Direct N-arylation of purines with aryl halides†

Purine is a ubiquitous heterocyclic scaffold of fundamental importance, and is considered to be a privileged structure in medicinal chemistry. Purine-based compounds, including N-aryl purines, exhibit a wide range of biological and pharmaceutical activities, such as antiviral, antibacterial and anticancer effects. In light of their importance, there is a surprising paucity of efficient methods for N-arylation of purines. Despite the many methods for metal-catalysed C–N bond formation, only few examples involving purines are reported. Arylboronic acids and diaryliodonium salts have been used to achieve a Cu-mediated regioselective N-arylation or N-arylation of various purine derivatives in moderate to very good yields under relatively mild conditions, but these reactions often have a narrow substrate scope and N-arylguanines have only been prepared by the arylation of protected or masked nucleobases. Aryl halides are abundantly available and are generally more stable than boronic acids and diaryliodonium salts; however, only three publications describe the N-arylation of purines with aryl halides, all in moderate yields. Based on the hypothesis that electron-rich 1,10-phenanthroline ligands improve the performance by better stabilisation of the proposed Cu(III)-intermediate in the catalytic cycle, we recently found that 4,7-dipyrrolidinyl-1,10-phenanthroline (L1, DPPhen) catalyse N-arylation of various N-heterocycles with aryl halides in water. This system was also able to N-arylate adenine, 2,6-diaminopurine and theophylline, albeit only in moderate yields. Herein, we report a more general method for the direct synthesis of N-arylated purines with high and predictable selectivity for the Nor N-position over other potential coupling positions and complete selectivity over other nucleophilic sites including aromatic amines. Themethod is exemplified with various purines and a broad selection of aryl halides.