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Related Concept Videos

Preparation of Amines: Reductive Amination of Aldehydes and Ketones01:38

Preparation of Amines: Reductive Amination of Aldehydes and Ketones

Carbonyl compounds and primary amines undergo reductive amination first to produce imines, followed by secondary amines in the same reaction mixture, using selective reducing agents like sodium cyanoborohydride or sodium triacetoxyborohydride. Reductive amination produces different degrees of substitution of amines depending on the starting amine substrate.
Preparation of Amines: Reduction of Amides and Nitriles01:13

Preparation of Amines: Reduction of Amides and Nitriles

Nitriles can be reduced to primary amines using reducing agents like lithium aluminum hydride or catalytic hydrogenation. The reduction introduces an amino group with an extra carbon in the skeleton. Nitriles are formed from the reaction between alkyl halides and sodium cyanide through the SN2 mechanism. Primary alkyl halides are the preferred substrates to prepare nitriles.
Amides can be reduced to primary, secondary, and tertiary amines using catalytic hydrogenation, active metals like Fe,...
Nitriles to Amines: LiAlH4 Reduction00:55

Nitriles to Amines: LiAlH4 Reduction

Nitriles are reduced to amines in the presence of strong reducing agents like lithium aluminum hydride through a typical nucleophilic acyl substitution. The reaction requires two equivalents of the reducing agent. The reducing agent acts as a source of hydride ions.
As shown below, the mechanism involves three steps. Firstly, the hydride ion acting as a nucleophile attacks the nitrile carbon to form an anion. In the second step, a second equivalent of the hydride ion attacks the anion to...
Amides to Amines: LiAlH4 Reduction01:20

Amides to Amines: LiAlH4 Reduction

Amide reduction with strong reducing agents like lithium aluminum hydride proceeds through a nucleophilic acyl substitution to form amines. Primary, secondary, and tertiary amides yield primary, secondary, and tertiary amines, respectively.
Amide reduction requires two equivalents of the reducing agent, acting as a source of hydride ions. As shown in the figure, the reaction is initiated with a nucleophilic attack by the hydride ion at the carbonyl carbon to form a tetrahedral intermediate.
Preparation of 1° Amines: Azide Synthesis01:22

Preparation of 1° Amines: Azide Synthesis

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

Preparation of 1° Amines: Gabriel Synthesis

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...

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Related Experiment Video

Updated: Jun 21, 2026

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives
08:43

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Published on: January 19, 2016

Direct asymmetric reductive amination.

Dietrich Steinhuebel1, Yongkui Sun, Kazuhiko Matsumura

  • 1Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, USA. dietrich_steinhuebel@merck.com

Journal of the American Chemical Society
|July 30, 2009
PubMed
Summary

A novel catalytic method using a ruthenium (Ru) chiral catalyst enables highly efficient asymmetric reductive amination of beta-keto amides. This process yields unprotected beta-amino amides with excellent enantioselectivity, including the synthesis of sitagliptin.

More Related Videos

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate
06:46

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Published on: June 21, 2017

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis
07:06

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

Published on: February 16, 2020

Related Experiment Videos

Last Updated: Jun 21, 2026

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives
08:43

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Published on: January 19, 2016

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate
06:46

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Published on: June 21, 2017

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis
07:06

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

Published on: February 16, 2020

Area of Science:

  • Organic Chemistry
  • Catalysis
  • Asymmetric Synthesis

Background:

  • Beta-keto amides are versatile synthetic intermediates.
  • Developing efficient methods for synthesizing chiral beta-amino amides is crucial in medicinal chemistry.
  • Existing methods may suffer from limited substrate scope or require protection/deprotection steps.

Purpose of the Study:

  • To develop a highly enantioselective and efficient method for the direct synthesis of unprotected beta-amino amides.
  • To explore the utility of a specific chiral ruthenium catalyst system for asymmetric reductive amination.
  • To demonstrate the application of this methodology in the synthesis of a pharmaceutically relevant compound, sitagliptin.

Main Methods:

  • Asymmetric reductive amination of beta-keto amides using a chiral ruthenium catalyst, specifically Ru(OAc)2((R)-dm-segphos).
  • A one-pot reaction procedure was employed.
  • The reaction conditions were optimized for yield, chemoselectivity, and enantioselectivity.

Main Results:

  • High yields and excellent enantioselectivities (94.7-99.5% ee) were achieved for a range of unprotected beta-amino amides.
  • The methodology demonstrated broad substrate scope.
  • Sitagliptin was synthesized in 99.5% ee and 91% assay yield using this one-pot approach.
  • The ruthenium catalyst system exhibited high tolerance to ammonium ion, high chemoselectivity, and high enantioselectivity.

Conclusions:

  • The developed asymmetric reductive amination is a highly efficient and enantioselective method for producing unprotected beta-amino amides.
  • The one-pot methodology offers a practical and scalable route for synthesizing complex chiral amines.
  • This catalytic system provides a valuable tool for the synthesis of active pharmaceutical ingredients like sitagliptin.