Research Article Proficient Procedure for Preparation of ...downloads.hindawi.com/archive/2015/743094.pdf · Research Article Proficient Procedure for Preparation of Quinoline Derivatives

Research ArticleProficient Procedure for Preparation of Quinoline DerivativesCatalyzed 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

Correspondence should be addressed to Mohammad Ali Nasseri; [email protected]

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 AttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the originalwork is properly cited.

Quinolines, an important class of potentially bioactive compounds, have been synthesized by treatment of o-aminoaryl ketonesand carbonyl compound utilizing niobium (V) chloride (NbCl

5) 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 reactiontimes (20–90min). Not only diketones but also ketones afforded the desired products in good to excellent yields. The reactiontime of 2-amino-5-chlorobenzophenone and dicarbonyl compounds was longer than that of 2-aminobenzophenone. The reactionof cyclic diketones took place faster than open chain analogues. These reactions also proceeded with acetophenone derivatives. Inthese cases the reaction times are longer.

1. Introduction

The synthesis of quinolines has been of considerable interestto chemists because their oxygen heterocyclesmay contributeto potential antimalarial, antibacterial, antiasthmatic, antihy-pertensive, anti-inflammatory, and antiplatelet properties [1–3]. For the synthesis of quinolines, variousmethods have beenreported including the Skraup [4], Conrad-Limpach-Knorr[5], Pfitzinger [6], Friedlander [7], and Combes [8]. However,the Friedlander condensation is still considered as a popularmethod for the synthesis of quinoline derivatives [9–14]. Inthismethod, 𝑜-amino benzophenone condenses with ketonesor 𝛽-diketones to yield quinolines.

Solvents are chemical substances used in huge amountsfor many different applications. One of the key areas ofGreen Chemistry is the elimination of solvents in chemicalprocesses or the replacement of hazardous solvents with envi-ronmentally benign solvents. Glycerol, which is a nontoxic,biodegradable liquid manufactured from renewable sources,shows similar properties as an ionic liquid and has a highpotential to serve as green solvent for organic syntheses. It hasa very high boiling point and negligible vapor pressure; it iscompatible with most organic and inorganic compounds anddoes not require special handling or storage. Glycerol permitsturning 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 valenceNb(V) has enabled it to act as the reagent/catalyst for severalLewis acid-mediated reactions such as the intramolecularoxidation-reduction process [16], the Diels-Alder reaction[17], allylation of aldehydes and imines [18, 19], and complexformations [20, 21].

Nevertheless the development of new synthetic methodsfor the efficient preparation of heterocycles containing quino-line fragment is therefore an interesting challenge.Therefore,in this report we describe synthesis of quinoline derivativesby treatment of 2-aminobenzophenonewith various carbonylcompounds usingNbCl

5as available catalysts in glycerol with

high yields.

2. Experimental

Carbonyl compounds and 𝑜-aminobenzophenone were pur-chased from Merck Chemical Company. Purity determina-tions of the products were accomplished by TLC on silica-gelPolyGram SILG/UV 254 plates. Melting points were deter-mined in electrothermal 9100 system open capillaries. IRspectrawere taken on a Perkin Elmer 781 spectrometer inKBrpellets and reported in cm−1. NMR spectra were measured

Hindawi Publishing CorporationJournal of Applied ChemistryVolume 2015, Article ID 743094, 7 pageshttp://dx.doi.org/10.1155/2015/743094

2 Journal of Applied Chemistry

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

Entry Solvent Yield (%)1 Solvent-free (80∘C) 352 Solvent-free (100∘C) 583 n-Hexane (r.t) 154 CH2Cl2 (r.t) 205 CHCl3 (r.t) 456 THF (r.t) 487 CH3CN (r.t) 608 CH3CN (80∘C) 769 1,2-Dichloroethane (r.t) 5510 1,2-Dichloroethane (80∘C) 6811 EtOH (r.t) 5212 EtOH (80∘C) 6313 MeOH (r.t) 8214 Glycerol (80∘C) 8315 Glycerol (100∘C) 9516 Glycerol (110∘C) 98

Table 2: Effect of temperature and the amount catalyst on thesynthesis of 2-quinoline derivatives via a condensation of 2-aminobenzophenone and 1,3-cyclohexadione in the presence ofNbCl5 in glycerol.

Entry Catalyst (mmol) Yield (%)r.t 60∘C 80∘C 110∘C

1 None — 10 15 332 0.01 15 20 25 523 0.05 25 40 56 784 0.1 55 76 88 985 0.2 60 78 90 98

on a Bruker DPX 400MHz spectrometer in DMSO-d6with

chemical shift given in ppm relative to TMS as internalstandard.

2.1. General Procedure for the Preparation ofQuinolineDeriva-tives. NbCl

5(0.1mmol) in glycerol (2mL) was added to a

mixture of carbonyl compounds (1.0mmol) and 2-amino-5-chlorobenzophenone or 2-aminobenzophenone (1.0mmol).Themixture was stirred at 110∘C for appropriate reaction time(Table 3).The progress of the reaction was monitored by thinlayer chromatography. After complete reaction, the mixturewas quenched by the addition of saturated aq NaHCO

3

solution and the reaction mixture was filtered and washedwith ethanol. The crude solid product was crystallized fromEtOH to afford the pure product and characterized by 1HNMR, IR, and MS spectroscopy analysis.

3a: 9-phenyl-3,4-dihydro-1-2H-acridinone: Yellow solid;mp 158∘C; 1H NMR (400MHz, CDCl

3) 𝛿 2.24 (q, 2H, 𝐽 =

6.4Hz), 2.68 (t, 2H, 𝐽 = 6.4Hz), 3.39 (t, 2H, 𝐽 = 6.4Hz),7.21–8.05 (m, 9H); IR (KBr, cm−1) ]max 3028, 2983, 2873, 1695,1544, 1473, 1382, 1216.

3b: 7-chloro-9-phenyl-3,4-dihydro-1-2H-acridinone: Yel-low solid; mp 184∘C (Lit [22] 185∘C); 1H NMR (400MHz,CDCl

3) 𝛿 2.26 (q, 2H, 𝐽 = 6.4Hz), 2.72 (t, 2H, 𝐽 = 6.4Hz),

3.37 (t, 2H, 𝐽 = 6.4Hz), 7.17 (t, 2H), 7.42 (s, 1H), 7.53 (m, 3H),7.69 (d, 1H, 𝐽 = 8.8Hz), 8.01 (d, 1H, 𝐽 = 8.8Hz); IR (KBr,cm−1) ]max 3024, 2975, 2870, 1698, 1549, 1476, 1380, 1210, 1075,1007, 970, 838, 697; MS (𝑚/𝑧, %): 308 ((M + 2) − 1, 34), 306(M−1, 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-etha-none: Yellow solid; mp 157∘C; 1H NMR (400MHz, CDCl

3)

𝛿 2.00 (s, 3H), 2.50 (s, 3H), 7.30–7.85 (m, 8H); IR (KBr,cm−1) ]max 2985, 2873, 1715, 1532, 1450, 1382, 1216.

3f : methyl-6chloro-2-methyl-4-phenyl-3-quinolinecar-boxylat: Yellow solid; mp 135∘C, (Lit [22] 135∘C); 1H NMR(400MHz, CDCl

3): 𝛿 2.74 (s, 3H), 3.56 (s, 3H), 7.25–8.01 (c,

8H). 13C NMR (62.9MHz, CDCl3) 𝛿 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 (𝑚/𝑧,%): 313 (M + 2, 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-cyclohep-ta[b]quinolone: Yellow solid; mp 195∘C, (Lit [23] 195∘C); 1HNMR (400MHz, CDCl

3): 𝛿: 1.60 (s, 2H), 1.84 (s, 4H), 2.68 (m,

2H) 3.26 (m, 2H), 7.22–7.96 (m, 8H); 13C NMR (62.9MHz,CDCl

3) 𝛿 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 (𝑚/𝑧, %): 308 ((M + 2) − 1, 33),306 (M − 1, 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; mp206∘C, (Lit. [23] 208∘C); 1H NMR (400MHz, CDCl

3): 𝛿:

7.25–8.19 (m, 14H); 13C NMR (62.9MHz, CDCl3) 𝛿 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(𝑚/𝑧, %): 316 (M + 2, 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, devel-opment of synthetic methods, enabling easy access to thesecompounds, is desirable. Therefore, in this paper we reportsynthesis of quinoline derivatives in the presence of niobium(v) chloride as an inexpensive and available catalyst. Inorder to evaluate the catalytic efficiency of NbCl

5and to

determine the most appropriate reaction conditions, initiallya model study was carried out on the synthesis of quinoline3 (Scheme 1) by the condensation of 2-aminobenzophenone1 and 1,3-cyclohexadione 2 in different sets of reactionconditions.

In preliminary experiment, this reaction was carried outin various solvents, with NbCl

5(0.1mmol) as a catalyst. The

Journal of Applied Chemistry 3

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

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

11aOPh

NH2

2aO

O

3a

N

O15 95

21bOCl PhNH2

2a

3b

N

OCl 20 98

3 1a2b

O O

3c

N

O25 93

4 1b 2b

3d

N

OCl

35 95

5 1a2c

OO

O

3e

N

CO2Me 50 87

6 1b 2c

3f

N

Cl CO2Me 60 78

7 1a2d

OO

O

3g

N

CO2Et45 82

8 1b 2d

3h

N

Cl CO2Et 50 85

9 1b2e

OPhPh

O

3i

N PhPh

OCl 70 80

10 1a2f

PhO O

CF3

3j

NPh

O

CF3

60 78


Table 3: Continued.


11 1b 2f

3k

N

O

PhCl

CF3

45 84

12 1a2gO

3l

N

75 81

13 1a2hO

3m

N

50 79

14 1b2iO

3n

NCl 40 85

15 1b

2jO

3o

NCl 55 82

16 1b 2h

3p

N

Cl45 89

17 1b2kO

3q

N

Cl45 90

18 1b2l

O

3r

N

Cl

Ph

90 84

19 1b2m

OMeO

3s

NCl

OMe90 88

20 1a2n

OOMe

3t

NOMe 90 86


Table 3: Continued.


21 1b

2oO

MeO

3u

NOMe

Cl 90 91

22 1a

2pO

Cl

3v

NCl

90 79

23 1a2s

OCl

3w

NCl 90 76

aReaction conditions: carbonyl compounds (1.0mmol), 2-amino-5-chlorobenzophenone or 2-amino benzophenone (1mmol), NbCl5 (0.1mmol), and glycerol(2mL); reactions conducted at 110∘C.bThe yield refers to pure isolated product.

reaction proceeded perfectly in polar solvents (Table 1, entries7–16), but the yields decreased when the reaction was carriedout in low-polar solvents (Table 1, entries 3–6). It was verysurprising that the reaction proceeded in excellent yields(98%) in glycerol medium (Table 1, entry 16). The reactioncould be carried out under solvent-free condition and gavelow yield (Table 1, entries 1, 2).

To obtain the optimized reaction conditions, we alsochanged temperature and the amount of catalyst. The resultsare summarized in Table 2. Consequently, among the testedtemperature and the amount of catalyst, the condensationof 2-aminobenzophenone and 1,3-cyclohexadione was bestcatalyzed by 0.1mmol of NbCl

5in glycerol at 110∘C. Control

experiments indicate that, in the absence of the catalyst, thereaction at the same condition gives quinoline in a rather lowyield of 33% (Table 2, entry 1).

To establish the generality and applicability of thismethod, 2-amino-5-chlorobenzophenone/2-aminobenzo-phenone and carbonyl compounds were subjected to thesame reaction condition to furnish the correspondingquinolines in good to excellent yields (Scheme 2, Table 3).

Not only diketones (Table 3, entries 1–11) but also ketones(Table 3, entries 12–17) afforded the desired products in goodto excellent yields (76–90%) in short reaction time (40–75min). It is delighted that the reaction time of 1,3-diphenylpropane-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-chlorobenzophenoneand dicarbonyl compounds was longer than that of 2-aminobenzophenone. The reaction of cyclic diketones tookplace faster than open chain analogues.

These reactions also proceeded with acetophenonederivatives (Table 3, entries 18–23). In these cases the reac-tion times are longer. It may be due to the less activityof acetophenone derivatives than dicarbonyl compounds.All the aforementioned reactions (Table 3) delivered goodproduct yields and accommodated a wide range of aromaticcarbonyl compound bearing both electron-donating andelectron-withdrawing substituents.The reactivity of differentaromatic carbonyl compounds was influenced by the natureand position of the substituents on the aromatic ring. Thearomatic carbonyl derivatives having an electron-donatingsubstituent were highly reactive and gave the products inexcellent yields (entries 19–21). When the aromatic carbonylcompounds containing electron-withdrawing group wereused, the reaction yield was decreased (entries 22, 23).

4. Conclusion

In conclusion, efficient synthesis of quinoline derivativeshas been achieved by a one-pot coupling reaction of car-bonyl compounds and 𝑜-aminobenzophenone using catalyticamounts of NbCl

5in glycerol. Simple reaction procedures,

inexpensive catalysts, and single product formation makethis an attractive protocol over the existing procedures. Thisprotocol offers flexibility in tuning the molecular complexityand diversity.

Conflict of Interests

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


O

N

Ph

Ph

O

O

1 2 3

O

+

NH2

Scheme 1

PhO

O

N

Ph

O

N

Ph

R

O

N

Ph

( (

N

Ph OR

O OR

R

+

++

+

NH2

R1

R1

R2R2NbCl5(10mol%)Glycerol/110∘C

NbCl5(10mol%)Glycerol/110∘C

NbCl5(10mol%)Glycerol/110∘C

NbCl5(10mol%)Glycerol/110∘C )n

)n

Scheme 2

Acknowledgment

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

References

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Research Article Proficient Procedure for Preparation of ...downloads.hindawi.com/archive/2015/743094.pdf · Research Article Proficient Procedure for Preparation of Quinoline Derivatives