Non-Decarboxylative Ruthenium-Catalyzed Rearrangement of 4-Alkylidene-isoxazol-5-ones to Pyrazole- and Isoxazole-4-carboxylic Acids

Treatment of 4-(2-hydroaminoalkylidenyl)- and 4-(2-hydroxyalkylidenyl)-substituted isoxazol-5(4H)-ones with catalytic amounts of [RuCl2(p-cymene)](2), without any additive, afforded pyrazole- and isoxazole-4-carboxylic acids, respectively. The presence of an intramolecular H-bond in these substrates was the key to divert the classical mechanism toward a ring-opening non-decarboxylative path that is expected to generate a vinyl Ru-nitrenoid intermediate, the cyclization of which affords the rearranged products. A gram scale protocol demonstrated the synthetic applicability of this transformation.

Automated summary

Treatment of aldehyde-substituted isoxazol-5(4H)-ones with [RuCl2(p-cymene)](2) as the catalyst generates pyrazole-4-carboxylic acids, while treatment of alcohol-substituted isoxazol-5(4H)-ones produces isoxazole-4-carboxylic acids. The presence of intramolecular hydrogen bonding in the substrates plays a crucial role in diverting the reaction towards ring-opening non-decarboxylative pathway.