Development of an efficient route to CF3-substituted pyrrolopyrimidines through understanding the competition between Michael and aza-Henry reactions?

Organic & Biomolecular Chemistry Pub Date: 2014-11-25 DOI: 10.1039/C4OB02233E

Abstract

The regioselective base-catalyzed addition of nitromethane to 2-oxo-4-trifluoromethyl-1,2-dihydropyrimidine-5-carboxylates is reported. It was found that the Michael-like pathway is highly reversible and substantially dominating under conditions of kinetic control (0–5 °C, 10 h) whereas the aza-Henry reaction leads to thermodynamically stable adducts after 8–24 h exposure at room temperature. The adjacent nitro and alkoxycarbonyl groups were exploited to demonstrate the synthetic potential of the obtained products by converting to the isomeric trifluoromethylated pyrrolo[3,4-d]pyrimidine-2,5-diones. With this aim an efficient protocol for selective reduction of nitro-derivatives to the corresponding 4- or 6-aminomethyl-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates and their subsequent thermal cyclocondensations was applied.

Graphical abstract: Development of an efficient route to CF3-substituted pyrrolopyrimidines through understanding the competition between Michael and aza-Henry reactions
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