Polyfunctional pyrazoles 5*. preparative synthesis of 1-aryl-4-formylpyrazole- 3-carboxylic acids

Abstract

Keywords: methyl pyruvate N-arylhydrazones, 1-aryl-4-formylpyrazole-3-carboxylic acids, VilsmeierHaack reaction.Polyfunctional pyrazole-3-carboxylic acids are of interest for chemical and biological investigation. In particular, esters and amides of 4-halo(nitro)-1-glucosylpyrazole-3-carboxylic acid show clear antiviral and antitumor activity [2]. Fungicidal activity has been observed in 1-(2,4-dinitrophenyl)-4-formylpyrazole-3-carboxylate [3] which have also been used in the synthesis of the potential calcium channel blockers 4-(3-carboxypyrazol-4-yl)-1,4-dihydropyridines [4]. 1-Aryl-5-chloro-4-formylpyrazole-3-carboxylic acids are important intermediates in the preparation of 2,6-dihydropyrazolo[3,4-d]pyridazin-7-ones as novel antagonists of the cannabinoid receptor 1 (CB 1 -R) [5]. As a whole, the synthetic potential of 4-formylpyrazole-3-carboxylic acid and its derivatives remains unexplored to this time and this is due, to a large degree, to the absence of convenient preparative methods.The synthesis of a series of 5-substituted 4-formylpyrazole-3-carboxylic acids via formylation of the corresponding 3-ethoxycarbonylpyrazol-5-ones [6] and also by reduction of 4-[oxo(phenyl)acetyl]-1,5-diphenylpyrazole-3-carboxylic acid [7,8] has been reported. The method discussed in [3, 4] of a Vilsmeier-Haack preparation of 4-formylpyrazole-3-carboxylic acid is limited to examples using only the 4-nitro-and 2,4-dinitrophenylhydrazones of alkyl pyruvate and, because of the marked acceptor properties of the aryl substituents, its universality cannot be judged. It should also be noted that the N-arylhydrazones of pyruvates are generally obtained from acids least stable on storage with subsequent esterification of the carboxyl group [9][10][11].

Polyfunctional pyrazoles. 7*. Ethyl 1-aryl-4-formylpyrazole-3-carboxylates in the synthesis of 2-aryl-2,4-dihydro-6H-thieno-[3,4-c]pyrazol-6-ones

“…Melting points for the compounds prepared were determined on a Koffler hot stage apparatus, and are not corrected. Compounds 1a-d were prepared as reported in [11].…”

“…In the present work, we demonstrate the ready construction of such a fragment based on our recently developed preparative synthesis of 4-formylpyrazole-3-carboxylic acids [11].…”

Optimizing Scale Up Yield to Pyridazines and Fused Pyridazines

“…Elnagdi et al [1] have reviewed recent developments in this area. resonance forms 2 and 3) [3,6]. These workers recognized that the hydrazone carbon in hydrazones 1 would be nucleophilic as a result of lone pair delocalization (cf.…”