Synthesis of 13 C‐labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction
Synthesis of 13 C‐labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction
复制标题
使用 Houben–Hoesch 反应从同位素富集的苯酚合成 13 C–标记的对羟基苯甲酸酯
DOI：
10.1002/jlcr.3992
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发表时间：
2022
影响因子：
1.8
通讯作者：
Gujarati, Priyansh D.
中科院分区：
文献类型：
--
作者：
Reber, Keith P.;Sivey, John D.;Vollmuth, Matthew;Gujarati, Priyansh D.
对羟基苯甲酸酯是广泛存在于消费品中的抗菌添加剂。然而，对羟基苯甲酸酯在废水消毒过程中形成的卤代化合物是一个潜在的环境问题。为了鉴定这些转化产物并研究其形成机制，开发了在苯环内特定位置用稳定同位素碳-13标记的对羟基苯甲酸乙酯的合成路线。这种有效的两步法从市售的13 C标记的苯酚开始，包括（1）通过与三氯乙腈的Houben-Hoesch反应对苯酚进行初始酰化，然后（2）对所得三氯甲基酮进行改进的卤仿反应，以65%-80%的总产率得到相应的13 C标记的对羟基苯甲酸乙酯。还研究了改进的卤仿反应的范围，允许合成衍生自伯醇或仲醇的其他对羟基苯甲酸酯，包括13 C-和氘标记的酯。此外，4-羟基苯甲酸可以在用氢氧化锂处理后直接由常见的三氯甲基酮中间体形成。该方案补充了现有的13 C标记的对羟基苯甲酸酯衍生物的标记方法，并提供了在Houben-Hoesch反应中表现出完全区域选择性（以形成对位二取代产物）和避免在形成对羟基苯甲酸酯的改良卤仿反应中需要保护基团的特定优势。
Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon‐13 at specific positions within the benzene ring was developed. This efficient two‐step procedure starts from commercially available13C‐labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding13C‐labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including13C‐ and deuterium‐labeled esters. In addition, 4‐hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing13C‐labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form thepara‐disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters.