Dihydropyrimidine

When the aromatic aldehyde is omitted from a Biginelli reaction mixture, a dihydropyrimidine is still formed. Thus, for example, phenylacetaldehyde (2 mol) and urea (1 mol) react to give 4-benzyl-5-phenyl-3,4-dihydropyrimidin-2(li/)-one (676) (33JA3361). 

Having a 5-methyl group, thymine is not nitrated or halogenated normally, but with aqueous bromine it does give the dihydropyrimidine (948) (25JBC(64)233) its other reactions parallel those of uracil although its behavior on irradiation is somewhat different (Section 2.13.2.1.4). 

Orotic acid (971) has a chequered history. It was isolated in 1905 from the whey of cows milk in Italy and it was subsequently synthesized in the United States in 1907. However, the workers involved were discouraged by some difference in melting points and no direct comparison of specimens was ever made. To make matters worse, the same laboratories prepared the isomeric 5-hydroxy-2-oxo-l,2-dihydropyrimidine-4-carboxylic acid and announced it as orotic acid, again without any direct comparison. Only in 1930 did a German worker actually compare directly natural and the original synthetic orotic acid, thereby showing them to be identical (30CB1000). 

There are at least eight syntheses of orotic acid in the literature. The most practical in the laboratory is that involving the condensation of diethyl oxalacetate (972) with S-methylthiourea to give 2-methylthio-6-oxo-l,6-dihydropyrimidine-4-carboxylic acid (973) which undergoes either direct acidic hydrolysis or a less smelly oxidative hydrolysis, via the unisolated sulfone (974), to afford orotic acid (971) (B-68MI21303). 

If one replaces one of the two equivalents of P-dicarbonyl with urea, such that the reaction is now carried out with one equivalent of aldehyde 123, one equivalent of P-dicarbonyl 124 and an equivalent of urea 125 in acidic ethanol solution, then dihydropyrimidines 126 are formed. This class of reactions has been named Biginelli reactions and are reviewed in section 10.6... 

The Biginelli reaction involves an one-pot reaction between aldehyde 1, 1,3-dicarbonyl 2, and urea 3a or thiourea 3b in the presence of an acidic catalyst to afford 3,4-dihydropyrimidin-2(l//)-one (DHPM) 4. This reaction is also referred to as the Biginelli condensation and Biginelli dihydropyrimidine synthesis. It belongs to a class of transformations called multi-component reactions (MCRs). 

In 1893 Pietro Biginelli reported the first synthesis of 4-aryl-3,4-dihydropyrimidin-2(l//)-ones (DHPMs) via an one-pot process using three components. Thus, DHPM 7 was synthesized by mixing benzaldehyde (5), ethyl acetoacetate (6), and urea (3a) in ethanol at reflux in the presence of a catalytic amount of HCl. 

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. 

A likely pathway is also that in which the key stage is the addition of the second formamide molecule to the carbonyl group of the intermediate 157 to form the amide 159. The latter, with loss of water, closes the dihydropyrimidine ring 160, which undergoes aromatization to 4-metylpyrimidine via 1,4-hydrogen shift and decarbonylation. 

Dipolar cycloadditions of dihydropyrimidine-fused mesomeric betaines 389, 391 and 394 with different dipolarophiles afforded 6-oxo-6H-pyrido[l,2-n]pyrimidine-3-carboxylates 390, 392, 393 and 396 (97JOC3109). 

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