Molecular Sieve Supported Lanthanum Catalyst for the Efficient Synthesis of Polyhydroquinolines via Hantzsch Synthesis

Molecular sieve supported lanthanum catalyst proved to be an efficient heterogeneous catalyst for the one-pot, four-component synthesis of polyhydroquinoline derivatives from aromatic aldehydes, dimedone, ethyl acetoacetate and ammonium acetate in ethanol via Hantzsch reaction. The method has several advantages such as simple reaction conditions, short reaction time, high yields and simple workup procedure, which make it an attractive route for the synthesis of polyhydroquinolines. The catalyst could be reused several times without the loss of its initial activity.

ionic liquids as catalysts [23]. Their syntheses have also been reported under catalyst-free conditions, in refluxing water, but this method suffered from longer reaction times [24]. PHQs have also been synthesized under microwave irradiation conditions [25,26]. However, many of the described methods suffer from disadvantages such as long and tedious preparation of the catalyst [17,18], use of toxic and corrosive reagents [8,9,15,19,20], and the use of expensive materials as catalyst [10]. Thus, the development of a simple and efficient method for the preparation of polyhydroquinoline derivatives is still has a synthetic importance.
Heterogeneous catalysts offer several advantages over the homogeneous ones; they are easily separable from the reaction mixture by filtration, often reusable, more selective, non-toxic, non-corrosive, easy to handle, thus their use is more preferable from environmental point of view. As they are easily separable, the contamination of the product either by the catalyst (metal) or by the ligand usually necessary for the homogeneous catalysis can be avoided [27].
Our research group works on the development of new heterogeneous catalytic methods for the preparation of organic compounds using supported metal catalysts. During this work several metals, such as palladium, nickel, copper [28,29], titanium [30] or lanthanum [31] on different supports (Mg:La 3:1 mixed oxide, 4 Å molecular sieve) were used successfully in different organic syntheses [32]. As the 4 Å molecular sieves are readily available [33] and beside of their good water binding ability, their slightly basic property might accelerate organic reactions, we developed several metal catalysts on 4 Å molecular sieve support.
In this paper we report a method for the one-pot four-component synthesis of polyhydroquinolines promoted by a heterogeneous, 4 Å molecular sieve supported lanthanum catalyst under mild basic conditions.

Results and Discussion
The structure of the La 3+ /4A catalyst was investigated by scanning electron microscopy (SEM). The characteristic cuboctahedron shape of the molecular sieve support can be seen on Fig. 1. The particles are well defined both in shape and size. The lanthanum is evenly distributed on the surface of the support [31]. EDS showed 3.65 w/w% lanthanum on the surface (Fig. 2). The lanthanum content determined by ICP-OES was 3.88 w/w%. The catalyst has slightly basic properties, its pH value is 8.40, while the pH value of the unmodified support is 10.42 (see Experimental). From the nitrogen adsorption/ desorption measurements the specific surface of the catalyst is 35 m 2 /g.  The results are summarized in Table 1. As shown, a variety of benzaldehydes were successfully applied to prepare the corresponding polyhydroquinoline derivatives in high yields. Benzaldehyde and other aromatic aldehydes containing electron-withdrawing groups (such as nitro group, halide) or electron-donating groups (such as alkoxy group) were tested in the reaction and gave the desired product in good to excellent yields. The lower yield in the case of 4b may be explained by solubility problems. There was no significant steric effect observed, as ortho-, meta-, and para-derivatives gave results of the same order (see Table 1 entries 10-12). There is a difference between the observed melting point and the data found in the literature in the case of 2-fluorophenyl-derivative (4f), however the 1 H and 13 C NMR spectra of the compound corresponds to the literary spectra and DSC showed only one sharp melting point.
The workup of the reaction mixtures was simple, the catalyst was filtered, washed with ethanol, then the filtrate was evaporated. The residue was diluted with diethyl ether; the precipitated solid was filtered and subjected to 1 H and 13 C NMR spectroscopy. No side product was observed.
Although the reaction has been described generally with acidic catalysts, in our case the slightly basic heterogeneous catalyst gave good results. As the EDS measurement showed, the lanthanum is located on the surface of the support, forming potentially acidic sites. The reaction may happen on these parts of the catalysts. Meanwhile the bulk basic phase may help to avoid the potential disadvantageous, acid-catalysed side reactions or a possible decomposition if an acid-sensitive compound or functional group is present (e.g. 4-methoxybenzaldehyde [21]).
The reusability of the lanthanum catalyst was studied in the model reaction of 4-chloro-benzaldehyde (1e), dimedone (2), ethyl acetoacetate (3) and ammonium acetate in refluxing ethanol. After the reaction the solid was filtered and washed with ethanol, then heated at ca. 150 °C for 1 h. The catalyst has been reused in 2 more runs without considerable decrease in its activity; the isolated yields for the three successive runs were 96% each time, which clearly demonstrates the practical recyclability of this catalyst. Taking into account the same results obtained, we did not consider necessary to examine the reusability further.

Experimental Section
Morphology of the catalyst samples was investigated by a JEOL 6380LVa (JEOL, Tokyo, Japan) type scanning electron microscope and elemental mapping was also accomplished using the energy-dispersive X-ray detector of the equipment. Each specimen was fixed by conductive double-sided carbon adhesive tape (using a JEOL 1200 instrument). Applied accelerating voltage and working distance were between 15 and 30 kV and 10 and 12 mm, respectively.
Nitrogen adsorption/desorption isotherms were measured at -196 °C with a computer controlled Nova 200e (Quantachrome) instrument. Transformation of the primary adsorption data was performed with the Quantachrome software. The apparent surface area (S BET ) was calculated using the Brunauer-Emmett-Teller (BET) model. Samples were evacuated for 24 h at 110 °C prior to the adsorption measurement.
GC-MS measurements were performed on an Agilent 6890 N-GC-5973 N-MSD chromatograph, using a 30 m x 0.25 mm Restek, Rtx-5SILMS column with a film layer of 0.25 μm. The initial temperature of column was 45 °C for 1 min, followed by programming at 10 °C/min up to 310 °C and a final period at 310 °C (isothermal) for 17 min. The temperature of the injector was 250 °C. The carrier gas was He and the operation mode was splitless.
1 H and 13 C NMR spectra were made on BRUKER Avance-500 instrument using TMS as internal standard, in CDCl 3 .
Melting points were determined on Gallenkamp apparatus and were uncorrected, or on SETARAM DSC 92 apparatus, where the initial temperature was 25 °C, followed by programming at 10 °C/min up to 300 °C under nitrogen atmosphere.

Preparation of the catalyst
4 Å molecular sieve (4A) was impregnated with La(NO 3 ) 3 x 6H 2 O as follows: 1 mmol of the metal salt was dissolved in 100 mL of deionised water and stirred with 1 g 4A at room temperature for 24 h. The solid was filtered, washed with deionised water and with acetone, then dried in an oven at 150 °C for 1 h.

Determination of the pH of the catalyst
The catalyst (1 g) was stirred in 30 mL deionised water under continuous measuring of the pH. The values were accepted after reaching a constant value at least during 10 min.

Typical reaction conditions
A typical reaction was carried out in a 10 mL flask. Aldehyde (1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol), ammonium acetate (1.5 mmol), La 3+ /4A (0.1 g) and ethanol (3 mL) were stirred at reflux temperature for 4 h. The progression of the reaction was monitored by TLC. After completion, the solid was filtered, and washed with ethanol, then the filtrate was evaporated. The residue was suspended in diethyl ether, the precipitated solid was filtered and subjected to 1 H and 13 C NMR spectroscopy.
All products have satisfactory spectral data ( 1 H and 13 C NMR). The spectral data of the known compounds were identical with those reported in the literature. Representative physical and spectroscopic data of the products: Ethyl 2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,

Conclusions
In conclusion, lanthanum on 4 Å molecular sieve support proved to be useful catalyst for the one-pot, four-component synthesis of polyhydroquinolines under mild conditions, using slightly basic heterogeneous catalyst, which is almost unprecedented in the literature. The catalyst could be prepared simply and can be reused with good result without the loss of activity.