REACTIVITIES AND ELECTRONIC ASPECTS OF NUCLEIC-ACID HETEROCYCLES .8. REGIOSELECTIVE RADICAL METHYLATION OF CARBON-2 AND CARBON-8 OF 6-AND 3,6-SUBSTITUTED PURINES

The pseudo-first-order rate constants for the reaction of the 2 and 8 positions of 6- and 3, 6-substituted purines in acidic and neutral media with methyl radical produced by the photolysis of tert-butyl peracetate were determined. Under acid conditions, hypoxanthine (1), 6-methoxypurine (3), and 6-methylthiopurine (5) yielded the corresponding 8-methylpurine predominantly. Conversely, 3-methylhypoxanthine (2), 6-methoxy-3-methylpurine (4), and 3-methyl-6-methylthiopurine (6) were methylated mainly at the 2 position. This regioselectivity was correlated with the site of cation formation via 1H NMR analysis of the aromatic protons in acidic and neutral media. Methylation was found to occur fastest on the carbon atom whose proton resonated at lowest field in the acid spectrum. This has led to the reassignments of the literature values for the H-8 resonance of the cations of 3 and 5. These competitive 2- vs. 8-methylations are depicted in Scheme II as a substitution occurring on the major cationic forms. In neutral solution, the previous preference for the 2 position of 3, 6-substituted purines was reversed, favoring 8-methylation instead. On the other hand, the methyl radical specificity for carbon-8 of the 6-substituted purines declined drastically, resulting in both the 2- and 8-methylation products although the latter was still the major isomer. Such regioselectivity displayed by the methylation reaction of two series of purine compounds in neutral media is compatible with an SEAr mechanism involving a radical μ complex as shown in Scheme III. © 1979, American Chemical Society. All rights reserved.