Elsevier

Catalysis Communications

Volume 8, Issue 12, December 2007, Pages 2119-2124
Catalysis Communications

Iron(III) trifluoroacetate and trifluoromethanesulfonate: Recyclable Lewis acid catalysts for one-pot synthesis of 3,4-dihydropyrimidinones or their sulfur analogues and 1,4-dihydropyridines via solvent-free Biginelli and Hantzsch condensation protocols

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Abstract

Iron(III) trifluoroacetate [Fe(CF3CO2)3] or trifluoromethanesulfonate [Fe(CF3SO3)3] catalyzes three component coupling of β-dicarbonyl compounds, aldehydes and urea or thiourea to afford the corresponding 3,4-dihydropyrimidinones or their sulfur analogues under solvent-free conditions. Also, these catalysts were used for one-pot synthesis of 1,4-dihydropyridines via solvent-free Hantzsch reaction. This new protocol allows the recycling of catalysts with no loss in their potency.

Introduction

Dihydropyrimidinones (DHPMs) have attracted increasing interest due to their diverse therapeutic and pharmacological properties, such as antiviral, antibacterial, antihypertensive and antitumor effects [1]. Several alkaloids isolated from marine sources also exhibit interesting biological activities, whose molecular structures contain the dihydropyrimidinone moiety [2]. Therefore, their synthesis has been the focus of much interest for organic and medicinal chemists [3]. The original Biginelli protocol for the preparation of DHPMs consisted of heating a mixture of the three components included β-ketoester, aldehyde and urea in ethanol containing a catalytic amount of HCl [4]. The major drawbacks associated with this protocol are the use of strong acid as well as the low yields in the case of substituted aromatic and aliphatic aldehydes. As Biginelli reaction for the synthesis of DHPMs has received renewed attention, several improved procedures have been reported based on metal-catalyzed Biginelli reaction during the last decade. Among the simple metal/ammonium salts with nucleophilic anions, LiBr [5], NH4Cl [6], MgBr2 [7], FeCl3 · 6H2O [8], Mn(OAc)3 · 2H2O [9], InBr3 [10], ZnI2 [11], CdCl2 [12] and CuI [13] are active catalysts. The catalytic effect of metal cations is even more pronounced with methods based on metal salts with non-nucleophilic anions such as LiClO4 [14], CuSO4 · 5H2O [15], Cu(OTf)2 [16], Al(HSO4)3 [17], trimethylsilyl triflate [18], which allow the preparation of DHPMs in good to high yields. Additionally, the Biginelli reaction can strongly be accelerated by various procedures including heteropoly acids [19], silica sulfuric acid [20] and ferric chloride/tetraethyl orthosilicate [21].

The chemistry of 1,4-dihydropyridines (DHPs) was reviewed by Eisner and Kuthan in 1972 [22], and by Stout and co-workers in 1988 [23]. DHP drugs such as nifedipine, nicardipine, amlodipine and others are effective cardiovascular agents for the treatment of hypertension [24]. The remarkable drug activity of DHPs not only attracted many chemists to synthesize this heterocyclic nucleus but also became an active research area of continuing interest. Starting from Hantzsch protocol [25] more than a century ago, it has been mostly reported that there are a plethora protocols applicable to synthesize a wide range of DHPs. Many of the reported procedures involve the use of molecular iodine [26], Silica gel/NaHSO4 [27], microwave/ultrasound irradiation [28], 2,4,6-trichloro [1,3,5]triazine (TCT, cyanuric chloride) [29], ionic liquid/3,4,5-trifluorobenzeneboronic acid [30], fermenting bakers’ yeast [31], and high temperature in refluxing solvent [32].

However, a number of the reported protocols to synthesize DHPs and DHPMs requiring solvents and catalysts are not acceptable in the context of green synthesis, utilize reagents and catalysts which are either toxic or expensive and stoichiometric use of reagents with respect to reactant. Additionally, the clean handling of some anhydrous metal halides is not easy enough in the laboratory apart from their hygroscopic nature due to strong tendency for hydrolysis. However, the developments in this area demand further searches for better catalysts that could be superior to the existing ones with regard to toxicity, handling, and recyclability. In this respect, we are interested to introduce potential catalysts to overcome these limitations.

Recently, we have shown that solvolytic and non-solvolytic ring-opening reactions of epoxides is facilitated in the presence of iron(III) trifluoroacetate [33]. Also, iron(III) triflate is a novel Lewis acid, which has attracted little attention as a catalyst [34]. Very recently, Oriyama and co-workers reported that iron(III) triflate catalyzes one-pot synthesis of acetal-type protected cyanohydrins from carbonyl compounds [35]. A literature survey clearly shows that there is no report on the application of Fe(CF3CO2)3 or Fe(CF3SO3)3 as Lewis acid catalysts for Biginelli and Hantzsch condensation protocols. In recent years, there has been an increasing interest in reactions that proceed in the absence of solvents due to their reduced pollution, low costs and simplicity in process and handling [36]. Here we wish to report the capacity of Fe(CF3CO2)3 and Fe(CF3SO3)3 as recyclable, non-hygroscopic and potential Lewis acid catalysts for the one-pot synthesis of 3,4-dihydropyrimidinones or their sulfur analogues and 1,4-dihydropyridines via solvent-free Biginelli and Hantzsch condensation protocols, respectively.

Section snippets

Catalysts and general remarks

Iron(III) trifluoroacetate [33] and iron(III) trifluoromethanesulfonate [34] were prepared according to reported procedures. Purity was confirmed by Mp and/or GC analysis. Yields refer to isolated products after purification. Melting points were measured on an Electrothermal 9100 apparatus, and are uncorrected. IR spectra were recorded on a Perkin–Elmer Spectrum GX FT-IR spectrophotometer. 1H NMR, 13C NMR spectra were recorded on a Bruker Avance DPX 200 (200 and 50.3 MHz, respectively)

Advantages of Fe(CF3CO2)3 and Fe(CF3SO3)3

Iron(III) trifluoroacetate and trifluoromethanesulfonate (triflate) have several advantages over other conventional Lewis acids. For example they are stable in water and therefore do not decompose under aqueous work-up conditions. Thus, recyclization of the iron(III) trifluoroacetate or trifluoromethanesulfonate (triflate) is often possible and renders the procedure relatively environmentally acceptable by utilizing these properties. The highly stable and non-hygroscopic nature, easy

Conclusion

In conclusion, we have developed potential catalysts as interesting alternatives to liquid, hygroscopic and expensive ones as mentioned in introduction. Moreover, compatibility with various functional groups and environmentally friendly nature of the procedure should make the present method useful and important in addition to the known methodologies for the Biginelli and Hantzsch reactions.

Acknowledgement

We gratefully acknowledge the Kermanshah University of Medical Sciences Research Council for financial support.

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