Pictet-Spengler reactions mechanism

The mechanism of this reaction is still not clear. It has always been thought that the Pictet-Spengler reaction proceeds via a spiroindolenine intermediate 20 followed by a Wagner-Meenvein rearrangement to 21 (way A). On the other hand in the case of very reactive electrophiles it was shown that the cyclization can occur by direct attack at the C-2 position of the indole (way B). However, after deprotonation of 21 compound 7 is formed.10... 

On the basis of a rapid and reversible spiroindolenine mechanism, a pathway for the Pictet-Spengler reaction was proposed recently, which is consistent with all these stereochemical fmdings. ... 

Scheme 5. The Pictet-Spengler reaction (a) and proposed mechanism (b). EDG = electron-donating group, EWG = electron-withdrawing group.

NCS catalyzes isoquinoline formation via an asymmetric Pictet-Spengler reaction (ii). The reaction entails an acid-catalyzed electrophilic addition of an iminium ion. The mechanism is a two-step process in which the iminium ion is generated first from the condensation reaction between the aldehyde carbonyl (such as 4-HPAA) and dopamine. Two types of NCS (CjNCSl and CjPRlOA) have been isolated from Coptis japonica cells and characterized [21]. CjPRlOA has been sufficiently expressed in an active form in E. coli. Conversely, CjNCSl forms a larger complex in plant cells. Therefore, the recombinant enzyme expressed in E. coli cells has considerably lower activity than that of the native enzyme. 

Tryptophan-derived 1,2,3,4-tetrahydro-P-carboline and 3-carboline alkaloids result in foods through a Pictet-Spengler condensation (a special case of the Mannich reaction) of indoleamines, such as tryptophan and tryptamine, with aldehydes. The mechanism of the Pictet-Spengler reaction leading to... 

An efficient method of selective synthesis of the oxidized and reduced forms of imidazo[l,5-a]quinoxalines via modified Pictet-Spengler reaction of 2-imidazolyl anilines with arylaldehydes (the possible mechanism is shown in Scheme 4.42) has been described (Verma et al. 2013). The reaction proceeds under mild conditions... 

Scheme 4.42 Plausible mechanism of the Pictet-Spengler reaction...

In addition to (V-acyUminium ions, the protioiminium ions (X19) could be activi-ated in a similar anion-binding mechanism (Scheme 2.79). The same group then developed chiral thiourea (289a)-catalyzed two-component Pictet-Spengler reaction of tryptamines 21 and aldehydes under mild conditions. Benzoic acid used as the cocatalyst provided the products desired, with excellent results [110a]. Later, Lee... 

A recent formal synthesis of the alkaloid (—)-mitralactonine relied on a reaction that allowed the simultaneous creation of three new bonds, two of them a and one ft with respect to the quinolizine nitrogen. As shown in Scheme 112, treatment of triptamine with chiral aldehyde 480 in the presence of acid directly gave a mixture of diastereo-meric indoloquinolizidines 481 and 482 through a mechanism involving a Pictet-Spengler cyclization and a N-alkylation reaction <2007SL79>. 

Mechanism 2, which constitutes a retro Pictet-Spengler type process, has long been held responsible for the acid-catalysed epimerization reaction... 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

Scheme 3.63 depicts a proposed mechanism where amine 164 and aldehyde react to generate the expected Pictet-Spengler product 202 via the iminium species 205. Evidence for the intermediate formation of 202 was observed through LC/MS monitoring, and the reaction with the protonated isonitrile 203 affords the final exocyclic amidine moiety 204. 

Subsequently, this anion-binding-based mechanism was transferred to various other anions and reactions [20-22]. In 2007, Jacobsen reported the organocatalytic enantioselective Pictet-Spengler cyclization shown in Scheme 3 [23]. In the course of the reaction, thiourea derivative 5 binds to chloride liberated from intermediate 4 (which is generated in situ from the corresponding hydroxy lactam). This... 

Jacobsen has also developed an organocatalysed asymmetric addition of nucleophiles with iV-acyl-iminium ions (Pictet-Spengler) and oxocarbe-nium ions, potentially useful reactions in medicinal chemistry (Scheme 14.97). The mechanism involves the formation of an anionic catalyst-chloride complex which acts as a chiral counter ion directing the approach of nucleophiles to one face of the cationic species. 

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