Advanced Catalyst-Free Pseudo-Six-Component Synthesis of Tetrahydrodipyrazolopyridines in Water by Using Ammonium Carbonate as an Ecofriendly Source of Nitrogen

Abstract

This work describes an improved environmentally friendly method for the synthesis of tetrahydrodipyrazolopyridines (THDPPs) in water through a catalyst-free pseudo-six-component reaction of alkyl acetoacetates, hydrazine hydrate, and ammonium carbonate with an aldehyde in a mole ratio of 2:2:1:1 at room temperature. The ammonium carbonate serves as a green source of nitrogen for the central 1,4-dihydropyridine ring in the THDPPs. Methyl acetoacetate reacts faster than either ethyl or propyl acetoacetate in this method. The product precipitates during the reaction and is simply collected by filtration. Advantages of this environmentally benign method include no use of an organic solvent, no hazardous waste, rapid clean reactions, and excellent yields of products.

Nanoalkalinecellulose immobilized on magnetic nanoparticles as a green catalyst for the synthesis of tetrahydrodipyrazolopyridines and mechanistic insights under base catalysis

“…As performance results show, the organic–inorganic hybrid catalyst Fe 3 O 4 @NAC with advantages of simple handling and easy separation at mild conditions enhances the reaction yield and rate more efficiently than the cited previous protocols in Table 1. Besides, superiority of this magnetic base catalyst and procedure are higher than the reported homogeneous base catalysts for the same MC synthesis of THDPP1 in water [ 28,33,38 ] (Figure 8).…”

“…[25] Although the first synthesis of THDPPs is a Hantzsch [26] type pseudo-multicomponent reaction (p-MCR) directed by Zhao et al, [27] a recently modified acid-catalyzed p-MCR of hydrazine, ethyl acetoacetate, ammonium acetate, and aldehyde (2:2:1:1) has been developed for the synthesis of THDPPs. [28][29][30][31] We have also settled synthesis of THDPPs in water using new DESs or nonhygroscopic nitrogen sources, [31][32][33] although all acid-catalyzed protocols emphasized the 3-methylpyrazolone (A) as the reaction intermediate. However, no detail is available for the less hazardous heterogeneous base-catalyzed synthesis of THDPPs.…”

Pseudo-multicomponent reactions

“…Afterwards, intermediates 511 are attacked by ammonia producing 513, which upon a subsequent intramolecular condensation, the desired products 514a–l are formed. Other collection of tetrahydrodipyrazolopyridines 515a–l ( Scheme 53b ) were synthetized by Tamaddon and Khorram 82 using a similar strategy in water. This environmentally friendly procedure involved alkyl acetoacetates (two equivalents), hydrazine hydrate (two equivalents), ammonium carbonate and a variety of aromatic aldehydes.…”

Melamine phosphate-modified magnetic chitosan: a novel biocompatible catalyst for the synthesis of biological tetrahydrodipyrazolopyridine and pyrazolopyranopyrimidine derivatives

“…Moving into the realm of heterocyclic chemistry, pyrazoles emerge as critical due to their diverse biological features and active role in drug design ( Devi et al, 2018 ). Pyrazoles serve as the pharmacophore of commercial drugs such as metamizole, aminophenazone, phenylbutazone, and dipyrone ( Naim et al, 2016 ), and act as the building blocks of coenzymes ( Tamaddon and Khorram, 2020 ). Additionally, pyrazole compounds find application in industry as agricultural nutrients and market dyes ( Zhang et al, 2016 ).…”