Synthesis of 7-Acyl-2,4-disubstituted Pteridines by Radical Nucleophilic Substitution and Displacement Reactions

Abstract

2,4-Disubstituted pteridine derivatives (1-3) react with acyl radicals very selectively in position 7 by a nucleophilic Substitution mechanism (4-10). Oxidation of the 2-methylthio group proceeds with m-chloroperbenzoic acid in good yields to the corresponding 7-acyl-2-methylsulfonyl-4-aminopteridines (11-16). The methylsulfonyl group can easily been displaced by nucleophiles such as aliphatic amines (27, 29, 32-42, 45), cyclic amines (56-61), aromatic amines (30, 31) and amino acids (43-54). Oxygen nucleophiles lead to 7-acyl-isopterin derivatives (62-66). The acyl side-chain is also prone to structural modifications leading to the corresponding secondary alcohols on NaBH4 reduction (74-77) or to imino derivatives on reactions with amines (67-73) which can analogously been reduced to 2,4-disubstituted 7-( l-aminoalkyl)pteridines (80-85). An interesting H-shift was observed during heating of 32, 78 and 79 with benzylamine leading not to the benzylimines but the isomeric benzylideneamino derivatives 86-88. Various acetylations by acetic anhydride (AC2O) gave 89-93 and reduction of the pyrazine moiety to the 5,6,7,8-tetrahydro-pteridine derivatives 94-96 proceeded in the expected manner. The characterization of ther newly synthesized pteridine derivatives was performed by 1H-NMR spectra, UV-spectra and elemental analyses. Measurements of the basic pKa values of a selection of 2,4,7-trisubstituted pteridines were pteridines to characterize the dication, monocation and the neutral species by their UV-spectra.

Keywords

• pteridines
• synthesis
• displacement reaction
• nucleophilic substitution
• radical