Isoxazoles by a Consecutive 3CR of Acid Chlorides, Alkynes, and Nitrile Oxides

1 Isoxazoles by a Consecutive 3CR of Acid Chlorides, Alkynes, and Nitrile Oxides 

The pronounced biological activity has rendered many substituted isoxazoles an important motif in medicinal chemistry. For instance, isoxazoles are potent and selective agonists of human cloned dopamine D4 receptors [87], they exhibit GABAa antagonist [88] analgesic, antiinflammatory, ulcerogenic [89] COX-2 inhibitory [90, 91] antinociceptive [92], and anticancer [93] activity. 

Besides carbonyl and alkynone condensation [94, 95] of hydroxylamine, the (2-i-3)-cycloaddition of aromatic nitrile oxides, a class of propargyl type 1,3-dipoles, is a very general access to isoxazoles [96, 97]. Since aromatic nitrile oxides tend to be very unstable, it is favorable to generate them in situ by dehydrochlorlnation of the corresponding hydroximinoyl chlorides with a suitable base. If triethylamine is the base, this step can be expected to be fully compatible with a preceding alkynone formation. 

Besides the mild conditions and excellent chemo- and regioselectivity the scope of this one-pot coupling-cycloaddition isoxazole synthesis is fairly broad. Due to acid chlorides as halide coupling partners, amines and hydroxy groups inevitably need to be protected prior to the reaction. Therefore, the use of acid chlorides 7 is principally limited to (hetero)aromatic compounds and derivatives without ot-hydrogen atoms. As an exception, the cyclopropyl group is tolerated as a 

Cyclic voltammetry revealed that all ferrocene derivatives can be reversibly oxidized. The number of reversible waves in the cyclic voltammograms corresponds to the number of the redox sensitive moieties in the molecule. With respect to ferrocene the half-wave potentials of the compounds are shifted anodically. Furoxanes were isolated in minor amounts as the expected byproducts resulting from dimerization of the nitrile oxides. 

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