Dialkyl barbituric acid

The barbiturate series of hypnotics are easily and cheaply made from phosgene [577]. Typically, a dialkyl malonic ester is treated with strong aqueous ammonia to give the diamide of the substituted malonic acid. Equation (4.14). This substance is then heated in an autoclave with phosgene for several hours at about 100 C to give the corresponding dialkyl barbituric acid [577]. 

When the same domino reaction was performed with N,N-dialkyl barbituric acid 29 as a Michael donor and catechol 25, the reaction did not provide the expected benzofuran derivatives. Interestingly, a new type of domino reaction took place, which gave polycycHc dispiropyrimidinone 30 in excellent yield. 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

Problem 16.55 Barbiturates are sedative-hypnotic varieties of 5,5-dialkyl substituted barbituric acids. Write the reaction for the formation of Veronal (5,5-diethylbarbituric acid) from the condensation of urea with diethylmalonic ester. [See Problem 17.13(a)]. ... 

The barbiturates are S.S-disubstitutcd barbituric acids, fbe following. scheme shows how the. A.S-dialkyl com-pnunds are synthesized. Substitution of thiourea for urea in ibe reaction produces the 2-thiobarbiturates, u.seful as induction anesthetics. 

Unsubstituted, 1-mono- or 1,3-dialkyl- and/or phenyl-substituted barbituric acids (68) can be converted to 5-formimidoyl derivatives by a reaction with s-triazine241 [Eq. (4)]. 

R. McKeown, First thermodynamic dissociation constants of 5,5-disubstituted barbituric acids in water at 25 °C. Part 1. 5,5-Dialkyl-, 5-alkenyl-5-alkyl-, 5-alkyl-5-aryl-, 5,5-dialkenyl-, 5,5-diaryl-, and 5,5-dihalogeno-barbituric acids, /. Chem. Soc. (Perkin 11), 1980,504-514. 

N,S-Dialkylation of barbituric acids, 2-thio- 29, 408 Dialkylboranes, hindered 24, 48 suppl. 29... 

The barbiturates were widely used as sedative-hypnotic drugs. Barbital was introduced as a drug in 1903. The method of synthesis for thousands of its analogs has undergone little change. Urea reacts with various derivatives of malonic acid, usually a diethyl ester of a dialkyl substituted malonic acid. This is a classic example of a nucleophilic acyl substitution. A derivative of ammonia reacts with esters to form an amide, only in this case a cyclization to a strainless six-membered ring results because of the proximity of the bifunctionality. 

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