Pictet-Spengler reaction

What is Pictet-Spengler reaction?

The Pictet-Spengler reaction is a well-known method for synthesizing tetrahydroisoquinoline or tetrahydro-β-carboline derivatives. The reaction involves the condensation of an arylethylamine and a carbonyl compound, usually an aldehyde, to form the desired product. This reaction was first reported in 1911 by Pictet and Spengler, and is commonly referred to as the Pictet-Spengler reaction.

Pictet-Spengler reaction - general reaction scheme - Pictet-Spengler cyclization - Pictet-Spengler condensation - Pictet-Spengler synthesis - Pictet-Spengler heterocyclization
Pictet-Spengler reaction
  • R = electron-donating substituent
  • R’ = alkyl, aryl with electron-withdrawing group
  • R” = H (preferred), alkyl (see list of acronyms)

There are several variations of the reaction, including the Pictet-Spengler cyclization, Pictet-Spengler condensation, or Pictet-Spengler synthesis, as well as the Pictet-Spengler heterocyclization. The reaction typically proceeds via the formation of an imine intermediate from the aldehyde and arylethylamine, which then attacks the aromatic ring to give the desired product. In some cases, a similar reaction can be carried out with ketones, which may involve the formation of an enamine intermediate.

While arylethylamines such as phenylethylamine, phenylalanine, and tyrosine are suitable amines for this reaction, certain aldehydes and ketones may not be suitable candidates. The reaction is best carried out under acidic conditions, although basic conditions can also be used.

The N-acyliminium Pictet-Spengler reaction is an extension of this reaction, which involves the formation of an N-acyliminium intermediate from the acylation of the imine with an acyl halide. The reaction can also be adapted to solid-support conditions promoted by a Lewis acid.

Another variation of the reaction involves the cyclization of 2-aryl ethanol under similar reaction conditions to give [3,4]-benzo-dihydropyran derivatives, which is referred to as the oxa-Pictet-Spengler reaction.

Recent studies of this reaction focus on the diastereoselective and enantioselective synthesis of tetrahydroisoquinolines via chirality transfer from the auxiliary group of either the arylethylamine or the carbonyl component, as well as the application of chiral Lewis acids. The use of HCl and trifluoroacetic acid in aqueous solution has been found to be superior to other acids.

References

Pictet, A. and Spengler, T. (1911), Über die Bildung von Isochinolin-derivaten durch Einwirkung von Methylal auf Phenyl-äthylamin, Phenyl-alanin und Tyrosin. [On the formation of isoquinoline derivatives by the action of methylal on phenyl-ethylamine, phenyl-alanine and tyrosine.] Ber. Dtsch. Chem. Ges., 44: 2030-2036. https://doi.org/10.1002/cber.19110440309

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