Intermediates Biginelli

Since the 1930s several mechanistic pathways have been proposed for the Biginelli In 1933, Folkers and Johnson reported that one of three intermediates... 

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 addition to modification of the catalyst, several variants of the Biginelli reaction have emerged as viable alternatives however, each method requires pre-formation of intermediates that are normally formed in the one-pot Biginelli reaction. First, Atwal and coworkers reported the reaction between aldol adducts 39 with urea 40a or thiourea 40b in the presence of sodium bicarbonate in dimethylformamide at 70°C to give 1,4-dihydropyrimidines 41. DHPM 42 was then produced by deprotection of 41. 

In addition, Namazi and coworkers expanded the DHPM core by constructing pyrrolo[3,4-rf pyrimidines via the classical approach. First, DHPM 59 was delivered in 60% yield using the standard Biginelli conditions. 59 was then brominated in high yield to afford 60. Substitution of bromide 60 with methylamine followed by cyclization of the intermediate amino ester furnished pyrrolo[3,4-rf pyrimidine 61 in 53% yield. 

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. 

When R2 substituent is flourocontaining alkyl group, the transformation 17 18 becomes hindered and its proceeding requires some special methods. For example, in [48] Biginelli-like cyclocondensations based on three-component treatment of 3-amino-l,2,4-triazole or 5-aminotetrazole with aldehydes and fluorinated 1,3-dicarbonyl compounds were investigated. It was shown that the reaction can directly lead to dihydroazolopyrimidines 20, but in the most cases intermediate tetrahydroderivatives 19 were obtained (Scheme 10). To carry out dehydration reaction, refluxing of tetrahydroderivatives 19 in toluene in the presence of p-TSA with removal of the liberated water by azeotropic distillation was used. The same situation was observed for the linear reaction proceeding via the formation of unsaturated esters 21. 

In the currently accepted mechanistic pathway outlined in Scheme 7, the key step in the Biginelli sequence involves the acid-catalyzed formation of an Wacyliminium ion intermediate of type 719 from the aldehyde and urea precursors <1997JOC7201, 2000ACR879, 20040R1>. Interception of the iminium ion 719 by the CH-acidic carbonyl component 715, presumably through its enol tautomer, produces an open-chain ureide 720, which subsequently cyclizes to hexahydropyrimidine 721. Acid-catalyzed elimination of water from 721 ultimately leads to the... 

P. Biginelli 5 observed that phosphine unites with mercuric chloride to form a yellow mass and P. Lemoult observed the formation of an unstable intermediate product when phosphine acts on an aq. soln. of mercuric chloride and potassium chloride. If the gas be confined over the liquid and suddenly shaken, the resulting yellow precipitate can be dried in va.euo over sulphuric acid. Its composition corresponds with phosphorus triochloromercuriate, P(HgCl)3, or HgCl2.PHg2Cl. 

The Biginelli synthesis (Scheme 3) is an important route to dihydropyrimidilies, e.g. (25),46a with many variants of the original reactants now established. The mechanism has now been re-investigated using 1H- and 13C-NMR.46b The first step does not appear to involve aldol condensation or a carbenium-ion intermediate rather, condensation of benzaldehyde and urea gives an A-acyliminium ion intermediate (26), which then goes on to react with ethyl acetoacetate. 

The synthesis of small arrays of organic compounds derived from multicomponent condensations was recently reported by Studer et al. (119). A 10-member amino acid amide library L7 (Fig. 8.21) was prepared using the fluorous Ugi ( Flugi ) condensation, and another 10-member dihydropyrimidine library L8 (Fig. 8.21) was prepared using the Biginelli ( Fluginelli ) condensation adapted to the fluorous phase. The key intermediates for library preparation were the silyl bromide 8.36, prepared from a fluorous iodide (120), and the acyl bromide 8.37 and the acid 8.38, prepared from an orthothiobenzoate (121), as shown in Fig 8.21. The structure of the fluorous tag was... 

To create stereochemical diversity within MCRs there is need for stereoselective (or -specific) reactions. Since many MCRs involve flat intermediates, like imines and a,p-unsaturated ketones, they result in the formation of racemic products. Moreover, often mixtures of diastereomers are obtained if more than one stereo-genic centre is formed. However, there are several examples known of asymmetric induction, by the use of chiral building blocks (diastereoselective reactions). For example, it has been successfully applied to the Strecker, Mannich, Biginelli, Petasis, Passerini, Ugi, and many other MCRs, which has been excellently reviewed by Yus and coworkers [33]. Enantioselective MCRs, which generally proved to be much harder, have been performed with organometaUic chiral catalysts and orga-nocatalysts [33, 34]. 

Conversely, neutral and ambient conditions lead to the formation of the kineti-cally controlled Biginelli product 144 (eight examples, 51-70%). The authors found that sonication was required to obtain the final product, since simple stirring of the three components at rt did not result in any desired reaction. They explained this observation by the improved mass transfer through cavitation phenomena. This reaction presumably involves intermediate 143. 

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. 

Kappe, C. O., Falsone, S. F., Fabian, W. M. F., Belaj, F. Synthesis and reactions of Biginelli compounds. 13. Isolation, conformational analysis and x-ray structure determination of a trifluoromethyl-stabilized hexahydropyrimidine - an intermediate in the Biginelli reaction. Heterocycles 1999, 51, 77-84. 

Overman, L. E., Rabinowitz, M. H. Studies toward the total synthesis of (+)-ptilomycalin A. Use of a tethered Biginelli condensation for the preparation of an advanced tricyclic intermediate. J. Org. Chem. 1993, 58, 3235-3237. 

A novel solid-phase version of the Biginelli three-component condensation has been recently disclosed [359]. Since the reaction proceeds via formation of an N-acyliminium ion intermediate from the aldehyde and the urea precursors, these components were first combined and then reacted with the resin-bound fi-ketoe-ster (454). Highly loaded (2.53 mmol g ) fi-ketoester Wang resin was utilized in order to increase the amount of final product (Scheme 94). Using this strategy, eleven different dihydropyrimidones (458) have been prepared. 

In a solid-phase split-pool Biginelli synthesis of DHPMs, a urea derivative 23 studded with polystyrene macrobeads was condensed with an aldehyde to obtain a stable acylimine 24 intermediate on the bead, which upon reaction with p-ketoesters furnished 25. Upon cleavage of the resin, 25 yielded N-l functionalized DHPM derivatives 26 (Scheme 10) (04OL3237). 

It has been documented that the Biginelli reaction involves an aldehyde-urea condensation to form A/ -acyliminium ion as the key intermediate, followed by the addition of a 7r-nucleophile to the electron-deficient A/ -acyliminium ion and finally a ring closure, as illustrated below. 

An MS investigation of the three-component base-mediated Biginelli synthesis of dihydropyrimidines has found evidence for a hemiacetal intermediate (117), but no sign of a bis-ureide (118). ° A prolinamide gives up to 99% ee in Biginelli cyclocondensations of urea, aldehyde, and ethyl acetoacetate. ... 

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