A one-step synthesis of 2-(2-Pyridyl)-3H-indol-3-one N-oxide: is it an efficient spin trap for hydroxyl radical?
A one-step synthesis of 2-(2-Pyridyl)-3H-indol-3-one N-oxide: is it an efficient spin trap for hydroxyl radical?
复制标题
2-(2-吡啶基)-3H-吲哚-3-酮N-氧化物的一步合成：它是羟基自由基的有效自旋陷阱吗？
DOI：
10.1021/jo0006122
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Halpern,HJ
中科院分区：
文献类型：
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作者：
Rosen,GM;Tsai,P;Barth,ED;Dorey,G;Casara,P;Spedding,M;Halpern,HJ
生物学中的自由基领域起源于20世纪60年代后期的一系列出版物，其中首次描述了黄嘌呤氧化酶酶循环期间超氧化物（O2·-）的分泌。1此后不久，发现一种含Cu/Zn的酶将这种自由基不成比例地转化为O2和H2 O2。[2]这种酶被称为超氧化物歧化酶（SOD），在定义O2·-和其他由O2·-产生的自由基的普遍存在性方面发挥了关键作用。3在这期间，已经开发了多种方法来检测生物环境中的自由基。其中，自旋捕获/EPR光谱是奇异的，在其能力，以表征特定的自由基，产生在原位，并确定在动物模型中的真实的时间。[4]基于我们早期在小鼠腿部肿瘤中成功识别HO·的实验，[5]我们对合成新的自旋捕获器特别感兴趣，这些自旋捕获器将允许在其他实验范式下对HO·进行体内原位检测。在我们的研究过程中，我们研究了3-取代的5，5-二甲基-1-吡咯啉N-氧化物和一些咪唑啉N-氧化物对HO·的特异性。[6]然而，最近，一篇文章引起了我们的兴趣，其中报道了2-（2-吡啶基）-3H-吲哚-3-酮N-氧化物4可以自旋捕获HO·。相应的自旋捕获加合物2-羟基-2-（2-吡啶基）-3H-吲哚-3-酮-1-氧基（11）与寿命较短的3-羟基-5，5-二甲基-1-吡咯啉-1-氧基（13）相比表现出显著的稳定性。[7]然而，对这种稳定性的热情必须受到这样一个事实的限制，即由于在R-碳上缺少一个氢原子，4失去了自旋捕获的优势之一，额外的超精细分裂可以帮助表征母体自由基。8尽管如此，有许多实验范例将极大地受益于容易获得的2-芳基-3H-吲哚-3-酮N-氧化物来源。已经有许多合成2-芳基-3H-吲哚-3-酮N-氧化物的方法，包括2-（2-吡啶基）-3H-吲哚-3-酮N-氧化物（参见例如方案1和2）。然而，多步途径，特别是那些中间体暴露于阳光下以获得所需产物的途径，往往导致令人垂涎的硝酮的产率很低。9
The field of free radicals in biology has its origins in a series of publications in the late 1960s in which the secretion of superoxide (O2•-) during the enzymic cycling of xanthine oxidase was first described. 1 Soon thereafter, a Cu/Zn-containing enzyme was found to disproportionate this free radical into O2 and H2O2. 2 This enzyme, which became known as superoxide dismutase (SOD), has played a pivotal role in defining the ubiquitous nature of O2•-and other free radicals generated from O2•-. 3 In the intervening years, a variety of methods have been developed to detect free radicals in biological milieu. Of those, spin trapping/EPR spectroscopy is singular in its ability to characterize specific free radicals, generated in situ, and identified in animal models in real time. 4 Based on our earlier success at identifying HO• in irradiated leg tumors of mice, 5 we have become particularly interested in syntheses of newer spin traps that would allow the in vivo in situ detection of HO• under other experimental paradigms. During the course of our investigations, we have studied the specificity of 3-substituted 5, 5-dimethyl-1-pyrroline N-oxides and a number of imidazoline N-oxides toward HO•. 6 Recently, however, a publication caught our fancy7 in which 2-(2-pyridyl)-3H-indol-3-one N-oxide 4 was reported to spin trap HO•. The corresponding spin trapped adduct, 2-hydroxy-2-(2-pyridyl)-3H-indol-3-on-1-oxyl (11), exhibited remarkable stability when compared to the shorter lifetime of 3-hydroxy-5, 5-dimethyl-1-pyrrolin-1-oxyl (13). 7 However, enthusiasm for such robustness must be tempered by the fact that 4, by lacking a hydrogen atom at the R-carbon, has lost one of the strengths of spin trapping, additional hyperfine splittings that can aid in the characterization of the parent free radical. 8 Despite this, there are a number of experimental paradigms that would greatly benefit from readily available sources of 2-aryl-3H-indol-3-one N-oxides.There have been a number of synthetic approaches to 2-aryl-3H-indol-3-one N-oxides, including 2-(2-pyridyl)-3H-indol-3-one N-oxide (see, for instance, Schemes 1 and 2). However, multistep pathways, especially those in which intermediates are exposed to sunlight to obtain the desired product, have often resulted in poor yields of the coveted nitrone. 9