Multi-component reactions (MCRs) are extremely valuable procedures in organic and medicinal chemistry owing to their high atom economy and applications in combinatorial chemistry [1,2]. Heterocycles are important scaffolds and make up the pharmacophores of many successful drugs [3]. Polyarylpyridine derivatives in particular have attracted increased attention recently as they are present in a range of pharmaceuticals such as antimalarials,vasodilators,anesthetics,anticonvulsants and antiepileptics,and are also found in agrochemicals such as fungicides,pesticides,and herbicides [4, 5, 6].
A multi-component approach for the synthesis of 5H-indeno [1,2-b]pyridin-5-one derivatives has been published. In this procedure,the Knoevenegal products of several 1,3- indandiones and aromatic aldehydes react with substituted cyanoacetamides,phenyl acetonitrile or ethyl phenylacetate in the presence of ammonium acetate [7]. Other reported approaches for the synthesis of 5H-indeno[1,2-b]pyridines include PPA cyclization of 2-aryl-3-nicotinic acids [8, 9],oxidative thermal rearrangement of 2-indanone oxime O-allyl ethers [10,11],direct cyclization of 2-aryl-3-methylpyridines followed by oxidation,Pummerer reaction of imidosulfoxides [12],Pd(0)- catalyzed cross-coupling between arylboronic acids and 2- halopyridines [13] and the MCR of 1,3-indandione,propiophenone,aromatic aldehydes,and ammonium acetate using CAN as a catalyst [5]. Tu and co-workers further developed the procedure by reacting aldehydes,1,3-indandione or 1- indenone and aromatic ketones in the presence of ammonium acetate under microwave irradiation [14,15].
There are several disadvantages to these synthetic methods,however,such as low yields,the use of expensive reagents,strongly basic and acidic conditions,multi-step reactions,side reactions and the need for microwave irradiation and high temperatures. Thus,there is still a strong need for a mild and efficient method for the synthesis of these important heterocyclic compounds.
Nanocrystalline materials have received considerable attention because of their unique properties and potential application in the manufacture of nano devices [16, 17, 18, 19]. ZnO is one of the most important metal oxides owing to its wide range of technologically important applications,including the production of electrical,optoelectronic,and gas sensing devices [20]. Furthermore,ZnO has medical applications because of its low toxicity and antibacterial activity [21].
The properties of ZnO can be tailored to fit the specific needs of a reaction by doping with various metals. There are a large number of reports on transition metal-doped ZnO systems,but hardly any of the reports focus on Cu-doped ZnO. Cu is an important doping metal because: (1) it can modify the luminescence of ZnO crystals by creating localized impurity levels [22],(2) it has many physical and chemical properties similar to Zn,and (3) it can alter the microstructure and the optical properties of ZnO [23].
We wish to report a simple and efficient method for the synthesis of indenopyridine derivatives by the Cu-doped ZnO nanocrystalline powder catalyzed MCR between aldehydes,1,3-indandione,aromatic ketones,and ammonium acetate (Scheme 1).
All materials were purchased from Merck. The reactions were monitored by TLC using silica gel plates and the products were purified by flash column chromatography on silica gel (Merck,230-400 mesh). They were identified by comparison of their 1H NMR and 13C NMR spectra and physical data with those of the authentic samples. 1H NMR and 13C NMR spectra were recorded with Bruker DRX500 AVANCE (400 MHz) spectrometers,using CDCl3 as solvent. Melting points (MPs) were measured on an Electrothermal 9100 apparatus. The morphology and elemental composition were characterized using a digital scanning electron microscope (SEM) (VEGA 3 SB; TESCAN Co.,s.r.o.,Brno,Czech Republic) and an energy dispersive X-ray spectrometer (EDS) attached to the SEM with an operating voltage of 15 kV,respectively.
Synthesis of Zn1-xCuxO (1% Cu-doped) nanopowder was carried out using a modified procedure [24]. The targets were specifically designed using high purity Zn(NO3)2·6H2O (99.99%) and CuSO4·5H2O (99%) powders. The Cu-doped ZnO catalyst was prepared by a two-step procedure: (1) preparation of the precursor by co-precipitation; (2) formation of the Cu/ZnO nanopowder by thermal decomposition. This method has been considered to be efficient and inexpensive,allowing for the production of high purity,homogeneous,and fine crystalline powders.
Stoichiometric quantities of Zn and Cu salts were dissolved in 100 mL of deionized double distilled water (solution A). Separately,a solution was prepared by dissolving appropriate amounts of NaOH and Na2CO3 in deionized double distilled water (solution B). Solution A was heated to 85 °C and solution B was added dropwise into it with constant stirring. The temperature was maintained at 85 °C and the reaction mixture was stirred for 1 h and refluxed through a water condenser. The resulting solution was cooled to room temperature and the green precipitate that formed was washed with 3 × 20 mL of de-ionized water and dried under vacuum overnight at 50 °C. Finally,the precursors were calcined at 450 °C for 90 min in a muffle furnace under air atmosphere to obtain the nanocrystalline Cu/ZnO powder.
Figure 1 shows the SEM image of a nanocrystalline Zn1-xCuxO sample. Figure 2 shows the EDX spectra of a nanocrystalline sample,in which the estimated amount of Cu dopant is approximately 1%. The similarity of the Zn and Cu peak line intensity demonstrates that Zn and Cu are homogeneously distributed within the nanoparticle.
Aldehyde (1 mmol),1,3-indandione (1 mmol),propiophenone or acetophenone derivatives (1 mmol) and ammonium acetate (1.3 mmol) were stirred in a 10-mL round-bottomed flask in the presence of 10 mol% of Cu-doped ZnO nanocrystalline powder in a mixture of C2H5OH:H2O = 1:1.5 (volume ratio) at room temperature for the stipulated time. The progress of the reaction was monitored by TLC. After completion of the reaction,the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4,concentrated and recrystallized from hot ethanol to afford the pure product.
We used the Cu-doped ZnO nanocrystalline powder catalyzed MCR of benzaldehyde,1,3-indandione,propiophenone,and ammonium acetate as a model system by which to optimize the reaction conditions. We initially evaluated the effect of different solvents and found that protic solvent systems such as EtOH/H2O afforded the indenopyridine product in high yields and short reaction time (Table 1).
Next we investigated alternative amounts of Cu-doped ZnO nanocrystalline powder (5 and 15 mol%) in the same model system. The optimum yield of the indenopyridine product was obtained when 10 mol% of Cu-doped ZnO nanocrystalline powder was used (Table 2).
We also investigated the optimal amount of Cu doping in the catalyst. Increasing the amount of doping Cu from 1% to either 3% or 5 % had no effect on the product yield,but resulted in slightly longer reaction time (Table 2,entries 2,4,and 5).
To show that doping is necessary for efficient catalytic activity,the control reactions were carried out using ZnCl2,CuCl2·2H2O,and bulk ZnO; the product yields were much lower than the Cu-doped ZnO catalyst results (Table 2,entries 6,7,and 8).
Subsequently,we used the optimized reaction conditions to prepare a variety of indenopyridines from a range of aldehydes,1,3-indandione,propiophenone or acetophenone derivatives,and ammonium acetate. The results are summarized in Table 3.
In the optimized reaction conditions,aldehydes (1 mmol),1,3- indandione (1 mmol),propiophenone or acetophenone derivatives (1 mmol) and ammonium acetate (1.3 mmol) in ethanol/H2O (5 mL) were stirred with Cu-doped ZnO nanocrystalline powder (10 mol%) at room temperature for 1.5-2 h.
When electron-withdrawing substituents are present in the aldehyde,the reaction rate increases,whereas the effect is reversed in the case of aldehydes with electron-donating substituents.
Recycling the catalyst is a major advantage of this system from an economical and environmental point of view. We therefore examined the reusability of the Cu-doped ZnO nanocrystalline powder in the reaction of benzaldehyde,1,3- indandione,propiophenone,and ammonium acetate under the optimized reaction conditions. The catalyst could be reused four times after it was separated from the reaction mixture by filtration,washed with CH2Cl2 and dried (Table 4).
We compared one of our results with the data reported in the literature (Table 5). Our method gives a higher yield of product under mild reaction conditions with a green solvent.
A tentative mechanism for Cu-doped ZnO nanocrystalline powder catalyzed synthesis of indeno[1,2-b]pyridines has been proposed (Scheme 2) . We suggest that the reaction proceeds through the activation of the aldehyde carbonyl oxygen by the Cu-doped ZnO nanocrystalline powder by virtue of its inherent Brönsted acidity. This promotes subsequent condensation with 1,3-indandione to form enedione intermediate (B). Intermediate (B) then condenses with enamine (A) to form intermediate (C) which cyclizes to give dihydropyridines (D),and then oxidation produces the final product.
We have developed an efficient and versatile method for the synthesis of substituted indenopyridines using aldehydes,1,3- indandione,propiophenone or acetophenone derivatives,and ammonium acetate in the presence of Cu-doped ZnO nanocrystalline powder as a heterogeneous catalyst. The simple reaction,work-up procedure,catalyst preparation,excellent yields and low catalyst loadings are notable advantages of this method.
Financial support of this work from the Research Council of Mazandaran University is gratefully acknowledged.
2014, Vol. 35 Issue (4): 560-564
PDF (424KB)
2014, Vol. 35 Issue (4): 560-564
PDF (424KB)