A highly efficient synthesis of trisubstituted quinolines using sodium hydrogensulfate on silica gel as a reusable catalyst

o-Aminoaryl ketones underwent smooth condensation with a variety of α -methylene ketones in the presence of NaHSO 4 .silica gel as a solid acid catalyst to afford 1,2,3-trisubstituted quinolines in excellent yields. The reusability of the catalyst has made the protocol simple, cost–effective and environmentally benign.


Introduction
2][3] In addition, quinolines have also been employed in the study of bio-organic and bio-organometallic processes 4 .Due to such a wide range of applicability in medicinal, bioorganic, industrial as well as in the fields of synthetic organic chemistry, there has been increasing interest in the development of efficient methodologies for the synthesis of quinolines.
Friedlander quinoline synthesis is one of the most straightforward approach practiced for the synthesis of quinolines.Few recent protocols reported for the synthesis of quinolines involve the use of catalysts such as SnCl 2 , 5a BiCl 3 5b , I 2 5c , montmorillonite-KSF, 6 ionic liquids, 7 Bi(OTf) 3 , 8 Y(OTf) 3,9 silverdodecatungstophosphate (Ag 3 POW 12 O 40 ), 10 silica sulfuric acid 11a , sulfamic acid 11b , neodymium nitrate 11c , etc.However, these methods suffer from the serious drawbacks of harsh reaction conditions, use of expensive catalysts, longer reaction times, etc.Thus, a simple and environmentally benign protocol involving the use of inexpensive and readily available reagents is desirable.
In recent years, the use of heterogeneous catalysts has received considerable interest in various disciplines including organic synthesis.They are advantageous over their homogeneous ARKAT counterparts due to the prime advantage that in most of the cases the catalyst can be recovered easily and reused. 12Similarly the avoidance of the solvent helps in making the process environmentally benign and economically viable.Sodium hydrogen sulfate supported on silica gel 13 has been proved to be a heterogeneous catalyst of choice of many researchers, due to its ease of preparation using readily available reagents as well as its high catalytic efficiency.It has been used earlier in α-bromination of ketones, 14 in the cleavage of MOM-ethers and prenyl esters 15a,15b , in the synthesis of dihydropyridines 16a as well as homoallylic amines 16b , etc.Our earlier experiences with the use of heterogeneous solid acid catalyst 17 as well as the recent surge in the development of solvent-free and environmentally benign protocols prompted us to test the feasibility of sodium hydrogen sulfate.SiO 2 for the synthesis of quinolines and we wish to report herein a highly efficient, cost effective and environmentally benign protocol for the synthesis of 2, 4, 6-trisubstituted quinolines (Scheme 1).
R Scheme 1

Results and Discussion
In a typical reaction, a mixture of 2-aminobezophenone 1 (2 mmol), ethyl acetoacetate 2 (2.1 mmol) and NaHSO 4 .SiO 2 (200 mg) was stirred at room temperature (Scheme 1).The careful examination of TLC (6 h) showed the formation of a new product but the reaction did not go to completion even after stirring overnight.However, heating the reaction mixture for 3 h at 70 o C resulted in the formation of desired quinoline derivative viz.ethyl-2-methyl-4-phenyl-3quinoline carboxylate, 3a (95 %) as characterized by comparison of the mp and spectral data with that reported in the literature. 8he studies on the optimization of the reaction conditions with respect to the amount of catalyst used as well as temperature revealed that, the desired quinoline 3a couldn't be obtained in the same yield (95 %) at the temperature lower than 70 o C. Furthermore, the use of common organic solvents like CHCl 3 , CH 3 CN or EtOH was not found to have any influence on the yield of 3a and the best results were obtained under solvent-free conditions.
The synthetic utility of the reaction under the optimized reaction conditions was evaluated by performing the reactions between 2-aminobezophenone as well as 2-amino-5chlorobenzophenone with a variety of ketones like cyclohexanone, cyclopentanone, cyclohexan-ARKAT 1,3-dione, dimedone as well as acetyl acetone.In all the cases, the corresponding quinoline derivatives were obtained in acceptable yield and purity.However, the reaction of 2aminoacetophenone with various ketones proved to be sluggish as compared to that with 2aminobenzophenone.The results of all these studies are summarized in Table 1.
Finally, the efficacy of the NaHSO 4 .SiO 2 as a catalyst for the synthesis of 3a as a model compound, was compared with that of other reported catalysts such as Ag 3 PW 12 O 40 , sulfamic acid, Bi (OTf) 3 , Y(OTf) 3 and KSF-Clay (Table 2).It revealed that NaHSO 4 .SiO 2 is an equally efficient, cost-effective and environmentally benign catalyst useful in the synthesis of quinoline derivatives.From the practical point of view, the catalyst is easier to prepare from the readily available reagents and except for the isolation step wherein the solvent was essential, the reaction proceeded under solvent-free conditions.Furthermore, like other heterogeneous catalysts, it can also be reused.For example, the reaction of 2-amino-5-chlorobenzophenone and ethyl acetoacetate afforded corresponding quinoline derivative in 92, 90, and 86 % yields over three successive runs.
In conclusion, we have described a highly efficient, cost-effective and environmentally benign protocol for the synthesis of 2,4,6-trisubstituted quinolines using NaHSO 4 .SiO 2 as a heterogeneous and reusable catalyst.This operationally simple procedure can be used as a useful alternative to the existing protocols for the synthesis of trisubstituted quinolines.

Experimental Section
General procedure.A mixture of o-amino ketone (2 mmol), ethyl acetoacetate / acetylacetone (2.1 mmol) and NaHSO 4 .SiO 2 (200 mg, 0.52 mmol) was heated with stirring at 70 o C until completion of reaction (TLC).The reaction mixture was diluted with chloroform, the catalyst was filtered and washed with chloroform.From the combined filtrate solvent was removed under vacuum and the residue was filtered through a short column of silica gel to afford pure quinoline derivative.

Table 2 .
Comparison of the efficiency of NaHSO 4 .SiO 2 for synthesis of 3a