Pictet–Spengler reaction

The Pictet -Spengler reaction is a chemical reaction for the preparation of heterocycles. β - arylethylamines, such as tryptamine, cyclize with an aldehyde elimination of water. The reaction is usually acid catalyzed and carried out in the heat. Particularly reactive aromatics give good yields even under physiological conditions. The Pictet -Spengler reaction is a special case of the Mannich reaction.

The reaction was described in 1911 by Amé Pictet ( 1857-1937 ) and Theodor Spengler and has developed into an important reaction for the synthesis of alkaloids and pharmaceutical agents.

Especially nucleophilic aromatic compounds such as indoles or pyrroles under mild conditions, the cyclization products in good yields. Little nucleophilic aromatic such as phenyl, however, lead to poor yields or require high temperatures and strong acids. The published by Pictet and Spengler reaction was carried out with β - phenethylamine and formaldehyde dimethyl acetal with hydrochloric acid and the product tetrahydroisoquinoline was obtained.

As the Mannich reaction yield the less reactive ketones either low yields or go no correct response.

The Pictet -Spengler reaction has been successfully applied in solid-phase synthesis in combinatorial chemistry. The analogous reaction with aryl - β -ethanol (instead of the amine ) is called oxa- Pictet -Spengler reaction.

Reaction mechanism

The aldehyde initially reacts with the amine. After protonation and subsequent elimination of water produced an iminium ion. The driving force of the reaction is the electrophilicity of the iminium ion which can be attacked by the electron-rich aromatic ring now. After elimination of a proton ( under rearomatization ) of the heterocycle is obtained. The reaction is a 6 -endo -trig reaction which is preferred according to Baldwin's rules.

Variants

Tetrahydroisoquinoline synthesis by Pictet -Spengler

According to the principle of the Pictet -Spengler reaction tetrahydroisoquinolines can be synthesized. The reaction conditions are relatively drastically, there are higher temperatures and stronger acids such as hydrochloric acid, trifluoroacetic acid, or even super acids needed ..

N- acyliminium variant of the Pictet -Spengler reaction

Unreactive aromatic compounds can be reacted under mild conditions. This exploits that an N - Acyliumiminiumion is an excellent electrophile. By reaction of an acylating agent (eg an acid chloride or anhydride ), the amine is activated, and the reaction takes place, the N- Acyliumiminiumion as a reactive intermediate product instead.

Tadalafil was prepared via the N- acyliminium Pictet -Spengler reaction.

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