Elsevier

Tetrahedron

Volume 69, Issue 38, 23 September 2013, Pages 8245-8249
Tetrahedron

β-Cyclodextrin-assisted synthesis of Biginelli adducts under solvent-free conditions

https://doi.org/10.1016/j.tet.2013.07.024Get rights and content

Abstract

A simple, green and efficient protocol was developed using β-cyclodextrin as a solid catalyst for the solvent-free synthesis of various Biginelli adducts. The advantages of our protocol included the following: (i) a metal-free methodology; (ii) high yields; (iii) simple and efficient work-up procedures; (iv) improved results under solvent-free conditions. β-cyclodextrin-catalyzed the Biginelli reactions for various aldehydes, demonstrating that it is an efficient and eco-friendly catalyst for the preparation of heterocyclic compounds.

Introduction

In recent years, multicomponent reactions (MCRs) have emerged as a powerful synthetic tool for generating structurally complex molecular entities with fascinating biological properties through the formation of several carbon–carbon and carbon–heteroatom bonds in a one-pot operation. The convergent character, atom economy, ease of a one-pot operation, and access to structurally diverse libraries of compounds provided by MCRs is advantageous compared to linear multistep synthesis.1

3,4-Dihydropyrimidin-2(1H)-one/-thione derivatives, also named Biginelli adducts, have attracted much attention as important structural motifs in medicinal chemistry because of their significant therapeutic and biological activities, such as antihypertensive, potassium channel antagonist, antiepileptic, antimalarial, antimicrobial, antitumor, antibacterial, anticancer, and antiflammatory properties.2

During the last few years, numerous catalytic methods have been developed to improve the reaction yield, lower the reaction time and/or broaden the scope of the Biginelli reaction. Although numerous methods for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones are known, few use Brønsted-Lowry or Lewis acids as catalysts for the Biginelli reaction.3 The use of ionic liquids,4 microwave irradiation,5 solid phase reagents,6 baker's yeast,7 polymer-supported catalysts,8 zeolite,9 surfactants,10 and PEG11 has also been reported. Only a few examples of organocatalysts have been described for the Biginelli reaction.12 However, most of these methods require expensive reagents, long reaction times, harsh reaction conditions, and tedious work-up procedures or provide unsatisfactory yields.

Cyclodextrins (CDs), obtained from the enzymatic degradation of starch, are cyclic oligosaccharides that catalyze a wide range of chemical reactions through the formation of a reversible host–guest complex via non-covalent interactions.13 Recently, Luo and co-workers described the use of hydrochloric acid-β-cyclodextrin catalysts in the Biginelli reaction and excellent yields were obtained.14 Tajbakhsh and co-workers disclosed the use of sulfonated β-cyclodextrin as an efficient and recyclable heterogeneous catalyst for Biginelli reactions.15 However, the first method required a co-catalyst, HCl, and the second method requires the sulfonation of β-cyclodextrin using chlorosulfonic acid, a hazardous and corrosive reagent, to prepare the catalyst.

Herein, we have disclosed a simple, effective and eco-friendly approach to the synthesis of Biginelli adducts using β-cyclodextrin (β-CD) as a reusable catalyst under solvent-free conditions.

Section snippets

Results and discussion

We first examined the reaction with a series of cyclodextrins (catalysts) and solvents as well as performing the reaction under solvent-free conditions. In these reactions we studied the Biginelli one-pot condensation reaction of benzaldehyde (1a; 3.0 mmol), ethyl acetoacetate (2; 4.5 mmol), and urea (3; 4.5 mmol) using 0.5 mol % of different cyclodextrins [α-cyclodextrin (α-CD); β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), and methyl-β-cyclodextrin

Conclusions

In conclusion, we describe a novel protocol for the preparation of 3,4-dihydropyrimidin-2(1H)-ones/-thiones using the three-component Biginelli reactions of aldehydes, ethyl acetocetate, and urea or thiourea under solvent-free conditions. This procedure offers several notable advantages including operational simplicity, reuse of the catalyst (β-CD), good or high yields, solvent-free conditions, and recrystallization from ethanol, all of which contribute to the minimization of waste. Therefore,

General techniques

Unless noted, all commercial reagents were used as purchased without further purification. The reaction monitoring was accomplished by layer chromatography (TLC) was carried out using 0.2 mm Kieselgel F254 (Merck) silica plates and compounds were visualized using UV irradiation at 365 nm. Melting points were measured by an MQAPF-301 Microquímica micromelting point apparatus and are uncorrected. Infrared spectra were recorded as neat using an FT-IR Varian 660 Fourier Transform Infrared

Acknowledgements

We thank the Brazilian agencies CNPq for research fellowships (A.F. and S.A.F.) and FAPEMIG, FUNARBE and CAPES for financial support.

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