Scandium triflate-catalyzed one-pot multi-component synthesis of 2-amino-6-thiopyridine-3,5-dicarbonitriles

Introduction

The rapid assembly of molecular diversity is an important goal of synthetic organic chemistry and one of the key paradigms of modern drug discovery. One approach to address this challenge involves the development of multi-component reactions (MCRs), in which three or more reactants are combined together in a single reaction flask to generate a product incorporating most of the atoms contained in the starting materials (Orru and de Greef, 2003). In addition to the intrinsic atom economy and selectivity underlying such reactions, simpler procedures and equipment, time and energy savings, as well as environmental friendliness have all led to a sizable effort to design and implement MCRs in both academia and industry (Ramo’n and Miguel, 2005). The pyridine nucleus is of considerable interest as this ring is the key constituent in a range of bioactive compounds, both naturally occurring and synthetic, and often of considerable complexity. 2-Amino-6-thiopyridine-3,5-dicarbonitrile derivatives show diverse pharmacological activities such as anticancer (Cocco et al., 2005), antihepatitis B virus (Chen et al., 2005), antiprion (Perrier et al., 2000), antibacterial (Levy et al., 2005), and are potassium channel openers for treatment of urinary incontinence (Harada et al., 2002). Several of these compounds are used as highly selective ligands for adenosine receptors (Beukers et al., 2004), which are recently recognized as potential targets for the development of new drugs for the treatment of Parkinson’s disease, asthma, epilepsy, cancer, kidney disease, and hypoxia (Fredholm et al., 2001).

Thus, the synthesis of highly substituted pyridines has attracted much attention and a number of procedures have been developed (Anabha et al., 2007). Among these, one of the convenient approaches that attracted our attention is the three-component condensation of aldehyde, malononitrile, and thiol to the highly substituted pyridines developed by Evdokimov et al. (2006). Recently, a modification to this method was reported by making use of basic ionic liquid (Ranu et al., 2007). Conversely, the synthesis of 2-amino-6-thiopyridine-3,5-dicarbonitrile derivatives in the presence of Lewis acid ZnCl₂ in moderate to good yield has been reported (Sridhar et al., 2009). Syntheses of 2-amino-6-thiopyridine-3,5-dicarbonitrile derivatives via MCRs using catalysts KF/alumina (Singh and Singh, 2009), NAP-MgO (Kantam et al., 2010), and o-iodoxybenzoic acid (Takale et al., 2012) have also been reported.

As part of our continuing program on scandium(III) triflate (Kottawar et al., 2009), herein we describe a mild and efficient method for the synthesis of 2-amino-6-thiopyridine-3,5-dicarbonitrile derivatives using scandium(III) triflate as a Lewis acid catalyst (Scheme 1). This method is not only an excellent complement to the other reported methods but is also eco-friendly in that it avoids the use of hazardous acids or bases and harsh reaction conditions. The advantages of this method are inexpensive reagents, mild reaction conditions, experimental operational ease, and good yields of pyridine products in the range of 65–85%.

Scheme 1

Results and discussion

Scandium triflate is a new type of Lewis acid, differing from typical Lewis acids such as AlCl₃, BF₃, and SnCl₄. It does not undergo decomposition or deactivation in the presence of water and works as a catalyst where other Lewis acids are required in a stoichiometric amount. Moreover, many nitrogen containing compounds can be activated in the presence of a catalytic amount of Sc(OTf)₃ in both organic and aqueous solvents (George et al., 1993). Scandium triflate is used as catalyst in a variety of reactions (Cho et al., 2006). Scandium triflate can be recovered almost quantitatively after the reaction is completed and can be recycled for the subsequent uses without any loss of activity. The reactions described herein were conducted in ethanol and were completed after 2 h. Using other solvents such as toluene, dimethyl sulfoxide, N,N-dimethylformamide, methanol, and 1,2-dichloroethane afforded products 4 in lower yields ranging from 17% to 75% after a much longer period of time up to 12 h.

It was observed that the process tolerates both electron donating and electron withdrawing substituent on the aldehyde. Good yields of the products were obtained after purification by column chromatography. All the compounds were characterized by melting point, ¹H NMR, ¹³C NMR, and HR-MS.

Conclusion

A mild and efficient method for the synthesis of 2-amino-6-thiopyridine-3,5-dicarbonitriles 4 by using scandium(III) triflate as a Lewis acid catalyst is described. This general synthesis does not require the use of hazardous acids or bases and is conducted under mild conditions.

Experimental

All solvents were used as commercial anhydrous grade without further purification. Merck aluminum sheets 20×20 cm coated with silica gel 60 F₂₅₄ were used for thin layer chromatography to monitor progress of reaction. Column chromatography was carried out using silica gel (80–120 mesh). Melting points were determined in open capillaries and are uncorrected. ¹H NMR spectra (400 MHz) and ¹³C NMR spectra (100 MHz) were recorded on a Bruker 400 spectrometer in DMSO-d₆.