1. Reaction mechanism

2. Variations
    Pictet–Spengler tetrahydroisoquinoline synthesis  N-acyliminium ion Pictet–Spengler reaction  Asymmetric Pictet–Spengler reaction 

3. See also

4. References

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.^[1] Traditionally an acidic catalyst in protic solvent was employed with heating,^[2] however the reaction has been shown to work in aprotic media without acid catalysis in superior yields for a variety of cases.^[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 imine generated from the condensation of the aldehyde and amine. This helps to explain the need for an acidic medium in some substrates, as the imine may not be electrophilic enough for ring closure to occur but the Iminium ion is capable of undergoing the reaction.

The Pictet-Spengler reaction is widespread in both human industry and biosynthesis. It has remained an important reaction in the fields of alkaloid and pharmaceutical synthesis since its inception, where it has been employed in the development of many beta-carbolines. The enzyme strictosidine synthase is an example of nature utilizing the Pictet-Spengler reaction, which generates an intermediate common in the biosynthesis of many complex natural products. 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 with good yields and mild conditions, while less nucleophilic aromatic rings such as benzene 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 forming a tetrahydroisoquinoline.

Like the Mannich reaction, aldehydes give good yields while ketones tend to give lower conversion.{{dubious|date=November 2010}}{{Citation needed|reason=contradicting evidence exists|date=November 2010}}

The Pictet–Spengler reaction has been applied to solid-phase combinatorial chemistry with great success.^[3][4]

An analogous reaction with an aryl-β-ethanol is called Oxa-Pictet–Spengler reaction^[5]

Reaction mechanism

The reaction mechanism occurs by initial formation of an iminium ion (2) followed by electrophilic addition at the 3-position, in accordance with the expected nucleophilicity of indoles, to give the spirocycle 3. After migration of the best migrating group, deprotonation gives the product (5).

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, trifluoroacetic acid or superacids.^[6][7]

N-acyliminium ion 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-acyliminium ion is a very powerful electrophile and most aromatic ring systems will cyclize under mild conditions with good yields.^[8]

Asymmetric Pictet–Spengler reaction

When the Pictet–Spengler reaction is performed with an aldehyde other than formaldehyde, a new chiral center is created. Several substrate- or auxiliary-controlled diastereoselective Pictet–Spengler reactions have been developed.^[11][12] Additionally, List et al. have published a chiral Brønsted acid that catalyzes asymmetric Pictet–Spengler reactions.^[13]

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).^[14][15]

See also

• Bischler–Napieralski reaction
• Pomeranz–Fritsch reaction

References

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