8-Azapurine methylation

Covalent hydration has been demonstrated in the following families of compounds 1,6-naphthyridines, quinazolines, quinazoline. 3-oxides, four families of l,3,x-triazanapththalenes, both l,4,x-triazanaphthalenes, pteridines and some other tetraazanaphthalenes, and 8-azapurines these compounds are discussed in that order. In general, for any particular compound (e.g. 6-hydroxypteridine) the highest ratio of the hydrated to the anhydrous species follows the order cation > neutral species > anion. In some cases, however, anion formation is possible only when the species are hydrated, e.g. pteridine cf. 21 and N-methyl-hydroxypteridines (Section III, E, 1, d). Table V in ref. 10 should be consulted for the extent of hydration in the substances discussed here. 

Hydroxy-8-azapurine was shown by rapid-reaction techniques (see Section II, E) to be anhydrous in the anion and hydrated in the neutral species. The hydration reaction has a half-time of about 0.5 second, which is too rapid for exact measurements with existing apparatus. The cation of 2-amino-8-azapurine was shown to have an anomalous value and ultraviolet spectrum, although its 6-methyl derivative is quite normal. Hydration in this case proved to be too fast to register in the rapid-reaction apparatus. 

A -Triazolines (350) are easily converted into the corresponding 8-azapurines (351) on treatment with ethyl formate and sodium ethoxide (Equation (31)) <88S879>. When 5-amido-A -l,2,3-triazoline (352) is treated with trifluoroacetic acid, the 2-methyl-1,2,3-triazole (353) is afforded (Scheme 67) <91JCS(P1)3361>. 

Equilibrium ratios for the hydrated-anhydrous cationic species of 8-azapurine (6) and its 2-methyl and 2-amino derivatives were similarly determined, and also for the neutral species of 2-amino-8-azapurine and 8-azapurin-2-one, the latter being substantially hydrated as the neutral... 

To summarize the cations of 8-azapurine and its 7- and 8-methyl derivatives are almost completely hydrated at equilibrium, whereas that of the 9-methyl isomer shows little evidence of hydration. None of the corresponding neutral species is appreciably hydrated.13... 

First-order rate constants for hydration and dehydration at 20° were obtained11 for 8-azapurine and its 2-methyl-, 2-amino-, and 2-oxo-derivatives in the pH range 2-7. Strong acceleration of hydration was observed in the cation. 

Azapurines are important compounds, if only because of the involvement of some of them in cancer chemotherapy. From the viewpoint of this review they present, moreover, the interesting possibility of another tautomeric form with the proton fixed at N-8 of the pentagonal ring. Very recent experimental isolation of the N-methylated derivatives of the three tautomeric forms, N(7)H,... 

Methylation of 8-azapurine 42 with dimethyl sulfate in aqueous alkali provided 7-, 8-, and 9-methyl-8-azapurine 43 in approximately equal amounts [69JCS(C)1084] (Scheme 8). 

Methylation of 7-amino-l,2,3-triazolo[4,5-d]pyrimidine (8-azaadenine) (140) with dimethyl sulfate afforded the N-3 and N-9 methylated isomers 141 and 142, respectively, which upon further methylation with methyl iodide or benzenesulfonic acid methyl ester gave 3,7- and l,9-dimethyl-8-azaadeninium salts 144 and 145, respectively. Thermal decomposition of the dimethyl derivatives led to a transmethylation to give 6-methylamino-9-methyl-8-azapurine (143), whose methylation afforded 1- and 7-methyl-6-methylamino-9-methyl-8-azapurinium salts 146 and 147 (80ZOR2204) (Scheme 28). 

Penta-azaindenes (8-Azapurines). Part III. A New Route to the 7-Methyl-8-azapurines. 

C-Hydroxy-8-azapurines do not exist as such but as equilibrium mixtures (e.g., 8 9) in which the cyclic amide tautomers greatly preponderate over the hydroxy tautomer. This behavior parallels what was found in the pyridine, pyrimidine, and purine series on evidence from ionization constants and the UV spectra of C- and A -methyl derivatives. A formal name for9 is 1,6-dihydro-8-azapurin-6-one but such specification of the hydrogen atom s position is, in the absence of data, risky for example, pyrimidin-4-one is an equilibrium mixture in which tautomers with mobile hydrogen on N-3 and N-1 preponderate in a 5 2 ratio, respectively. Hence the simpler names, such as 8-azapurin-6-one, will be used in this review. 

Primary amines in the 8-azapurine series present no evidence of any measurable proportion of imino-tautomer at equilibrium. An interesting variant is 6-amino-3-methyl-8-azapurine (10), which, like 6-amino-3-meth-ylpurine, ° is a much weaker acid than the unmethylated analog. 

Azapurin-2,6-dione (azaxanthine) (monohydrate) carries protons on N-8, N-3, and N-1, and 3-methyl-8-azaguanine hydrobromide (monohydrate) on N-8 and N-1. ... 

Ultraviolet and H-NMR measurements supported these assignments. The UV absorption of 6- and 9-methyl-8-azapurine cations (which do not undergo detectable hydration) give the same values in anhydrous trifluoro-acetic acid as they do in dilute hydrochloric acid. By contrast, the cations of 8-azapurine and its 1-, 2-, 7-, and 8-methyl derivatives have different UV spectra in these two solvents (a large shift of to shorter wavelengths occurs in the presence of water ). This shift indicated conversion of a double bond to a single bond by hydration. Similarly the H-NMR spectrum of the anhydrous cation showed peaks at S 9.60 and 10.69 (for H-6 and H-2, respectively), whereas corresponding peaks for the hydrated cation (in DjO, DCl) were at d 6.81 and 8.54, respectively. ... 

When the formation of the cation of 8-azapurine was observed (by UV) in a rapid-reaction apparatus, using solutions of increasing acidity, this cation was found to add water too fast for measurement. The more tractable 2-methyl-8-azapurine gave (by the same technique) a pAT, of 1.08, which, being the equilibrium between two totally anhydrous species, is termed the true anhydrous value and forms a contrast with the equilibrium pAT, of 3.00 obtained in a 20-min potentiometric titration. It was calculated from these results that the pAT, of anhydrous 8-azapurine is approximately zero. 

The rapid-reaction method was used in reverse to obtain the true pK, of hydrated 7-methyl-8-azapurine, which was 4.05 (cf. 1.92 for the value obtained by slow potentiometry). By contrast, the change from equilibrium titration to rapid-reaction technique raised the pAT, of 8-methyl-8-azapurine much less (from 3.18 to 4.2), which signifies much greater hydration (about 10%) in the neutral species. All of these hydrations were found to be first-order reactions, with 0.5 varying from < 1 to 150 sec. 

Prevention of hydration by the presence of a methyl group in the 6 position has been traced to a combination of both steric and electronic factors most other substituents in the 6 position diminish hydration. It is not known why a methyl group in the 9 position of 8-azapurine decreases hydration. Substituents in the 2 position of 8-azapurines favor 1,6 hydration if they are mesomeric donors (-1- M) e.g., NHj or O those that are inductive acceptors (—1) (e.g., SMe) oppose hydration by lowering the polarization of the 1,6 bond ° (cf. the similar responses of the 2 position in quinazolines ). The hydration of 8-azapurin-2-one stands apart from the above examples by being manifested mainly in the neutral species the hydration of 8-azapu-rine-2-thione is barely detectable. 

Some representative p/iT, values are presented in Table I. Other pA, values will be found in the references of that table " and also in refs. 52-55. It can be seen from Table I that N-methylation of azapurin-6-one increases the acidic strength of the CONH ionization by eliminating the coulombic effect of the first ionization. 

Other points of interest, illustrated in Table III, are the hydration of the cation of 2-amino-8-azapurine and the spectra of some 1,6- hydro-azapu-rines. The spectra of substituted l,6-dihydro-6-imino-l-methyl-8-azapu-rines (15) are similar to those of the isomeric 6-methylamino-8-azapurines to which they are readily converted, but only the latter show coupling (5 Hz) between protons of HNCH3... 

The parent substance, 8-azapurine, was first prepared in 1957, but its alkylation was not studied until 1969. Dimethyl sulfate in cold, aqueous sodium hydroxide (the pH held above 7) gave equal proportions of the 7-, 8-, and 9-methyl derivatives. These were separated by taking advantage of the lower basic strength of the 9 isomer (Table I), then proceeding by thin-layer chromatography. ... 

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