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Preparation of 1° Amines: Azide Synthesis01:22

Preparation of 1° Amines: Azide Synthesis

3.9K
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...
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Preparation of 1° Amines: Gabriel Synthesis01:28

Preparation of 1° Amines: Gabriel Synthesis

3.6K
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...
3.6K
Aldehydes and Ketones with Amines: Imine Formation Mechanism01:23

Aldehydes and Ketones with Amines: Imine Formation Mechanism

5.6K
Imine formation involves the addition of carbonyl compounds to a primary amine. It begins with the generation of carbinolamine through a series of steps involving an initial nucleophilic attack and then several proton transfer reactions. The second part includes the elimination of water, as a leaving group, to give the imine.
Imines are formed under mildly acidic conditions. A pH of 4.5 is ideal for the reaction.
If the pH is low or the solution is too acidic, the reaction slows down in the...
5.6K
Diazonium Group Substitution with Halogens and Cyanide: Sandmeyer and Schiemann Reactions01:20

Diazonium Group Substitution with Halogens and Cyanide: Sandmeyer and Schiemann Reactions

1.9K
Arenediazonium substitution reactions occur when the diazonium group is substituted by various functional groups such as halides, hydroxyl, nitrile, etc. For instance, arenediazonium salts react with copper(I) salts of chloride, bromide, or cyanide to form corresponding aryl chlorides, bromides, and nitriles. These reactions are named Sandmeyer reactions. Although the mechanism of this reaction is complicated, as illustrated in Figure 1, they are believed to progress via an aryl copper...
1.9K
Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN101:14

Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN1

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Treating arylamines with nitrous acid gives aryldiazonium salts that are effective substrates in nucleophilic aromatic substitution reactions. The diazonio group in these salts can be easily displaced by different nucleophiles, yielding a wide variety of substituted benzenes. The leaving group departs as nitrogen gas, and this easy elimination is the driving force for the substitution reaction.
In the Sandmeyer reaction, for example, the diazonio group is replaced by a chloro, bromo,...
2.1K
Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview01:07

Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview

3.2K
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.
3.2K

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Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
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A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates.

Jake D Selingo1, Jacob W Greenwood1, Mary Katherine Andrews1

  • 1Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.

Journal of the American Chemical Society
|December 28, 2023
PubMed
Summary
This summary is machine-generated.

This study introduces a novel pyridine ring-opening and ring-closing method to synthesize N-(hetero)arylpiperidines, crucial pharmaceutical compounds. The efficient strategy utilizes Zincke imine intermediates and high-throughput experimentation for library generation.

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Area of Science:

  • Organic Chemistry
  • Medicinal Chemistry

Background:

  • Piperidine scaffolds are prevalent in pharmaceuticals.
  • Efficient synthesis of diverse piperidine derivatives is essential for drug discovery.

Purpose of the Study:

  • To develop a general strategy for synthesizing N-(hetero)arylpiperidines.
  • To establish a method utilizing pyridine ring-opening and ring-closing via Zincke imine intermediates.

Main Methods:

  • Pyridinium salt formation from substituted pyridines and (hetero)aryl anilines.
  • Hydrogenation and nucleophilic addition reactions to yield piperidine derivatives.
  • Application of high-throughput experimentation (HTE) for optimization.

Main Results:

  • Successful synthesis of diverse N-(hetero)arylpiperidine derivatives.
  • Development of a one-pot process using anilines as nucleophiles.
  • Demonstration of viability for generating piperidine libraries.

Conclusions:

  • The presented strategy offers a versatile approach to N-(hetero)arylpiperidines.
  • This method facilitates the convergent coupling of complex molecular fragments.
  • The approach is suitable for creating diverse piperidine libraries for pharmaceutical applications.