6-Azauracils

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. 

According to the triazine nomenclature, 5-azauracil is 2,4-dioxo-l,2,3,4-tetrahydro-l,3,5-triazine (2). The subject index of Chemical Abstracts prefers s-triazine-2,4(lH,3H)-dione. Furthermore, some authors use a name derived from the lactim structure, 2,4-dihydroxy-s-triazine (3). The numbering of the substituents is the same for all these types of nomenclature. 

The common method of preparation of 6-alkyl-2,4-dioxotetrahydro-triazines is the cyclization of acyl-biurets by aqueous hydroxide. Formyl biuret which should by analogy 3deld 5-azauracil had not been known until recently. Its transient formation can be expected during further synthesis of 5-azauracil. Piskala and GuP achieved... 

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. ... 

By a more detailed study of the reaction of 5-azauracil with diazo-methane it was found that this reaction is considerably accelerated by the presence of a small amount of water, methanol, or dimethyl-formamide. It does not proceed appreciably in absolute ether. By... 

Works on the oxidation of uric acid has unequivocally established the triazine structure > ° (9) of oxonic acid. This is further confirmed by the straightforward synthesis described by Piskala and Gut. ° The reaction of biuret (11) with potassium ethyloxalate yielded a potassium salt (24), that with ethyl oxamate, the amide of oxonic acid (25). Both these compounds were converted to 5-azauracil. An analogous reaction with diethyloxalate which should produce an ester of oxonic acid resulted in a mixture of urethane and parabanic acid, however. 

Other derivatives of s-triazine, in particular the 2,4-disubstituted ones, are usually prepared by total synthesis and are therefore not closely linked with the chemistry of 5-azauracil unlike the analogous derivatives of 1,2,4-triazine. 2,4-Dimethoxy-l,3,5-triazine was mentioned earlier (e.g., Section II,A,2,a), the other substances are not related to the present subject. 

According to systematic triazine nomenclature, 6-azauracil is 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (42). The indexes of the Chemical Abstracts describe it as as-triazine-3,5(2H,4H)-dione. In addition ... 

The chemistry of the 6-aza analogs of pyrimidine bases which has been developed from the biochemical aspect since about 1956 was based on work reported in relatively numerous older papers. In spite of the fact that 6-azauracil was prepared only in 1947 and suitable syntheses were described only quite recently, substances of this type and methods of their preparation had been known for a long time. The chemistry of 6-aza analogs of pyrimidine bases is therefore relatively closely linked with the chemistry of the 1,2,4-triazine derivatives. 

In this connection the possibility of oxidation of these substances to the tetrahydro derivatives should be mentioned. It was made use of by Thiele and Bailey for the preparation of 6-methyl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine (6-azathymine) (46) and only recently by Grundman et al. for that of 6-azauracil (42). 

With semicarbazones of lower a-keto acids the reaction proceeds with some difficulty or not at all. Thus, the semicarbazones of pyruvic acid cannot be cyclized and that of glyoxylic acid is predominantly hydrolyzed so that the yield of the cyclization product is only 20-25%. ° This reaction was used in work with a different object, for preparing 6-azauracil, for the first time. 

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. °... 

The cyclization of thiosemicarbazones has therefore recently served as the basis for further syntheses of 6-azauracil and 6-azathymine. Barlow and Welch proceeded from thiosemicarbazone of mesoxalic acid (51, 52 R = COOH). The corresponding methylmercapto derivative (53 R = COOH, R = CHs) was hydrolyzed and decarboxylated... 

In a further synthesis, Gut ° used the cyclization of the thiosemi-carbazone of glyoxylic acid (56) the 2-thioxo-5-oxo-2,3,4,6-tetra-hydro-l,2,4-triazine (57) formed was converted to 6-azauracil by applying aqueous solution of chloroacetic acid. (This reaction will be discussed later, e.g.. Section II,B,4,b.) The same procedure was used... 

Using a single-step process, 6-azauracil can be prepared from chloral 3-methylisothiosemicarbazone (59), The apparent intermedi-... 

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. 

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-... 

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. ... 

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 sodium or potassium salt of 6-azauracil in aqueous ethanol, anhydrous ethanol, or ethylene glycol reacted with methyl iodide practically exclusively to give the 3-methyl derivative (63). In toluene the sodium, potassium, and mercuric salts produced no methylated derivatives whereas the silver salt also yielded the 3-methyl derivative, Similarly, the 3-methyl derivative was prepared from the mercuric salt of 6-azathymine, and its structure was established by hydrolysis to pyruvic acid 4-methylthiosemicarbazone. ... 

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 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. 

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. 

The reaction of ethylene carbonate with acid imides which yields V-hydroxyethyl derivatives w as applied to 6-azauracil. In agreement with the foregoing findings, 6-azauracil produced a 3-(2-hydroxyethyl) derivative (65) which w as treated with thionyl chloride to convert... 

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. ... 

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. 

Some of them were obtained for the first time by an enzymatic procedure which, of course, can result only in the aza analogs of natural nucleosides, i.e., ribofuranosyl-6-azauracil (6-azauridine) (75) and 2 -deoxyribofuranosyl-6-azathymine (6-azathymidine). The first of these was prepared by Skoda et ai. and a modification of their procedure was used by Handschumacher, In this way it is possible to obtain the crystalline nucleoside on the large scale. 

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. 

Handschumacher applied a similar procedure to 6-azauracil and obtained a mixture of two monoribosyl derivatives from the mercuric salt of 6-azauracil, with the 3-substituted derivative predominating. 

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