Synthesis of Pyrimido[2,1-b][1,3,5]Thiadiazines Containing Polyfluoroalkyl- and Amino Acid Fragments

The data about formation of pyrimido[2,1-b]thiadiazine moiety are quite limited [1-4]. The method for the synthesis of this heterocyclic system is based on regiospecific annelation of 2-thiouracils with a thiadiazine ring, based on a sequential double aminomethylation reaction (double Mannich reaction) with formaldehyde and primary amines at the nucleophilic centers SH and N-3. The possibilities of this method are limited to the use of 2-thiouracils. Such a synthesis can be accomplished with 2-thiouracils containing a substituent at position 5 [1, 2], since the Mannich reaction of 2-thiouracil and 6-methyl-2-thiouracil at the CH nucleophilic center gives 5-aminomethylated thiouracils [5-7]. We have recently found that 6-polyfluoroalkyl-2-thiouracils are convenient substrates for the preparation of 3-substituted 8-polyfluoroalkylpyrimido[2,1-b]-[1,3,5]thiadiazines, which becomes possible due to the deactivating effect of the electron-withdrawing polyfluoroalkyl substituent at