Barbituric acid, formation

The direct formation of dipyrimidin-5-yl sulfides occurs on treatment of appropriate 5-unsubstituted pyrimidine substrates with sulfur mono- or di-chloride. Thus, reaction of uracil (83 R = H) with sulfur monochloride in boiling formic acid gives diuracil-5-yl sulfide in good yield sulfur dichloride gives a poor yield. Simple derivatives of uracil and barbituric acid undergo similar reactions but not cytosine, isocytosine, 2,4-bismethylthiopyrimidine or pyrimidine-4,6-dione (59). The mechanism is unknown (72AJC2275). 

The rather low values for the methylene groups of barbituric acid and its 2-thio derivative indicated a particularly easy adduct formation (84) which proceeds in water in excellent yield. 

In an interesting variation on this theme, the bis acid chloride of diethylmalonate (138) is condensed with the 0-methyl ether of urea to afford the imino ether of the barbituric acid (139). Heating this ether at 200°C results in 0 to N migration of the methyl group and formation of metharbital (140). ... 

The thus-washed crude product is dissolved in a mixture of 12 parts of ethanol and 20 parts of benzene, with mild warming if necessary. 1 Part of sodium chloride and 1.5 parts of saturated aqueous sodium chloride solution are added to the obtained solution in ethanol-benzene, and whole thoroughly admixed. When the brine layer has settled. It is separated and the afore-described washing repeated. The clear solution is concentrated under reduced pressure until incipient formation of crystals and is then poured into 30 parts of benzene, whereupon a thick crystalline pulp is forthwith formed which, after being cooled to room temperature, is centrifuged off. The so-obtained 5-allyl-5-( 3-hydroxypropyl)-barbituric acid is dried at 70°C under reduced pressure and can be used for therapeutic purposes without further purification. Melting point 164 °C to 165°C. Yield 5 parts. 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

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. 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

Under analogous conditions, the 3-cyanomethylene-2-indolones 213 react with barbituric acid and its derivatives 191 with the formation of spiro-annulated pyranopyrimidines 223 (88JIC202, 90H(31)31)... 

Figure 6.7 Illustration of multipoint hydrogen bonding based self-assembly (a) hydrogen bond formation between barbituric acid functionalized gold nanoparticles and Hamilton receptor functionalized block copolymers and (b) selective deposition of nanoparticles on a microphase-separated block copolymer film. Reprinted with permission fi om Binder et al. (2005). Copyright 2005 American Chemical Society.

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)]. ... 

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... 

Friedel-Crafts reactions are almost unknown in pyridine and azine chemistry. Direct electrophilic alkylation in the pyrimidine 5-position can be carried out on pyrimidines with at least two strongly donating groups, and more readily with three such groups. Thus, a-haloketones and a-bromocarboxylic esters can be used for direct alkylation of 6-aminouracils (118), for example in the formation of (119). The 5-position can also act as the nucleophile for Michael additions (e.g. 118 — 120, where a subsequent elimination occurs) (92AHC(55)129). For similar reactions in barbituric acids see (85AHC(38)229). 

The uses of constant-current coulometry for the determination of drugs in biological fluids are few, basically due to sensitivity restriction. Monforte and Purdy [46] have reported an assay for two allylic barbituric acid derivatives, sodium seconal and sodium sandoptal, with electrogenerated bromine as the titrant and biamperometry for endpoint detection. Quantitative bromination required an excess of bromine hence back titration with standard arsenite was performed. The assay required the formation of a protein-free filtrate of serum with tungstic acid, extraction into chloroform, and sample cleanup by back extraction, followed by coulometric titration with electrogenerated bromine. The protein precipitation step resulted in losses of compound due to coprecipitation. The recoveries of sodium seconal and sodium sandoptal carried through the serum assay were approximately 81 and 88%, respectively. Samples in the concentration range 7.5-50 pg/mL serum were analyzed by this procedure. 

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). 

Barbituric acid 228 (Scheme 46) has been allylated, the methylene group between the carbonyls reacting first. Only when two substituents have been introduced at carbon, does the third one incorporate into a nitrogen atom as in the formation of 229 and 230 (88T7205). 

The complex between melamine and cyanuric acid (1 1) was reported in the literature in the late 1970s, but it was only in the early 1990s that the contributions from Whitesides and the concept of self-assembly popularized these systems [45]. Whitesides and co-workers reported the formation of tapes (Fig. 11.11), crinkled tapes and cyclic hexamers (rosettes) formed between barbituric acid and N,N -bis(p-substituted phenyl)melamine [46], In this they effectively blocked one face of melamine and, by manipulating substituents at the para position, different structures were obtained. Whiteside s putative suggestion that melamine/cyanuric acid formed an extended array (Fig. 11.12) was confirmed recently by Rao et al. with the crystal structure [47]. Hamilton and coworkers reported the crystal structure of a 5-substituted isophthalic acid derivative, which forms a cyclic aggregate held together with six pairs of hydrogen bonds, which in a way resembles the trimesic acid (Fig. 11.13) [48]. 

As in the case of electrochemical reduction, the photochemical transformation of 5-fluorouracil derivatives differs from that of the other 5-halogeno uracils. The primary photoproduct of 5-fluorouracil, its glycosides and poly(5-FU) is the photohydrate. However, at shorter wavelengths of irradiation, e.g. 254 nm where the photohydrate exhibits absorption, there is elimination of HF from the 5,6 bond and formation of barbituric acid 129 13I>. There is also some evidence for acetone photosensitized formation of cyclobutane dimers of 5-fluorouracil132), as well as dimer formation in irradiated poly(5-FU)133>. 

---