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Regioselective Formation of Enolates01:33

Regioselective Formation of Enolates

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As depicted in the figure below, the unsymmetrical ketones can form two possible enolates: less substituted or more substituted enolates. Usually, the thermodynamic enolates are formed from the more substituted α-carbon atom, while the kinetic enolates are formed faster by deprotonation from the less substituted position. The thermodynamic enolates have lower energy, so they are more stable. But the energy required to form kinetic enolates is less.
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Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation01:27

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation

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Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).
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Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction01:26

Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction

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α-Substituted ketones or aldehydes can be synthesized from enamines by the Stork enamine reaction, named after its pioneer Gilbert Stork. Enamines are useful synthetic intermediates where the lone pair on nitrogen is in conjugation with the C=C bond. They resemble enolate ions, as the resonance forms of both species have a nucleophilic α carbon.
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Alkylation of β-Diester Enolates: Malonic Ester Synthesis01:14

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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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α-Alkylation of Ketones via Enolate Ions01:10

α-Alkylation of Ketones via Enolate Ions

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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...
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Vicinal Diols via Reductive Coupling of Aldehydes or Ketones: Pinacol Coupling Overview01:27

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Wilhelm Rudolph Fittig discovered the pinacol coupling reaction in 1859. It is a radical dimerization reaction and involves the reductive coupling of aldehydes or ketones in the presence of hydrocarbon solvent to yield vicinal diols.
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A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species
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Modular isoquinoline synthesis using catalytic enolate arylation and in situ functionalization.

Ben S Pilgrim1, Alice E Gatland, Charlie T McTernan

  • 1Department of Chemistry, University of Oxford , Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K., and GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.

Organic Letters
|November 21, 2013
PubMed
Summary

A novel one-pot synthesis efficiently produces substituted isoquinolines using palladium catalysis. This method combines readily available starting materials, offering a high-yield route to valuable heterocyclic compounds.

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Area of Science:

  • Organic Chemistry
  • Synthetic Chemistry
  • Heterocyclic Chemistry

Background:

  • Isoquinolines are important heterocyclic scaffolds found in numerous natural products and pharmaceuticals.
  • Efficient synthetic methods for constructing substituted isoquinolines are highly sought after in medicinal chemistry and drug discovery.

Purpose of the Study:

  • To develop a novel, efficient, and versatile one-pot synthetic protocol for substituted isoquinolines.
  • To explore the scope of the reaction using various starting materials, including tert-butyl cyanoacetate.

Main Methods:

  • A four-component, three-step, one-pot coupling procedure was employed.
  • The key steps involved palladium-catalyzed α-arylation of an enolate, in situ trapping with an electrophile, and aromatization using ammonium chloride.
  • A modified protocol using tert-butyl cyanoacetate allowed for functionalization and decarboxylation.

Main Results:

  • Substituted isoquinolines were synthesized in overall yields of up to 80%.
  • The protocol demonstrated versatility by accommodating different methyl ketones, aryl bromides, and electrophiles.
  • 3-Amino-4-alkyl isoquinolines were prepared in high yield via the modified protocol.

Conclusions:

  • The developed one-pot protocol provides an efficient and high-yielding method for synthesizing diverse substituted isoquinolines.
  • This approach offers a valuable tool for accessing complex heterocyclic structures relevant to medicinal chemistry.
  • The reaction's adaptability suggests potential for further development and application in organic synthesis.