Uracil 6-azauracil

Price, S. L. and Wiley K. S. (1997). Predictions of crystal packings for uracil, 6-azauracil and allopurinol the interplay between hydrogen bonding and close packing. J. Phys. Chem. A, 101, 2198-206. [184]... 

The names of these compounds as aza analogs were coined in the same way as those of the 6-aza analogs employing the frequently used numbering of uracil (1). This nomenclature is most often used for the principal aza analogs of pyrimidine bases (e.g., 5-azauracil) it is rarely used for further systematic derivatives. 

A determination of the dissociation constants of the compounds reveals that 5-azauracil (pi a = 6.73) is practically of the same acidity as 6-azauracil and considerably more acidic than uracil, A fundamental difference between 5-azauracil, on the one hand, and 6-azauracil and uracil, on the other, lies in the low stability of 5-azauracil toward acid and especially to alkaline hydrolysis. This fact appears to be in agreement with the differences in electron densities of these substances computed by the simple MO-LCAO method. ... 

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. °... 

Salts of 6-azauracil were studied in greater detail and their individual composition established. 6-Azauracil, in common with uracil, is very resistant both toward acid and toward alkaline hydrolysis. 

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. ... 

It should be mentioned that a similar comparison of the dissociation constant values of uracil monoalkyl derivatives does not permit the determination of the sequence of dissociation on account of the small differences between the pEo values. However, the pH dependence of the XJV spectra showed that the first dissociation of uracil occurs at the NH group in position 1 and thus differently than in 6-azauracil. This, together with different acidity, represents the main differences between the properties of uracil and its 6-aza analogs. 

Acetylation of 6-azauracil thus proceeds in the same way as the acetylation of uracil and the properties of the acetyl derivatives are also roughly identical. 

By comparing the dissociation constant of 6-azauracil and 6-aza-uridine with those or uracil and uridine, 6-azauridine is now considered to be 1-ribofuranosyl derivative (2-ribofuranosyl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine), The same was shown more exactly by comparing the UV and IR spectra and the dissociation constants of 6-azauridine with the two monomethyl derivatives of 6-aza-uracil," Enzymatic synthesis thus, proceeds, in the same way in natural bases and in their aza analogs. 

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... 

Direct bromination readily yields the 6-bromo derivative (111), just as with uracil. Analogous chlorination and iodination requires the presence of alkalies and even then proceeds in low yield. The 6-chloro derivative (113) was also obtained by partial hydrolysis of the postulated 3,5,6-trichloro-l,2,4-triazine (e.g.. Section II,B,6). The 6-bromo derivative (5-bromo-6-azauracil) served as the starting substance for several other derivatives. It was converted to the amino derivative (114) by ammonium acetate which, by means of sodium nitrite in hydrochloric acid, yielded a mixture of 6-chloro and 6-hydroxy derivatives. A modified Schiemann reaction was not suitable for preparing the 6-fluoro derivative. The 6-hydroxy derivative (115) (an isomer of cyanuric acid and the most acidic substance of this group, pKa — 2.95) was more conveniently prepared by alkaline hydrolysis of the 6-amino derivative. Further the bromo derivative was reacted with ethanolamine to prepare the 6-(2-hydroxyethyl) derivative however, this could not be converted to the corresponding 2-chloroethyl derivative. Similarly, the dimethylamino, morpholino, and hydrazino derivatives were prepared from the 6-bromo com-pound. ... 

It may be said in conclusion that the reactivity of position 5 (i.e., 6 of the triazine ring) is similar to that of uracil. The only difference seems to be in the failure to prepare 5-nitro-6-azauracil although this reaction proceeds readily with uracil. 

On reaction with aged phosphoroxychloride, 6-azauracil formed 3,5-dichlorotriazine (117) in only a 10% yield. " A somewhat higher yield (30%) was obtained from the reaction of 6-bromodioxotriazine which gave 3,5,6-trichloro-l,2,4-triazine. Similar reactions take place much more readily with uracil and in better yield. " Thus,... 

Because activated 4-0-trimethylsilylated-2, 3, 5 -0-acyluridines such as 3 are also obtained as reactive intermediates in the Friedel-Crafts-catalyzed silyl-Hilbert-Johnson reaction [59, 59 a] of persilylated uracils or 6-azauracils such as 227 with sugars such as l-0-acetyl-2,3,5-tri-0-benzoyl-/9-D-ribofuranose 228 in the presence of SnCl4, treatment of the reactive intermediate 229 with a large excess of pyrrolidine neutralizes the SnCLi. used and aminates 229 to afford the protected 6-aza-cytidine 230, although in 57% yield only [49, 59] (Scheme 4.20). 

The deoxy analogs of 2.1 were prepared by coupling l-benzyloxy-2-chloromethoxypropane with silylated thymine, 6-azathymine, uracil, and 6-azauracil to give the anticipated nucleosides 1194 in addition to minor quantities of benzyloxymethylated produce 1195 of type 5.1 (94MI15). None of the deprotected nucleosides exhibited significant activity against HIV. 

Azauracil [1,2,4-triazine-3,5(2,4)-dione] inhibits the growth of various micro-organisms. When grown in the presence of 6-azauracil- -C, Streptococcus jaecalis accumulates radioactive metabolites in the acid-soluble fraction of the cells. A major metabolite is D-ribofuranosyl-6-aza-uracil. This material is identical with material prepared by condensing tri-O-benzoyl-D-ribofuranosyl chloride with the mercuric derivative of 6-azauracil, followed by debenzoylation. A second major metaboUte was tentatively shown to be D-ribosyl-6-azauracil 5-phosphate. Bacteria develop resistance against 6-azauracil and its D-ribosyl derivative. Resistant Streptococcus faecalis will not convert 6-azauracil to its D-ribosyl derivative or to other bound forms, and the bacterium has also lost the ability to incorporate uracil into the nucleic acids of its cells. 

Dihalogenmaleinimides (DBMI) have been found to be powerful photo-cyclophiles toward uracils [80AG1066, 80AG(E)1026, 80CB(92)1066], including 6-azauracils (Scheme 31). 

A few attempts have been made to observe the n tt transitions in uracils. No Cotton effect derived from an n tt transition is observed in the CD spectrum of uridine. Such transitions are observed in some 6-azauracil nucleosides, but they are located at the long-wavelength side of the first band (Ban). On the other hand, Eaton and... 

Photoaddition of alkenes to the azathymine (227) affords the adducts (228) the structures of which were determined by -ray crystallography. Acetone-sensitized irradiation of the azauracil derivative (229) yields the cyclobutane (230). Irradiation of the uracil (231) in isotropic solvents is known to yield all four (2-1 2)-dimers in low yield especially at low concentrations. A study has shown that dimerization in smectic media affords a high yield (94X) of the trans-anti dimer (232). In frozen solutions the specificity is reversed and the CIS-anti dimer (233) is formed. The influence of a variety of media on this process was studied in detail. A theoretical treatment of the photochemical addition of alkenes to psoralens such as (234) has been published. ... 

A determination of ihe dissociation constants of the compounds reveals that 5-azauracil (pifa = 6.73) is practically of the same acidity as 6-azauracil and considerably more acidic than uracil. 

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