Nano palladium coordination complexes, incorporating pincer ligands are reported to be highly efficient catalysts for C–C coupling reactions, giving excellent yields with low catalyst loading.1–8 A relatively new amino pincer palladium complex has been reported by Frech for C–C bond formation via the Heck, Sonogashira, Stille, Hiyama and Suzuki-Miyaura reactions.3–7 A myriad of palladium complexes exist to promote these C–C bond forming processes.9 However, a serious limitation to the use of these reactions for the synthesis of bioactive molecules stems from the lack of thermal stability and functional group tolerance of many palladium complexes as well as the requirement for relatively high catalyst loadings.4 Decomposition of catalysts at normal reaction temperatures (140–150°C) can result in highly contaminated products that require extensive purification, which markedly decreases the yields.8,10 Conventional catalysts also give modest results with heterocyclic substrates.11,12 In contrast, the Frech catalyst exhibits robust thermal stability due, in large part, to the P-Pd-P (PCP) moiety of the pincer ligand.5,13 This thermal stability, together with its inertness to oxygen and water, are unique qualities of the Frech catalyst and allow it to maintain high activity under a variety of reaction conditions.13 In the present work, we have evaluated the Frech catalyst and compared it with two conventional palladium catalysts for coupling highly-substituted, heterocyclic substrates in the final step of a synthesis of 2,4-diaminopyrimidine-based antibiotics, which have demonstrated activity against inhalation anthrax14–16 and multi-drug resistant staph.17 We now report results which validate the potential of this new catalyst in reactions involving multi-functional heterocyclic substrates. Initially, an evaluation was made of the catalyst, base, and solvent required for the Heck reaction of 2,4-diamino-5-(5-iodo-3,4-dimethoxybenzyl)pyrimidine (1) with (±)-1-(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one (2a) to generate 3a (Scheme 1).14,15,18 Two conventional catalysts, (Ph3P)2PdCl2 and Pd(OAc)2,18 as well as the Frech complex, were examined and compared. The use of (Ph3P)2PdCl2 under standard conditions (round-bottomed flask, 1.25 mol% catalyst relative to substrates 1 and 2a, 1.10 equivalents of N-ethylpiperidine, DMF, argon atmosphere, 140–150°C, 18 h) gave a low yield (37%) of the coupled product 3a with a significant number of impurities. An improved return (42%) was realized in a sealed tube under the same conditions, but impurities still persisted. The use of Pd(OAc)2 (1.25 mol%) provided the products in similar yields (50–52%) under both standard and sealed tube conditions, but with only a slightly improved impurity profile. By comparison, the Frech catalyst afforded consistently high yields (80%) with far fewer contaminants at a loading of just 0.12 mol%. Moreover, the Frech catalyst allowed the reaction to be performed on a larger scale (see below). Scheme 1 Preparation of 3a by Heck Coupling. Heck reactions using pincer catalysts are often critically influenced by the solvent and base employed for the coupling process.19,20 To determine the optimum protocol, several solvents, including DMF, THF, and PhCH3, were studied. For the current application, DMF afforded the best results due to its superior solvating properties for the substrates and high boiling point. A series of bases, which included K2CO3, Cs2CO3, Et3N, DBU and N-ethylpiperidine, was also evaluated. In DMF, N-ethylpiperidine provided the highest yields of coupled products. Reaction temperatures were also varied to optimize the conditions. Using DMF and N-ethylpiperidine, maximum conversions were realized at 140–150°C. Reactions at lower temperatures (110–120°C) were slow and gave low yields even after prolonged heating (36 h). At more elevated temperatures (≥160°C), complex mixtures were formed which hindered purification of the desired products. For catalyst comparison studies, reactions using (Ph3P)2PdCl2, Pd(OAc)2, and the Frech complex were run at 140–150°C for 16–20 h, although 3h–3j required only 8–12 h. Without exception, the Frech catalyst gave higher yields and cleaner products that were more easily purified. Finally, catalytic loading for each catalyst was investigated. Our optimization studies indicated that 1.25 mol% of (Ph3P)2PdCl2 and Pd(OAc)2 was required to achieve complete conversions. Greater amounts of catalyst slightly decreased the yields and increased the number of impurities, while less catalyst resulted in incomplete reactions. In sharp contrast, the Frech complex afforded essentially complete conversions to products at a catalytic loading of only 0.12 mol%. For the class of compounds examined, isolated yields of products were highly reproducible with this quantity of catalyst. Under optimized conventional conditions, the reactions of 1.30 mmol each of 1 with 2a–j were carried out using 1.42 mmol of N-ethylpiperidine and 1.55 × 10−3 mmol (0.12 mol%) of the Frech catalyst in 4 mL of DMF under argon at 140–150°C for 16–20 h. The R groups [propyl (3a), isobutyl (3b), isobutenyl (3c), cyclohexyl (3d), phenyl (3e), 4-methylphenyl (3f), 4-fluorophenyl (3g), benzyl (3h), 4-methylbenzyl (3i) and 4-trifluoromethoxybenzyl (3j)] were carefully chosen to provide a range of agents with potential activity as antibiotics and also to ascertain the structural diversity tolerated by the catalyst. The results are summarized in Table 1. Products 3a–j were highly polar and retained water (from chromatography) or methanol (from recrystallizations) despite extensive efforts to remove them.21 Finally, though our study compared reactions run on a 1.30-mmol scale, the Frech catalyst (at a loading of 0.17 mol%) allowed us to run 20.0-mmol preparative scale reactions to generate lead compounds 3a and 3c in essentially undiminished yields of 78% and 74%, respectively. Table 1 Yields of 3a–j using Three Catalysts Coupling of substrates incorporating such wide functional diversity–a diaminopyrimidine ring, two ethers, a tertiary amide, an imine and (in some cases) fluorine–is rare. The closest analogy to our work involved the use of the Frech catalyst to couple a variety of aryl halides to N,N-dimethylacrylamide.13 In this investigation, the reported transformations were assessed to be nearly quantitative by GC/MS analysis. Table 1 reports of products isolated in our current study. Although our optimized catalyst loading was 0.12 mol%, compared to 0.01 mol% for the acrylamide,13 this parameter would be expected to vary for different compounds. Nevertheless, the marked flexibility of the Frech catalyst to operate effectively on systems bearing such a large range of functional groups is remarkable and of great significance in organic synthesis. In summary, we have used the Frech pincer catalyst to efficiently prepare a series of highly functionalized 2,4-diaminopyrimidine-based antibacterials for biological evaluation. The Frech catalyst proved superior to conventional palladium-based Heck catalysts, giving the desired products in higher yields and with fewer contaminants. The Frech catalyst also exhibited superior activity and thermal stability and reduced the required catalytic loading by a factor greater than ten compared to the other catalysts examined. Such remarkable utility, broad scope of action, and multi-functional group tolerance by the Frech catalyst mandates further exploration in organic synthesis.

中文翻译：

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Frech催化剂与两种常规催化剂在合成2,4-二氨基嘧啶类抗生素中的比较研究

基于 4-二氨基嘧啶的抗生素，已证明对吸入性炭疽14-16 和多重耐药葡萄球菌有活性。17 我们现在报告的结果验证了这种新催化剂在涉及多功能杂环底物的反应中的潜力。最初，对 2,4-二氨基-5-(5-碘-3,4-二甲氧基苄基)嘧啶 (1) 与 (±)-1- 的 Heck 反应所需的催化剂、碱和溶剂进行了评估(1-丙基-2(1H)-phthalazinyl)-2-propen-1-one (2a) 生成 3a（方案 1）。14,15,18 两种常规催化剂，(Ph3P)2PdCl2 和 Pd(OAc)2 ,18 以及 Frech 复合体进行了检查和比较。(Ph3P)2PdCl2 在标准条件下的使用（圆底烧瓶，相对于底物 1 和 2a，1.25 mol% 催化剂，1.10 当量 N-乙基哌啶，DMF，氩气气氛，140–150°C，18 h) 得到低产率 (37%) 的偶联产物 3a，其中含有大量杂质。在相同条件下，在密封管中实现了改进的回报 (42%)，但杂质仍然存在。在标准管和密封管条件下，使用 Pd(OAc)2 (1.25 mol%) 可提供相似产率 (50–52%) 的产品，但杂质分布仅略有改善。相比之下，Frech 催化剂以仅 0.12 mol% 的负载量提供了始终如一的高产率 (80%) 和更少的污染物。此外，Frech 催化剂允许反应以更大规模进行（见下文）。方案 1 通过 Heck 偶联制备 3a。使用钳形催化剂的 Heck 反应通常受到偶联过程中使用的溶剂和碱的严重影响。 19,20 为了确定最佳方案，几种溶剂，包括 DMF、THF 和 PhCH3。对于目前的应用，DMF 提供了最好的结果，因为它对底物具有优异的溶剂化性能和高沸点。还评估了一系列碱，包括 K2CO3、Cs2CO3、Et3N、DBU 和 N-乙基哌啶。在 DMF 中，N-乙基哌啶提供最高产率的偶联产物。还改变反应温度以优化条件。使用 DMF 和 N-乙基哌啶，在 140–150°C 下实现了最大转化率。在较低温度（110-120°C）下反应缓慢，即使在长时间加热（36 小时）后，产率也很低。在更高的温度 (≥160°C) 下，会形成复杂的混合物，从而阻碍了所需产品的纯化。对于催化剂比较研究，使用 (Ph3P)2PdCl2、Pd(OAc)2、和 Frech 复合物在 140-150°C 下运行 16-20 小时，尽管 3h-3j 只需要 8-12 小时。无一例外，Frech 催化剂的产量更高，产品更清洁，更容易纯化。最后，研究了每种催化剂的催化负载。我们的优化研究表明，实现完全转化需要 1.25 mol% 的 (Ph3P)2PdCl2 和 Pd(OAc)2。较大量的催化剂略微降低了产率并增加了杂质的数量，而较少的催化剂导致反应不完全。与此形成鲜明对比的是，Frech 络合物在催化负载仅为 0.12 mol% 的情况下基本上完全转化为产物。对于所研究的那类化合物，使用该数量的催化剂可以高度重现产物的分离产率。在优化的常规条件下，1. 使用 1.42 mmol N-乙基哌啶和 1.55 × 10-3 mmol (0.12 mol%) Frech 催化剂在 4 mL DMF 中在氩气下在 140-150°C 下进行 30 mmol 1 与 2a-j –20 小时。R基团[丙基(3a)、异丁基(3b)、异丁烯基(3c)、环己基(3d)、苯基(3e)、4-甲基苯基(3f)、4-氟苯基(3g)、苄基(3h)、4-甲基苄基 (3i) 和 4-三氟甲氧基苄基 (3j)] 被仔细选择以提供一系列具有潜在抗生素活性的试剂，并确定催化剂耐受的结构多样性。结果总结在表 1 中。 产物 3a-j 是高极性和保留水（来自色谱法）或甲醇（来自重结晶），尽管进行了大量努力以去除它们。 21 最后，尽管我们的研究比较了在 1.30 mmol 规模上运行的反应，Frech 催化剂（负载量为 0. 17 mol%) 使我们能够运行 20.0 mmol 制备规模的反应，以分别以 78% 和 74% 的产率基本上未减少的产率生成先导化合物 3a 和 3c。表 1 使用三种催化剂的 3a-j 产率 结合如此广泛的功能多样性的底物偶联——一个二氨基嘧啶环、两个醚、一个叔酰胺、一个亚胺和（在某些情况下）氟——是罕见的。与我们的工作最接近的类比是使用 Frech 催化剂将各种芳基卤化物与 N,N-二甲基丙烯酰胺偶联。13 在本次调查中，通过 GC/MS 分析评估报告的转化几乎是定量的。表 1 报告了我们当前研究中分离出的产品。尽管我们优化的催化剂负载量为 0.12 mol%，而丙烯酰胺为 0.01 mol%，13 但预计该参数会因不同化合物而异。尽管如此，Frech 催化剂在具有如此大范围官能团的系统上有效运行的显着灵活性是显着的，并且在有机合成中具有重要意义。总之，我们使用 Frech 钳形催化剂有效地制备了一系列用于生物学评价的高度功能化的 2,4-二氨基嘧啶类抗菌剂。事实证明，Frech 催化剂优于传统的钯基 Heck 催化剂，能够以更高的收率和更少的污染物提供所需的产品。与其他检测的催化剂相比，Frech 催化剂还表现出优异的活性和热稳定性，并将所需的催化负载降低了 10 倍以上。如此显着的实用性，广泛的作用范围，