Pyrimidines barbituric acid

Tatsumi K, Fukushima M, Shirasaka T et al. Inhibitory effects of pyrimidine, barbituric acid, and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res 1987 78 ... 

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). 

As mentioned above (Section 2.13.2.1.3), bipyrimidine photoproducts can arise, probably by reaction between two radicals. Thus, irradiation of an aqueous solution of 5-bromouracil (ill R=Br) in the absence of oxygen produces a variety of products including uracil, barbituric acid, 5-carboxyuracil (111 R = CO2H), several non-pyrimidine compounds and, as a stable end-product, the biuracil (114 R = H). A similar product (114 R = Me) is formed from 5-bromo-l,3-dimethyluracil (ilS). When two such related uracil derivatives are irradiated together, a mixed bipyrimidine product is formed, inter alia (B-76MI21302). 

Barbituric acid — see also Pyrimidine-2,4,6-trione, perhydro-acidic pK, 3, 60 bromination, 3, 70 fluorination, 3, 70 structure, 3, 68 tautomerism, 2, 27 in thermography, 1, 392 Barbituric acid, iV-alkyl-chlorination, 3, 70 Barbituric acid, 5-aminomethylene-synthesis, 3, 524 Barbituric acid, 5-arylidene-pyridopyrimidines from, 3, 227 Barbituric acid, 1,3-dicyclohexyl-synthesis, 3, 113 Barbituric acid, 2-thio-sensitizing dye... 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

Ethyl-5-phenyl-2,4,6(l//,3//,5//)-pyrimidinetrione synonym 5-ethyl-5-phenylbarbituric acid. 5-Ethyl-1-methyl-5-phenylbarbituric acid. 5-Ethyl-5-phenyldihydro-2-thioxo-4,6(lEf,5H)-pyrimidine-dione synonym 5-ethyl-5-phenyl-2-thiobarbituric acid. 5-Ethyl-5-hexyl-2-thiobarbituric acid. 5-Ethyl-5-isopentylbarbituric acid. 5-Ethyl-5-(l-methylbutyl)-2-thiobarbituric acid. 5-(l-Cyclo-hexen-l-yl)-l,5-dimethylbarbituric acid. 5-Ethyl-5-(l-methylbutyl)barbituric acid. 5-(l-Cyclohexen-l-yl)-5-ethylbarbituric acid. 

The preparation of barbiturates illustrates many of the synthetic methods covered in this chapter. The preparation employs the reaction of urea (C0(NH2)2) with malonic ester to form barbituric acid. The general reaction is presented in Figure 15-30. The stable pyrimidine and other resonance forms help drive the reaction. By alternating the substituent at carbon number five (C5), various pharmacologically active substances can be formed. Barbital, a sedative, and phenobarbital, a sleeping aid, are shown in Figure 15-31. 

Apart from tautomerism between identical structures, NMR can also be used to investigate tautomeric equilibria between states of different energy. Thus it can be shown that barbituric acid exists as a urea derivative and is only formally a pyrimidine derivative. 

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). 

Dave and Shah have reported a Gould-Jacod type reaction for the microwave-assisted synthesis of thieno[3,2-e]pyrimido[ 1,2-c]pyrimidines via intermediate thieno[2,3-d ] pyrimidines (Scheme 3.46)73. A one-pot synthesis of pyrano [2,3-d]pyrimidines was also described by Kidwai and co-workers starting from thiobarbituric acids. The thio-barbituric acid intermediates were also prepared by microwave heating, using basic alumina as the solid support (Scheme 3.46)74. 

Fig. 46. X-Ray structure (left) of the cocrystal of the 1 1 species (right) formed by two complementary components derived from barbituric acid BA (A = ethyl) and 2,4,6-triamino-pyrimidine TAP (B = butyl) [9.119].

---