Revisiting the amine-catalysed cross-coupling
Revisiting the amine-catalysed cross-coupling
复制标题
重新审视胺催化的交叉偶联
作者：
Z. Novák;Réka Adamik;J. T. Csenki;F. Béke;Regina Gavaldik;B. Varga;Bálint Nagy;Z. May;J. Daru;Zsombor Gonda;Gergely L. Tolnai
1ELTE“Lendület”催化和有机合成研究小组，化学研究所，Eötvös Loránd 大学，布达佩斯，匈牙利。 2Eötvös Loránd 研究网络自然科学研究中心，匈牙利布达佩斯。 3Lehrstuhl für Theoretische Chemie，鲁尔波鸿大学，波鸿，德国。 4ELTE Tolnai 研究小组，化学研究所，Eötvös Loránd 大学，布达佩斯，匈牙利。 5目前地址：匈牙利布达佩斯罗兰大学化学研究所达鲁研究小组。 ✉电子邮件：novakz@ttk.elte.hu；可能.zoltan@ttk.hu; janos.daru@ttk.elte.hu； gondazs@elte.hu； tolnai@chem.elte.hu 最近，研究证明特殊的胺分子能够催化铃木-宫浦偶联反应。在这里，我们表明，在最近的转化中存在顺势疗法钯杂质和痕量磷物质。这些源自有机催化剂合成所使用的条件，并且代替胺类物质负责催化效果。这一发现证实了钯在交叉偶联中的作用，并引起了人们对该化学研究领域中杂质效应的关注。钯催化的 Suzuki-Miyaura 交叉偶联反应是有机化学中最强大的工具之一，特别是在药物合成中1-3。最近，徐等人。开发了一种替代的无金属胺催化铃木-宫浦型偶联反应来获得联芳基系统4。在我们的研究中，我们修改了胺在新型偶联过程中的作用，并揭示了钯杂质 5-10 在 C-C 键形成反应中的催化作用。这些发现为高活性催化剂系统的应用和机理解释提供了新的机会。在分析了原始程序4后，我们怀疑胺催化剂的合成和纯度分析是这种有机催化方法中最关键的问题。转化的关键化合物是通过一两个连续的钯催化反应制备的，钯催化剂负载量相对较高（3-5 mol%）。众所周知，过渡金属催化反应的产物即使经过色谱纯化也含有大量金属杂质11,12，这可能会在后续反应中引起催化活性5-10。此外，一些技术设备，例如搅拌棒，可以在反应中提供痕量的过渡金属9。胺产品中钯含量的测定是研究的重点。根据文献 4，根据电感耦合等离子体质谱分析 (ICP-MS) 结果，经过色谱纯化后，胺中仅含有亚 ppb (<μg kg-1) 水平的 Pd。然而，样品制备中使用的条件似乎不合适。在最初的方法中，消化是在环境温度下用 1% 硝酸溶液代替高温（150–200 °C）下的浓酸进行的。因此，应重新评估Pd含量测定方法。首先，按照Xu等人4的程序（补充方法），我们在3 mol% Pd存在下通过2,6-二氨基甲苯（1）和2-溴甲苯（2）的Buchwald-Hartwig偶联毫无困难地制备了最有效的二胺催化剂（AmineCat-30）。作为其程序的扩展，我们通过在色谱纯化后进行额外的重结晶来制备目标胺催化剂（AmineCat-30-RC）。然后，我们改变反应条件，以低得多的钯负载量进行相同的胺化。我们在 1,000 ppm 钯催化剂存在下成功实现了偶联，并在色谱纯化后以 91% 的收率分离出了胺产物 (AmineCat-1)。一批产品通过重结晶（AmineCat-1-RC）进一步纯化，用于分析和反应性研究（图1a）。最后，我们的目标是在不使用钯的情况下制备苯胺衍生物。我们设计了一种基于使用双邻甲苯碘鎓盐作为芳基化剂的无过渡金属方案13，并以 7% 的产率获得了所需的胺 (AmineCat-0)。获得同一胺的五个不同样品后，我们用电感耦合等离子体光发射光谱法（ICP-OES）和ICP-MS分析测量了它们的痕量金属含量（图1b）。我们的 ICP-OES 分析（补充方法）显示，根据 Xu 等人 4 (AmineCat-30) 制备的胺样品含有显着更高的 Pd 含量（519 mg kg-1，而 Xu 等人 4 报道的 <1 μg kg-1）。此外，该样品含有 136 mg kg-1 磷，这对于解释催化活性来说是一个突破性发现。通过色谱纯化，各种连接的 Pd-P 物质可以与胺共洗脱。因此，胺被金属和磷物质污染，这些物质可以作为铃木-宫浦反应的催化剂。在胶束条件下，在 Pd 负载量为 1,000 ppm 的情况下进行偶联，确保了产品 AmineCat-1 的 Pd 和 P 含量较低（353 mg kg-1 Pd 和 101 mg kg-1 P），特别是在重结晶之后（AmineCat-1-RC 的含量为 <0.16 mg kg-1 Pd 和 <20 mg kg-1 P）。无 Pd 方法得到的胺样品 AmineCat-0 具有更低的 Pd 和 P 含量（0.08 mg kg-1 Pd 和 <20 mg kg-1 P）。 Koide 及其同事14,15 开发的荧光检测方法也用于 AmineCats 中钯杂质的可视化（图 1d 和补充方法）。这种简单的分析方法提供了一种简单快速的可视化方法来检测样品中的钯杂质，甚至是 mg kg-1 水平。绿色荧光清楚地表明 AmineCat-30、AmineCat-1 和 AmineCat-30-RC 中存在 Pd（图 1c）。我们测试了所制备和分析的胺在苯基硼酸和 4-溴苯甲腈的偶联中的反应性，重新审视胺催化的交叉偶联
1ELTE “Lendület” Catalysis and Organic Synthesis Research Group, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary. 2Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary. 3Lehrstuhl für Theoretische Chemie, Ruhr–Universität Bochum, Bochum, Germany. 4ELTE Tolnai Research Group, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary. 5Present address: Daru Research Group, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary. ✉e-mail: novakz@ttk.elte.hu; may.zoltan@ttk.hu; janos.daru@ttk.elte.hu; gondazs@elte.hu; tolnai@chem.elte.hu Very recently, it was demonstrated that special amine molecules are able to catalyse the Suzuki–Miyaura coupling reaction. Here we show that in this recent transformation homeopathic palladium impurities and trace phosphorous species are present. These originate from the conditions used for the organocatalyst synthesis and are responsible for the catalytic effect instead of the amine species. This finding confirms the power of palladium in cross-coupling and draws attention to the impurity effect in this field of chemical research. The palladium-catalysed Suzuki–Miyaura cross-coupling reaction is one of the most powerful tools in organic chemistry, especially in the synthesis of pharmaceuticals1–3. Very recently, Xu et al. developed an alternative, metal-free amine-catalysed Suzuki– Miyaura-type coupling reaction to access biaryl systems4. In our study, we revised the role of the amines in the novel coupling procedure and revealed the catalytic role of palladium impurities5–10 in the C–C bond-forming reaction. These findings provide new opportunities for the applicability of highly active catalyst systems and mechanistic interpretations. Having analysed the original procedure4, we suspected that the synthesis and purity analysis of the amine catalysts are the most critical issues of this organocatalytic approach. The key compounds of the transformation were prepared in one or two sequential palladium-catalysed reactions with a relatively high Pd catalyst loading (3–5 mol%). It is known that products of transition-metal-catalysed reactions contain considerable amounts of metal impurities even after chromatographic purification11,12, which can cause catalytic activities in subsequent reactions5–10. Moreover, some technical equipment, such as stir bars, can supply traces of transition metals in a reaction9. The determination of the palladium content of the amine products was a key point of the research. According to the literature4, the amines contained only sub ppb (<μg kg–1) levels of Pd after chromatographic purification on the basis of the inductively coupled plasma–mass spectrometry analysis (ICP–MS) results. However, seemingly inappropriate conditions were used for the sample preparation. In the original method, the digestion was carried out with a 1% nitric acidic solution at ambient temperature instead of concentrated acids at elevated temperatures (150–200 °C). Thus, the Pd content determination method should be re-evaluated. First, following the procedure (Supplementary Methods) of Xu et al.4, we prepared the most efficient diamine catalyst through the Buchwald–Hartwig coupling of 2,6-diaminotoluene (1) and 2-bromotoluene (2) in the presence of 3 mol% Pd without difficulty (AmineCat-30). As an extension of their procedure, we prepared the target amine catalyst by performing an additional recrystallization after chromatographic purification (AmineCat-30-RC). Then, we changed the reaction conditions to perform the same amination with much lower palladium loading. We successfully achieved the coupling in the presence of 1,000 ppm palladium catalyst and isolated the amine product (AmineCat-1) in 91% yield after chromatographic purification. One batch of the product was further purified by recrystallization (AmineCat-1-RC) for the analysis and reactivity study (Fig. 1a). Finally, we aimed to prepare the aniline derivative without the utilization of palladium. We designed a transition-metal-free protocol based on the utilization of a bi-o-tolyliodonium salt as the arylating agent13, and we obtained the desired amine in 7% yield (AmineCat-0). After five different samples of the same amine were obtained, we measured their trace metal content with inductively coupled plasma–optical emission spectrometry (ICP–OES) and ICP–MS analysis (Fig. 1b). Our ICP–OES analysis (Supplementary Methods) revealed that the amine sample prepared according to Xu et al.4 (AmineCat-30) contains dramatically higher Pd content (519 mg kg–1 versus the <1 μg kg–1 reported in Xu et al.4). Additionally, this sample contained 136 mg kg–1 phosphorous, which is a breakthrough discovery for the interpretation of the catalytic activity. Various ligated Pd–P species can co-elute with the amine through chromatographic purification. Consequently, the amine is contaminated by both metal and phosphorous species, which could act as possible catalysts for the Suzuki–Miyaura reaction. Coupling under the micellar conditions in the presence of a 1,000 ppm Pd loading ensured a lower Pd and P content of the product AmineCat-1 (353 mg kg–1 Pd and 101 mg kg–1 P), especially after recrystallization (AmineCat-1-RC has a content of <0.16 mg kg–1 Pd and <20 mg kg–1 P). The Pd-free method gave the amine sample AmineCat-0 with even lower Pd and P contents (0.08 mg kg–1 Pd and <20 mg kg–1 P). A fluorometric detection method developed by Koide and co-workers14,15 was also applied for the visualization of palladium impurities in the AmineCats (Fig. 1d and Supplementary Methods). This simple analytical method offers an easy and fast visualization method to detect palladium impurities in the samples, even at mg kg–1 levels. The green fluorescent colour clearly shows the presence of Pd in AmineCat-30, AmineCat-1 and AmineCat-30-RC (Fig. 1c). We tested the reactivity of the prepared and analysed amines in the coupling of phenylboronic acid and 4-bromobenzonitrile under Revisiting the amine-catalysed cross-coupling
影响因子：
3.4
作者：
Bu, Xiaodong;Koide, Kazunori;Welch, Christopher J.
通讯作者：
Welch, Christopher J.