支鏈硝基共軛烯炔與鄰苯二胺之有機催化連鎖反應合成1,5-苯二氮平衍生物

Organocatalytic Cascade Synthesis of Functionalized 1,5-Benzodiazepine with o-Phenylenediamines and Branched Nitroenynes

徐智威(Hsu Chih-Wei)

指導教授 ： 陳焜銘

國立臺灣師範大學/理學院/化學系/碩士(2021年)

https://doi.org/10.6345/NTNU202100875

摘要

苯二氮平衍生物常用為精神類疾病藥物，目前有許多合成應用的例子已被探討。本篇研究以支鏈硝基共軛烯炔為起始物，與雙親核試劑的鄰苯二胺進行加成反應，在無金屬試劑的有機催化系統中，以乙腈為溶劑，反應生成苯二氮平。共軛烯炔為良好的親電子試劑，具有兩個親電子中心，可與雙親核試劑的鄰苯二胺進行加成反應，第一次共軛加成後，形成高活性中間產物丙二烯，可與親核試劑進行第二次的加成，形成七員雜環產物。此有機連鎖反應成功在反應中建構兩個碳氮鍵。在本篇研究十一個例子中，可以得到中等至良好的產率（48.8-75.5%），推測DABCO鹼及親核性試劑之雙功能催化，在反應中扮演重要的角色，使反應能夠在十分鐘內完成。
另外，亦發現產物分子在鹼性條件下分離到重排反應產物。形成產物後，如加入DBU使得結構上的硝基與苯基掉換，生成重排產物。推測是七員環開環後，生成亞胺的中間體，硝基與氮上的氫形成氫鍵，促使苄基的碳與亞胺進行加成反應，形成熱力學穩定的重排產物。

關鍵字

有機催化合成 ； 連鎖反應 ； 共軛硝基烯炔 ； 苯二氮平 ； 重排反應

並列摘要

Benzodiazepine is used to be spirit drug. There have been many synthetic examples of benzodiazepine derivatives. In this research, the reaction was performed with versatile electrophile, conjugated 1,3-enyne, and o-phenylenediamine catalyzed by DABCO in acetonitrile at 40℃. Conjugated 1,3-enyne is a good electrophilic reagent with two electrophilic centers, which can undergo addition reaction with o-phenylenediamine of dinucleophile. After the first conjugate addition, a highly active intermediate allene is formed, which can be added with the other nucleophile to form a seven-member heterocyclic product. This organocascade reaction successfully constructed two carbon-nitrogen bonds in the reaction. In the eleven instance of the study, moderate to good yields can be obtained（48.8-75.5%）. It is plausible that the bifunctional catalysis of DABCO, base and nucleophilic reagent, play an important role in the reaction, enabling completed within ten minutes.
In addition, we founded the rearrangement product under base conditions. The nitro and phenyl group was exchanged, if DBU was added after the first reaction completed. We purpose that an intermediate was produced after the seven-membered ring opened . The nitro group forms a hydrogen bonding with the hydrogen on the nitrogen. That promotes the addition reaction between carbon of the benzyl group and the in-situ iminium to form thermodynamically rearrangement product.

並列關鍵字

organocatalytic synthesis ； cascade reaction ； conjugated 1,3-enyne ； benzodiazepine ； rearrangement reaction

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