Selective reduction of barbituric acids using SmI2/H2O: synthesis, reactivity, and structural analysis of tetrahedral adducts.
Selective reduction of barbituric acids using SmI2/H2O: synthesis, reactivity, and structural analysis of tetrahedral adducts.
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使用 SmI2/H2O 选择性还原巴比妥酸：四面体加合物的合成、反应性和结构分析。
DOI：
10.1002/anie.201306484
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Szostak M
中科院分区：
文献类型：
--
作者：
Szostak M
自1864年阿道夫·冯·拜尔（Adolf von Baeyer）的里程碑式发现以来，[1]巴比妥酸在医学和有机合成中发挥了重要作用。巴比妥酸支架存在于超过5000种具有生物活性的化合物中，包括常用的抗惊厥药、催眠药和抗癌药（图1a）。[2]此外，作为一种容易获得的原料，它是有机合成中非常有用的构建单元。[3]然而，尽管巴比妥酸盐已经被广泛研究了超过世纪，巴比妥酸的一般单还原仍然未知[4]，即使它在药物，材料和聚合物的生产和发现方面具有相当大的潜力。有趣的是，巴比妥酸盐单还原产物将正式构成一类新的酰胺键加成反应的四面体中间体，其中只有少数已被成功地分离，因为它们的瞬态性质。[5]单电子转移反应开辟了未探索的反应空间，其化学选择性和反应性水平难以通过离子反应机制获得。[6]在这方面，由于SmI 2具有优异的化学选择性和通过单电子还原事件实现羰基极性反转的潜力（图1b），因此用SmI 2生成酮基型自由基特别有价值。[7，8]然而，用SmI 2选择性还原酰胺羰基是具有挑战性的，并且目前没有实现这种高度期望的转化的通用方法。[9]在此，我们证明了SmI 2/H2O试剂[10]可以将巴比妥酸选择性单还原为相应的半缩醛胺（图1c）。据我们所知，这些是此类体系单还原的第一个一般性例子[4]，也是用SmI 2还原酰胺型羰基的第一个一般性例子。[7，8]半缩醛胺产物类似于衍生自酰胺加成反应的四面体中间体。[5]此外，由单电子还原形成的自由基中间体已被用于烯烃的分子内加成。这是第一次在任何SmI 2介导的酰基型自由基的交叉偶联反应中，[11]这些加成反应完全控制了非对映选择性。[12]此外，提供了实验证据的乙烯基自由基中间体的异构化SmI 2/H2O反应条件下。这一发现为SmI 2/H2O在级联还原过程中使用C-中心自由基打开了大门。[13]总的来说，这些研究为形成多功能半缩醛胺产物的多种方法提供了基础（参见半缩醛）通过形式酰胺极性反转事件。[6]We假设巴比妥酸（环状1，3-二酰亚胺）单电子还原成它们各自的自由基阴离子可以为开发用于还原宽范围酰胺官能团的通用系统提供基准。我们认为：1）在巴比妥酸体系中，其中一个酰亚胺羰基的还原将是
Since the 1864 landmark discovery by Adolf von Baeyer,[1] barbituric acids have played a prominent role in medicine and organic synthesis. The barbituric acid scaffold occurs in more than 5000 pharmacologically active compounds, including commonly used anticonvulsant, hypnotic, and anticancer agents (Figure 1a).[2] Moreover, as an easily accessible feedstock material, it is an extremely useful building block for organic synthesis.[3] However, despite the fact that barbiturates have been extensively studied for over a century, the general monoreduction of barbituric acids remains unknown,[4] even though it would have considerable potential for the production and discovery of pharmaceuticals, materials, and polymers. Interestingly, the barbiturate monoreduction products would formally constitute a new class of tetrahedral intermediates of amide bond addition reactions, only few of which have been successfully isolated to date because of their transient nature.[5] Single-electron-transfer reactions open up unexplored reaction space charted with chemoselectivity and reactivity levels difficult to access by ionic reaction mechanisms.[6] The generation of ketyl-type radicals with SmI2 is particularly valuable in this regard because of the excellent chemoselectivity imparted by the reagent and the potential to effect polarity reversal of the carbonyl group through a singleelectron-reduction event (Figure 1b).[7, 8] However, the selective reduction of amide carbonyls with SmI2 is challenging and no general method to achieve this highly desirable transformation is currently available.[9] Herein, we demonstrate that the SmI2/H2O reagent [10] can perform the selective monoreduction of barbituric acids to the corresponding hemiaminals (Figure 1c). To our knowledge these are the first general examples of monoreduction of such systems [4] as well as the reduction of amide-type carbonyls with SmI2.[7, 8] The hemiaminal products are analogous to tetrahedral intermediates derived from amide addition reactions.[5] Moreover, the radical intermediates formed by the one-electron reduction have been utilized in intramolecular additions to alkenes. For the first time in any SmI2-mediated cross-couplings of acyl-type radicals,[11] these additions proceed with full control of diastereoselectivity.[12] Furthermore, experimental evidence is provided for the isomerization of vinyl radical intermediates under SmI2/H2O reaction conditions. This discovery opens the door for the use of SmI2/H2O in cascade reductive processes employing C-centered radicals.[13] Overall, these studies provide a basis for multiple methodologies to form versatile hemiaminal products (cf. hemiacetals) by a formal amide polarity reversal event.[6]We hypothesized that single-electron reduction of barbituric acids (cyclic 1, 3-diimides) to their respective radical anions could provide a benchmark for the development of a general system for the reduction of a wide range of amide functional groups. We considered that 1) in the barbituric acid system the reduction of one of the imide carbonyls would be