Pictet-Spengler reaction
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The 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.
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[edit] Reaction mechanism
The reaction mechanism of the Pictet-Spengler reaction 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. While iminium ions are power electrophiles, the Pictet-Spengler reaction will only succeed with intramolecular iminium ions. The reaction shown is an example of a 6-endo-trig reaction, which is favoured by Baldwin's ring closure rules.
[edit] Variations
[edit] Pictet-Spengler isoquinoline synthesis
Replacing an indole with a 3,4-dimethoxyphenyl group give the reaction named the Pictet-Spengler isoquinoline synthesis. Reaction conditions are generally harsher than the indole variant, and require refluxing conditions with strong acids like hydrochloric acid or trifluoroacetic acid.
[edit] N-acyliminium Pictet-Spengler reaction
Instead 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. This reaction can also be catalyzed by AuCl3 and AgOTf.
[edit] Asymmetric Pictet-Spengler reaction
When 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.
[edit] References
- ↑ Pictet, A.; Spengler, T. Ber. 1911, 44, 2030.
- ↑ Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74. (Review)
- ↑ Hahn, Ludewig, Ber. 1934, 2033
- ↑ Nielsen, T. E.; Diness, F.; Meldal, M. Curr. Opin. Drug Discov. Devel. 2003, 6. 801-814. (Review)
- ↑ Nielsen, T. E.; Meldal, M. J. Comb. Chem. 2005, 7, 599 - 610. (DOI:10.1021/cc050008a)
- ↑ Bonnet, D.; Ganesan, A. J. Comb. Chem. 2002, 4(6), 546-548. (Abstract)
- ↑ Youn, S. W. J. Org. Chem. 2006, 71, 2521 - 2523. (DOI:10.1021/jo0524775)
- ↑ Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett. 2000, 2, 1955-1958. (DOI:10.1021/ol006034t)
- ↑ a) The intermolecular Pictet-Spengler condensation with chiral carbonyl derivatives in the stereoselective syntheses of optically-active isoquinoline and indole alkaloids Enrique L. Larghi, Marcela Amongero, Andrea B. J. Bracca, and Teodoro S. Kaufman Arkivoc (RL-1554K) pp 98-153 2005 (Online Review); b) Teodoro S. Kaufman “Synthesis of Optically-Active Isoquinoline and Indole Alkaloids Employing the Pictet-Spengler Condensation with Removable Chiral Auxiliaries Bound to Nitrogen”. in “New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles”; Ed.: J. L. Vicario. ISBN 81-7736-278-X. Research SignPost, Trivandrum, India. 2005. Chapter 4, pp. 99-147.
- ↑ Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086 - 1087. (DOI:10.1021/ja057444l)
