Regioselective alkylation of the exocyclic nitrogen of adenine and adenosine by the Mitsunobu reaction

A novel synthetic route to N(6)-substitution of adenine is presented, employing the Mitsunobu reaction as the key step. A range of primary and secondary alcohols all coupled in very good to excellent yields within 30 min at 45 degrees C, offering a milder alternative to the traditional nucleophilic aromatic substitution of 6-chloropurine. The utility of this protocol is further demonstrated by its application to the syntheses of N(6),N(9)-di-substituted adenines, including the potent and selective A(1) adenosine receptor agonist N(6)-cyclopentyladenosine. (C) 2010 Elsevier Ltd. All rights reserved.