23.11 Carbonyl Condensations with Enamines: The Stork Enamine Reaction

Enamines are powerful tools in organic synthesis, formed by reacting ketones with secondary amines. They're more nucleophilic than enolates, making them ideal for creating new carbon-carbon bonds. Their unique structure and reactivity open up exciting possibilities for building complex molecules.

The Stork enamine reaction showcases enamines in action, allowing for selective α-alkylation of carbonyl compounds. This three-step process - enamine formation, Michael addition, and hydrolysis - offers advantages over traditional enolate chemistry, including milder conditions and fewer side reactions.

Carbonyl Condensations with Enamines

Formation and structure of enamines

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• Enamines form by condensation reaction between ketone and secondary amine (pyrrolidine, morpholine)
  • Equilibrium process involves nucleophilic addition of secondary amine to ketone followed by elimination of water
  • Reaction catalyzed by acid which protonates ketone making it more electrophilic
• Enamines have carbon-carbon double bond conjugated with nitrogen atom
  • Nitrogen atom typically part of secondary amine or cyclic amine
  • Carbon-carbon double bond usually located at $\alpha$-position relative to original carbonyl group
• Structure of enamines represented by two resonance forms
  • One form has carbon-carbon double bond and neutral nitrogen atom
  • Other form has carbon-nitrogen double bond and negatively charged $\alpha$-carbon atom
• Enamines more nucleophilic than corresponding enolate ions due to higher electron density on $\alpha$-carbon atom

Mechanism of Stork enamine reaction

• Stork enamine reaction is method for [object Object],[object Object]-alkylation of ketones or aldehydes via enamine intermediate
• Reaction involves three main steps:
  1. Enamine formation: Ketone or aldehyde reacts with secondary amine to form enamine intermediate in acid-catalyzed equilibrium process
  2. Michael addition: Enamine (acting as a nucleophile) undergoes 1,4-addition with $\alpha,\beta$-unsaturated carbonyl compound (enone or enal) to give iminium ion after protonation of resulting enolate intermediate
  3. Hydrolysis: Iminium ion hydrolyzed by water under acidic conditions (aqueous acetic acid) to regenerate secondary amine catalyst and give final $\alpha$-alkylated carbonyl product

Enamines vs enolate ions in synthesis

• Enamines have advantages over enolate ions in Michael-like reactions for synthesis of 1,5-dicarbonyl compounds
  • More nucleophilic leading to faster reaction rates and higher yields
  • Less basic reducing risk of side reactions (self-condensation, polymerization)
  • Neutral species more compatible with wider range of electrophiles and reaction conditions
• Enolate ions have disadvantages compared to enamines
  • More basic and can lead to side reactions especially with acidic protons present
  • Charged species can limit solubility and reactivity in certain solvents or with certain electrophiles
  • Often require strong bases (LDA, NaH) for generation which can be incompatible with sensitive functional groups
• Overall, use of enamines in Michael-like reactions offers milder and more selective approach for synthesis of 1,5-dicarbonyl compounds compared to use of enolate ions

Resonance and Conjugation in Enamines

• Resonance stabilization contributes to the reactivity of enamines
• Extended conjugation in enamines enhances their nucleophilicity
• Alkylation occurs at the α-carbon due to resonance effects
• Electrophiles preferentially attack the most electron-rich position in the conjugated system