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Pictet-Spengler reactionThe Pictet-Spengler reaction is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ringclosure after condensation with an aldehyde. Usually an acidic catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields already at physiologic conditions. The Pictet-Spengler reaction can be considered a special case of the Mannich reaction. The reaction was discovered in 1911 by Amé Pictet and Theodor Spengler. It has remained an important reaction in the fields of alkaloid and pharmaceutical synthesis. The Pictet-Spengler reaction product of tryptophan and aldoses can be identified in foodstuffs such as soy sauce and ketchup. Nucleophilic aromatic rings such as indole or pyrrole give products with good yields and mild conditions, while less nucleophilic aromatic rings such as phenyl give poor yields despite high temperatures and strong acid. The original Pictet-Spengler reaction was the reaction of β-phenethylamine with the dimethyl acetal of formaldehyde and hydrochloric acid. Like the Mannich reaction, aldehydes give good yields while ketones tend not to give products at all. The Pictet-Spengler reaction has been applied to solid-phase combinatorial chemistry with great success. An analogous reaction with an aryl-β-ethanol is called Oxa-Pictet-Spengler reaction. Additional recommended knowledge
Reaction mechanismIt is the electrophilicity of the imine double bond that is the driving force of the cyclization. The reaction mechanism occurs by initial formation of an iminium ion (4) followed by electrophilic substitution at the 2-position. After deprotonation, the desired product {6) is formed. The reaction shown is an example of a 6-endo-trig reaction, which is favoured by Baldwin's ring closure rules. VariationsPictet-Spengler tetrahydroisoquinoline synthesisReplacing an indole with a 3,4-dimethoxyphenyl group give the reaction named the Pictet-Spengler tetrahydroisoquinoline synthesis. Reaction conditions are generally harsher than the indole variant, and require refluxing conditions with strong acids like hydrochloric acid or trifluoroacetic acid. N-Acyliminium Pictet-Spengler ReactionInstead of catalyzing the Pictet-Spengler cyclization with strong acid, one can acylate the iminium ion forming the intermediate N-acyliminium ion. The N-acylimimium ion is a very powerful electrophile and most aromatic ring systems will cyclize under mild conditions with good yields. Tadalafil is synthesized via the N-acyliminium Pictet-Spengler reaction.AuCl3 and AgOTf. This reaction can also be catalyzed byAsymmetric Pictet-Spengler reactionWhen the Pictet-Spengler reaction is done with an aldehyde other than formaldehyde, a new chiral center is created. Several substrate- or auxiliary-controlled diastereoselective Pictet-Spengler reactions have been developed. Additionally, Seayad et al. have published a chiral Lewis acid that catalyzes asymmetric Pictet-Spengler reactions. Tryptophans: Diastereocontrolled reaction References
See also
Categories: Condensation reactions | Heterocycle forming reactions |
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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Pictet-Spengler_reaction". A list of authors is available in Wikipedia. |