A Mild, Efficient Synthesis of gem-Difluorodihydrouracils

Abstract

Carbodiimides react effectively with β-aryl/alkyl-β-hydroxy-α,α-difluorocarboxylic acids to afford a vast array of fully substituted gem-difluorodihydrouracils through a two step reaction sequence. In the first step, condensation between the two reactants leads in most cases to the formation of a mixture of the desired dihydrouracils and N-acylurea co-products. However, the latter could be easily recovered and efficiently converted into the target compounds. The sequence works well in very mild conditions (CH₂Cl₂, 20 ˚C) and the reaction resulted to be completely regioselective when asymmetric carbodiimides were used. When the N-acylurea derivatives are not sufficiently stable for isolation, the process could be done in a one-pot fashion leading to the direct formation of the desired dihydrouracils, although in lower yields.

Key words

N-heterocycles - fluorine - dihydrouracils - carbodi­imide - domino reaction - N-acylureas

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21

It is worth nothing that NAU derivatives are stable under the reaction condition for days and did not interconvert into the corresponding DHUs.

23

The hypothesis that DHU derivatives are directly formed via a carbocation intermediate, rather than via intramolecular nucleophilic substitution, is supported by the following experiment. Conversion of the hydroxy group of compound 11 into a good leaving group, such as a mesylate, followed by ester hydrolysis, and reacting the resulting acid 12 with carbodiimide 4b afforded the NAU derivative 13 as the only product (Scheme  [7] ) (no traces of the DHU derivative were detected by ^¹H NMR spectroscopy).

Scheme 7