The PictetâÂÂSpengler reaction is a chemical reaction in which a ò-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 â 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. The PictetâÂÂSpengler 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 iminium ion generated from the condensation of the aldehyde and amine under acid conditions. This explains the need for an acid catalyst in most cases, as the imine is not electrophilic enough for ring closure but the iminium ion is capable of undergoing the reaction.
The PictetâÂÂSpengler reaction is widespread in both industry and biosynthesis. It has remained an important reaction in the fields of alkaloid and organic synthesis since its inception, where it has been employed in the development of many beta-carbolines. Natural PictetâÂÂSpengler reaction typically employ an enzyme, such as strictosidine synthase. PictetâÂÂSpengler 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 in high yields and mild conditions, while less nucleophilic aromatic rings such as a phenyl group give poorer yields or require higher temperatures and strong acid. The original PictetâÂÂSpengler reaction was the reaction of phenethylamine and dimethoxymethane, catalysed by hydrochloric acid forming a tetrahydroisoquinoline.
The PictetâÂÂSpengler reaction has been applied to solid-phase combinatorial chemistry with great success.
An analogous reaction with an aryl-ò-ethanol is called oxa-PictetâÂÂSpengler reaction.
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).
Replacing an indole with a 3,4-dimethoxyphenyl group give the reaction named the PictetâÂÂSpengler 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.
Instead of catalyzing the PictetâÂÂSpengler 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.
Tadalafil is synthesized via the N-acyliminium PictetâÂÂSpengler reaction. This reaction can also be catalyzed by AuCl<sub>3</sub> and AgOTf.
When the PictetâÂÂSpengler reaction is performed with an aldehyde other than formaldehyde, a new chiral center is created. Several substrate- or auxiliary-controlled diastereoselective PictetâÂÂSpengler reactions have been developed. Additionally, List et al. have published a chiral BrønstedâÂÂLowry acid that catalyzes asymmetric PictetâÂÂSpengler reactions.
Tryptophans: diastereocontrolled reaction<br/> The reaction of enantiopure tryptophan or its short-chain alkylesters leads to 1,2,3,4-tetrahydro-ò-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<sub>b</sub>-benzylated tryptophans, which are accessible by reductive amination. The benzyl group can be removed hydrogenolytically afterwards. As a rough rule, <sup>13</sup>C NMR signals for C1 and C3 are downfield shifted in cis products relative to trans products (see steric compression effect).