6- Azauracil alkyl derivatives

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. ... 

During methylation of 6-azauracil with a theoretical amount of diazomcthane, the 3-methyl derivative (63) was obtained in very good yield. Excess reagent produces the dimethyl derivative (64). During none of the alkylation reactions was it possible to observe the formation of 0-alkyl derivatives of 6-azauracil. This can be taken as evidence that 6-azauracil does not react in the lactim form (e.g., Section II,B, b). 

The preparation of W-alkyl derivatives of 6-benzyl-3,5-dioxo-l,2,4-triazine by hydrolysis of the corresponding alkylmercapto derivatives was systematically studied by Cattelain. The conversion to known alkyl derivatives of dioxotriazines was used to determine the structure of alkylated methylmercapto derivatives. As will be shown later (e.g., Section H,B,4,b) this procedure has a general preparative significance for 1-alkyl derivatives of 6-azauracil. ... 

In agreement with the results of Cattelain, further methylation of the 3-methylmercapto derivative (96) results practically exclusively in 2-methyl-3-methylmercapto-5-oxo-2,5-dihydro-l,2,4-triazine (97). Further methylation of 5-methylmercapto derivative (90) yields 2-methyl-5-methylmercapto-3-oxo-2,3-dihydro-l,2,4-triazine (100). Their structure was confirmed by acid hydrolysis leading to 2-methyl-3,5-dioxo derivatives (62), As was already mentioned, this reaction is a suitable general procedure for preparing the 1-alkyl derivatives of 6-azauracil. ... 

As mentioned in chapter 4.2.3, aliphatic imines are photochemically rather unreactive. When the C—N double bond is conjugated to an electron withdrawing group (e.g. carbonyl group), as in O-alkyl derivatives of succinimide and phthalimide, the reactivity increases and azetidines are obtained in cycloadditions to olefins486). A somehow similar example is the photoaddition of a 6-azauracil derivative to 2,3-dimethyl-2-butene... 

Indeed, N-alkylation of l,2,4-triazin-3,5-diones has been considered as a synthetic approach to A -alkyl derivatives of azauracils, as antagonists of hormone receptors (Scheme 113) <2005BML4363>. 

A detailed investigation of the tautomeric structure of 6-azauracil was carried out by Jona and Gut and by Horak and Gut. They measured the UV and IR spectra and compared similar systems and their derivatives in which the lactam or lactim configuration was fixed by A - or 0-substitution (as will be seen later no 0-alkyl deriva-... 

The alkylation of 6-azauracil will be treated later. The first, but not exactly identified dimethyl derivative was prepared by Grundmann." The course of alkylation was studied in greater detail by Gut et al. These authors found that in aqueous alkaline solution and on using alkyl halides or dialkyl sulfates, the main alkylation product is the 1,3-dialkyl derivative (64). Since, however, the alkylation is to some... 

The course of alkylations of 6-azauracil is in good agreement with the results of determination of the dissociation constants of 6-azauracil and of its two monomethyl derivatives. On the assumption that a methyl group does not much affect the dissociation constant, and on the basis of the lactam structure, it may be concluded from the values of the dissociation constants iKa of 6-azauracil = 7.00, of l-methyl-6-azauracil = 6.99, and of 3-methyl-6-azauracil = 9.52) that dissociation takes first place at the NH group in position 3. The same results are obtained independently by comparing the pH dependence of the XJV spectra of these compounds. These results represent an exact confirmation of the older observation by Cattelain that the monoalkyl derivatives of 6-substituted dioxotriazines possess different acidity. 

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... 

The numerous 6-substituted 3-thioxo-5-oxo derivatives prepared by earlier authors are reviewed by Erickson et ak Subsequently a number of alkyl, and further 4-acetaminophenyl, 2-thienyl, 4-pyridyl," 4-antipyryl, " and 2-aminoethyP derivatives were prepared plus some others mentioned in the section on the synthesis of 6-azauracil. 

Alkylation reactions were recently performed with all the thio derivatives of 6-azauracil and 6-azathymine. In agreement with previous findings, the methylmercapto derivatives were obtained by alkylation of all these substances in alkaline solution. Thus, e.g., 3-ihethylmercapto-6-oxo-2,5-dihydro-l,2,4-triazine (96), 5-methylmer-capto-3-oxo-2,3-dihydro-l,2,4-triazine (90), and 3,5-dimethylmer-capto-l,2,4-triazme (91) were obtained. The last-named of these was... 

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