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

Abstract

An efficient and high-yielding strategy to prepare “unsymmetrical” 4-aryl-isoxazol-3,5-dicarboxylic acid derivatives from nitroacetic esters and aromatic aldehydes has been developed. The strategy is based on the isolation and usage of the previously missed intermediate of the Dornow reaction5-hydroxy-6-oxo-4-aryl-6H-1,2-oxazine-3-carboxylates. In addition, the mechanism of the Dornow reaction was partially revised.

A review of recent synthetic strategies and biological activities of isoxazole

“…A well‐organized and good yield‐producing approach to formulate “unsymmetrical” 4‐aryl‐isoxazole‐3,5‐monocarboxylic acid ( 4 , 6 , 7 , 9 – 16 ) and 4‐aryl‐isoxazole‐3,5‐dicarboxylic acid (8) analogues by nitroacetic esters 1 with aromatic aldehydes 2 reported (Scheme 39) [60].…”

“…The [2 + 2 + 1] cycloaddition reaction route mediated by copper nitrate was utilized to create a series of S C H E M E 3 9 Synthesis of "unsymmetrical" 4-aryl-isoxazol-3,5-dicarboxylic acid derivatives [60] isoxazole and isoxazoline analogues. The reaction of fluoraldehyde 1 and different aryl-carboxylic acid 2 as the starting precursor yielded 3-aryl isooxazoline 3, which then further treatment substituted aryl enones 4 produces different substituted isoxazoles 5.…”

Primary nitro compounds: progress in the synthesis of isoxazoles by condensation with aldehydes or activated ketones

“…A recent re-examination of the process 79 has shown that dinitroglutarate, under appropriate reaction conditions, undergoes a different ring-closure to oxazinones 34 (Scheme 18) and a general synthesis of these compounds is reported from nitroacetic esters and aromatic aldehydes (1, R = Ar) in acetonitrile and Et 2 NH (Baranov and his co-workers). 79,80 The two CO groups differentiated in oxazinones prompted the way for selectively preparing isoxazole-5-carboxyamide derivatives ). 80 The Dornow reaction is updated 34 with further insight into its mechanism.…”

“…79,80 The two CO groups differentiated in oxazinones prompted the way for selectively preparing isoxazole-5-carboxyamide derivatives ). 80 The Dornow reaction is updated 34 with further insight into its mechanism. It may be noted that one of the 3,4-diaryl-5ethoxycarbonylisoxazoline N-oxides reported above, 30 (R 1 = CO 2 Et, R = [2,5-(MeO) 2 -3,4-OCH 2 OC 6 H], 76 has been reported to be converted into the corresponding oxazinone (33%) on treatment with a very strong base (DBU) in MeCN.…”

An overview of metal-free synthetic routes to isoxazoles: the privileged scaffold

“…Subsequently, intermediates 111 were reacted with various functionalized amines in the presence of chloroform at 70 °C for 12 h, which furnished the 3,4,5-trisubstituted isoxazole derivatives 112 ( Scheme 27 ). 39 …”