Journal of Applied Chemistry
Volume 2015 (2015), Article ID 743094, 7 pages
http://dx.doi.org/10.1155/2015/743094

Research Article

Proficient Procedure for Preparation of Quinoline Derivatives Catalyzed by NbCl₅ in Glycerol as Green Solvent

Mohammad Ali Nasseri, Batol Zakerinasab, and Sayyede Kamayestani

Department of Chemistry, College of Sciences, University of Birjand, Birjand 97175-615, Iran

Received 30 August 2014; Revised 14 December 2014; Accepted 15 December 2014

Academic Editor: Hongxing Dai

Copyright © 2015 Mohammad Ali Nasseri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Quinolines, an important class of potentially bioactive compounds, have been synthesized by treatment of o-aminoaryl ketones and carbonyl compound utilizing niobium (V) chloride (NbCl₅) as an available and inexpensive catalyst. The quinoline derivatives were prepared in glycerol, an excellent solvent in terms of environmental impact, with high yields (76–98%) and short reaction times (20–90 min). Not only diketones but also ketones afforded the desired products in good to excellent yields. The reaction time of 2-amino-5-chlorobenzophenone and dicarbonyl compounds was longer than that of 2-aminobenzophenone. The reaction of cyclic diketones took place faster than open chain analogues. These reactions also proceeded with acetophenone derivatives. In these cases the reaction times are longer.

1. Introduction

The synthesis of quinolines has been of considerable interest to chemists because their oxygen heterocycles may contribute to potential antimalarial, antibacterial, antiasthmatic, antihypertensive, anti-inflammatory, and antiplatelet properties [1–3]. For the synthesis of quinolines, various methods have been reported including the Skraup [4], Conrad-Limpach-Knorr [5], Pfitzinger [6], Friedlander [7], and Combes [8]. However, the Friedlander condensation is still considered as a popular method for the synthesis of quinoline derivatives [9–14]. In this method, -amino benzophenone condenses with ketones or β-diketones to yield quinolines.

Solvents are chemical substances used in huge amounts for many different applications. One of the key areas of Green Chemistry is the elimination of solvents in chemical processes or the replacement of hazardous solvents with environmentally benign solvents. Glycerol, which is a nontoxic, biodegradable liquid manufactured from renewable sources, shows similar properties as an ionic liquid and has a high potential to serve as green solvent for organic syntheses. It has a very high boiling point and negligible vapor pressure; it is compatible with most organic and inorganic compounds and does not require special handling or storage. Glycerol permits turning to the advantages of both water (low toxicity, low price, large availability, and renewability) and ionic liquids (high boiling point, low vapour pressure) [15].

On the other hand, the oxophilicity of high valence Nb(V) has enabled it to act as the reagent/catalyst for several Lewis acid-mediated reactions such as the intramolecular oxidation-reduction process [16], the Diels-Alder reaction [17], allylation of aldehydes and imines [18, 19], and complex formations [20, 21].

Nevertheless the development of new synthetic methods for the efficient preparation of heterocycles containing quinoline fragment is therefore an interesting challenge. Therefore, in this report we describe synthesis of quinoline derivatives by treatment of 2-aminobenzophenone with various carbonyl compounds using NbCl₅ as available catalysts in glycerol with high yields.

2. Experimental

Carbonyl compounds and -aminobenzophenone were purchased from Merck Chemical Company. Purity determinations of the products were accomplished by TLC on silica-gel PolyGram SILG/UV 254 plates. Melting points were determined in electrothermal 9100 system open capillaries. IR spectra were taken on a Perkin Elmer 781 spectrometer in KBr pellets and reported in cm⁻¹. NMR spectra were measured on a Bruker DPX 400 MHz spectrometer in DMSO-d₆ with chemical shift given in ppm relative to TMS as internal standard.

2.1. General Procedure for the Preparation of Quinoline Derivatives

NbCl₅ (0.1 mmol) in glycerol (2 mL) was added to a mixture of carbonyl compounds (1.0 mmol) and 2-amino-5-chlorobenzophenone or 2-aminobenzophenone (1.0 mmol). The mixture was stirred at 110°C for appropriate reaction time (Table 3). The progress of the reaction was monitored by thin layer chromatography. After complete reaction, the mixture was quenched by the addition of saturated aq NaHCO₃ solution and the reaction mixture was filtered and washed with ethanol. The crude solid product was crystallized from EtOH to afford the pure product and characterized by ¹H NMR, IR, and MS spectroscopy analysis.

3a: 9-phenyl-3,4-dihydro-1-2H-acridinone: Yellow solid; mp 158°C; ¹H NMR (400 MHz, CDCl₃) δ 2.24 (q, 2H,  Hz), 2.68 (t, 2H,  Hz), 3.39 (t, 2H,  Hz), 7.21–8.05 (m, 9H); IR (KBr, cm⁻¹) 3028, 2983, 2873, 1695, 1544, 1473, 1382, 1216.

3b: 7-chloro-9-phenyl-3,4-dihydro-1-2H-acridinone: Yellow solid; mp 184°C (Lit [22] 185°C); ¹H NMR (400 MHz, CDCl₃) δ 2.26 (q, 2H,  Hz), 2.72 (t, 2H,  Hz), 3.37 (t, 2H,  Hz), 7.17 (t, 2H), 7.42 (s, 1H), 7.53 (m, 3H), 7.69 (d, 1H,  Hz), 8.01 (d, 1H,  Hz); IR (KBr, cm⁻¹) 3024, 2975, 2870, 1698, 1549, 1476, 1380, 1210, 1075, 1007, 970, 838, 697; MS (, %): 308 (, 34), 306 (, 100), 281(5), 280(29), 278(15), 253(4), 244(10), 215(27), 188(12), 153(17), 120(20), 107(15).

3d: 7-chloro-1-2-methyl-4-phenyl-quinolin-3-yl-ethanone: Yellow solid; mp 157°C; ¹H NMR (400 MHz, CDCl₃) δ 2.00 (s, 3H), 2.50 (s, 3H), 7.30–7.85 (m, 8H); IR (KBr, cm⁻¹) 2985, 2873, 1715, 1532, 1450, 1382, 1216.

3f: methyl-6chloro-2-methyl-4-phenyl-3-quinolinecarboxylat: Yellow solid; mp 135°C, (Lit [22] 135°C); ¹H NMR (400 MHz, CDCl₃): 2.74 (s, 3H), 3.56 (s, 3H), 7.25–8.01 (c, 8H). ¹³C NMR (62.9 MHz, CDCl₃) 23.7, 52.2, 125.2, 125.8, 128.0, 128.5, 128.8, 129.1, 130.5, 131.2, 132.4, 134.9, 145.5, 146.1, 145.9, 154.9, 168.6; IR (KBr, cm⁻¹): : 3035, 2958, 2900, 1749, 1561, 1455, 1402, 1297, 1237, 1182, 1070, 872, 767; MS (, %): 313 (, 31), 311 (M⁺, 100), 296(6), 281(50), 279(97), 254(14), 251(16), 236(4), 211(10), 189(34), 175(52), 108(37), 94(33), 74(17).

3n: 2-chloro-11-phenyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolone: Yellow solid; mp 195°C, (Lit [23] 195°C); ¹H NMR (400 MHz, CDCl₃): : 1.60 (s, 2H), 1.84 (s, 4H), 2.68 (m, 2H) 3.26 (m, 2H), 7.22–7.96 (m, 8H); ¹³C NMR (62.9 MHz, CDCl₃) 26.9, 28.4, 30.7, 31.8, 40.1, 125.1, 127.7, 127.9, 128.6, 129.0, 129.3, 130.3, 131.3, 134.8, 136.9, 144.2, 144.7, 165.1; IR (KBr, cm⁻¹): : 3080, 3050, 2930, 2850, 1615, 1600, 1500, 1470, 1360, 1180, 990, 870, 820, 680; MS (, %): 308 (, 33), 306 (, 100), 292(9), 280(15), 277(12), 252(13), 242(17), 228(18), 215(18), 201(10), 188(10), 127(23), 120(25), 107(15).

3r: 6-chloro-2,4-diphenylquinoline: Yellow solid; mp 206°C, (Lit. [23] 208°C); ¹H NMR (400 MHz, CDCl₃): : 7.25–8.19 (m, 14H); ¹³C NMR (62.9 MHz, CDCl₃) 120.5, 124.5, 126.5, 127.5, 128.7, 128.8, 128.9, 129.4, 129.6, 130.4, 131.7, 132.2, 137.5, 139.2, 147.2, 148.4, 157.1; IR (KBr, cm⁻¹): : 3019, 2985, 1580, 1508, 1465, 1355, 1150, 1005, 840, 790, 755; MS (, %): 316 (, 43), 314 (M⁺, 100), 280(27), 277(18), 250(6), 236(7), 201(17), 175(13), 139(57), 125(19).

3. Results and Discussion

Due to the pharmacological properties of quinolines, development of synthetic methods, enabling easy access to these compounds, is desirable. Therefore, in this paper we report synthesis of quinoline derivatives in the presence of niobium (v) chloride as an inexpensive and available catalyst. In order to evaluate the catalytic efficiency of NbCl₅ and to determine the most appropriate reaction conditions, initially a model study was carried out on the synthesis of quinoline 3 (Scheme 1) by the condensation of 2-aminobenzophenone 1 and 1,3-cyclohexadione 2 in different sets of reaction conditions.

Scheme 1

In preliminary experiment, this reaction was carried out in various solvents, with NbCl₅ (0.1 mmol) as a catalyst. The reaction proceeded perfectly in polar solvents (Table 1, entries 7–16), but the yields decreased when the reaction was carried out in low-polar solvents (Table 1, entries 3–6). It was very surprising that the reaction proceeded in excellent yields (98%) in glycerol medium (Table 1, entry 16). The reaction could be carried out under solvent-free condition and gave low yield (Table 1, entries 1, 2).

Table 1: The effect of various solvent in the reaction of 2-amino-benzophenone (1 mmol), 1,3-cyclohexadione (1 mmol), catalyst (0.1 mmol), and solvent (2 mL).

Entry
Solvent
Yield (%)

1
Solvent-free (80°C)
35

2
Solvent-free (100°C)
58

3
n-Hexane (r.t)
15

4
CH₂Cl₂ (r.t)
20

5
CHCl₃ (r.t)
45

6
THF (r.t)
48

7
CH₃CN (r.t)
60

8
CH₃CN (80°C)
76

9
1,2-Dichloroethane (r.t)
55

10
1,2-Dichloroethane (80°C)
68

11
EtOH (r.t)
52

12
EtOH (80°C)
63

13
MeOH (r.t)
82

14
Glycerol (80°C)
83

15
Glycerol (100°C)
95

16
Glycerol (110°C)
98

To obtain the optimized reaction conditions, we also changed temperature and the amount of catalyst. The results are summarized in Table 2. Consequently, among the tested temperature and the amount of catalyst, the condensation of 2-aminobenzophenone and 1,3-cyclohexadione was best catalyzed by 0.1 mmol of NbCl₅ in glycerol at 110°C. Control experiments indicate that, in the absence of the catalyst, the reaction at the same condition gives quinoline in a rather low yield of 33% (Table 2, entry 1).

Table 2: Effect of temperature and the amount catalyst on the synthesis of 2-quinoline derivatives via a condensation of 2-aminobenzophenone and 1,3-cyclohexadione in the presence of NbCl₅ in glycerol.

Entry
Catalyst (mmol)
Yield (%)

r.t
60°C
80°C
110°C

1
None
—
10
15
33

2
0.01
15
20
25
52

3
0.05
25
40
56
78

4
0.1
55
76
88
98

5
0.2
60
78
90
98

Table 3: Synthesis of quinolones by the NbCl₅-catalyzed in glycerolea.

Entry
Substrate 1
Substrate 2
Quinoline 3
Reaction time (min)
Yield (%)b

1
1a 

2a 

3a 

15
95

2
1b 

2a
3b 

20
98

3
1a
2b 

3c 

25
93

4
1b
2b
3d 

35
95

5
1a
2c 

3e 

50
87

6
1b
2c
3f 

60
78

7
1a
2d 

3g 

45
82

8
1b
2d
3h 

50
85

9
1b
2e 

3i 

70
80

10
1a
2f 

3j 

60
78

11
1b
2f
3k 

45
84

12
1a
2g 

3l 

75
81

13
1a
2h 

3m 

50
79

14
1b
2i 

3n 

40
85

15
1b
2j 

3o 

55
82

16
1b
2h
3p 

45
89

17
1b
2k 

3q 

45
90

18
1b
2l 

3r 

90
84

19
1b
2m 

3s 

90
88

20
1a
2n 

3t 

90
86

21
1b
2o 

3u 

90
91

22
1a
2p 

3v 

90
79

23
1a
2s 

3w 

90
76

aReaction conditions: carbonyl compounds (1.0 mmol), 2-amino-5-chlorobenzophenone or 2-amino benzophenone (1 mmol), NbCl₅ (0.1 mmol), and glycerol (2 mL); reactions conducted at 110°C.

bThe yield refers to pure isolated product.

To establish the generality and applicability of this method, 2-amino-5-chlorobenzophenone/2-aminobenzophenone and carbonyl compounds were subjected to the same reaction condition to furnish the corresponding quinolines in good to excellent yields (Scheme 2, Table 3).

Scheme 2

Not only diketones (Table 3, entries 1–11) but also ketones (Table 3, entries 12–17) afforded the desired products in good to excellent yields (76–90%) in short reaction time (40–75 min). It is delighted that the reaction time of 1,3-diphenyl propane-1,3-dione was longer than that of acetylacetone, which is probably due to low reactivity of carbonyl groups. Also, the reaction time of 2-amino-5-chlorobenzophenone and dicarbonyl compounds was longer than that of 2-aminobenzophenone. The reaction of cyclic diketones took place faster than open chain analogues.

These reactions also proceeded with acetophenone derivatives (Table 3, entries 18–23). In these cases the reaction times are longer. It may be due to the less activity of acetophenone derivatives than dicarbonyl compounds. All the aforementioned reactions (Table 3) delivered good product yields and accommodated a wide range of aromatic carbonyl compound bearing both electron-donating and electron-withdrawing substituents. The reactivity of different aromatic carbonyl compounds was influenced by the nature and position of the substituents on the aromatic ring. The aromatic carbonyl derivatives having an electron-donating substituent were highly reactive and gave the products in excellent yields (entries 19–21). When the aromatic carbonyl compounds containing electron-withdrawing group were used, the reaction yield was decreased (entries 22, 23).

4. Conclusion

In conclusion, efficient synthesis of quinoline derivatives has been achieved by a one-pot coupling reaction of carbonyl compounds and -aminobenzophenone using catalytic amounts of NbCl₅ in glycerol. Simple reaction procedures, inexpensive catalysts, and single product formation make this an attractive protocol over the existing procedures. This protocol offers flexibility in tuning the molecular complexity and diversity.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

The authors gratefully acknowledge the support of this work by the Birjand University Research Council.

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