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Acid Halides to Ketones: Gilman Reagent01:14

Acid Halides to Ketones: Gilman Reagent

2.7K
Lithium dialkyl cuprate, also known as Gilman reagents, selectively reduces acid halides to ketones. The acid chloride is treated with Gilman reagent at −78 °C in the presence of ether solution to produce a ketone in good yield.
As shown below, the mechanism proceeds in two steps. First, one of the alkyl groups of the reagent acts as a nucleophile and attacks the acyl carbon of the acid chloride to form a tetrahedral intermediate. This is followed by the reformation of the carbon–oxygen...
2.7K
Amides to Amines: LiAlH4 Reduction01:20

Amides to Amines: LiAlH4 Reduction

4.6K
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.
4.6K
α-Alkylation of Ketones via Enolate Ions01:10

α-Alkylation of Ketones via Enolate Ions

3.0K
Ketones with α protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the α carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the α carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the...
3.0K
Acid-Catalyzed α-Halogenation of Aldehydes and Ketones01:21

Acid-Catalyzed α-Halogenation of Aldehydes and Ketones

3.6K
By replacing an α-hydrogen with a halogen, acid-catalyzed α-halogenation of aldehydes or ketones yields a monohalogenated product
In the first step of the mechanism, the acid protonates the carbonyl oxygen resulting in a resonance-stabilized cation, which subsequently loses an α-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the –OH group. Consequently, the double bond attacks an electrophilic halogen to form a...
3.6K
Acid Halides to Amides: Aminolysis01:07

Acid Halides to Amides: Aminolysis

2.6K
Aminolysis is a nucleophilic acyl substitution reaction, where ammonia or amines act as nucleophiles to give the substitution product. Acid halides react with ammonia, primary amines, and secondary amines to yield primary, secondary, and tertiary amides, respectively.
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
2.6K
Alkylation of β-Diester Enolates: Malonic Ester Synthesis01:14

Alkylation of β-Diester Enolates: Malonic Ester Synthesis

3.3K
Malonic ester synthesis is a method to obtain α substituted carboxylic acids from ꞵ-diesters such as diethyl malonate and alkyl halides.
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Updated: Jun 9, 2025

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones
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Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones

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Copper-Catalyzed γ-C(sp3)-H Lactamization and Iminolactonization.

Tao Sheng1, Zhe Zhuang1, Zhihan Zhao1

  • 1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.

Angewandte Chemie (International Ed. in English)
|October 28, 2024
PubMed
Summary

This study introduces a novel copper-catalyzed method for synthesizing γ-lactams and γ-iminolactones from tosyl-protected amides. The reaction offers switchable selectivity and access to diverse, biologically relevant chemical structures.

Keywords:
carboxylic amidescopperγ-iminolactonizationγ-lactamization

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Area of Science:

  • Organic Chemistry
  • Synthetic Chemistry

Background:

  • γ-Lactamization reactions for pyrrolidinone synthesis are challenging, especially for aliphatic amides.
  • Existing methods using cyclometallation, C-H insertion, or radical C-H abstraction have limitations.

Purpose of the Study:

  • To develop a practical and efficient copper-catalyzed method for γ-C(sp3)-H lactamization and iminolactonization of aliphatic amides.
  • To achieve switchable selectivity between γ-lactams and γ-iminolactones.
  • To synthesize structurally diverse lactams and iminolactones.

Main Methods:

  • Copper-catalyzed γ-C(sp3)-H functionalization of tosyl-protected aliphatic amides.
  • Utilized Selectfluor as the sole oxidant.
  • Employed two distinct sets of reaction conditions to control selectivity.

Main Results:

  • Successfully achieved copper-catalyzed γ-lactamization and iminolactonization.
  • Demonstrated switchable selectivity for either γ-lactams or γ-iminolactones.
  • Synthesized a variety of spiro-, fused-, and bridged-lactams/iminolactones, and isoindolinones.
  • Showcased further derivatization into γ-amino acids, δ-amino alcohols, and pyrrolidines.

Conclusions:

  • Developed a versatile and practical method for accessing γ-lactams and γ-iminolactones.
  • The method provides access to valuable synthetic intermediates for biologically important molecules.
  • Offers a new strategy for pyrrolidinone synthesis and related heterocycles.