Preparation of benzofuran-2-carbohydrazide and its utilization for benzofuran-bearing 1,2,4-triazole and 1,3,4-oxadiazole synthesis

Abstract

Benzofuran, triazole and oxadiazole spontaneously occur in natural compounds with highly desired bioactivities, such as antibacterial, antifungal, antiviral and anticancer. These cyclic scaffolds happen in a variety of commercial medicines as well as developed drugs in late-stage clinical trials (eg. amiodarone, ramelteon, zibotentan, and ataluren). Benzofuran-bearing triazole and oxadiazole can be synthesized by click reaction, requiring an alkynyl group. The formation of the alkynyl group can be achieved by treating the precursor with sodium azide, a poisonous chemical that needs safe conditions for manipulation. In this study, a simple and convenient reflux-based method for the synthesis of benzofuran-involved triazole and oxadiazole was developed. Firstly, benzofuran-2-carbohydrazide (3) was prepared by the reaction of salicylaldehyde and ethyl chloroacetate, followed by the treatment with hydrazine hydrate. Subsequently, compound (3) reacted with KOH, CS2 and hydrazine hydrate to afford 4-amino-1,2,4-triazole-3-thiol derivative (4), existing in a tautomeric form with its thione isomer (4b) in 1:3 of molar ratio. Intriguingly, the reaction of (3) and 4-fluorobenzaldehyde afforded N'-(4-fluorobenzoyl)-1-benzofuran-2-carbohydrazide (6) instead of 1,3,4-oxadiazole derivatives. Their structures were confirmed by NMR and MS. Altogether, this study implies the potential of using the simple and cost-effective reflux-based method for benzofuran-bearing triazole and oxadiazole synthesis.

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