V. Snieckus, K. Guimarães
Oct 1, 2014
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Abstract
Significance: Pyrimido[4,5-d]pyrimidine2,4(1H,3H)-dione derivatives have potential chemotherapeutic use (A. Nagarajan et al. J. Heterocycl. Chem. 1997, 34, 1581). Hence, their analogue pyrimido[4,5-d]pyrimidine-2,4(1H,3H)dithiones may also be expected to be of biological interest. Surprisingly, there is only one previous report on the synthesis of this class of compounds (R. Evers, E. Fischer Z. Chem. 1980, 20, 412). Reported is the synthesis of this class of heterocycles and the corresponding 1,3-disubstituted 4-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin2(1H)-one derivatives. The starting materials are easily acquired from the commercially available 4,6-dichloro-2-(methylthio)pyrimidine (1). All steps of the synthesis are conveniently carried out under mild conditions. The LDA metalation step is precedented (K. Kobayashi et al. Heterocycles 2012, 85, 1405). Comment: Although the provided synthetic routes are convenient, there are some limitations. First, the use of 4-chloro-6-methoxypyrimidine as starting material instead of the 4-chloro-6-methoxy-2(methylsulfanyl)pyrimidin (2) resulted in no product. This result suggests that the presence of the methylsulfanyl group in C2 is required, in spite of its potential to undergo SMe deprotonation. Furthermore, reaction feasibility for C2 electrondonating and -withdrawing substrates was not demonstrated. The second limitation was the use of isocyanates instead the isothiocyanates in the conversion of 3 into 4. Furthermore, although PhNCO participated in the reaction to give the product in lower yield, the reaction failed for n-butyl isocyanate. Extension of the scope of this reaction would be useful. N