JOCR Journal of Organic Chemistry Research 2330-5231 Scientific Research Publishing 10.12677/JOCR.2022.103011 JOCR-56311 JOCR20220300000_34501921.pdf 化学与材料 无金属条件下的酰胺脱水反应 Dehydration of Amides under Nonmetallic Conditions 张 宗卫 1 * 浙江师范大学，化学与生命科学学院，浙江 金华 01 09 2022 10 03 111 117 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

酰胺作为广泛存在于自然界与药物分子中的含氮化合物，在工业，医药，农药等领域发挥了重要作用。因此，酰胺反应的研究逐渐受到合成化学家的广泛关注。文献调研后，本文对无金属条件下的酰胺脱水反应和无金属条件下的酰胺脱水重排反应进行了总结和探讨，并对该脱水反应的发展做出展望。 Amides are widely existing in nature, and drug molecules play an important role in the industry, medicine, pesticides and other fields. Therefore, the study of amides has gradually attracted the attention of synthetic chemists. After a literature review, this paper summarizes and discusses the dehydration and rearrangement of amides under metal-free conditions and looks forward to the development of this dehydration reaction.

酰胺，脱水反应，脱水重排, Amide Dehydration Reaction Dehydration Rearrangement 摘要

酰胺作为广泛存在于自然界与药物分子中的含氮化合物，在工业，医药，农药等领域发挥了重要作用。因此，酰胺反应的研究逐渐受到合成化学家的广泛关注。文献调研后，本文对无金属条件下的酰胺脱水反应和无金属条件下的酰胺脱水重排反应进行了总结和探讨，并对该脱水反应的发展做出展望。

 关键词

酰胺，脱水反应，脱水重排

 Dehydration of Amides under Nonmetallic Conditions<sup> </sup>

Zongwei Zhang

College of Chemistry and Life Science, Zhejiang Normal University, Jinhua Zhejiang

Received: Aug. 31st, 2022; accepted: Sep. 19th, 2022; published: Sep. 27th, 2022

 ABSTRACT

Amides are widely existing in nature, and drug molecules play an important role in the industry, medicine, pesticides and other fields. Therefore, the study of amides has gradually attracted the attention of synthetic chemists. After a literature review, this paper summarizes and discusses the dehydration and rearrangement of amides under metal-free conditions and looks forward to the development of this dehydration reaction.

Keywords:Amide, Dehydration Reaction, Dehydration Rearrangement

Copyright © 2022 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

酰胺是一类重要的有机化合物，广泛存在于多种具有生物活性的药物中间体、天然产物以及多种聚合物材料中。如聚酰胺、色素和染料、药物、农用化学品等 [ 1 ]。一直以来关于酰胺反应的研究都被研究人员广泛关注，其中，以金属催化的形式进行的酰胺脱水反应在近几十年得到了巨大发展 [ 2 ] - [ 12 ]，但该类方法普遍存在反应条件苛刻、原材料昂贵且制备过程繁琐、易导致重金属污染等问题。相比之下，无金属条件下的酰胺脱水反应具有非常大的研究价值。本文将对无金属条件下的酰胺脱水反应的研究进展进行总结和探讨，重点分为无金属条件下的酰胺脱水成腈及无金属条件下的酰胺脱水重排两个部分。

 2. 无金属条件下的酰胺脱水成腈 2.1. 无金属条件下酰胺脱水剂脱水

早在1892年Pinner等人 [ 13 ] 就发现一些腈可能可以通过乙酰氯或苯甲酰氯与酰胺的作用来制备腈。而在1945年Mitchell等人 [ 14 ] 对酰胺进行定量分析时发现伯酰胺与3,5-二硝基苯甲酰氯反应可形成腈(图1)。1951年Thompson等人 [ 15 ] 在对酰胺进行二酰化的过程中同样发现，强羧酸的卤化物会使酰胺脱水形成腈，但皆未进行具体报道。

图1. 伯酰胺与3,5-二硝基苯甲酰氯发生定量反应形成腈

直到1954年Pilgrim等人 [ 16 ] 才首次报道，芳基磺酰卤化物-吡啶混合物在温和条件下可将伯酰胺转化为腈(图2)。

图2. 芳基磺酰卤化物-吡啶将酰胺脱水成腈

1970年Dennis等人 [ 17 ] 报道了以硅烷、氯硅烷、烷氧基硅烷和氨基硅烷为脱水试剂对酰胺进行脱水。反应在轻度碱性、中性或酸性条件下都可以顺利进行，且腈易于分离(图3)。但取代酰胺如N-甲基苯甲酰胺及乙酰胺产率分别只有43%和27%，这些反应通常需要加热到200℃以上才能反应。

图3.苯甲酰胺或乙酰胺在180~200℃下反应得到苯甲腈或乙腈

Casini课题组 [ 18 ] 在1977年发现1,2,3-茚三酮与ch-酸化合物形成加合物脱水的过程中发现，三氟乙酸酐可以很容易将伯酰胺转化成腈(图4)。

图4. 三氟乙酸酐作为脱水剂对酰胺脱水

2006年，Shia课题组 [ 19 ] 利用二氯磷酸乙酯/DBU为温和脱水剂，开发了一种操作简单、高产率的将伯酰胺转化为相应的腈的方法(图5)。这种新开发的方法具有广泛的合成用途，特别是用于制备热力学不稳定的腈。

图5. 二氯磷酸乙酯/DBU脱水剂脱水

2011年，Unnikrishnan等人 [ 20 ] 发现Burgess reagent (伯吉斯试剂)可以使酰胺在回流的条件下脱水形成腈(图6)。原料易于制备(Burgess reagent目前已是商用试剂)，为酰胺类化合物脱水反应提供了一条新路径。

图6. 伯吉斯试剂脱水成腈

 2.2. 无金属有机催化的酰胺脱水

1996年Mioskowski课题组 [ 21 ] 报道了醛催化水转移将伯酰胺转化为相应的腈的方法(图7)。与以前报道的方法相比，该方法不需要强脱水或复杂的试剂，并且反应底物范围广泛。

图7. 醛催化水转移将伯酰胺转化为相应的腈

Beller等人于2009年 [ 22 ] 提出了一种在催化量氟(TBAF)的作用下，用硅烷对芳香族和脂肪族酰胺进行脱水的方法(图8)。与以往的不易制备的脱水试剂相比，该方法使用的是商用试剂，反应易于处理且对环境友好。值得注意的是，脂肪族腈和芳香族腈的合成在该方法温和的条件下具有较高的选择性。

图8. 氟催化脱水成腈

2018年，Malkov等人 [ 23 ] 开发了一种appel型酰胺脱水成腈的高效方法。该方法以1 mol%的三苯基氧磷为催化剂，在10 min以内即可完成。与appel反应相比，该方法用草酰氯代替了对肾脏有毒的四氯化碳，并且催化量的三苯基氧磷使得反应产物易于分离。同年，Sun课题组 [ 24 ] 亦受到appel反应的启示，发现在三乙胺的存在下，用催化量的二甲亚砜可以将伯酰胺脱水形成腈(图9)，为初级酰胺或醛酰胺脱水制备腈提供了一种实用的替代方法。

图9. 三苯基氧磷和二甲亚砜催化酰胺脱水

2019年，Manda课题组 [ 25 ] 报道了第一个无金属催化硅烷作用下的伯酰胺在室温下脱水成腈的方法(图10)。证明了α-NHC可以作为一种伯酰胺脱水反应的高效无金属催化剂。通过DFT计算，反应通过低能垒的β-消除得到相应的腈，因而具有广泛的底物适用范围。

图10. NHC催化酰胺脱水

 3. 无金属酰胺脱水重排

Brannock等人于1965年 [ 26 ] 首次报道酰胺重排成腈的方法(图11)，重排将N-烯丙基酰胺转化为烯丙基腈。他们假定N-烯丙基烯酮亚胺作为中间产物，并提出这种重排过程可能是3-aza-Claisen反应的一个例子。与相似的[3,3]-σ重排反应 [ 27 ] [ 28 ] [ 29 ] 相比，Brannock的反应条件更加温和。

图11. N-烯丙基酰胺重排为烯丙基腈

1991年Walters等人 [ 30 ] 受到Brannock的启发，在Brannock反应的基础下进行进一步的研究，开发了一种非常温和的3-aza-Claisen反应，N-烯丙基酰胺在室温中性条件下转化为中等到良好产率的戊烯基腈(图12)。

图12. 温和的3-氮杂-克莱森反应

1993年Walters [ 31 ] 对N-烯丙基酰胺重排方法进行了探索(图13)。以简单的N-烯丙基酰胺为底物重排形成戊烯基腈为基础，探索该反应方法的灵活性，总结出了以下合成方法。

图13. 3-氮杂-克莱森重排的反应条件

1994年，Walters [ 32 ] 对反应进行了计算(图14)，过渡态结构的几何构型和能量计算表明烯酮亚胺的重排是一个非常放热的反应过程，比起其它3-aza-Claisen变体，烯酮亚胺过渡态结构更类似于初始材料。通过MP4(SDTQ)/6-31G*//MP2/6-31G*对中性、带电分子以及假定的烯酮亚胺中间体进行理论计算，为烯酮亚胺中间体的形成提供了有力支撑。

图14. MP2/6-31G*优化中性的(1)带电的(2)和烯酮亚胺(3) 3-氮杂-共轭烯的过渡态的几何构型

 4. 总结

本文系统介绍了在无金属条件下的酰胺脱水反应，并从1) 无金属条件下的酰胺脱水成腈；2) 无金属条件下脱水重排两个方面介绍了反应的机理、底物适用范围、官能团兼容性等问题。相比于金属催化的酰胺脱水体系，无金属条件下的脱水反应的相关报道仍然较少，因此，该反应类型在酰胺脱水领域还有较大的发展空间。

 文章引用

张宗卫. 无金属条件下的酰胺脱水反应Dehydration of Amides under Nonmetallic Conditions[J]. 有机化学研究, 2022, 10(03): 111-117. https://doi.org/10.12677/JOCR.2022.103011

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