylsilane reagent. Heteroaryl electrophiles also underwent the methylation in modest …