Uracils, 1-alkylation

Like pyridones, oxy-diazines are readily deprotonated under mild conditions, to give ambident anions which can be alkylated conveniently by phase-transfer methods, alkylation usually occurring at nitrogen. " M-Arylations of uracils also proceed in this way with, for example, l-fluoro-4-nitrobenzene."" 3-Pyridazinones alkylate cleanly on N-2 under phase-transfer conditions," but the regiochemistry of uracil alkylation is sometimes difficult to control (see also below). Uracils are sufficiently acidic to take part in Mitsunobu reactions." ... 

For unsubstitUted or lower alkylated dioxotriazines, it is advantageous to cyclize semicarbazones by sodium ethylate in ethylene glycol as described by Chang and XJlbricht. In this reaction 6-aza-uracil is obtained in 66% yield. The procedure was used for the preparation of labeled 6-azauracil ° and later for the synthesis of a number of 6-alkyl derivatives including 6-azathymine. °... 

Azauracil and its alkyl derivatives are readily reducible by polarography, in contrast with uracil. This makes it possible to exploit the method analytically. More detailed studies of the polaro-graphic behavior of these substances are in good agreement with the results of spectral studies about the tautomeric form and type of dissociation. ... 

Azauridine was also synthesized using the knowledge of the course of alkylation of 6-azauracil 2-methylmercapto derivatives (e.g., Section II,B,4,b). The 1-ribofuranosyl derivative obtained by reaction of the mercury salt of the 2-methylmercapto derivative with tri-O-benzoyl-jS-D-ribofuranosyl chloride on removal of the methyl-mercapto and then benzoyl groups yielded crystalline 6-azauridine, The main difference between uracil and 6-azauracil nucleosides consists in the preparation of cyclic nucleosides. It is known that uridine can be readily converted to cyclic nucleosides by the reaction of 2 (50-O-mesyl derivatives with nucleophilic agents, Analogous... 

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

The aerobic degradation of several azaarenes involves reduction of the rings at some stage, and are discussed in Chapter 10, Part 1. Illustrative examples include the degradation of pyridines (3-alkyl-pyridine, pyridoxal) and pyrimidines (catalyzed by dihydropyrimidine dehydrogenases). Reductions are involved in both the aerobic and the anaerobic degradation of uracil and orotic acid. 

In the early days of meteorite analysis, it was difficult to detect N-heterocycles later, the Murchison meteorite was shown to contain xanthine, hypoxanthine, guanine, adenine and uracil (about 1.3 ppm in total). This meteorite seems to contain various classes of basic and neutral N-heterocycles, as well as isomeric alkyl derivatives. 

Finally, the most complex synthetic reaction clearly catalysed by RNA molecules generated by in vitro selection is the formation of the C-N bond of a nucleoside (Scheme 7), from 4-thiouracil and most of the natural substrate for the natural (uracil phos-phoribotransferase) reaction.1461. (Thiouracil was used because it is easily tagged by alkylation on sulfur.) The catalytic RNAs produced by 11 rounds of selection required Mg++ cations and had kcat as high as 0.13 min-1,with kcaJKM at least 107 times greater than the (undetectable) uncatalyzed reaction. Once again these systems are convincing, rather efficient enzyme mimics. 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Deprotonation provides the necessary electron push to kick out the electron pair joining C(6) with the nitrobenzene oxygen. If, however, N(l) is alkylated (as with the nucleosides and nucleotides), OH catalysis is much less efficient since it now proceeds by deprotonation from N(3) (with the uracils) or from the amino group at C(4) (with the cytosines). In these cases the area of deprotonation is separated from the reaction site by a (hydroxy)methylene group which means that the increase in electron density that results from deprotonation at N(3) is transferable to the reaction site only through the carbon skeleton (inductive effect), which is of course inefficient as compared to the electron-pair donation from N(l) (mesomeric effect) [26]. Reaction 15 is a 1 1 model for the catalytic effect of OH on the heterolysis of peroxyl radicals from pyrimidine-6-yl radicals (see Sect. 2.4). 

CASRN 314-40-9 molecular formula C9Hi3BrN202 FW 261.12 Soil Metabolites tentatively identified in soil were 5-bromo-3-(3-hydroxy-l-methylpropyl)-6-methyluracil, 5-bromo-3-5ec-butyl-6-hydroxymethyluracil, 5-bromo-3-(2-hydroxy-l-methylprop-yl)-6-methyluracil, and carbon dioxide. The presence of uracil products suggests that bromacil was degraded via hydroxylation of the side chain alkyl groups. In the laboratory, 25.3% of C-bromacil degraded in soil to carbon dioxide after 9 wk but mineralization in the field was not observed. The half-life of bromacil in a silt loam was 5-6 months (Gardiner et al, 1969). 

Thymine derivatives - 5-[7V-(2-Amino-4-hydroxy-6-methyl-5-pyrimidinyl-propyl)-p-carboxyanilinomethyl] uracil (XXXIII) was synthesized for study as a possible intermediate in the enzymatic synthesis of thymidylate. It is active as an enzyme inhibitor against thymidylate synthetase isolated from E. coli [298]. Certain thymine derivatives containing a 2-thioimidazole moiety (XXXIV, R = alkyl) inhibit growth of Ehrlich ascites carcinoma (fluid form) in mice [299]. 

Uracil and thymine are both reported to have electroshock anticonvulsant activity [371]. A series of 5- and 6-alkyl derivatives was prepared [373] and tested for electroshock as well as for metrazole protection [374]. It was found that most compounds of this type were active in the electroshock test. There is a trend toward increased activity with increased size of the alkyl groups, and introduction of 1,3-dimethyl substituents is also of benefit. Against metrazole-induced shock, however, there are no obvious structure-activity relationships. 

Pharmacological actions - 5-Alkyl derivatives of (LXVI) are also cited as having diuretic activity [431]. Certain 1,3-dimethyl-6-alkylaminouracils are reported to have diuretic activity similar to that of theophylline [432]. 1,3-Dimethyl-5-ethyl-6-(methylamino)uracil (LXVII) was found to be among the most active of the compounds tested. Diuretic and hypotensive activity are also claimed with anils of 5-amino derivatives, such as (LXVIII) [433]. 

Cyanoethyl derivatives of 1-alkyl and 1,3-dialkyl-6-amino uracils (LXX) are reported to have activity as anti-ulcer agents. Inhibition of appetite and hypo-cholesterolemic activity are also claimed [437]. 

At a dose of 200 mg/kg, 5-bromo-5,6-dihydrothymine (LXXXVI) retards the tumour growth of Crocker sarcoma [658]. 5-Fluorodihydrouracils (LXXXVII X = F, R = H, alkyl) are useful as germicides [659]. 5-Thiocyanato-5,6-dihydro-uracil (LXXXVII X = -SCN, R = H) shows a high level of antibacterial activity [660]. 

Alkylation of pyridazinone 945 with 4-bromoacetoacelic acid 944 did not give the 2 -oxo-4 -carboxylic acid analogs, but gave 946 of type 4.1. The uracil derivatives were prepared similarly (90MI4). 

Alkylation of the uracil derivatives with the epoxide 1097 gave 1098, whose hydroxylation gave 1099, which had no significant activity against herpes simplex virus type 1 (94MI6). Uracil derivatives derived from 1068 were also prepared. 

A few 2,2,5,5-tetrasubstituted 1,4-dioxane derivatives were reported OR substituents tend to adopt, because of the anomeric effect, axial positions [94AX(C)625, 94MI1]. By contrast, fra J-2,5-di-OCOOR- and 2,5-di-CH2. COOR-l,4-dioxane derivatives (R = aryl, alkyl) (84JHC1197), 2-(T-uracil)-6-CH20H-l,4-dioxane (92MI2), and 2,5-di-0H-3,6-di-CH20H-l,3-... 

---