A novel synthesis of substituted 3-amino and 3-thio pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

Fervenulin is a natural product that has been extensively studied due to its molecular features and breadth of biological activities. Published studies have reported the generation of numerous analogues of the bicyclic pyrimidotriazinodione core. One underrepresented subclass are compounds with electron releasing atoms bonded directly to the C-3 position. We report an efficient and straightforward synthesis of compounds with substituted amino and thio functionality attached to the C-3 position. These are derived from a common 3-chloro precursor that is made in six steps in 15.8% overall yield from a starting chlorouracil. Our methodology should be applicable to the synthesis of C-3 ether congeners also, and through previously described chemistry be expandable to incorporating diversity at the N-6 position of the pyrimidotriazinodione core. The chemistry reported herein expands possibilities for the generation of diverse libraries of substituted pyrimidotriazinediones for future studies.