A systematic study of the factors influencing and products yielded from purine and pyrimidine alkylation reactions.

Purine and pyrimidine adducts offer great potential for use in the pharmaceutical industry as either agents and/or polymeric materials. While the preferable synthetic route to N-substituted nucleic acid bases is direct alkylation, numerous ambiguities and/or misinterpretations of the site of alkylation under certain conditions have been reported, raising questions regarding the reliability of this method. Thus, systematic studies on the alkylation patterns of purines and pyrimidines were performed. It was determined that inherent tautomeric stability, steric hinderance, solvent polarity, and nature and quantity of base are all influential in adenine alkylation, yielding N9-substituted adenine as the major product under basic conditions. The minor product N3-substituted adenine was also observed. Reactions performed at higher temperatures and under neutral conditions resulted in the opposite trend, yielding the N3-substituted moiety as the major product and the N9-substituted moiety the minor product. Characteristic 1H-NMR peaks for both the N9 and N3 products were identified. Cytosine alkylation consistently resulted in the N1-alkylated products, without the need for protection of the amino group. Reactions proceeded well in aqueous solvents due to the enhanced stability of the N1H amino-oxo tautomer of cytosine under these conditions. Employment of these observations enabled the design of a benign, atom-economical synthesis of 1-(4-vinylbenzyl)cytosine that greatly improves upon previously published syntheses of this moiety. Alkylation reactions of thymine and uracil consistently yielded both mono- and di-alkylated products. The similar solubilities of these products often require painstaking separation techniques. However, it was found that conversion of the crude product mixture of hydroxyethyl-substituted pyrimidines to the respective chloro moieties gave a mixture of products having sufficiently different solubilites such that the mono-substituted moiety could easily be obtained without intermediate isolation. Solubility differences also allowed for simple isolation of the versatile monomers 1-(4-vinylbenzyl)thymine (VBT) and 1-(4-vinylbenzyl)uracil. These monomers were incorporated into amphiphilic block copolymers, which were subsequently used to form core-bound micellar aggregates. These micelles demonstrated enhanced stability due to both the hydrogen bonding and crosslinking capabilities of the thymine residues.