Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

Abstract

A simple scalable procedure for the synthesis of 3,4‐diaryl‐isoxazole‐5‐carboxamides 6 under mild conditions from readily available material was developed. The targeted compounds 6, structural analogues of heat shock protein inhibitors, were obtained by the rearrangement of intermediate 3,4‐diaryl‐5‐carboxamido‐isoxazoline N‐oxides 5. In contrast to carboxamido‐isoxazoline oxides 5, base‐catalyzed recyclization of 3,4‐diaryl‐5‐(ethoxycarbonyl)isoxazoline N‐oxides 9c unexpectedly yielded 5‐hydroxy‐1,2‐oxazin‐6‐ones 17c instead of ethyl 3,4‐diaryl‐isoxazole‐5‐carboxylates 10. Crystal and molecular structure of 4‐(2,5‐dimethoxy‐3,4‐methylenedioxyphenyl)‐5‐hydroxy‐3‐phenyl‐6H‐1,2‐oxazin‐6‐one 17c was established by single‐crystal X‐ray diffraction study. In a phenotypic sea urchin embryo assay, carboxamide 6f showed moderate antimitotic antitubulin activity compared to 5‐unsubstituted 3,4‐diarylisoxazoles 15, which featured strong microtubule destabilizing effect.

Nitroacetic Esters in the Regioselective Synthesis of Isoxazole-3,5-dicarboxylic Acid Derivatives

“…6,10 Our results suggest that both of these processes actually take place. Thus, the predominant formation of esters 1 in the case of aldehydes with electron-withdrawing substituents (Scheme 2, bottom) can be explained by the increased acidity of the proton at position 4, which is necessary for the passage of the reaction along path C. At the same time, formation of oxazolinones 2 (as well as related diaryl compounds in other publications 11 ) confirms the formation of oximes III.…”

Five-Membered Hetarene N-Oxides: Recent Advances in Synthesis and Reactivity

“…Thus, a condensation of arylnitromethanes 3 with benzaldehydes affords nitrostilbenes 4 which upon interaction with 2-amino-2-oxoethylpyridinium chlorides undergo tandem Michael addition/intramolecular cyclization resulting in diastereomerically pure trisubstituted isoxazoline N-oxides 5ai (Scheme 2). 11…”

“…21 Upon base treatment, isoxazoline N-oxides are easily converted to the corresponding isoxazoles. 10,11 Although the reaction has a broad substrate scope, there is an exception for several isoxazoline N-oxides bearing ester moiety at the C(5) position of the ring.…”

“…A treatment of 5ethoxycarbonylisoxazoline N-oxides with DBU promotes the ring cleavage and subsequent recyclization to 4-hydroxy-1,2oxazin-6-one. 11 Isoxazoline N-oxides also undergo selective ring cleavage upon interaction with halonium ions. For example, tandem halogenation/oxidation protocol of condensed isoxazoline N-oxides 25 mediated by Nbromosuccinimide (NBS) or trichloroisocyanuric acid (TCICA) afforded 2-halomethylene-3-oxoketoximes 27.…”

“…Upon treatment with a base, isoxazoline N-oxides are easily converted into the corresponding isoxazoles. 10,11 Although the reaction has a broad substrate scope, there is an exception for several isoxazoline N-oxides bearing an ester moiety at the C(5) position of the ring. Treatment of 5ethoxycarbonylisoxazoline N-oxides with DBU promotes ring cleavage and subsequent recyclization to give 4-hydroxy-1,2-oxazin-6-ones.…”