Base induced alkylation of 4-methoxy-1H-pyrazolo[3,4-d]pyrimidine with iodomethane in dioxane resulted in a product with an unusual X-ray crystal structure defining a water solvated 4-methoxy-2-methyl-2H-pyrazolo[3,4-d]pyrimidine dimer complex with sodium iodide (1). This structure inspired a hypothesis that the six-membered ring nitrogen atom (N7), key to interacting with sodium in the dimer-structure, was a controlling element in the N2-alkylation regioselectivity observed for pyrazolopyrimidines in less polar solvents (see 2) as compared to polar solvents where the selectivity was reversed (see 3). Presuming a complex similar to this dimer forms with the sodium anion of the heterocycles in THF then sterics would direct alkylation to favor N2 over N1. A polar solvent would disassociate any solution dimer-complex allowing for the thermodynamically favored N1-anion to be alkylated. With pyrazolo[3,4-d]pyrimidines and related deaza-analogs N1/N2-alkylation selectivity ratios often went from 1:5 to 5:1 just by changing the solvent of the reaction from THF to DMSO. This study was extended to purines, [1,2,3]triazolo[4,5-d]pyrimidines and deaza-analogs. These heterocycles, when containing the key nitrogen (N7) showed selectivity for alkylation of N3 when performed in THF (2). Of additional note, when performed in DMSO, the alkylation regioselectivity was reversed for pyrazolo[3,4-d]pyrimidines, purines and related deaza-analogs, but this did not depend on X7 being nitrogen (3). This is the first report of a method for selective alkylation of N2 in pyrazolo[3,4-d]pyrimidines and related deaza-analogues.

Solvent controlled regioselective reversal in N-alkylation reactions of fused-ring azole heterocycles including pyrazolo[3,4-d]pyrimidines, purines, [1,2,3]triazolo[4,5-d]pyrimidines and related deaza-compounds

253rd National Meeting (2017)

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