Pictet–Spengler reaction
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Pictet-Spengler reaction | |
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Named after | Amé Pictet Theodor Spengler |
Reaction type | Ring forming reaction |
Identifiers | |
RSC ontology ID | RXNO:0000059 |
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine undergoes condensation with an aldehyde or ketone followed by ring closure. The reaction was first discovered in 1911 by Amé Pictet and Theodor Spengler (22 February 1886 – 18 August 1965).[1] Traditionally, an acidic catalyst in protic solvent was employed with heating;[2] however, the reaction has been shown to work in aprotic media in superior yields and sometimes without acid catalysis.[3] The Pictet–Spengler reaction can be considered a special case of the Mannich reaction, which follows a similar reaction pathway. The driving force for this reaction is the electrophilicity of the iminium ion generated from the condensation of the aldehyde and amine under acid conditions. This explains the need for an acid catalyst in most cases, as the imine is not electrophilic enough for ring closure but the iminium ion is capable of undergoing the reaction.
The Pictet–Spengler reaction is widespread in both industry and biosynthesis. It has remained an important reaction in the fields of alkaloid and organic synthesis since its inception, where it has been employed in the development of many beta-carbolines. Natural Pictet–Spengler reaction typically employ an enzyme, such as strictosidine synthase. Pictet–Spengler products can be isolated from many products initially derived from nature, including foodstuffs such as soy sauce and ketchup. In such cases it is common to find the amino acid tryptophan and various aldoses used as the biological feedstock.
Nucleophilic aromatic rings such as indole or pyrrole give products in high yields and mild conditions, while less nucleophilic aromatic rings such as a phenyl group give poorer yields or require higher temperatures and strong acid. The original Pictet–Spengler reaction was the reaction of phenethylamine and dimethoxymethane, catalysed by hydrochloric acid forming a tetrahydroisoquinoline.
The Pictet–Spengler reaction has been applied to solid-phase combinatorial chemistry with great success.[4][5]
An analogous reaction with an aryl-β-ethanol is called oxa-Pictet–Spengler reaction.[6]