Barbituric acids, enolization

As expected, heterocyclic enols and potential enols (i.e, compounds existing mainly in the CH form) behave toward diazomethane similarly to the open chain and isocyclic enols, i.e. they form enol methyl ethers by reactions of the SnI type (cf. footnote 29). Examples of this behavior are barbituric acid, picrolonic acid, dchydroacetic acid (64), 3-methyl-l-phenylpyrazolin-5-one, 1-phenylpyrazoli-dine-3,5-dione, 1,2-diphenylpyrazolidine-3,5-dionc, 3-hydroxy-... 

It is, however, more likely that the discrepancies observed in the periodate oxidation of malonaldehyde concern mainly the hydroxylation step. In the mechanism proposed (5) for this reaction, it is the enol form of malonaldehyde which is hydroxylated. However, titrations of a solution of malonaldehyde, prepared by hydrolysis of an aqueous solution (33) of carefully distilled 1, 3, 3-tri-ethoxypropene (46, 47), both with strong base and with iodine, indicate that only about 80% of the enol form is present in the equilibrium solution. On the other hand, the thio-barbituric acid test (58, 59) gave consistently higher values for the malonaldehyde content of the solution. The fact that only about 80% of the enol form is present in the equilibrium solution is all the more important as it can be shown (56) by titration with strong base that the enolization is slow, and moreover does not seem to go to completion. 

Cesium fluoroxysulfate reacts with ketones, diketones and enol acetates to give monofluoro products,27 28 e.g. formation of 22, 23 and 24. but barbituric acid is converted into 5.5-di-fluorobarbituric acid.29... 

Barbituric acid (83) may be regarded as 2,4,6-trihydroxypyrimidine, but in the crystalline state it exists as the triketo-form (95). In aqueous solution the compound is remarkedly acidic as the result of ionisation of the mono-enolic form (96) with the formation of a resonance stabilised anion (97). 

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). ... 

Pulse radiolysis studies using optical detection suggested the main species in equilibrium to be the ot-aminoalkyl radical (31) and the A -protonated ot-aminoalkyl radical (32) whereas results from ESR studies were indicative of protonation at the a-carbon site to form the iV-centered radical cation (30). A subsequent study showed that these results could be attributed to kinetic and thermodynamic factors [84]. Thus iV-protonation resulting in the formation of 32 is kinetically favored and is hence observed in the short time-scales involved in pulse-radiolysis systems. In the longer times involved in ESR measurements the thermodynamically more stable N-centered radical cation will be observed. The pA a of 30 and 32 were estimated as 8.0 and 3.6 by use of pulse radiolysis [84]. Using the equation for similar keto enol tautomerism of barbituric acid [97], the ratio of 30/32 was estimated to be 10 /10 = 10", indicating the N-centered radical (30) to be the predominant protonated species. 

The pharmacological activity of barbiturates is also influenced by their acidity, which is attributed to the lactam-lactim tautomer-ism that can occur in all derivatives in which at least one of the ring nitrogens is unsubstituted keto-enol tautomerism also takes place in 5-unsubstituted or mono-substituted compounds (Equation 5.17). Barbiturates must have acidity within certain limits to possess hypnotic activity (156). For example, barbituric acid (Ri, R2, R3, R4 = H), which has a pifa of 4.1 and is >99% dissociated at physiological pH, and the neutral N, iV -disubstituted compound (Ri, R2, R3 = Et, R4 = Ph) that is completely undissociated, are devoid of hypnotic... 

Fig. 2. Coupling components in azo dyes. The preferred positions of coupling are indicated by arrows and the usual pH conditions are noted. (1) 1-Naphthol [90-15-3], (2) 2-naphthol [135-19-3] (3) 3-hydroxy-2-naphthanilide [92-77-3], (4) aceto acetanilide [102-01-2] (5) 3-methyl-l-phenyl-5-pyrazoline [89-25-8] (enol form) (6) 8-amino-l-naphtol-3,6-disulfonic acid [90-20-0] (H-acid) (7) phenol [108-95-2] (8) resorcinol [108-46-3] (1 and 2 indicate the first and second substitution sites) (9) 2-naphthylamine [91-59-8] (10) 1-naphthylamine [134-32-7], (11) N,N-dimethylaniline [121 -69-7] (12) barbituric acid [67-52-7] (13) Fischer s base [118-12-7] (14) 8-hydroxyquinoline [148-24-3] (15) 2,4-dihydroxyquinoline [86-95-3],...

In the solid (crystalline) form the barbituric acid exists in the triketo or lactam form. In aqueous solution tautomerism to the enolic lactim occurs the enolic hydroxyl (at C-2) is acidic acid and is ionized according to the particular drug s pKa (e.g., pentobarbital = 8.0, phenobarbital = 7.5). Titrating such a solution with a stoichiometric equivalent of base such as NaOH will convert the lactam quantitatively to the barbiturate s sodium salt, which can be isolated. Many barbiturates are commercially produced both in the lactam and in the sodium enolate salt form. Of course, the salts are water soluble and thus are used to formulate injectable dosage forms including those for IV anesthetic use. 

Barbituric acid like parabanic acid exhibits keto-enol tautomerism as illustrated below ... 

Keto-enol tautomerism exists in parabenic acid and barbituric acid. Explain. 

This structure may not look like it is in the pyrimidine state, but this relation can be observed if we draw barbituric acid in its tri-enol form, 4.23. 

Room temperature fluorination of cyclic enol acetates by (1) gives cK-fluorocycloalkanones in high yield (70-90%). p-Diketones and barbituric acid give the corresponding gem-difluorinated derivatives. Room temperature fluorination of uridine in methanol followed by treatment with EtsN gives 5-fluorouridine (79%). Similarly, 1,3-dimethyluracil gives the 5-fluoro derivative (89%). ... 

Mechanochemical grinding reactions are known for providing a pathway to products that are not accessible by any other procedures due to the essentially solid reaction environment. In the context of solid-state tautomerism, the mechanochemistry has recently almost become an unavoidable technique, yielding new tautomeric forms as in the case of the keto form of thiobarbituric acid [25] or the enol form of barbituric acid [78]. Milling was also used for facilitating the solid-state transformation between the solid tautomeric forms, such as the mechanochemical conversion of keto-amino tautomer of 6-[(3-hydroxy-pyridin-2-ylamino)-methylene]-cyclohexa-2,4-dienone to more stable enol form. Scheme 13.10 [45]. These examples will be discussed in more detail in the latter sections. 

Scheme 13.20 Keto (1) and enol (2) tautomers of barbituric acid (H3BA).

Scheme 13.22 The synthons observed in the enol desmotrope (form IV) of barbituric acid. Main chain is stabilized by R22(8) hydrogen bonds and interacts with other chains (here noted as A-D) through O-H- 0 hydrogen bonds.

A plethora of weakly acidic pharmaceutical substances may be titrated effectively by making use of a suitable non-aqueous solvent with a sharp end-point. The wide spectrum of such organic compounds include anhydrides, acids, amino acids, acid halides, enols (viz., barbiturates), xanthines, sulphonamides, phenols, imides and lastly the organic salts of inorganic acids. 

Theoretically, the purine- and pyrimidine-based nucleic acid constituents and the barbiturates have the potential to occur in several tautomeric forms of the keto/ enol and amino/imino type where the aromatic character of the six-membered pyrimidine ring is fully or, as in the barbiturates, partially retained, as illustrated in Fig. 15.4. In these molecular species, which are all feasible on the basis of organic chemical considerations, the hydrogen-bonding donor/acceptor properties of the functional amino, imino, enol and keto groups vary considerably, being donor in one form and acceptor in the other. 

Most barbiturates are made from diethyl malonate. The methylene protons between the two carbonyl groups are acidic and will give a highly stabilized enolate anion. 

The synthesis of barbiturate 36 (see Scheme 4.7) was performed next. The sodium enolate of diethyl malonate was reacted with 43, providing 44, which was converted to 2,2-disubstituted malonate 45 by reaction with allyl bromide. Reaction of 45 with urea in the presence of t-BuOK as base afforded the barbiturate 46, which was submitted to oxidative one-carbon demolition by the action of KMn04 to give carboxylic acid 47. Compound 47 was esterified with ethanol to give the target 36, but unfortunately in modest yields. 

Dieckmann cyclization of, 835 Diethyl malonate acidity of, 842 barbiturates from, 845-846 enolate... 

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