Nitro-Substituted Aryl Lithium Compounds in Microreactor Synthesis: Switch between Kinetic and Thermodynamic Control
Nitro-Substituted Aryl Lithium Compounds in Microreactor Synthesis: Switch between Kinetic and Thermodynamic Control
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DOI：
10.1002/anie.200904316
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Yoshida, Jun-ichi
中科院分区：
文献类型：
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作者：
Nagaki, Aiichiro;Kim, Heejin;Yoshida, Jun-ichi
硝基是最强的吸电子基团之一。它在激活有机分子以驱动和指导原本难以进行的反应方面具有巨大潜力。然而，硝基化合物在有机合成中的应用非常有限[1]，可能是因为它们与各种亲核和亲电子试剂不相容。[2]例如，硝基与有机金属化合物如有机锂和格氏试剂反应非常迅速。[3]因此，仅在非常低的温度下才可能产生在邻位具有硝基的芳基锂和芳基镁化合物。[4，5]此外，据报道，以常规方式生成间硝基或对硝基取代的芳基锂和芳基镁化合物非常困难。[6]我们设想，闪化学的概念可以提供一个解决这个问题。[7]在本文中，我们报告了微流系统[8，9]能够以受控的方式生成和转化o-，m-和p-硝基取代的芳基锂化合物。[10]此外，动力学上优选的或化学上优选的芳基锂试剂可以通过控制停留时间来选择性地使用。在初步研究中，我们发现PhLi是卤代硝基苯的卤素-锂交换的有效试剂，而MeLi、nBuLi和sBuLi的产物产率较低（详见支持信息）。因此，我们决定在以下研究中使用PhLi。所使用的微流系统由两个T形微混合器（M1和M2）和两个微管反应器（R1和R2;图1）组成。通过改变R1中的冷却浴温度（T）和停留时间（tR），由邻碘硝基苯（1a）、间碘硝基苯（1b）和对碘硝基苯（1c）生成芳基锂试剂，并在R2中用甲醇捕集。图2总结了通过改变温度和停留时间获得的结果。无论取代模式如何，产物都以高产率（> 80%）形成。
The nitro group is one of the strongest electron-withdrawing groups. It has great potential in the activation of organic molecules to drive and direct reactions that are otherwise difficult to perform. However, the use of nitro compounds in organic synthesis [1] has been very limited, presumably because of their incompatibility with various nucleophilic and electrophilic reagents.[2] For example, a nitro group reacts with organometallic compounds, such as organolithium and Grignard reagents, very rapidly.[3] Therefore, the generation of aryl lithium and aryl magnesium compounds with a nitro group in the ortho position is possible only at very low temperatures.[4, 5] Moreover, the generation of m-or p-nitrosubstituted aryl lithium and aryl magnesium compounds in a conventional manner has been reported to be very difficult.[6] We envisioned that the concept of flash chemistry could provide a solution to this problem.[7] Herein we report that a microflow system [8, 9] enables the generation and transformation of o-, m-, and p-nitro-substituted aryl lithium compounds in a controlled manner.[10] Furthermore, either the kinetically preferred or the thermodynamically preferred aryl lithium reagent can be used selectively through control of the residence time. In preliminary studies, we found that PhLi was an effective reagent for the halogen–lithium exchange of halonitrobenzenes, whereas MeLi, nBuLi, and sBuLi gave the products in low yields (see the Supporting Information for details). Therefore, we decided to use PhLi in the following studies.The microflow system used consisted of two T-shaped micromixers (M1 and M2) and two microtube reactors (R1 and R2; Figure 1). Aryl lithium reagents were generated from o-iodonitrobenzene (1a), m-iodonitrobenzene (1b), and piodonitrobenzene (1c) by varying the temperature (T) of the cooling bath and the residence time (tR) in R1, and were trapped with methanol in R2. Figure 2 summarizes the results obtained by varying the temperature and residence time. Irrespective of the substitution pattern, the products were formed in high yields (> 80%)