Access to a Library of Pyrano[3,2-c]quinolines Using NiFe2O4@SiO2 Bonded Ionic Liquid

Pyrans and quinolines are at the core of bioactive materials with interesting pharmacological effects. Several compounds containing quinoline fused to pyrans, such as pyr-ano[3,2-c]quinolines, have also shown valuable properties. Pyranoquinoline frameworks have been identified in important natural compounds, including oricine, huajiaosimu-line and flindersine (Scheme 1). Similar structures have a broad range of such pharmacological properties as anti-inflammatory, antibacterial, antitubercular, antiproliferative and anti-tubulin activities; some are selective r 1 receptor ligands, and some are mitotic kinesin-5 inhibitors. 1 – 10

The solvent has a significant effect on the product yield. Aqueous ethanol produced high yields. The productivity of the reaction is low in water and under solvent-free condition. No product was obtained when catalyst was absent. Use of 0.025 g of (A) as a catalyst and ethanol (50%, at reflux) produced the best yield over a reaction time of 100 min (94%).
With the best reaction conditions having been determined, several derivatives of pyrano [3,2-c]quinoline were prepared, using 4-hydroxyquinolin-2(1H)-one, malononitrile and aromatic aldehydes bearing both electron-withdrawing and electron-donating groups. The results are summarized in Table 2 (products 1d-16d). Yields were excellent (mean 91%). The reactions were monitored by thin layer chromatography (TLC). It was noted that some aldehydes with electron-withdrawing/halogen groups (NO 2 , Cl, Br) achieved TLC completion somewhat faster than those containing electron-donating groups (CH 3 , OCH 3 ). The NMR and elemental analysis data were consistent with the structures proposed for the products.  Thus the 1 H-NMR spectrum of compound 1d showed the amide hydrogen (N-H) located at d 0.71 as a singlet. The 13 C-NMR spectrum of compound 1d revealed 17 carbon signals, among these the C ¼ O carbon at d 161.2.
The catalyst could be recovered from the reaction medium by an external magnet (see Experimental section) and then used for new reactions for the preparation of (1d), remaining effective through a substantial number of cycles (Table 3).
Summing up, the title catalyst permitted the preparation of pyranoquinolines under mild conditions from 4-hydroxyquinolin-2(1H)-one, malononitrile and substituted benzaldehydes. Yields were excellent. The products were isolated from the reaction mixtures in a simple procedure. The procedure has the advantage of using a recoverable heterogeneous catalyst.

Experimental section
All reagents were purchased from Merck and Aldrich and used without further purification. All yields refer to isolated products after purification. The powder X-Ray diffraction patterns were measured with a Bruker D8 Advance diffractometer using Cu-Ka irradiation. The NMR spectra were recorded on a Bruker Avance DPX 400 MHz instrument. The spectra were measured in DMSO-d 6 relative to TMS (0.00 ppm). Elemental analysis was performed on a Heraeus CHN-O-Rapid analyzer. FE-SEM coupled with EDAX was taken using a Hitachi S-4160 photograph to examine the shape and metallic composition of the samples. Melting points were obtained on a Electrothermal IA9200 instrument and are uncorrected. Infrared spectra were taken using a Shimadzu IRTracer-100 instrument.

Preparation of NiFe 2 O 4
NiCl 2 Á6H 2 O (molecular weight 237 g/mol, 65 mmol, 15.4 g) and FeCl 3 Á6H 2 O (molecular weight 270 g/mol, 130 mmol, 35.1 g), with the molar ratio of 1:2, were dissolved in  200 mL of deionized water under mechanical stirring. The final weight ratio of salts/ water was 1/4. A dilute solution of NH 4 OH was added dropwise to the mixture until the pH was 11. After precipitation, the solid was filtered, washed with deionized water and calcined in an electric furnace at 700 C.

Preparation of NiFe 2 O 4 @SiO 2
To a dispersion of NiFe 2 O 4 nanoparticles (3 g) in 150 mL ethanol, tetraethyl orthosilicate (TEOS) (7 mL) was added and mechanically stirred for 1 h. Afterward the pH of the solution was adjusted to 8.5 with 20% aqueous ammonium hydroxide. After 48 of mechanically stirring the mixture, NiFe 2 O 4 @SiO 2 was separated with an external magnet, washed with water (25 mL) three times, and dried at 100 C in air.

Preparation of the title nanoparticles (A)
(3-Chloropropyl)trimethoxysilane (3 mmol) was combined with N-methyl imidazole (3 mmol) in 20 mL of toluene and the mixture was kept at reflux for 24 h. Next, the mixture was combined with NiFe 2 O 4 @SiO 2 (3 g) and stirred for 24 h at reflux. Finally, the mixture was washed with ethanol (20 mL) twice, dried, and dispersed in 100 mL of CHCl 3 , to which was added dropwise sulfuric acid (4 mmol, 98%), and the mixture refluxed for 6 h. Next, the resulting solid was separated, washed with diethyl ether (25 mL), and dried. The characterization data for the catalyst are available in the Supplementary Materials of the online version of this article or from the corresponding author upon request.