The Pictet-Spengler reaction uses catalytic acid to convert a β-arylethylamine and an aldehyde or ketone to a substituted tetrahydroisoquinoline. First β-arylethylamine attacks the carbonyl carbon, forming a tetrahedral intermediate, which is dehydrated to afford the corresponding Schiff base. Upon protonation, a 6-endo-trig cyclization occurs, disrupting ring aromaticity. Loss of an aryl proton then restores aromaticity, giving rise to the tetrahydroisoquinoline product.

  • Reagents: Catalytic Protic Acid (HCl, H2SO4, etc.) or Lewis Acid (BF3·OEt2)
  • Reactant: β-Arylethylamine, Aldehyde or Ketone
  • Product: Substituted Tetrahydroisoquinoline
  • Type of Reaction: Condensation
  • Bond Formation: N-C and C-C

Lab Tips

  • Only β-arylethylamines with electron-donating substituents afford high yields.
  • This reaction is influenced by the number of electron-donating groups on the ring. For instance, two alkoxy groups allows the reaction to proceed under physiological conditions, important in the biosynthesis of alkaloids.
  • Carrying out the reaction with a slight excess of the carbonyl compound ensures the complete consumption of the amine in either protic or aprotic solvents.
  • The Schiff base can be prepared separately and later subjected to a protic or Lewis acid.
Kürti, L., Czakó, B. (2005). Strategic Applications of Named Reactions in Organic Synthesis; Background and detailed mechanisms. Burlington, MA: Elsevier Academic Press.


Top Citations

Original Paper

Related Reactions

  • Synthesis of Cyclopentenones

Related Compounds

  • Catalytic Acid
  • Aldehyde
  • Ketone
By shuhan yang


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