Magnetic Nano Cobalt Ferrite Catalyzed Synthesis of 4 H-Pyrano [ 3 , 2h ] quinoline Derivatives under Microwave Irradiation

A microwave irradiated magnetically separable nano cobalt ferrite catalyzed green method for the synthesis of 4-phenyl-4H-pyrano[3,2-h]quinolin-2-amine and 2-amino-4-phenyl-4H-pyrano[3,2-h] quinoline-3-carbonitrile derivatives through cyclization of aromatic aldehyde, acetonitrile/malononitrile and 8-hydoxyquinoline is developed and presented in this paper. The cubic magnetic cobalt ferrite nano particles were synthesized by sol-gel citrate precursor method and characterized by FT-IR, XRD, SEM and TEM techniques and the structures of the synthesized pyranoquinoline derivatives were assigned by IR, MASS and 1H NMR techniques. The reaction is carried out in a domestic microwave oven with a heat-resistant microwave safe glass container with a lid.


Introduction
Microwave irradiation is a powerful tool and efficient method for the synthesis of biological active compounds due to selective absorption of microwave energy by polar molecules [1].The wide applications of microwave irradiation are to enhance the rate of the reaction and usage of non-conventional energy source for product syn-thesis [2].
Most of the multicomponent reactions (MCRs) proceed through convergent reaction pathway, in which two or more starting materials react to form a single product in one-pot manner without any intermediate formation [3].Multicomponent reactions play an important role in organic chemistry due to their excellent yields, ideal atom efficiency, convergence, exploratory power leading to the straight forward synthesis of some heterocyclic compounds [4] and also they have wide applications in combinatorial synthesis [5]- [7].Pyranoquinolines are the important moieties in natural products [8]- [10] and these compounds have shown antimalarial [11], HIV inhibitors [12], pharmaceuticals [13], antischistosomal agents [14], antimicrobial [15] [16] and antitumor activity [17].
Here we are reporting an efficient improved procedure for one-pot multi-component synthesis of 4H-pyrano [3,2-h]quinoline derivatives through aromatic aldehyde, malononitrile/acetonitrile and 8-hydroxyquinoline in presence of magnetically separable nano cobalt ferrite catalyst under microwave irradiation (Scheme 1).

Chemicals and Apparatus
Chemicals used in this procedure are of AR grade without further purification.The calcined as-synthesized nano cobalt ferrite was characterized by XRD, SEM, FT-IR, BET and TEM.The XRD spectra were recorded on PA-Nalytical-Xpertpro diffractometer and the average crystallite size was determined from the corresponding XRD data.The microstructural morphology was studied with a Scanning Electron Microscope (SEM) model JEOL- JSM 6610 LV.FTIR spectra were recorded on BRUKER ALPHA FT-IR with Opus 6.1 version.Specific surface area (SBET) of sample was determined by BET surface area analyzer (Nova 2000 series, Quanta chrome Instruments, UK).KORYO microwave oven (model-KMS1911) with a power output-700W and microwave frequency-2450 MHz was used.The synthesized pyranoquinoline derivatives were characterized by IR, MASS and 1 H NMR. IR spectra recorded on a (Perkin Elmer Spectra-880) spectrophotometer by using KBr pellets in the region 400 -4500 cm −1 and 1 H NMR spectra was characterized by 400 MHz-(Bruker Avance) in CDCl 3 / DMSO-d 6 solvent and Mass spectra was recorded at 70 eV (MASPEC low resolution mass spectrometer).

Catalyst Preparation and Characterization
The nano cobalt ferrite has been synthesized by citrate precursor sol-gel method and characterized by FT-IR, SEM, TEM, XRD and particle size analysis as reported earlier by us [37].

General Procedure for the Synthesis of 4H-Pyrano[3,2-h]quinoline Derivatives
About 0.5 g of the catalyst was taken and activated at 500˚C for 2 hours and cooled to room temperature before the experiment.Equimolar quantities of aromatic aldehyde (10 mmol), acetonitrile/malononitrile (10 mmol) and 8-hydoxyquinoline (10 mmol) were mixed together in a microwave dish and dissolved in 5 mL of ethanol and the catalyst added homogenised.The reaction mixture was irradiated in microwave oven in 2 minute intervals at Defrost mode (40% power output) as higher power levels of the microwave oven resulted in evaporation of the solvent and reactants even before the products are formed).The progress and completion of the reaction was monitored by TLC using mobile phase (n-Hexane:ethyl acetate 3:1), the formed product mixture was cooled to room temperature and ethyl alcohol added until the product was dissolved.The products were isolated by removing the catalyst magnetically from the reaction mixture and the formed products were characterized and compared by IR, 1 H NMR and MASS spectral techniques (Table 1).

Catalytic Study
The procedure involves multi-component one pot cyclization reaction between aromatic aldehyde, acetonitrile/malononitrile and 8-hydoxyquinoline is described as a model reaction shown in Scheme 1.The feasibility of formation of pyranoquinoline derivatives and the reaction conditions are tabulated in Table 2.

Effect of Catalyst Loading on Synthesis of 4H-Pyrano[3,2-h]quinoline Derivatives
Investigation of the amount of catalyst loading was tested in this reaction procedure and the results are shown in Table 2. From this study, 500 mg of nano CoFe 2 O 4 catalyst was sufficient to synthesize 92% isolated yields of pyranoquinoline derivatives (Entry 4, Table 2).From these experimental studies low concentration of catalyst is not enough to synthesize higher yields of pyranoquinoline derivatives (Entry 2, Table 2), while high concentration of nano CoFe 2 O 4 catalyst loading did not produce considerable changes in the percentage of product yields (Entry 5, 6, Table 2).Hence, 500 mg of nano CoFe 2 O 4 catalyst is sufficient to synthesize 4H-pyrano[3,2-h] quinoline derivatives.

Comparative Study of Nano Cobalt Ferrite Catalyst with Other Catalysts for the Synthesis of 4H-Pyrano[3,2-h]quinoline Derivatives
Reaction times for the formation of pyranoquinoline derivatives with various catalysts are presented in Table 3.
It is observed that with other catalysts and particularly under reflux conditions the reactions times are very much higher.Under microwave conditions, synthesis of 4H-pyrano[3,2-h]uinoline derivatives catalyzed by InCl 3 [32] has been reported with shorter reaction times, the present method offers a comparatively very low cost and easily producible nano cobalt ferrite for effective results.

Recycling of the Catalyst
Catalyst reusability is of major concern in heterogeneous catalysis.Catalyst recycling was achieved by fixing the catalyst magnetically at the bottom of the microwave dish with a strong Neodymium magnet, after which the solution containing the product was taken off with a pipette, the catalyst washed thrice with ethyl acetate, dried and the fresh reactants dissolved in ethyl alcohol was introduced into the microwave followed by microwave irradiation, allowing the reaction to proceed for the next run.The catalyst was consecutively reused for five times without any noticeable loss of its catalytic activity.

Conclusion
In this present study, we report an efficient method for the synthesis of pyranoquinoline derivatives using nano cobalt ferrite as heterogeneous catalyst.This method has several advantages like improved yield of products, microwave assisted reaction, less reaction times, easy separation of the catalyst by strong Neodymium magnet, recyclability and reusability of the catalyst.

Derivatives Catalyzed by Nano CoFe 2 O 4
Initially acetonitrile/malononitrile undergo deprotanation in the presence of Lewis base (O 2− ) of nano CoFe 2 O 4

Table 1 .
Reactants and spectral data of pyranoquinoline derivatives.

Table 2 .
Effect of catalyst loading.

Table 3 .
Comparative study of nano CoFe 2 O 4 catalyst with other catalysts.carbanion which further react with aromatic aldehyde leads condensation reaction in the presence of Lewis acid (Fe 3+ ) to form an intermediate arylidenemalononitrile (1-Knovenagel product).This intermediate undergo Michael addition with 8-hydroxyquinoline, leads to cyclization followed by rearrangement reaction produce 4H-pyrano[3,2-h]quinoline derivatives shown in Scheme 2.