Facile and efficient access to 2,6,9-tri-substituted purines through sequential N9, N2 Mitsunobu reactions

A facile, efficient and mild synthesis of 2,6,9-tri-substituted purines is presented, starting from commercially available 2-amino-6-chloropurine, which employs sequential N9 then N2 Mitsunobu reactions as key steps. Importantly, our synthetic approach to N2-functionalization of the purine nucleus obviates the harsh conditions required by the traditional nucleophilic aromatic substitution of a 2-halo group with primary amines. Benzylic, allylic, propargylic and aliphatic alcohols all coupled in very good to excellent yields in both Mitsunobu reactions. Significantly, excellent chemoselectivity and N9-regioselectivity were observed for the first coupling, and reactions were complete within 15 min at room temperature. Our novel methodology may be readily adapted to furnish N 9 -mono- or N 2 , N 9 -di-functionalized guanine analogues, and the utility of our protocol is further demonstrated by the efficient synthesis of the CDK inhibitor bohemine.