Metal silicates: efficient catalysts for the three-component preparation of 2-amino-5-oxo-4-aryl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile derivatives

Introduction

Recently, developments of multicomponent reactions (MCRs) have become a praiseworthy tool in organic chemistry because of their high briefness on assembling drug-like molecules. Fundamentals and complex procedures for achieving a wide library of organic molecules could be simplified by using MCRs which minimize by-products, impurities, and vast organic reactions acquiring a green chemistry approach for researchers (Shafiee et al., 2013; Ghashang et al., 2014a,b,c, 2015, 2016a,b,c; Shafiee et al., 2014; Behmaneshfar et al., 2015; Ghashang, 2016a,b; Taghrir et al., 2016; Sheikhan-Shamsabadi and Ghashang, 2017). The use of MCRs for the preparation of pyran scaffolds is promising for a non-polluting and environmentally friendly synthesis of drug-like compounds. Pyran cores are the vital framework of the structure of various drugs.

On the other hand, 4H-pyran is a sub-category of pyran scaffolds. It is present in drug-like structures that revealed noteworthy pharmacological activities (Feuer, 1974; Seifi and Sheibani, 2008; Oskooie et al., 2011; Elinson et al., 2012; Ghashang et al., 2014a,b,c; Baziar and Ghashang, 2016; Ghashang, 2016a,b). A review of the synthetic procedures and some short discussion about these compounds have been collected in a book entitled ‘Green synthetic approaches for biologically relevant heterocycles’ edited by Goutam Brahmachari (2014).

Here, we attempted to synthesize a variety of 2-amino-5-oxo-4-aryl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile derivatives via a three-component reaction of malononitrile, aromatic aldehydes, and 1,3-indandione using different metal silicates as efficient catalysts (Scheme 1).

Scheme 1:

Preparation of 2-amino-5-oxo-4-phenyl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile derivatives.

Results and discussion

Initially, the cyclo-condensation of benzaldehyde (1.0 mmol), malononitrile, (1 mmol), and 1,3-indandione catalyzed by sodium silicate was performed in different solvents and catalyst dosages. The results are summarized in Table 1. No product was formed when a solvent with boiling points less than 70°C, e.g. Et₂O, CH₂Cl₂, and hexane, was used. The activation energy required to conduct the reaction could not be provided at temperatures below 70°C. In non-protic solvents including CH₃CN and EtOAc, a complex mixture was formed due to the reaction of solvents with starting materials and catalyst. Finally, we found that protic solvents such as EtOH and H₂O as well as solvent-free conditions are suitable for this transformation. The evidence is indicating that using 30 mol% of catalyst in water as a solvent gave higher yield.

It was proposed that the reaction begins with the Knoevenagel condensation of an aldehyde with malononitrile catalyzed by sodium silicate, which leads to the formation of arylidene malononitrile (1). At the same time, 1H-indene-1,3(2H)-dione at basic condition equilibrated with their enolate form which subsequently reacted with arylidene malononitrile to form intermediate (2). The cyclization of intermediate (2) form targeted molecules (Scheme 2).

Scheme 2:

A proposed mechanism for the metal silicate-catalyzed synthesis of dihydroindeno[1,2-b]pyran derivatives.

An ¹H-NMR spectrum of 2-amino-5-oxo-4-phenyl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile shows distinctive singlet (δ=4.63 and 7.06 ppm), triplet (δ=7.19 ppm), and doublet (δ=7.25 and 7.33 ppm) resonances that are assigned to H^a, NH₂, H⁷, H⁶, and H⁵, respectively. The complex pattern at δ=7.50–7.80 ppm is assigned to H¹, H², H³, and H⁴ (Scheme 3). A ¹³C-NMR spectrum shows signals at δ=44.7, 164.3, and 191.4 ppm that are assigned to the C³, C², and C⁵ carbon atoms, respectively. The signal for the C₄ carbon atom (the β-carbon of the enaminone system) appears at δ=58.7 ppm, and the CN carbon atom shows a signal at δ=120.4 ppm. The spectrum showed 12 more distinct resonances in agreement with the proposed structure (Scheme 3).

Scheme 3:

Chemical structure of 2-amino-5-oxo-4-phenyl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile.

Next, the effect of various metal silicates including Na₂SiO₃, K₂SiO₃, Li₂SiO₃, CaSiO₃, MgSiO₃, BaSiO₃, SrSiO₃, and ZnSiO₃ in aqueous media as well as under solvent-free conditions was investigated (Table 2). The results showed that the reaction rate decreased in the following sequence: K₂SiO₃>Na₂SiO₃>Li₂SiO₃>BaSiO₃>MgSiO₃>CaSiO₃> SrSiO₃>ZnSiO₃. All these catalysts showed excellent reactivity towards the product synthesis. However, SrSiO₃ and ZnSiO₃ are less reactive than the others. In all cases, the complete conversion of the starting materials was achieved. The basic character and consequently the catalytic activity of metal silicates are directly related to the difference in electronegativity of the metal cation and oxygen. Due to the lower differences in the electronegativities between cation and anion in SrSiO₃ and ZnSiO₃, their basic power and catalytic activity is lower than those of alkaline silicates (Duffy, 2004). In addition, K₂SiO₃, Na₂SiO₃, and Li₂SiO₃ are water-soluble while other metal silicates show low solubility.

Following by optimization the reaction conditions (Na₂SiO₃ (30 mol%), H₂O, reflux), next, several different aromatic aldehydes containing electron-withdrawing groups such as Cl, Br, and NO₂ substituents as well as electron-donating groups such as Me, OMe, and OH substituents were tolerated on the reaction delivering the desired 2-amino-5-oxo-4-aryl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile derivatives in high yields (Table 3). In general, the electronic nature of the substituents had little influence on the product yields, but has considerable influence on the reaction times. Aldehydes substituted with electron-withdrawing and halogen substituents react faster than those with electron-donating groups. Compared with 4-chlorobenzaldehyde, 2-chlorobenzaldehyde reacts slower, which indicates the effect of steric hindrance on slowing down the reaction rate.

Next, we evaluate the substrate scope of the liquid glass-catalyzed methodology using 30 mol% of the catalyst under solvent-free condition. The results are summarized in Table 3. The electron-withdrawing substituents on the aromatic ring of aldehyde have shorter reaction times than those with electron-donating substituents. Compared with solvent media, under solvent-free condition, the reaction times are shorter, but no considerable influence was detected on the product yields.

To continue, the generality of the method was explored using Li₂SiO₃ and BaSiO₃ as a catalyst. Noticeably, the results are similar with those obtained with Na₂SiO₃. However, Li₂SiO₃ showed a higher reactivity and BaSiO₃ showed less reactivity than Na₂SiO₃ (Table 3).

In comparison with various Lewis and Brønsted acid catalysts including CuO, ZnO, MgO, Al₂O₃, SiO₂, Fe₂O₃, SnO₂, SiO₂-SO₃H, and SiO₂-HClO₄, sodium silicate is a more reactive catalyst and could promote the synthesis of 2-amino-5-oxo-4-phenyl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile in higher yield (Table 4).

In summary, a practical reaction to the facile metal silicates which catalyzed the synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydroindeno[1,2-b]pyran-3-carbonitriles via one-pot reaction of an aromatic aldehyde, malononitrile, and 1,3-indandione was developed. Excellent yields of the products were achieved in all cases, including solvent and solvent-free media.

Experimental

All reagents were purchased from Merck and Aldrich (Tehran, Iran) and used without further purification. The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance DPX 400 MHz instrument (Bruker BioSpin, Fallanden, Switzerland). The spectra were measured in dimethyl sulfoxide-d₆ (DMSO-d₆) relative to tetramethylsilane (TMS) (0.00 ppm). Elemental analyses (C, H, N)were carried out on a Perkin-Elmer 2400 analyzer (Perkin Elmer, Norwalk, CT, USA). Melting points were determined in open capillaries with a BUCHI 510 melting point apparatus. Thin-layer chromatography (TLC) was performed on silica gel Polygram SIL G/UV 254 plates.