通过无表化聚胺合成制备N-基胺
Michael S Crocker1, Zihang Deng1, Jeffrey N Johnston1
1Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States.
Journal of the American Chemical Society
|September 6, 2022
概括
一种新的N-胺合成方法直接使用α-酸和N-氨基胺产生纯产物. 这种Umpolung胺合成 (UmAS) 方法避免了对药物开发至关重要的表皮化.
科学领域:
- 有机化学
- 合成化学
- 医学化学
背景情况:
- 氨基酸合成对于药物开发和合成至关重要,但目前的方法在废物减少和α-epimerization方面存在困难,特别是对于N-aryl氨基酸.
- 现有的胺形成协议主要依赖于与核胺反应的电友性基供体.
- 化胺合成 (UmAS) 提供化胺合成,但由于无法形成N-胺而受到限制.
研究的目的:
- 开发一种用于直接合成N-胺的新方法,解决当前胺形成策略的局限性.
- 能够合成具有挑战性的α-奇拉N-胺, 在药物发现中越来越重要.
- 建立一种保持立体化学完整性的N-aryl胺的催化,选择性合成.
主要方法:
- 使用布伦斯特德基促进剂的α-化与N-氨基胺的反应.
- 基于UMAS范式的机械学假设指导的反应机制的探索.
- 在完全保留酸富化时合成奇拉性α-氨基-N-胺.
主要成果:
- 通过α-化和N-化胺实现N-化的直接合成.
- 反应通过UmAS范式进行,直接产生N-胺.
- 在选择的性α- 氨基- N- 胺的合成中,观察到完全的性缩.
结论:
- 已经建立了一种新且高效的合成N-胺的方法,克服了以前的局限性.
- 开发的方法适用于制造对药物应用至关重要的纯氨基胺.
- 这种方法在胺合成中提供了显著的进步,特别是对于具有挑战性的基质和保持立体化学真实性.
相关概念视频
01:29Preparation of Amides
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Amides are synthesized by treating carboxylic acids with amines in the presence of dehydrating agents like dicyclohexylcarbodiimide (DCC).
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
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01:22Preparation of 1° Amines: Azide Synthesis
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Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide synthesis method can be used.
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum...
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum...
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01:07Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview
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In the presence of an aqueous base and a halogen, primary amides can lose the carbonyl (as carbon dioxide) and undergo rearrangement to form primary amines. This reaction, called the Hofmann rearrangement, can produce primary amines (aryl and alkyl) in high yields without contamination by secondary and tertiary amines.
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01:28Preparation of 1° Amines: Gabriel Synthesis
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Direct alkylation is not a suitable method for synthesizing amines because it produces polyalkylated products. Gabriel synthesis is the most preferred method to exclusively make primary amines. The method uses phthalimide, which contains a protected form of nitrogen that participates in alkylation only once to predominantly give primary amines.
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an...
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an...
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01:26Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism
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The Hofmann and Curtius rearrangement reactions can be applied to synthesize primary amines from carboxylic acid derivatives such as amides and acyl azides. In the Hofmann rearrangement, a primary amide undergoes deprotonation in the presence of a base, followed by halogenation to generate an N-haloamide. A second proton abstraction produces a stabilized anionic species, which rearranges to an isocyanate intermediate via an alkyl group migration from the carbonyl carbon to the neighboring...
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01:12Preparation of Nitriles
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One of the common methods to prepare nitriles is the dehydration of amides. This method requires strong dehydrating agents like phosphorous pentoxide or boiling acetic anhydride for converting amides to nitriles. Another reagent namely, thionyl chloride also accomplishes the dehydration of amides, where amide acts as a nucleophile. The first step of the mechanism involves the nucleophilic attack by the amide on the thionyl chloride to form an intermediate. In the next step, the electron pairs...
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