Pictet–Spengler reaction

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 (22 February 1886 – 18 August 1965). Traditionally, an acidic catalyst in protic solvent was employed with heating; however, the reaction has been shown to work in aprotic media in superior yields and sometimes without acid catalysis.

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

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).

600px|center|The mechanism of the Pictet–Spengler reaction

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.

center|500px|The Pictet–Spengler isoquinoline synthesis

N-acyliminium ion Pictet–Spengler reaction

Instead of catalyzing the Pictet–Spengler cyclization with strong acid, one can acylate the imine 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.

center|550px|The N-acyliminium Pictet–Spengler reaction

Tadalafil is synthesized via the N-acyliminium Pictet–Spengler reaction. This reaction can also be catalyzed by AuCl3 and AgOTf.

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. Additionally, List et al. have published a chiral Brønsted–Lowry acid that catalyzes asymmetric Pictet–Spengler reactions.

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 Nb-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).