Scholarly article on topic 'A Solvent-free Synthesis of Polyhydroquinolines via Hantzsch Multicomponent Condensation Catalyzed by Nanomagnetic-supported Sulfonic Acid'

A Solvent-free Synthesis of Polyhydroquinolines via Hantzsch Multicomponent Condensation Catalyzed by Nanomagnetic-supported Sulfonic Acid Academic research paper on "Chemical sciences"

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Academic research paper on topic "A Solvent-free Synthesis of Polyhydroquinolines via Hantzsch Multicomponent Condensation Catalyzed by Nanomagnetic-supported Sulfonic Acid"

A Solvent-free Synthesis of Polyhydroquinolines via Hantzsch Multicomponent Condensation Catalyzed by Nanomagnetic-supported Sulfonic Acid

Somayeh Otokesh, Nadiya Koukabi*, Eskandar Kolvari, Ali Amoozadeh*, Masoumeh Malmir and Saeede Azhari

Department of Organic Chemistry, Faculty of Chemistry, Semnan University, Semnan, Iran. Received 18 September 2014, revised 17 November 2014, accepted 18 November 2014.

ABSTRACT

A simple and efficient procedure for the synthesis of polyhydroquinolines was developed, involving a one-pot four-component Hantzsch condensation of aromatic aldehydes, 1,3-cyclohexanediones, alkyl acetoacetate and ammonium acetate in the presence of a catalytic amount of nanomagnetic-supported sulfonic acid under solvent-free conditions. The method offers several advantages including high yields, short reaction times, a simple work-up procedure and catalyst reusability for several runs. Furthermore, easy isolation of the catalyst from the reaction mixture was enabled by use of an external magnet.

KEYWORDS

Nanomagnetic-supported sulfonic acid, multicomponent reaction, solvent-free conditions, heterocyclic compound, Hantzsch reaction.

1. Introduction

Since the beginning of this century, different sciences have seen a rapid increase due to interest in materials at the nano-scale. Nanomaterials have attracted attention because of physical, electronic and magnetic properties. The field of nanomagnetic particles is a subset of nanomaterials. The applications for these materials are very diverse such as metal ion separations,1 enzyme immobilization,2 magnetic resonance imaging (MRI),3 drug delivery and catalysis.4 In chemistry, nanomagnetic catalysts have emerged as one of the most useful heterogeneous catalysts due to their numerous applications in organic synthesis.5 These catalysts have been studied in various significant protocols in organic chemistry because they are robust, inexpensive and readily available. Also, they can be easily prepared from their available metal salts and most importantly can be recycled for several runs without any loss of selectivity and activity.6

In the context of green chemistry, the design and development of organic synthesis performed through multicomponent reactions (MCRs) have become a significant area of research in organic chemistry since such processes improve atom economy, efficiency and convergence.7 Therefore, MCRs are often useful alternatives to sequential multistep synthesis. The synergistic use of nanomagnetic particles and MCRs allows efficient synthesis of diverse nitrogen-containing heterocycles. One of the most prominent methods to prepare these compounds is the Hantzsch condensation reaction providing polyhydroquinolines. The polyhydroquinoline moiety is a fertile source of biologically and pharmacologically important molecules such as vasodilator, bronchodilator, anti-atherosclerotic, hepto-protective, anti-tumor, anti-mutagenic, geroprotective, anti-diabetic agents, HIV protease inhibition and most importantly as calcium channel blockers.8-15 All mentioned cases demonstrate clearly the remarkable potential of the polyhydroquinoline derivatives as a source of valuable

* To whom correspondence should be addressed. E-mail: koukabl@gmall.com / aamozadeh@semnan.ac.lr

drugs.16,17 In continuation of our investigation on the use of nano-g-Fe2O3-SO3H as catalyst for MCRs and our interest in synthesis of heterocycles containing a nitrogen atom,1819 we report an efficient and facile synthesis of hexahydroquinolines under solvent-free conditions (Scheme 1).

2. Experimental

2.1. General

All chemicals were purchased from Merck, Fluka or Across companies and used without any further purification. Nano-g-Fe2O3-SO3H was prepared with the reported method.20 Melting points were recorded on electro thermal 9100 apparatus and are uncorrected. NMR spectra were recorded with a Bruker Avance spectrometer (1H NMR 300,400 MHz and 13C NMR 75,100 MHz) in pure deuteriated chloroform and DMSO with tetramethylsilane (TMS) as the internal standard. The IR spectra were recorded on a Perkin-Elmer model 783 spectrophotometer (Waltham, MA, USA). UV-Vis spectra were obtained as ethanol solutions (10-5M) on a Shimadzu UV-1650PC spectrophotometer.

2.2. General Method for the Synthesis of Polyhydroquinolines (5a-o)

A mixture of aromatic aldehyde (1 mmol), alkyl acetoacetate (1 mmol), 1,3-cyclohexanedione (1 mmol), ammonium acetate (1.1 mmol) and nano-g-Fe2O3-SO3H (0.031 g) was heated at 60 °C. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and triturated with hot ethanol (5 mL). In the presence of a magnetic stirrer bar, nano-g-Fe2O3-SO3H moved on to the stirrer bar steadily and the reaction mixture turned clear within 10 s. The catalyst was isolated by simple decantation. After evaporation of the solvent, the crude product was recrystallized from EtOH/H2O to give a pure product.

2.3. Spectral Data of Some Representative Compounds

Ethyl 2-Methyl-5-oxo-4-phenyl-4,6,7,8-tetrahydro-1H-quino-

ISSN ISSN 0379-4350 Online / ©2015 South African Chemical Institute / http://saci.co.za/journal DOI: http://dx.doi.org/10.17159 /0379-4350/2015/v68a3

Scheme 1

line-3-carboxylate (5j) (90 %) as a light cream solid.; (recrystallized from EtOH/HzO, TLC- n-hexane:ethyl acetate, 8:2, Rf = 0.14); M.p. 240-242 °C, nmax (KBr) 3296 (NH), 1641 (C=O) (acid), 1608 (C=O) (ketone), 1488 (OC2H5) (ester) cm1; ^ (300 MHz, CDCl3) 1.17 (t, 3H, CH3-CH2-O-C=O), 1.59 (m, 2H, CH2,7 H), 1.97 (m, 3H, CH3), 2.30-2.46 (m, 4H, 6,8 H), 4.05 (q, 2H, -O-CH2-CH3), 5.01 (s, 1H,4 H), 5.94 (s, 1H, NH), 7.08-7.31 (m, 5H, 2', 3', 4', 5', 6' H) ppm. UV (Imax in EtOH): 378 nm.

Ethyl 4-(p-Methoxyphenyl)-2-methyl-5-oxo-7-phenyl-4/6/7/8-tetra-hydro-1H-quinoline-3-carboxylate (5l) (96 %) as a white solid.; (recrystallized from EtOH/H2O, TLC- n-hexane:ethyl acetate, 8:2, Rf = 0.12); M.p. 236-238 °C, n max(KBr) 3280 (NH), 1689 (C=O) (acid), 1606 (C=O) (ketone), 1479 (OC2H5) (ester), 1222 (OCH3) (ether) cm-1; dh/ ppm (300 MHz, CDCl3) 1.27 (m, 3H, CH3-CH2-O-C=O), 2.23-2.37 (m, 3H, CH3), 2.38-2.52 (m, 5H,

6.7.8 H), 3.71 (s, 3H, CH3-O-Ph), 4.07 (m, 2H, -O-CH2-CH3), 5.05 (m, 1H, 4 H), 6.71-7.12 (m, 4H, 2', 3', 5', 6' H), 6.96 (s, 1H, NH), 7.17-7.29 (m, 5H, 2",3",4",5",6" H); do/ppm (75 MHz, CDQ3) 195.2 (C-5), 167.5 (C=OOC2H5), 157.8 (C-4'), 150 (C-2), 149.5 (C-1a), 143.4 (C-1"), 142.6 (C-1'), 139.7 (C-2' and C-6'), 139.3 (C-3" and C-5"),128.8 (C-2"and C-6"), 127 (C-4"), 126.6 (C-3' and C-5'), 113.2 (C-5a), 106.2 (C-3), 59.8 (O-CH2-CH3), 55.1 (O-CH3), 39.5 (C-6), 38.8 (C-4), 35.8 (C-8), 34.4 (C-7), 19.1 (1C, CH3 ), 14.2 (1C, CH3-CH2O). UV (Imax in EtOH): 224 nm; 417.19 (100.0 %), 418.20 (28.6 %), 419.20 (4.8 %) m/z: 417 (100),418 (28.6 %) and419 (4.8 %), (Found: C,74.82; H, 6.83; N, 3.37 %. Calcd. for C26H27NO4 (417.19); C,74.80; H,6.52; N 3.35 %).

Ethyl 2-Methyl-5-oxo-4/7-diphenyl-4/6/7/8-tetrahydro-1H-quino-line-3-carboxylate (5n) (99 %) as a white solid; (recrystallized from EtOH/H2O, TLC- n-hexane:ethyl acetate, 8:2, Rf = 0.13); M.p. 213-215 °C, nmax (KBr) 3276 (NH), 1701 (C=O) (acid), 1606 (C=O) (ketone), 1487 (OC2H5) (ester), cm-1; dH (400 MHz, DMSO-d6) 1.14 (t, 3H, CH3-CH2-O-C=O), 2.32 (s, 3H, CH3), 2.35 (dd, 1H, 8 H), 2.5 (d, 1H, 8 H), 2.59 (m, 1H, 7 H), 2.68 (dd, 1H, 6 H), 2.79 (dd, 1H, 6 H), 3.17 (s, 1H, NH), 4.0 (q, 2H, -O-CH2-CH3), 4.98 (s, 1H, 4 H), 7.11 (m, 1H, 4' H), 7.19-7.24 (q, 5H, 2', 4', 6', 2", 6" H), 7.3-7.36 (m, 4H, 3', 5', 3", 5" H), 9.21(s, 1H, NH) ppm;dC(100 MHz, DMSO-d6) 194.4 (C-5), 167.3 (C=OOC2H5), 151.1 (C-2), 148.1 (C-1a), 145.3 (C-1"), 143.9 (C-1'), 128.9 (C-2' and C-6'), 128.3 (C-3' and C-5'),

127.9 (C-3" and C-5"),127.4 (C-2" and C-6"), 127 (C-4"), 126.2 (C-4'), 111.2 (C-5a), 104.2 (C-3), 59.5 (O-CH2-CH3), 44.4 (C-6), 38.8 (C-4), 36.2 (C-8), 34 (C-7), 18.7 (1C, CH3), 14.6 (1C, CH3-CH2O),ppm.UV (Imax in EtOH): 361 nm; 387.18 (100.0 %), 388.19 (27.2 %), 389.19 (4.6 %) m/z: 417 (100), 418 (27.2 %) and 419 (4.6 %), (Found: C,77.47; H, 6.52; N, 3.63; 0,12.37 %. Calcd. for C25H25NO3 (387.18); C,77.47; H,6.52; N 3.63; O, 12.37 %).

Ethyl 4-(p-chlorophenyl)-2-methyl-5-oxo-7-phenyl-4/ 6/ 7/ 8-tetrahydro-1H-quinoline-3-carboxylate (5o) (98 %) as a white solid; (recrystallized from EtOH/H2O, TLC- n-hexane:ethyl acetate, 8:2, Rf = 0.12); M.p. 190-192 °C, nmax (KBr) 3274 (NH), 1701(C=O) (acid), 1606 (C=O) (ketone), 1487 (OC2H5) (ester),

848 (C-Cl) cm-1; dh (400 MHz, DMSO-d6) 1.12 (t, 3H, CH3-CH2-O-C=O), 2.3 (t, 1H, 8 H), 2.31 (s, 3H, CH3), 2.5 (t, 1H, 8 H), 2.54-2.59 (7,1H, 8 H), 2.59-2.66 (m, 1H, 6 H), 2.74-2.82 (m, 1H, 6 H),), 3.17 (t, 1H, NH), 3.98 (q, 2H, -O-CH2-CH3),4.90 (d, 1H, 4 H), 7.22-7.28 (m, 5H, 2',6', 2", 4", 6" H), 7.31-7.33 (m, 4H, 3', 5', 3", 5" H), 9.21 (d, 1H, NH)ppm;dC(100 MHz, DMSO-d6) 194.2 (C-5), 167.1 (C=OOC2H5), 151.3 (C-2), 150.8 (C-1a), 147.1 (C-1"), 145.7 (C-1'), 143.8 (C-4'), 130.7 (C-2' and C-6'), 129.8 (C-3' and C-5'), 128.8 (C-3" and C-5"), 128.1 (C-2" and C-6"), 127.1 (C-4"), 111.0 (C-5a), 103.6 (C-3), 44.3 (O-CH2-CH3), 43.7 (C-6), 38.8 (C-4), 36.0 (C-8), 33.7 (C-7), 18.7 (1C, CH3), 14.5 (1C, CH3-CH2O) ppm. UV (Imax in EtOH): 363 nm; 421.14 (100.0 %), 422.14 (32.3 %), 423.15 (27.2 %) m/z: 421 (100 %), 422 (32.3 %) and 423 (27.2 %), (Found: C,71.19; H, 5.71; N, 3.32; Cl, 8.40; O, 11.38 %. Calcd. for C25H24QNO3 (421.11); C,71.19; H,5.71; N, 3.32; Cl, 8.40; O, 11.38 %).

3. Results and Discussion

Hammett acidity function (H0) can be used to effectively express the ability and acidity strength of an acid in organic solvents.21 This method using 4-nitro aniline with Hammett indicators is a simple quantitative method, which can be obtained from the relative intensities of the absorption band by UV-visible spectrometer. The acidity of the solution can be calculated by using the following Hammett equation in the form of H0, the acidity function as given:

H0 = pK(I)aq + log[I]s /[HI+]s

where [I] represents the indicator base, pK(I)aq is the protonation constant of the dye in aqueous solution (for example the pK(I)aq value of 4-nitroaniline is 0.99), which can be obtained from many references, [I]s and [HI+]s are respectively the molar concentrations of solvated non-protonated and protonated forms of the indicator. According to the Beer-Lambert law, the value of [I]s/[IH+]s can be determined and calculated from UV-visible spectrum measurements. In the present experiment, 4-nitroaniline was chosen as the basic indicator and CCl4 was chosen as the solvent because of its aprotic nature. A dilute solution (10-4 M) of 4-nitroaniline in CCl4 was prepared and used as a stock solution throughout the experiments. The maximal absorbance of the non-protonated form of 4-nitroaniline was observed at 331 nm in CCl4. As shown in Fig. 1, the absorbance of the non-protonated form of the indicator in nano-g-Fe2O3-SO3H was weak compared to the sample of the indicator in CCl4, which indicated that the indicator was partially in the form of [IH+]. The results obtained are listed in Table 1, which shows the acidity strength of nano-g-Fe2O3-SO3H.

First, in order to optimize the conditions, the reaction of benzaldehyde, ethyl acetoacetate, 5,5-dimethyl-1,3-cyclohex-anedione and ammonium acetate was chosen as a model system under thermal conditions. The results listed in Table 2 show that nanomagnetic-supported sulfonic acid is the best catalyst affording the highest yield (Table 2, Entry 10), while both

Figure 1 Absorption spectra of (a) 4-nitroaniline (indicator) and (b) nano-g-Fe2O3-SO3H (catalyst) in CCl4.

bulk-Fe2O3 and bulk-Fe2O3-SO3H provide lower yields (Table 2, Entries 4, 6). This is due to its higher surface areas and surface vacancies which are responsible for the excellent catalytic activity. Finally, for comparison, iron chloride salts, FeCl2.4H2O and FeCl3.6H2O, were also investigated for synthesis of polyhydro-quinoline. The results showed that the conversions were trace amounts (Table 2, Entries 2,3). By screening different amounts of nano-g-Fe2O3-SO3H, we found that product 5a was obtained in yields ranging from 40 to 98 (Table 2, Entries 7-11). Thus, the best amount of catalyst was 0.031 g (8 mol%) (Table 2, Entry 10).

In the following study of the model reaction, we examined the influence of various temperatures on the reaction rate as well as yields of products. As indicated in Table 3, the best yield was obtained at 60 °C (Table 3 Entry 3), so we considered it as optimum temperature. Higher temperatures decreased the total yield by producing byproduct as shown by TLC (Table 3, Entries 4, 5).

The choice of solvent was crucial. To this end, the reaction was

carried out with different solvents (Table 4). Fortunately, when the reaction was carried out in solvent-free condition, good yields and short reactions times were achieved which was consistent with context of 'sustainable chemistry', concerning green chemistry aspects; 'the best solvent is no solvent at all'.

In order to show the merit of method in comparison with other reported results in the literature for similar reactions, we compared the results of nano-g-Fe2O3-SO3H with other catalysts used for the synthesis of polyhydroquinoline derivatives in Table 5. This method has the following advantages: Magnetic separation can eliminate expensive centrifugation (compared to methods using nano catalysts without magnetic properties22), nano-sized magnetic particles have large specific surface area so adsorption capacity is high, for this reason, the reaction rate increased leading to energy savings. In contrast to other meth-ods,23-34 the products are obtained in a shorter time. These results clearly indicate that nano-g-Fe2O3-SO3H is an efficient, magnetic and reusable acidic catalyst, and the present method is found to be very effective for the synthesis of polyhydroquinoline derivatives.

To determine the recyclability of the catalyst, the same model reaction was again studied under optimized conditions. The results are shown in Table 6. It is important to mention that our new conditions also provide a fast and facile work-up; after completion of the reaction, the mixture was triturated with hot ethanol. Within a few seconds, after stirring was stopped, the reaction mixture turned clear and the catalyst was deposited on the magnetic bar, which was easily removed with an external magnet, after being washed with acetone and dried in air, the nano-g-Fe2O3-SO3H catalyst could be used at least five times without significant loss of activity. This efficient recyclability is most probably due to bound covalently sulfonic groups (-SO3H) to magnetic nanoparticles. However, the slight reduction of catalytic activity of the catalyst after recycling is probably due to the blockage of active sites on the catalyst surface (Fig. 2).

In order to evaluate the generality of our new conditions, we studied the reaction of aromatic aldehydes with electron-

Table 1 Calculation of Hammett acidity function (H0) of nano-g-Fe2O3-SO3Ha.

Entry Catalyst ^max [I]s/% [IH+Js/% H0

1 _ 1.52 100 0 _

2 Nano-g-Fe2O3-SO3H 1.16 78.47 21.52 1.65

a Solvent, CCl4; indicator, 4-nitroaniline (pK(I)aq = 0.99), 1.44*10-4 mol/L; catalyst, nano-y-Fe2O3- -SO3H (20 mg), 25 °C.

Table 2 Iron-based catalyzed Hantzsch four-component condensation of polyhydroquinoline a.

Entry Catalyst Catalyst amount/mol% Time/min Yield b/%

1 None _ 300 Trace

2 FeCl2.4H2O 15 65 Trace

3 FeCl3.6H2O 15 65 Trace

4 Bulk-Fe2O3 19 65 34

5 nano-g-Fe2O3 19 65 50

6 Bulk-Fe2O3-SO3H 8 65 56

7 Nano-g-Fe2O3-SO3H 0.5 65 40

8 Nano-g-Fe2O3-SO3H 1 65 50

9 Nano-g-Fe2O3-SO3H 3 65 85

10 Nano-g-Fe2O3-SO3H 8 65 98

11 Nano-g-Fe2O3-SO3H 16 65 90

a Benzaldehyde (lmmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), ammonium acetate (1.1 mmol), solvent-free, at 60 °C. b Yields refer to isolated products.

Table 3 Effect of temperature on the reaction rate.a

Entry Temperature/°C Yield/%b

Figure 2 Reusability of nano-y-Fe2O3-SO3H.

1 25 Trace

2 50 70

3 60 98

4 70 85

5 80 83

a Benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), ammonium acetate (1.1 mmol) and 0.031 g nano-g-Fe2O3-SO3H, solvent-free, for 60 minutes.

b Yields refer to isolated products.

Table 4 Choice of suitable solvent for reaction.3

Entry Solvent Time/min Yield/%b

1 H2O 200 Trace

2 EtOH 130 53

3 CH3CN 105 61

4 DMF 120 57

5 CHCl3 85 71

6 CH2Cl2 120 70

7 DMF 120 57

8 DMSO 160 45

9 C6H5CH3 180 35

10 Free 65 98

a Benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), ammonium acetate (1.1 mmol) and 0.031 g nano-g-Fe2O3-SO3H, at 60 °C. b Yields refer to isolated products.

donating and electron-withdrawing groups, ethyl acetoacetate and different 1,3-cyclohexanediones in the presence of ammonium acetate and 0.031 g of nano-g-Fe2O3-SO3H under obtained conditions. The results are summarized in Table 7. In all cases,

the reactions were clean and rapid. The nature and location of substituent groups in the aromatic ring has been shown not to have much effect on the formation of the final product and afford the expected products in high yields.

The methodology was extended for large-scale synthesis of polyhydroquinolines. First, the reaction was done using benzaldehyde, ethyl acetoacetate, 5,5-dimethyl-1,3-cyclohex-anedione on 1 mmol scale (Table 8, Entry 1). Then, the same reaction was expanded with different amounts of benzaldehyde such as 1 g (9.4 mmol), 5 g (47 mmol), 10 g (94 mmol) and 20 g (188 mmol) without affecting the yield of the product 5a (Table 8, Entries 2-5). While scaling up the reaction, it was found that 8 mol% of the catalyst is sufficient to promote the reaction effectively without significantly affectingthe rate of the reaction. This procedure was also applied to several other substituted benz-aldehydes and the products 5b, 5d, 5e, 5j, 5l and 5m were also synthesized (Table 8, Entries 6-23). Finally, the methodology could successfully be used for the synthesis of polyhydroquino-lines on a large scale.

Table 5 Comparison of the results obtained for the synthesis of polyhydroquinoline catalyzed by nano-y-Fe2O3-SO3H with those recently reported catalysts.

Entry Catalyst/mol% Solvent Condition Time/min Yield c/%ref

1 Nanoparticles-TiO2/ 10 Ethanol Reflux 30 9222

2 Co NPs/ 10 Solvent-free r.t. 60 9523

3 p-TSA/ 10 Ethanol r.t. 120 93 24

4 GaCl3/ 2 Ethanol r.t. 120 9225

5 ZrCl4/ 5 Ethanol r.t. 120 94 26

6 Yb(OTf)3/ 5 Ethanol r.t. 300 9027

7 Sc(OTf)3/ 5 Ethanol r.t. 240 9328

8 CAN/ 10 Ethanol r.t. 60 9229

9 ¿-Proline/ 10 Ethanol Reflux 360 92 30

10 CTAB/ 1 Water Reflux 90 80 31

11 (bzacen) MnCl/ 2.5 Ethanol Reflux 20 90 32

12 ASA/ 20 Methanol 70 oC 120 92 33

13 Hf(NPf2)4/ 1 Solvent-free 60 oC 180 95 34

14 Bi(NO3)3.5H2O/ 5 Ethanol 80 oC 240 92 35

15 Nano-y-Fe2O3-SO3H/ 8 Solvent-free 60 oC 65 This work

Table 6 Reusability of nano-g-Fe2O3-SO3H in the synthesis of polyhydroquinoline.

Entry 1 2 3 4 5

Yield/%a 98 97 97 96 94

a Isolated yield

Table 7 Synthesis of polyhydroquinolines under solvent-free conditions at 60 °C by nano-g-Fe2O3-SO3H as a catalyst.a

Ar Rj R2,R3 Product Time/ min Yieldb/% M.P./ C

Foundref

Ph Et Me 5a 65 98 202-20436

P-MeCA Et Me 5b 105 99 261-26327

p-MeOC6H4 Et Me 5c 90 93 258-25927

p-HOCA Et Me 5d 50 93 232-234 27

2,6-DiClC6H4 Et Me 5e 210 91 244-246 37

p-Me2NC„H4 Et Me 5f 240 89 263-264 27

p-ClC6H4 Et Me 5g 70 90 245-24738

o-Cl-C6H4 Et Me 5h 100 93 208-209 38

2-HO-5-BrC6H3 Et Me 5i 110 95 24739

Ph 6 3 Et H 5j 330 90 240-242 40

p-ClC6H4 Et H 5k 300 93 248-249 40

p-MeOC6H4 Et H, Ph 5l 90 96 236-238 c

p-MeC6H4 Me Me 5m 175 95 283-285 41

Ph Et H, Ph 5n 170 99 213-215 c

p-ClC6H4 Et H, Ph 5o 130 98 190-192 c

a Aromatic aldehyde (1 mmol), alkyl acetoacetate (1 mmol), 1,3-cyclohexanedione (1 mmol), ammonium acetate (1.1 mol) and 0.031 g nano-g-Fe2O3-SO3H, solvent-free, at 60 °C.

b Yields refer to isolated products. c New compounds.

Table 8 Large-scale synthesis of polyhydroquinolines using nano-g-Fe2O3-SO3H.a

Product Amount of aldehyde/mmol Time/min Yield b/%

5a 1 65 98

5a 9.4 65 98

5a 47 65 96

5a 94 65 96

5a 188 65 93

5b 1 105 99

5b 8.3 105 97

5b 166.5 105 95

5d 1 50 93

5d 8.2 50 93

5d 163.8 50 91

5e 1 210 91

5e 5.7 210 90

5e 114.3 210 90

5j 1 330 90

5j 9.4 330 90

5j 188 330 88

5l 1 90 96

5l 7.3 90 94

5l 146.9 90 92

5m 1 175 95

5m 8.3 175 93

5m 166.5 175 92

a Reaction condition: nano-g-Fe2O3-SO3H (8 mol%), solvent-free, at 60 °C. b Isolated yield.

4. Conclusion

In conclusion, we have developed a simple new catalytic method for the synthesis of polyhydroquinoline derivatives via one-pot, four-component Hantzsch condensation of 1,3-cyclo-hexanedione, aryl aldehydes, alkyl acetoacetate and ammonium acetate in the presence of nanomagnetic-supported sulfonic acid as an efficient, reusable, and green heterogeneous catalyst under solvent-free conditions. Our new method offers several advantages including short reaction times, the use of mild reaction conditions, avoiding the use of harmful acids and involving a simple work-up procedure.

Acknowledgement

The authors gratefully acknowledge Semnan University Research Council for financial supporting this work.

Supplementary material

The IR, MS and NMR spectra for the novel compounds (5l, 5n and 5o) are presented as supplementary material.

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