Barbiturates alkyl derivatives

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). 

By using the same catalytic system, alkylations of 1,3-dimethylbarbituric acid with alcohols were also accomplished (Scheme 5.31) [68]. The Cp lr-catalyzed alkylation using 2-iodobenzyl alcohol, followed by palladium-catalyzed carbon-carbon bond formation with allene, gave spirocyclic barbituric acid derivatives in a one-pot process. 

Alkyl and 1-aralkyl-5,6-dihydrouracils (LXXIX), prepared by condensation of A -(2-carbamoylalkyl)aralkylamines with urea or by treating a suitable primary amine with an ester of acrylic acid followed by cyanic acid, are CNS depressants and anticonvulsants [639, 640], as well as anti-inflammatory agents [641]. Such compounds are to be compared with the corresponding barbituric acid derivatives in which not more than one hydrogen in the 5-position is substituted, and also with barbiturates in which the 5,5-substituents are similar to the R and groups of the 5,6-positions here. 

Curry, K. Novel amino carboxy alkyl derivatives of barbituric acid, WO 0179185. 

Using similar chemistry l,3-diaryl-2-thiobarbituric acid is acylated with chloroacetyl chloride in the presence of triethylamine. Subsequent (9-alkylation under the mildly basic conditions of sodium acetate yields the 5-oxo derivative <91H(32)907>. It is not necessary to use barbituric acid derivatives to accomplish synthesis of furopyrimidines. Other 6-oxopyrimidines serve well in developing analogues. For example, in a reaction similar to that described above, the acylated pyrimidine (215) undergoes cyclization to a 4-(substituted)amino compound (216) (Equation (74)) <92MI 707-03). 

This methodology has been used to provide efficient protocols for the asymmetric allylic alkylation of p-keto esters, ketone enolates, barbituric acid derivatives, and nitroalkanes. Several natural products and analogs have been accessed using asymmetric desymmetrization of substrates with carbon nucleophiles. The palladium-catalyzed reaction of a dibenzoate with a sulfonylsuccinimide gave an advanced intermediate in the synthesis of L-showdomycin (eq 3). ... 

The formation of some 5-alkyl or 5-arylmethylbarbituric acids has been studied by Sekiya et a/.236-238 The barbituric acid derivatives 65 (o-, m-, p-substituted phenyl, benzyl, styrenyl R1, R2 = H and/or methyl) containing a methylidene bond at the 5-position can be reduced by triethylammonium formate (TEAF) in high yield [Eq. (3)]. Similarly, 5-arylaminomethylene- and 5-alkylaminomethylene-substituted barbituric acids can be converted to 5-methylbarbituric acids.238... 

The imide hydrogen atoms in barbituric acids take part in tautomerism (Section II,A) so that the alkylation of these compounds leads to a mixture of N- and O-alkyl derivatives. Levina thoroughly discussed the N-alkylation.4... 

The exclusive formation of O-alkyl derivatives of barbituric acids was seldom observed, because in the course of alkylation a mixture of products is obtained (Section III,A). Nevertheless, only O-alkylation was observed in... 

Barbituric acid derivatives resemble uracils in their preference for A-alkylation with most reagents (76AJC1769, 78AJC2517>. Large alkyl groups may favor 0-alkylation. Diazomethane converts barbituric acid into 6-methoxy-l-methyluracil (72CJC880). Information is also available on the alkylation of perimidinones (81RCR816>. 

Barbituric acid derivatives have been alkylated with yields of more than 90%,407 and cyanoacetic esters with yields of 60-78%.382... 

Alkyl Bound to Carbon. These compounds may be considered as being derived by the substitution of an alkyl group for hydrogen in carbon compounds. Examples are alkylate for synthetic gasoline, ethylbenzene for styrene entering into the manufacture of plastics and rubber, and hexylres-orcinol, thymol, barbital, and other barbituric acid alkyl derivatives. 

As the number of carbon atoms at the fifth carbon position increases, the lipophilic character of the substituted barbituric acids also increases (44). Branching, unsaturation, replacement of alicyclic or aromatic substituents for alkyl substituents, and introduction of halogen into the alkyl substituents all increase the lipid solubility of the barbituric acid derivatives. A limit is reached, however, because as the lipophilic character increases, the hydrophilic character decreases. Although lipophilic character determines the ability of compounds to cross the blood-brain barrier, hydrophilic character also is important, because it determines solubility in biological fluids and ensures that the compound reaches the blood-brain barrier. Introduction of polar groups into the alkyl substituent decreases lipid solubility below desirable levels. Modifications at this position by variation of the alkyl substituents were of primary importance in the development of barbiturates with short (3-4 hours) to intermediate (6-8 hours) duration of action. These barbiturates were once extensively used as sedatives and hypnotics. 

The quantitative extraction of the lower alkyl derivatives, such as diethyl barbituric acid, from aqueous solution is difficult as the partition coefficients are not high. By determination of the K values for barbitone it can be shown that ethyl acetate is undoubtedly the best of the common solvents for extracting these derivatives, with ether and ether-chloroform as good substitutes. More complex mixed solvents such as chloroform, ethanol and ether are favoured by some workers they offer little advantage over ether for rapidity of extraction and the residues are less pure. Ether extracts are usually very pure and barbiturates can be extracted direct from urine with this solvent. 

Urea derivadves are of general interest in medicinal chemistry. They may be obtained cither from urea itself (barbiturates, sec p. 306) or from amines and isocyanates. The latter are usually prepared from amines and phosgene under evolution of hydrogen chloride. Alkyl isocyanates are highly reactive in nucleophilic addidon reactions. Even amides, e.g. sulfonamides, are nucleophilic enough to produce urea derivatives. 

Section 21 8 Alkylation of diethyl malonate followed by reaction with urea gives derivatives of barbituric acid called barbiturates, which are useful sleep promoting drugs... 

Suvorov, N. N., Velezheva, V. S Vampi-lova, V. V., and Gordeev, E. N., Indole derivatives. XII. Alkylation of barbituric acids by Mannich bases, Khim. Geterotsikl. Soedin.. 515, 1974 Chem. Abstr.. 81, 37532, 1974. 

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