Of ethyl acetoacetate with urea

Today there is a great variety of suitable reaction conditions for Biginelli condensations. For the condensation of ethyl acetoacetate with benzaldehyde and urea, at... 

Hinkel, L. E., Hey, D. H. The condensation of benzaldeyde and ethyl acetoacetate with urea and thiourea. Reel. Trav. Chim. Pays-Bas 1929,48, 1280-1286. 

The synthesis of 6-methyluracil from ethyl acetoacetate and urea was described first by Behrend.i The substance has been obtained also by the action of lead hydroxide on methylthiouracil in an alkaline medium, and by boiling benzalmethylhydroxypyri-midinhydrazine with hydrochloric acid. ... 

In 1893, the Italian chemist Pietro Biginelli (University of Florence) for the first time reported on the acid-catalyzed cyclocondensation reaction of ethyl acetoacetate 1, benzaldehyde 2, and urea 3 [1], The reaction was carried out by simply heating a mixture of the three components dissolved in ethanol with a catalytic amount of HC1 at reflux temperature. The product of this novel one-pot, three-component synthesis that precipitated on cooling the reaction mixture was identified as 3,4-dihydropyrimidin-2(lH)-one 4 (Scheme 4.1) [2]. This reaction is nowadays referred to as the Biginelli reaction , Biginelli condensation or as the Biginelli dihydropyrimidine synthesis . 

The reaction of ethyl acetoacetate, benzaldehyde, and urea leads to ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-5-pyrimidinecarboxylate. This reaction (the so called Biginelli reaction) was discovered over 100 years ago [93T6937], Interest in these dihydropyrimidines has increased rapidly mainly due to their close structural relationship to the pharmacologically important dihydropyridine calcium channel blockers of the nifedipine-type [93T6937], The dibromo (51) and monobromo derivatives (55) of the most simple Biginelli compounds mentioned above are readily obtained by bromination [93T6937], and the reactions of these derivatives with sodium azide have been studied recently [90LA505] [91 JCS(P1)1342],... 

Zubaidha et al. [121] reported the one-pot synthesis of 3,4-dihydropyrimidin-2(l//)-ones 78 irsing iodine as a catalyst (Scheme 10.57). Aldehyde 77 was synthesized by a known method [122] and subjected to cyclocondensation with ethyl acetoacetate and urea. 

Saxena et al. (2005) have reported a quick method for the condensation reaction of an aldehyde, ethyl acetoacetate, and urea or thiourea to synthesize substituted 3,4-dihydropyrimidin-2(lH)-ones using iodine-alumina as the catalyst under microwave irradiation and solvent-free conditions. This method required 1 min with a variety of aromatic, substituted aromatic, and heterocyclic aldehydes however, no aliphatic aldehyde has been nsed. 

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

Although acid catalysis is thought to be necessary for the Biginelli reaction, there has been a report disputing this requirement. Ranu and coworkers surveyed over 20 aldehydes and showed that excellent yields of DHPMs could be achieved at 100-105°C in 1 h in the absence of catalyst and solvent with no by-products formed. In contrast Peng and Deng reported no significant formation of DHPM 15 when a mixture of benzaldehyde (5), ethyl acetoacetate (6), and urea (3a) was heated at 100°C for 30 min. 

Amides such as DMF or ureas such as N,N-tetramethylurea react with bis(trimethylsilyl)selenide 604 in the presence of BF3-OEt2 to give selenoamides, for example 617, or selenoureas whereas esters such as n-butyl benzoate react with 604 in the presence of Bp3-Et20 and 2,3-dimethylbutadiene to give 619 via 618 [157]. On heating with P4Sio/sulfur and hexamethyldisiloxane 7 y9-ketoesters such as ethyl acetoacetate are converted to 3H-l,2-dithiole-3-thiones such as 620 in high yields [158] (Scheme 5.51 cf. also Section 8.6). 

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. 

Fig. 6. Optimization of reaction time and temperature for the Biginelli condensation involving ethyl acetoacetate, benzaldehyde, and urea [see Eq. (1)] in a 3 1 AcOH/EtOH solvent mixture with 10 mol% Yb(OTf)3 as a catalyst.

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