Pictet-Spengler reaction

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,^[1][2] but some reactive compounds give good yields already at physiologic conditions.^[3] 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.^[4][5]

An analogous reaction with an aryl-β-ethanol is called Oxa-Pictet-Spengler reaction.

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Reaction mechanism

It is the electrophilicity of the imine double bond that is the driving force of the cyclization.^[6] 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.

Variations

Pictet-Spengler tetrahydroisoquinoline synthesis

Replacing 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 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.^[7]

Tadalafil is synthesized via the N-acyliminium Pictet-Spengler reaction.^[8] This reaction can also be catalyzed by AuCl₃ and AgOTf.^[9]

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.^[10][11] Additionally, Seayad et al. have published a chiral Lewis acid that catalyzes asymmetric Pictet-Spengler reactions.^[12]

Tryptophans: Diastereocontrolled reaction
The reaction of enantiopure tryptophan or its short-chain alkylesters leads to 1,2,3,4-tetrahydro-β-carbolines in which a new chiral center at C-1 adopts either a cis or trans configuration towards the C-3 carboxyl group. The cis conduction is kinetically controlled, i.e. it is performed at lower temperatures. At higher temperatures the reaction becomes reversible and usually favours racemisation. 1,3-trans dominated products can be obtained with N_b-benzylated tryptophans, which are accessible by reductive amination. The benzyl group can be removed hydrogenolytically afterwards. As a rough rule, ¹³C NMR signals for C1 and C3 are downfield shifted in cis products relative to trans products (see steric compression effect).^[13][14]

References

1. ^  Pictet, A.; Spengler, T. Ber. 1911, 44, 2030.
2. ^  Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74. (Review)
3. ^  Hahn, Ludewig, Ber. 1934, 2033
4. ^  Nielsen, T. E.; Diness, F.; Meldal, M. Curr. Opin. Drug Discov. Devel. 2003, 6. 801-814. (Review)
5. ^  Nielsen, T. E.; Meldal, M. J. Comb. Chem. 2005, 7, 599 - 610. (doi:10.1021/cc050008a)
6. ^  Cox and Cook (1995): Chemical Reviews, Vol. 95, No. 6, p 1800, 1802.
7. ^  B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi, and C. A. Maryanoff, "Cyclizations of N-acyliminium ions", Chem. Rev., 104, 1431-1628 (2004). [review]
8. ^  Bonnet, D.; Ganesan, A. J. Comb. Chem. 2002, 4(6), 546-548. (Abstract)
9. ^  Youn, S. W. J. Org. Chem. 2006, 71, 2521 - 2523. (doi:10.1021/jo0524775)
10. ^  Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett. 2000, 2, 1955-1958. (doi:10.1021/ol006034t)
11. ^  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.
12. ^  Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086 - 1087. (doi:10.1021/ja057444l)
13. ^  Ungemach et al. (1980): JACS, Vol. 102, No. 23, p 6979. doi:10.1021/ja00543a012

See also

• Bischler-Napieralski reaction