Microwave-assisted ring closure reactions: Synthesis of 8-substituted xanthine derivatives and related pyrimido- and diazepinopurinediones

BACKGROUND: Poly-substituted xanthine derivatives are an important class of compounds in medicinal chemistry. Substitution at the 8-position of the purine ring is generally accessible by ring closure of a carboxamido-substituted uracil precursor. Although several procedures to accomplish this synthetic step have been suggested, it still remains difficult in many cases. RESULTS: Ring closure reaction with hexamethyldisilazane was studied under microwave conditions. Reaction times were dramatically reduced by the application of microwaves in the syntheses of the 8-styrylxanthine derivative istradefylline, and in the preparation of 2-substituted pyrimido [1,2,3-cd]purines. Furthermore, the new procedure allowed the preparation of a previously unaccessible diazepino [1,2,3-cd]purine. Yields were generally improved by the new method. The addition of THF as a co-solvent proved to be crucial. CONCLUSION: A new, fast, and efficient ring closure method for the imidazole ring of xanthine derivatives and related tricyclic compounds has been developed. Apart from improving the syntheses of known compounds, some of which are important pharmacological tools or in development as novel drugs, it allows the preparation of 2-substituted diazepino [1,2,3-cd]purines – a new class of tricyclic purine derivatives.