Biginelli Reaction Mechanism

SCHEME 9.6 Proposed Biginelli reaction mechanism using thiourea 24 as substrate. 

SCHEME 9.7 Proposed Biginelli reaction mechanism using urea 10 as substrate. 

The mechanism was then reexamined 25 years later in 1997 by Kappe. Kappe used H and C spectroscopy to support the argument that the key intermediate in the Biginelli reaction was iminium species 16. In the event, 5 reacted with 3a to form an intermediate hemiaminal 17 which subsequently dehydrated to deliver 16. Iminium cation 16 then reacted with 6 to give 14, which underwent facile cyclodehydration to give 15. Kappe also noted that in the absence of 6, bisureide 8 was afforded as a consequence of nueleophilic attack of 16 by urea (3a). This discovery confirmed the conclusion of Folkers and Johnson in 1933. As far as the proposal from 25 years earlier by Sweet and Fissekis, Kappe saw no evidenee by H and NMR spectroscopy that a carbenium ion was a required species in the Biginelli reaetion. When benzaldehyde (5) and ethyl... 

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

The first step in the mechanism of the Biginelli reaction is the acid-catalyzed condensation of the urea with the aldehyde affording an aminal, which dehydrates to an A/-acyliminium ion intermediate. Subsequently, the end form of the 3-keto ester attacks the A/-acyliminium ion to generate an open chain ureide, which readily cyclizes to a hexahydropyrimidine derivative. 

Since its first report in 1893, a number of alternative mechanisms have been put forward for the Biginelli reaction the iminium [75], the enamine [76], and the Knoevenagel [77] mechanisms, which Scheme 3.34 summarizes. 

In spite of the importance of the Biginelli reaction, its mechanism is still under discussion. Thus, the original accepted mechanism initially proposed by Folkers and Johnson [19] was more recently supported by Kappe [20] (Scheme 9.2). 

Three main mechanisms have been proposed for the Biginelli reaction. In 1933, Folkers and Johnson proposed three potential key intermediates (5-7) involved in the Biginelli reaction (Figure 3) [6]. Intermediate 5 could be formed via an iminium mechanism from the condensation of aldehyde and urea. Intermediate 6 may be formed via an enamine mechanism from the condensation of urea and 1,3-dicarbonyl compoxmd. The third option involves intermediate 7, which can be formed via a Knoevenagel condensation of an aldehyde and a 1,3-dicarbonyl compound. Folkers and Johnson believed that intermediate 5 was preferentially formed over 6 or 7. 

In 2012, Ramos and collaborators also studied this mechanistic pathway by means of ESI-MS, NMR, and theoretical calculations in their approach [9]. In this work, the mechanism of the Biginelli reaction was explored by studying the influence of Lewis acid catalysts in the presence of ionic liquids. Once again, the researchers noticed the exclusive formation of iminium intermediate m/z 149 (Figure 4), indicating that xmder Lewis Acid catalysis and in ionic liquids, the preferred mechanistic pathway was the iminium mechanism [9]. 

Sohn and colleagues [31] evaluated the use of L-proline esters (CAT-21, Table 4) in the Biginelli reaction. They also investigated the mechanism of CAT-21 asymmetric catalysis in such reactions. Initially, they evaluated three possible pathways that could influence the enantioselectivity observed for this reaction (Figure 7). One of these pathways involves the condensation of the aldehyde with mea leading to the formation of a chiral acyl imine. In this sense, the... 

In 2011, Li used a chiral calixarene (CAT-31) to perform an asymmetric version of the Biginelli reaction (Table 6). CAT-31 produced the Biginelli adducts in moderate yields and enantioselectivities (54% 44% ee). As possible additives, a piperidine-TFA salt and p-toluic acid were used to provide the Biginelli adducts in 42% yield and 68% ee. The monomer did not efficiently promote enantioselectivity in these reactions. From all tested aldehydes, those with substituents in the metfl-position had a better ee (80-98%), while those with substituents in the para-position had a lower ee (20-69%). The proposed mechanism by the authors involved the enamine intermediate, which interacts with the calixarene cavity in some manner, as confirmed by NMR experiments [42]. 

Since the revised Biginelli mechanism was reported in 1997, numerous papers have appeared addressing improvements and variations of this reaction. The improvements include Lewis acid catalysis, protic acid catalysis, non-catalytic conditions, and heterogeneous catalysis. In addition, microwave irradiation (MWI) has been exploited to increase the reaction rates and yields. 

The Passerini synthesis is one of the oldest and most important multicomponent reactions (chronologically preceded by the reaction of Biginelli [1] and followed by the equally well-known Ugi four-component condensation reaction [2], currently widely studied for its originality in terms of application and mechanism). Surprisingly, little information is available regarding its discoverer, the Florentine chemist Mario Passerini. The reasons for the lack of a biography of this scientist can be traced, in part, to Passerini s reserved nature, reserved to the point of erroneously being perceived as shadowy. ... 

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