Microwave-assisted organic synthesis is an area of increasing interest for promoting clean, reproducible, high-yielding reactions under mild conditions.1,2 This is evident from the large number of papers and reviews that have appeared on this topic in the recent literature.3–8 In the current work, microwave irradiation was employed to facilitate the intermolecular formation of C–C bonds using a palladium-catalyzed Heck coupling reaction. Microwave conditions have previously been used to accelerate this type of reaction9,10 as well as other metal-catalyzed processes such as the Suzuki, Sonogashira and Negishi couplings.11,12 However, the use of microwave irradiation to induce reactions of highly functionalized molecules has not been studied in detail. We, therefore, wish to report our work on a microwave-assisted Heck reaction to prepare a series of antibacterials bearing a variety of functional groups. The goal of the current project is the synthesis 2,4-diaminopyrimidine antibiotics 3a–h, which have potential for the treatment of inhalation anthrax, a bioterror threat. The most important aspect of these drugs is that they selectively inhibit the activity of Bacillus anthracis dihydrofolate reductase (DHFR) but not human DHFR.13,14 DHFR plays a critical role in folate metabolism and is a good target for antibiotic drug candidates. Furthermore, since our compounds incorporate several structural units common to drugs that inhibit DHFR, it is less likely that bacteria exposed to these agents will readily develop a resistance to them. The synthesis involves a Heck reaction of 2,4-diamino-5-(5-iodo-3,4-dimethoxy-benzyl)pyrimidine (1) with a series of (±)-1-(1-substituted-1H-phthalazin-2-yl)prop-2-en-1-ones 2, both of which are available by known methods.13,15 Earlier syntheses of certain examples of 3 by conventional Heck procedures13,15 gave yields of 10%–37%. The products obtained by this method, however, were difficult to purify from the reaction mixture due to extensive side-product formation. We have successfully improved the synthesis by employing microwave irradiation to assist the Heck coupling process. The conventional reactions were carried out using 2.07 mmol each of 1 and 2, 2.27 mmol of N-ethylpiperidine and 0.026 mmol (1.24 mol % relative to substrates 1 and 2) of bis(triphenylphosphine)palladium(II) dichloride catalyst in 8 mL of DMF under argon at 140°C–150°C for 18 h.13,15 This procedure generally afforded the coupled product in low yield (10%–37%) with substantial side-product formation. In an effort to improve this outcome, substrate concentrations and temperatures were varied, but neither of these changes resulted in significant improvement. Attempts to adjust the catalyst loading for this transformation were also examined. An increase in catalyst loading to 2.00 mol % decreased the yield of the product and added to the impurity profile, making isolation of the product more difficult. A decrease in catalyst loading to 0.96 mol % led to incomplete reaction and recovery of starting material along with the desired product. Thus, a catalyst loading of 1.24 mol % proved optimum for the complete conversion to the product with a minimum of side reactions. Finally, the use of other catalysts (e.g. Pd(OAc)2, PdCl2, (Ph3P)4Pd, Pd/C and CuI)13 and bases (e.g. Et3N, DBU, K2CO3 and Cs2CO3)13 failed to improve the conversion to product. Reactions were also carried out on the same molar scale in sealed tubes. This resulted in slightly improved yields (42%–65%), but side-reactions were still problematic. It is conceivable that prolonged heating under conventional and sealed tube conditions caused degradation of the substrates and the catalyst, leading to a more complex product mixture. Thus, a method was sought to decrease the reaction time, which led us to the use of microwave irradiation. Microwave-assisted reactions were run on the same scale as above at 400 W and 150°C under argon for 60–80 min and gave superior conversions to products with far fewer impurities. A comparison of yields obtained using conventional, sealed tube and microwave conditions is shown in Table 1. Microwave irradiation as an alternative source of heating expedited the reaction, decreased the required catalyst loading by 20% (to 0.96 mol %) and reduced the amount of solvent needed by 25%. A series of reactions was carried out with R = propyl, isobutyl, isobutenyl, phenyl, 4-fluorophenyl, benzyl, 4-methylbenzyl and 4-trifluoromethoxybenzyl to establish the generality of the method. Products prepared in this manner were conveniently purified by placing the crude reaction mixture directly onto a silica gel column and eluting with increasing concentrations of methanol in dichloromethane. The target molecules were isolated as hydrates or solvates16 and were characterized by elemental and spectral analysis. Table 1 Yields of 3 Using Conventional, Sealed Tube and Microwave Conditions 1+2a-h→N-ethylpiperidineDMF,Δ(Ph3P)2PdCl23a-h We have successfully developed a synthesis of 2,4-diaminopyrimidine-based antibiotics that utilizes a microwave-assisted Heck reaction on highly functionalized substrates in the final step. The reaction is superior to reactions performed under conventional or sealed tube conditions, requiring less solvent and catalyst. More importantly, the use of microwave conditions reduced reaction times and provided higher coupling yields with fewer side products.

中文翻译：

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微波辅助 Heck 合成取代 2,4-二氨基嘧啶类抗生素


微波辅助有机合成是在温和条件下促进清洁、可重复、高产反应的一个日益受到关注的领域。1,2 从最近文献中出现的大量关于该主题的论文和评论中可以明显看出这一点。 3-8 在当前的工作中，采用微波辐射通过钯催化的 Heck 偶联反应促进分子间 C-C 键的形成。微波条件以前曾被用来加速此类反应 9,10 以及其他金属催化过程，如铃木、Sonogashira 和 Negishi 偶联。 11,12 然而，使用微波辐射来诱导高度功能化分子的反应已成为可能。没有详细研究过。因此，我们希望报告我们在微波辅助赫克反应方面的工作，以制备一系列带有各种官能团的抗菌剂。当前项目的目标是合成 2,4-二氨基嘧啶抗生素 3a-h，它具有治疗吸入性炭疽（一种生物恐怖威胁）的潜力。这些药物最重要的一点是它们选择性抑制炭疽杆菌二氢叶酸还原酶 (DHFR) 的活性，但不抑制人类 DHFR。13,14 DHFR 在叶酸代谢中发挥着关键作用，是抗生素候选药物的良好靶点。此外，由于我们的化合物包含了抑制 DHFR 的药物常见的几个结构单元，因此接触这些药物的细菌不太可能轻易对它们产生耐药性。该合成涉及 2,4-二氨基-5-(5-碘-3,4-二甲氧基-苄基)嘧啶 (1) 与一系列 (±)-1-(1-取代-1H-酞嗪) 的 Heck 反应-2-基)丙-2-en-1-酮2，两者均可通过已知方法获得。13,15 早期通过传统 Heck 程序合成 3 的某些实例 13,15 的产率为 10%–37%。然而，由于大量副产物的形成，通过该方法获得的产物难以从反应混合物中纯化。我们通过采用微波辐射辅助赫克偶联过程成功地改进了合成。常规反应使用1和2各2.07mmol、2.27mmol N-乙基哌啶和0.026mmol(相对于底物1和2为1.24mol％)双(三苯基膦)二氯化钯(II)催化剂在8mL溶液中进行。 DMF 在氩气下于 140°C–150°C 反应 18 小时。13,15 该程序通常以低收率 (10%–37%) 提供偶联产物，并形成大量副产物。为了改善这一结果，改变了底物浓度和温度，但这些变化都没有带来显着的改善。还研究了调整该转化的催化剂负载量的尝试。催化剂负载量增加至 2.00 mol% 会降低产物的产率并增加杂质分布，使产物的分离变得更加困难。催化剂负载量减少至 0.96 mol% 导致反应不完全，并且起始材料与所需产物一起回收。因此，1.24 mol% 的催化剂负载量被证明是完全转化为产物且副反应最少的最佳选择。最后，使用其他催化剂（例如Pd(OAc)2、PdCl2、(Ph3P)4Pd、Pd/C和CuI)13和碱（例如Et3N、DBU、K2CO3和Cs2CO3）13未能提高产物的转化率。反应也在密封管中以相同的摩尔规模进行。这导致产率略有提高（42%–65%），但副反应仍然是个问题。 可以想象，在传统和密封管条件下长时间加热会导致基材和催化剂的降解，从而导致更复杂的产物混合物。因此，我们寻求一种减少反应时间的方法，这导致我们使用微波辐射。微波辅助反应在氩气下以与上述相同的规模在 400 W 和 150°C 下运行 60-80 分钟，并获得了杂质少得多的产物的优异转化率。表 1 显示了使用传统密封管和微波条件获得的产率比较。微波辐射作为替代加热源加速了反应，将所需的催化剂负载量减少了 20%（至 0.96 mol%），并减少了需要25%的溶剂。以R=丙基、异丁基、异丁烯基、苯基、4-氟苯基、苄基、4-甲基苄基和4-三氟甲氧基苄基进行一系列反应，以建立该方法的通用性。通过将粗反应混合物直接置于硅胶柱上并用增加浓度的甲醇/二氯甲烷洗脱来方便地纯化以此方式制备的产物。目标分子以水合物或溶剂化物的形式分离出来，并通过元素和光谱分析进行表征。表 1 使用传统密封管和微波条件 1+2a-h→N-乙基哌啶DMF,Δ(Ph3P)2PdCl23a-h 3 的产率 我们成功开发了一种利用微波合成 2,4-二氨基嘧啶类抗生素的方法在最后一步中辅助高功能化基材上的 Heck 反应。该反应优于传统或密封管条件下进行的反应，需要较少的溶剂和催化剂。 更重要的是，微波条件的使用减少了反应时间，并提供了更高的偶联产率和更少的副产物。