Barbiturate ring

A particular mechanism of barbiturate ring opening has been observed for some barbiturates hydroxylated on the side-chain. The mechanism and relevance of this tautomeric lactam-lactone equilibrium are discussed in Chapt. 11. 

Finally, there are numerous purely synthetic heterocycles. These are discussed in many places throughout this book. The hydantoin ring of phenytoin and the barbiturate ring of phenobarbital are good examples of these. There are a variety of drugs containing pyrrolidine, furan, pyrazole, pyridine, and indole rings. 

Ring scission of the barbituric ring leads to the formation of acetamides or acetyl urea derivatives. Both acetyl urea and acetamide derivatives are more hydrophilic than barbiturates. The biotransformations of barbiturates have been reviewed (11,12),... 

Oxidation and complete removal of substituents at carbon-5 N-dealkylation at N1 and N3 Desulfuration at carbon-2 (thiobarbiturates) Scission of the barbiturate ring at the 1 6 bond to give substituted malonylureas... 

For 5-alkyl substituents longer than ethyl, the extended conformation (Fig. 8b) is preferred.60,155,175,178 However, introduction of amethyl group at the a position results in a predominance of the conformation shown in Fig. 8c, where the methyl group is situated above the barbiturate ring.173,175,178... 

Quantum mechanical calculations by MINDO/3 suggest that barbiturates with alkyl and/or alkenyl substituents at the 5-position show in solution the same favored conformations as in the solid state109,182,183 (Fig. 8). This conclusion is also confirmed by the results of conformational analyses using H- and 13C-NMR spectroscopy.109,183 Moreover, Andrews et al. conclude that these preferred conformations in solution are independent of the ionization state of the barbiturate ring.109... 

Barbiturates smoothly undergo the Mannich reaction. Although the aminomethyl group is usually introduced in the 1- and/or 3-position of the barbituric ring (see Section III,B), there are known cases of this reaction at the 5-position. Sladowska obtained the series of l,3-dicyclohexyl-5-alkyl-5-aminomethylbarbituric acids (67 R = Et, allyl R = 1-piperidinyl, 1-pyr-rolidinyl, 1-morpholinyl) from l,3-dicyclohexyl-5-alkylbarbituric acids.240... 

The direct introduction of a hydroxyl group onto 1- or 3-positions in the barbituric ring system is difficult, and attempts to accomplish it by direct oxidation with hydrogen peroxide, peracetic, trifluoroperacetic, and... 

The hypothesis that the 1-2 hydrolytic opening of the barbiturate ring is associated with the undissociated form was not fully supported by experimental evidence.319,322 The 1-6 ring opening is favored in all barbiturates and the 1-2 opening is of minor importance, except when some steric factors, such as a bulky C-5 substituent or the presence of some N-substituents, inhibit the 1-6 alternative.329 The results of other studies support this view,305 308 312 313 344 but its definite and detailed experimental proof is still lacking. 

Loss of alkyl groups attached to nitrogen Desulfuration in the case of the thiobarbiturates Hydrolytic splitting of the barbiturate ring... 

These positional isomers (I) and (II) belong to the barbiturate family. However, these positional isomers speeifically diifer only in the formation of the 5-carbon side chain attached to the C-5 position to the barbiturate ring system. Thus, eompound (I) is a short-acting barbitnrate whereas, eompound (II) is an intermediate-acting barbiturate. 

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