Z. Neiman

Studies on the chemical reactivity and the physical properties of allopurinol (pyrazolo[3,4-d]pyrimidin-4-one) and related compounds

Pyrazolo [3,4-d]pyrimidines resemble purines by avoiding disubstitution at the peri-positions 1 and 7, but they also resist 1,2-disubstitution in the pyrazole ring. INDO calculations show that 1,2-disubstituted derivatives of allopurinol are the least stable.The anion of allopurinol is present as a mixture of tautomeric forms and yields upon methylation 1,5-, 2,5-, and 2,7-dimethyl derivatives. Alkylation of 4-methylthiopyrazolo[3,4-d]pyrimidine, either as the neutral molecule or as the anion, offers a convenient approach to the synthesis of many mono- and di-methyl derivatives, which serve as precursors for methylated allopurinols.

A nuclear magnetic resonance study of hindered rotation in 8-phenylpurines

Abstract In the PMR spectrum of 8-phenylpurines, the multiplet of the o-protons appears downfield of the multiplet, characteristic for m,p-protons. The separation of the centres of these two signals (Δ-value) diminishes with increasing steric interference between the phenyl ring and substituents in the imidazole moiety. The contribution of the purine ring current to the chemical shifts of the aromatic protons was calculated according to the theory of Johnson and Bovey, and the torsion angles θ between the phenyl ring and the plane of the purine system were derived. For 8-phenylpurines with an NH-group in the imidazole ring, θ is 10–15°; for compounds with an N-methyl group in this ring, θ ≈ 35–45°; in 3,9-dimethyl derivatives, Δ becomes zero, while θ is about 50°.

Oxidation of 7-azapteridines by mammalian xanthine oxidase

Abstract 4-Hydroxy-7-azapteridine undergoes a two-step oxidation by mammalian xanthine oxidase (xanthine: O2 oxidoreductase, EC 1.2.3.2). It is first attacked at position 2, at a rate 6 times faster than the oxidation of xanthine. The 2,4-dihydroxy-7-azapteridine, formed in the first step, is slowly converted to the 2,4,6-trihydroxyderivative. The successful attack at C-6 sharply contrasts with the refractoriness of this position in pteridines to enzymic oxidation. Molecular orbital calculations show that C-6 in 2,4-dihydroxy-pteridine carries a smaller positive charge and exhibits a lower superdelocalizability for nucleophilic attack than the corresponding position in the 7-aza analog.

Tautomerism and ionization processes in 6-thioxanthine and its N-methyl derivatives

U.v. and n.m.r. spectra have been measured for 6-thioxanthine and all its N-methyl derivatives. In aqueous solutions of 6-thioxanthines with a free NH-group in the imidazole ring, the 7-NH-tautomer is predominant, while the monoanion of 6-thioxanthine and its 1-methyl derivative are mainly present as the 9-NH-tautomers. Whenever possible, anion formation occurs first by dissociation of the 3-NH-group; the order of acidities is 3 > 7 > 1. The anions of 6-thioxanthine and its 1-methyl derivative tautomerize to the 9-NH form.Steric interactions between substituents (H and Me) at positions 3 and 9 are evident in the pK values of the 9-methyl-6-thioxanthines and in the large displacement to lower field of the n.m.r. signals of the 3- and 9-methyl groups in 3,9-dimethyl derivatives.

Tautomerism, protonation, and methylation in methylthiopurines; factors determining electrophilic attack on purines

The predominant tautomeric forms, the position of protonation in aqueous solution, and the course of methylation in aprotic solvents have been determined for all possible mono- and bis-methylthiopurines and for 2,6,8-trismethyl-thiopurine. As a rule, protonation creates resonating cations in which the charge is distributed over both rings. The site of methylation varies. Like purine itself, the 8-methylthio- and the 2,8-bismethylthio-derivatives are attacked by methyl iodide at N-1. In 6-methylthio-, 6,8-bismethylthio- and 2,6,8-trismethylthiopurine, N-3 undergoes alkylation. In 2-methylthio- and in 2,6-bismethylthio-purine, methylation takes place at both positions 7 and 9. These results are explained in terms of the combined influence of electronic and steric factors.

Tautomerism and ionisation processes in 6-methylthio-2-oxopurines

6-Methylthio-2-oxopurine (1) is present in aqueous solution mainly as the 3,7-di-NH tautomer. This supports the general assumption that purines avoid 3,9-disubstituted structures. Anion formation in structure (1) takes place first at the 7- and then at the 3-position. Cations bearing a 1-methyl group are unstable, undergoing hydrolysis, even at pH 4·5, to the corresponding xanthines. In the n.m.r. spectra of the 1-methyl derivatives of (1). steric interference causes a marked downfield shift of the 6-SMe signal.

Tautomerism and ionisation of purin-8-one and its N-methyl derivatives

U.v. and n.m.r. spectra show that in aqueous solutions purin-8-one is present predominantly as the 7H,9H-tautomer. Anion formation takes place preferentially at N-9. Protonation of purin-8-one and its 7- and 9-methyl derivatives occurs at N-1 and causes splitting of the 6-H and 2-H n.m.r. signals. In purin-8-one and its N-methyl derivatives, the 2-H is more deshielded than the 6-H; the reverse is the case for purine itself.