Recyclable nano copper oxide catalyzed synthesis of quinoline-2,3- dicarboxylates under ligand free conditions

Article abstract of DOI:10.1039/c3ra47212d

An efficient protocol was developed for the recyclable nano CuO powder catalyzed synthesis of quinoline derivatives from acetylenedicarboxylates and 2-aminocarbonyl compounds using acetonitrile as solvent at 40 °C in air. A variety of quinoline derivatives were synthesized in good yields with good chemoselectivity in the presence of a catalytic amount of CuO nano powder under ligand/additive free conditions. The catalyst is air-stable, inexpensive and recyclable up to four cycles. the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra47212d

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Recyclable nano copper oxide catalyzed synthesis
of quinoline-2,3-dicarboxylates under ligand free
conditions†
Cite this: RSC Adv., 2014, 4, 15154
*
Avudoddi Venkanna, Kokkirala Swapna and Pallapothula Venkateswar Rao
An efficient protocol was developed for the recyclable nano CuO powder catalyzed synthesis of quinoline
derivatives from acetylenedicarboxylates and 2-aminocarbonyl compounds using acetonitrile as solvent at
40 ꢀC in air. A variety of quinoline derivatives were synthesized in good yields with good chemoselectivity in
the presence of a catalytic amount of CuO nano powder under ligand/additive free conditions. The catalyst
is air-stable, inexpensive and recyclable up to four cycles.
Received 2nd December 2013
Accepted 27th January 2014
DOI: 10.1039/c3ra47212d
www.rsc.org/advances
quinoline synthesis. Many new methodologies are being
reported frequently using various starting materials.
Introduction
Recently Gabriele13 synthesized substituted quinolines from
Heterocyclic aromatic aza compounds especially quinoline
derivatives are widely used in several compounds1 (e.g.: quinine,
chloroquine, primaquine, meoquine etc. compounds are bio-
logically anti-malarial active (Fig. 1))1d and these pharmacolog-
ically active derivatives display a broad range of biological
activity.2 Quinolines are an important group of heterocyclic
compounds, which have been found to possess useful biological
activity, such as anti-malarial, anti-bacterial, anti-inammatory,
anti-asthmatic and anti-hypertensive properties3 and tyro-
kinase PDGF-RTK inhibiting agents, as well as being general
synthetic building blocks.4 In addition to medicinal applica-
tions, quinolines have been employed in the study of bioorganic
and bioorganometallic processes.5 These quinoline derivatives
are valuable synthons for the preparation of nano and meso-
structures with electronic and photonic functional applica-
tions.6–11 Skraup, Combes, Friedlander, Doebner–Von Miller
quinoline syntheses,12 are some well known methods for
2-amino arylketones by initial reaction with a Grignard reagent
and further cyclization in the presence of Cu/Pd catalysts.
Francis14 reported quinoline synthesis from 2-amino benzy-
lalcohol and a variety of ketones catalyzed by ruthenium cata-
lysts. Che15 and co-workers introduced gold catalyzed quinoline
synthesis under microwave-assisted conditions. Lewis acids,16
Brønsted acids,17 molecular iodine,18 proline,19 ionic liquids20
and transition metals21 were some of the catalysts used for
various types of quinoline syntheses, but many of the afore-
mentioned reactions require strong acids or bases, organic
solvents, hazardous and expensive catalysts at elevated
temperatures and the reaction conditions are also tedious and
yields are low even aer prolonged reaction times.
Verpoort et al. reported a ruthenium catalyzed approach to
the Friedlander quinoline synthesis in 1,4-dioxane as the solvent
at 80 C by using different basic conditions with good yields.30
ꢀ
Adapa and co-workers developed an efficient and rapid Fried-
lander synthesis of functionalized quinolines catalyzed by using
neodymium(III) nitrate hexahydrate as a catalyst in ethanol at
room temperature which afforded good yields.31 However, these
aforementioned reactions are also homogeneous.
There are few reports22 in the literature especially for the
preparation of 4-substituted quinoline-2,3-dicarboxylates. Tay-
lor synthesized quinoline-2,3-dicarboxylates from 2-amino-
benzophenone and dimethylacetylenedicarboxylate in benzene
under reux conditions. As 2-aminoacetophenone did not react
with dimethylacetylenedicarboxylate in one pot, they used basic
conditions (sodium methoxide in anhydrous conditions) to
enable the enamine adduct to cyclize in 26 h.23 Other methods
involved harsh reaction conditions, longer reaction times, toxic
organic solvents and very low yields. The chemical industry is a
major contributor to environmental pollution, largely due to
wide use of hazardous solvents. Benzene is one of the undesired
Fig. 1 Biologically active compounds with anti-malarial activity.
Department of Chemistry, Nizam College, Osmania University, Basheerbagh,
Nampally, 500029, India. E-mail: pallapothulavrao@gmail.com; Fax: +91-40-
23240806; Tel: +91-40-27037934
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47212d
15154 | RSC Adv., 2014, 4, 15154–15160
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
and environmentally hazardous solvents which belongs to red
category solvents due to its carcinogenicity and toxicity to
humans; hence there is a need to replace hazardous organic
solvents with environmentally benign solvents. A number of
procedures have been reported for the synthesis of quinolines
involving a variety of metal catalysts and Lewis acids.
Results and discussion
As part of our current studies28 on the development of new
routes in heterocyclic synthesis, we report an efficient synthetic
route to quinoline-2,3-dicarboxylates. Hence, the development
of ligand-free, air-resistant, inexpensive, recyclable catalytic
systems for the formation of quinoline derivatives is highly
desirable. To develop a simple, efficient, and reusable catalytic
system for the synthesis of quinoline-2,3-dicarboxylates under
ligand-free conditions, the role of nano-CuO as a recyclable
catalyst was investigated in the synthesis of quinoline and its
derivatives.
However, many of these methods suffer from harsh reaction
conditions, long reaction times, low yields, difficulties in work-
up, and the use of stoichiometric and/or relatively expensive
reagents. In view of these drawbacks, the reaction could be
further explored and rened to overcome some of these short-
comings by using an environmentally benign solvent with a
recyclable catalyst under mild reaction conditions. Moreover,
the above reactions are homogeneous, wherein catalyst recovery
is the major drawback, as well as the problems of product
contamination and the lack of catalyst recyclability.24 Hetero-
geneous catalysts are attractive both from economic and
industrial points of view as compared to homogeneous cata-
lysts.25 Furthermore, nanoscale catalysts are more advantageous
as more active surface area is available to bind the substrates
selectively and enhance the reaction efficacy.26
Initially the reaction between 2-aminoacetophenone and
dimethylacetylenedicarboxylate was carried out in acetoni-
trile solvent catalyzed by nano-CuO resulting in the forma-
tion of dimethyl 4-methylquinoline-2,3-dicarboxylate in one
ꢀ
pot at 40 C in 93% yield (Scheme 1). No product formation
was observed in the absence of metal catalyst even aer a
prolonged reaction time, while the reaction afforded a lower
yield of product with water as the solvent at 40 ꢀC for 10 h
(entries 1 & 2, Table 1).
The application of metal nanoparticles for organic reactions
has attracted immense attention in recent years.27 Since the
turn of the millennium, interest in metal nanoparticles catalysis
has considerably increased because this class of catalysts
appears as one of the most promising solutions toward efficient
reactions under mild and environmentally benign conditions in
the context of Green Chemistry.
First, the reaction was optimized with several copper sources
like Cu(acac)2, CuI, CuBr, Cu2O, all these were homogeneous
and heterogeneous CuO nanoparticles were proved to be best
for this reaction (entries 3–7, Table 1). Lower yield of the
product was observed at room temperature (entry 8, Table 1).
The optimal conditions for the desired product were found to be
1a (1 mmol)ꢀ, 2a (1 mmol), 3.0 mol% nano-CuO, acetonitrile
(2.0 mL), 40 C for 10 h.
To check the generality of the reaction, various 2-amino-
carbonyl compounds were used as substrates and all the
reactions proceeded to get the desired quinolines in good
yields. All these reactions were also conducted with diethy-
lacetylenedicarboxylate and di-tert-butylacetylenedicarboxy-
late in the present experimental conditions.
Scheme 1 Nano-CuO catalyzed synthesis of dimethyl 4-methyl-
quinoline-2,3-dicarboxylate.
Table 1 Optimization studies for the synthesis of quinoline and its derivativesa
Entry
Catalyst (mol%)
Solvent
Temperature
Yield (%)
1
2
3
4
5
6
7
8
—
CH3CN
Water
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
rt
C
C
C
C
C
C
C
—
40
30
35
30
93
45
30
Nano-CuO
Cu(acac)2
CuI
CuBr
Nano-CuO
Cu2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Nano-CuO
a
Reaction conditions: 2-aminoacetophenone (1.0 mmol), dimethylacetylenedicarboxylate (1.0 mmol), catalyst (3 mol%).
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 15154–15160 | 15155

View Article Online
RSC Advances
Paper
Table 2 Synthesis of quinolinedicarboxylates using the nano-CuO catalysta
Entry
R1
R2
R3
R4
Product
Yieldb (%)
1
2
3
4
5
6
CH3
Ph
Ph
H
Ph
H
H
Cl
Cl
H
OCH3
H
H
H
H
Br
OCH3
CH3
CH3
CH3
CH3
CH3
CH3
3a
3b
3c
3d
3e
3f
93
88
84
94
83
87
CH3
7
CH3
CH3
3g
86
8
9
10
11
12
13
CH3
Ph
Ph
H
Ph
H
H
Cl
Cl
H
OCH3
H
H
H
H
Br
OCH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
3h
3i
3j
3k
3l
3m
89
82
81
90
80
81
CH3
14
CH3
CH2CH3
3n
80
15
16
CH3
Ph
H
H
H
H
tBu
tBu
3o
3p
—
—
a
Representative reaction conditions: 2-aminoacetophenone (1 mmol), dimethylacetylenedicarboxylate (1 mmol), nano-CuO (3 mol%, 3 mg),
b
acetonitrile (2.0 mL), 40 ꢀC, 10 h. Isolated yield.
In general, all the reactions were very clean and neat, the (entries 1 & 8, Table 2) afforded good yield and electron-
quinoline derivatives were obtained in high yields. The donating
methoxy
substituted
2-aminoacetophenone
compounds were isolated by just passing through a silica gel compounds (entries 6, 7 & 13, 14, Table 2) resulted in a little
column. In these reactions, the substitution played a signicant lower yields. Similarly reaction with substituted 2-amino-
role in governing the reactivity of the substrate. Satisfactory benzophenone compounds gave lower yields compared to
yields were obtained in all the cases, in general the reaction of unsubstituted 2-aminobenzophenone compounds. Finally, it is
2-aminobenzophenone offered lower yields compared to also observed that reactions of 2-aminocarbonyl compounds
2-aminoacetophenone compounds. Among these 2-amino- with dimethylacetylenedicarboxylate resulted in higher yields
acetophenone derivatives, unsubstituted 2-aminoacetophenone when compared to those with diethylacetylenedicarboxylate. No
Scheme 2 Proposed mechanism for nano-CuO catalyzed synthesis of quinoline derivatives.
15156 | RSC Adv., 2014, 4, 15154–15160
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 3 Recovery of the catalysta
Cycle
Product isolated yield (%)
Catalyst recovery (%)
Native
93
88
85
80
96
1
2
3
91b
88b
80b
a
Reaction conditions: 2-aminoacetophenone (1.0 mmol), dimethylacetylenedicarboxylate (1.0 mmol), nano-CuO (3 mol%, 3 mg), CH3CN (2.0 mL),
b
40 ꢀC, 10 h. With recovered catalyst.
reaction was observed at elevated temperature with di-tert- same even aer recycling, which further conrmed the hetero-
butyldicarboxylate even aer prolonged reaction time and all geneous nature of the catalyst (Fig. 2).
the results are summarized in Table 2.
The actual mechanism of this reaction is not clear at present.
However, according to published results,32 the mechanism can
Conclusion
In conclusion, an inexpensive, air-stable recyclable catalytic
system was developed for the synthesis of quinoline and its
derivatives under ligand-free conditions. To the best of our
knowledge, this is the rst novel nano-CuO catalyzed
synthesis of quinoline-2,3-dicarboxylates, which is of poten-
tial industrial signicance because of its simplicity in opera-
tion, high yields, environmental and economic advantages,
using a commercially available, economically viable, air-
stable and recyclable heterogeneous catalyst.
be explained as shown in Scheme 2. Thus the two starting
materials of 1 and 2 reacted in the presence of nano-CuO in a
concerted manner to form complex I, which involves the initial
attack of the amine group on the polarized unsaturated diester,
followed by attack on the carbonyl group. Finally, the aromatic
product 3 is obtained by elimination of a water molecule.
To check the recyclability of the catalyst, aer each cycle, the
reaction mixture was allowed to cool and the catalyst was
recovered by ultracentrifugation, washed with ethyl acetate and
acetone, dried under vacuum, and reused for further catalytic
reactions. The catalyst maintained its high level of activity even
aer four cycles as shown in Table 3.
Transmission electron microscope (TEM) studies of both
fresh and used catalysts were carried out to understand the
shape and size of the particles. Fig. 2a and b show the TEM
images of the fresh and the used catalyst aer the fourth cycle,
respectively. Interestingly, it is observed that the shapes and
sizes (the CuO nanoparticle size is <50 nm) of the particles
remain unchanged (before and aer the reaction) and supports
the assumption that the morphology of the catalyst remains the
Experimental section
General methods
Nano-CuO (99.9%), all the starting materials (carbonyl and
acetylene compounds) were commercially available and
purchased from Sigma Aldrich and used without purication.
Column chromatography was carried out with 60–120 sized
mesh silica gel using ethyl acetate and hexane as eluents.
Analytical TLC was performed with Merck silica gel 60 F254
plates, and the products were visualized by UV detection. 1H
NMR and 13C NMR (Avance 300, Innova 400 MHz and Bruker
Gemini 200 MHz) spectra were recorded in CDCl3 using TMS as
an internal standard. Chemical shis (d) were reported in ppm,
and spin–spin coupling constants (J) are in Hz. Melting points
were determined on a Fischer-Johns melting point apparatus.
TEM analysis was recorded on Philips CM200 model instrument
˚
operating voltages at 20–200 kV and resolution was 2.4 A. EI-MS
were recorded on a Finnegan MAT 1020 mass spectrometer
operating at 70 eV.
Typical procedure for the synthesis of dimethyl 4-methyl-
quinoline-2,3-dicarboxylate. To a stirred solution of 2-amino-
acetophenone (1a) (1.0 mmol), dimethylacetylenedicarboxylate
(2a) (1.0 mmol) in acetonitrile (2.0 mL) was added CuO nano-
Fig. 2 TEM images of (a) fresh nano-CuO particles and (b) nano-CuO
particles after the fourth cycle.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 15154–15160 | 15157

View Article Online
RSC Advances
Paper
powder (3 mol%, 3 mg) and the reaction mixture was heated at d 167.1, 165.1, 147.2, 145.3, 144.9, 135.5, 133.7, 132.1, 129.1,
40 ꢀC under air. Aer the completion of the reaction over 10 h, 128.4, 125.3, 53.5, 52.5. Mass ESI (m/z) 280 (M + H)+. HRMS calcd
as monitored by TLC, the reaction mixture was extracted with C13H11NO4Cl (M + H)+: 280.0376, found 280.0386.
ethyl acetate (3 ꢁ 10 mL). The combined organic layers were
Dimethyl 7-bromo-4-phenylquinoline-2,3-dicarboxylate.29 (3e)
1
ꢀ
dried with anhydrous Na2SO4. The solvent was evaporated (entry 5, Table 2) Yellow solid, m.p. 166–167 C, H NMR (300
under vacuum to give the crude product, which was puried by MHz, CDCl3): d 8.26 (d, J ¼ 8.3 Hz, 1H), 7.80–7.75 (m, 1H), 7.65–
column chromatography with hexane and ethyl acetate as 7.53 (m, 4H), 7.26 (d, J ¼ 7.5 Hz, 2H), 4.01 (s, 3H), 3.62 (s, 3H). 13
C
eluent to get the expected product 3a (93%) as a yellow solid in (75 MHz, CDCl3): d 167.3, 165.3, 147.1, 146.5, 145.1, 133.2, 131.7,
good yield. The purity of the product was conrmed by 1H NMR, 131.2, 130.9, 130.6, 129.5, 127.2, 127.1, 126.1, 123.4, 53.5, 52.6.
13C NMR and mass spectroscopy and compared with the liter- Mass ESI (m/z) 400 (M + H)+. HRMS calcd C19H15NO4Br (M + H)+:
ature values.
400.0184, found 400.0174.
Representative procedure for recycling. Aer extraction of
Dimethyl 6,7-dimethoxy-4-methylquinoline-2,3-dicarboxy-
1
the organic compounds with ethyl acetate, the recovered late.29 (3f) (entry 6, Table 2) Brown solid, m.p. 135–136 C, H
heterogeneous catalyst was placed in a 25 mL round-bottomed NMR (400 MHz, CDCl3): d 7.48 (s, 1H), 7.26 (s, 1H), 4.02–3.66 (m,
ask. 2-Aminoacetophenone (1a) (1.0 mmol) and dimethylace- 12H), 2.60 (s, 3H). 13C (75 MHz, CDCl3): d 168.5, 165.4, 153.3,
tylenedicarboxylate (2a) (1.0 mmol) were added under air, fol- 151.8, 143.6, 142.5, 140.5, 126.3, 123.9, 109.1, 101.2, 56.1, 55.8,
lowed by addition of aceꢀtonitrile (2.0 mL) and the reaction 52.9, 52.6, 15.6. HRMS calcd C16H17NO6Na (M + Na)+: 342.0953,
mixture was stirred at 40 C for 10 h. Aer completion of the found 342.0952.
ꢀ
reaction (as monitored by TLC), the heterogeneous mixture was
Dimethyl
8-methyl-[1,3]dioxolo[4,5-g]quinoline-6,7-dicar-
then cooled to room temperature and treated with ethyl acetate boxylate.29 (3g) (entry 7, Table 2) Yellow solid, m.p. 223–224 ꢀC,
(2 mL). The aqueous layer was separated and extracted with 1H NMR (300 MHz, CDCl3): d 7.50 (s, 1H), 7.28 (s, 1H), 6.20 (s,
ethyl acetate (3 ꢁ 5 mL). The combined organic layers were 2H), 4.03 (s, 3H), 3.91 (s, 3H), 2.63 (s, 3H). 13C (75 MHz, CDCl3):
dried with anhydrous Na2SO4 and concentrated under reduced d 168.5, 165.6, 151.8, 150.9, 144.9, 142.5, 141.7, 125.8, 114.2,
pressure to yield the product, which was puried by column 107.4, 102.5, 99.6, 53.2, 52.9, 15.5. Mass ESI (m/z) 304 (M + H)+.
chromatography using silica gel (ethyl acetate–hexane) to
Diethyl 4-methylquinoline-2,3-dicarboxylate.29 (3h) (entry 8,
obtain the pure product 3a (89%) as a yellow solid. The product Table 2) Yellow oil, 1H NMR (300 MHz, CDCl3): d 8.14 (d, J ¼ 8.3
was characterized by 1H and 13C NMR, and MS analysis and Hz, 1H), 7.96 (d, J ¼ 8.3 Hz, 1H), 7.69 (t, J ¼ 6.7 Hz, 1H), 7.56 (t, J
compared with the literature values. The same procedure was ¼ 7.1 Hz, 1H), 4.46–4.31 (m, 4H), 2.65 (s, 3H), 1.44–1.30 (m, 6H).
extended for further cycles.
13C (75 MHz, CDCl3): d 167.1, 165.0, 146.3, 146.1, 143.1, 131.1,
130.3, 128.5, 127.8, 127.1, 123.8, 96.1, 61.9, 61.4, 15.3, 14.2, 14.0.
Mass ESI (m/z) 288 (M + H)+.
Spectroscopic data
Diethyl 4-phenylquinoline-2,3-dicarboxylate.29 (3i) (entry 9,
Dimethyl 4-methylquinoline-2,3-dicarboxylate.29 (3a) (entry 1, Table 2) Yellow solid, m.p. 95–97 ꢀC, 1H NMR (300 MHz, CDCl3):
1
ꢀ
Table 2) Light yellow solid, m.p. 95–97 C, H NMR (300 MHz, d 8.30 (d, J ¼ 8.3 Hz, 1H), 7.79 (t, J ¼ 6.7 Hz, 1H), 7.63–7.45 (m,
CDCl3): d 7.06 (d, J ¼ 8.3 Hz, 1H), 6.86 (d, J ¼ 8.4 Hz, 1H), 6.59 (t, J 5H), 7.38–7.33 (m, 2H), 4.56–4.47 (q, J ¼ 6.7 Hz, J ¼ 14.3 Hz, 2H),
¼ 6.9 Hz, 1H), 6.48 (t, J ¼ 8.1 Hz, 1H), 2.81 (s, 3H), 2.76 (s, 3H), 4.09–4.02 (q, J ¼ 6.7 Hz, J ¼ 14.3 Hz, 2H), 1.49 (t, J ¼ 6.7 Hz, 3H),
1.50 (s, 3H). 13C (75 MHz, CDCl3): d 168.3, 165.5, 146.1, 144.8, 0.99 (t, J ¼ 6.7 Hz, 3H). 13C (75 MHz, CDCl3): d 167.0, 165.2,
144.2, 131.0, 130.9, 129.2, 128.1, 127.3, 124.1, 53.4, 52.9, 15.6. 147.8, 147.0, 145.7, 134.6, 130.8, 130.5, 129.3, 128.9, 128.6,
Mass ESI (m/z) 260 (M + H)+.
128.1, 127.4, 126.9, 126.5, 62.5, 61.4, 14.1, 13.5. Mass ESI (m/z)
Dimethyl 4-phenylquinoline-2,3-dicarboxylate.29 (3b) (entry 350 (M + H)+.
1
2, Table 2) Yellow solid, m.p. 129–130 C, H NMR (300 MHz,
Diethyl 6-chloro-4-phenylquinoline-2,3-dicarboxylate.29 (3j)
ꢀ
CDCl3): d 8.39 (d, J ¼ 8.4 Hz, 1H), 7.83 (t, J ¼ 6.6 Hz, 1H), 7.68– (entry 10, Table 2) White solid, m.p. 154–155 ꢀC, 1H NMR (200
7.56 (m, 2H), 7.53–7.49 (m, 3H), 7.39–7.35 (m, 2H), 4.08 (s, 3H), MHz, CDCl3): d 8.61 (d, J ¼ 3.0 Hz, 1H), 8.12–8.04 (m, 1H), 7.89–
3.64 (s, 3H). 13C (75 MHz, CDCl3): d 167.4, 165.3, 148.3, 146.7, 7.85 (m, 4H), 7.77–7.70 (m, 2H), 4.55–4.44 (q, J ¼ 7.0 Hz, J ¼ 14.0
144.7, 134.3, 131.1, 130.4, 130.3, 129.2, 128.8, 128.2, 127.6, Hz, 2H), 4.09–3.98 (q, J ¼ 7.0 Hz, J ¼ 14.0 Hz, 2H), 1.46 (t, J ¼ 7.0
127.1, 126.5, 53.4, 52.4. Mass ESI (m/z) 322 (M + H)+.
Hz, J ¼ 14.0 Hz, 3H), 0.99 (t, J ¼ 7.0 Hz, J ¼ 14.0 Hz, 3H). 13C
Dimethyl 6-chloro-4-phenylquinoline-2,3-dicarboxylate.23 (3c) (75 MHz, CDCl3): d 167.5, 165.3, 146.3, 146.2, 143.1, 131.2,
1
ꢀ
(entry 3, Table 2) White solid, m.p. 162–164 C, H NMR (200 130.3, 128.6, 127.9, 127.2, 123.8, 61.9, 61.4, 14.3, 14.1. Mass ESI
MHz, CDCl3): d 8.26 (s, 0.5H), 8.25 (s, 0.5H), 7.77 (d, J ¼ 2.2 Hz, (m/z) 384.7 (M + H)+.
0.5H), 7.72 (d, J ¼ 2.9 Hz, 0.5H), 7.61–7.53 (m, 4H), 7.40–7.27 (m,
Diethyl 6-chloroquinoline-2,3-dicarboxylate.29 (3k) (entry 11,
2H), 4.08 (s, 3H), 3.62 (s, 3H). 13C (75 MHz, CDCl3): d 167.4, Table 2) Yellow solid, m.p. 99–100 ꢀC, 1H NMR (300 MHz,
165.2, 147.3, 145.6, 145.1, 135.5, 133.7, 132.2, 129.2, 129.1, 128.6, CDCl3): d 8.62 (s, 1H), 8.15–8.08 (m, 1H), 7.90 (s, 1H), 7.78–
128.4, 128.1, 125.3, 53.8, 52.5. Mass ESI (m/z) 356 (M + H)+.
7.70 (m, 1H), 4.59–4.45 (m, 4H), 1.47–1.39 (m, 6H). 13C (75
Dimethyl 6-chloroquinoline-2,3-dicarboxylate.29 (3d) (entry 4, MHz): d 166.2, 164.5, 150.9, 146.1, 138.1, 134.1, 132.8, 131.1,
Table 2) Brown solid, m.p. 163–164 ꢀC, 1H NMR (300 MHz, 127.3, 126.8, 123.1, 61.9, 61.8, 13.8, 13.9. Mass ESI (m/z) 308
CDCl3): d 8.56 (s, 1H), 8.05 (d, J ¼ 8.8 Hz, 1H), 7.82 (s, 1H), 7.70 (M + H)+. HRMS calcd C15H15NO4Cl (M + H)+: 308.0689, found
(d, J ¼ 9.0 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H). 13C (75 MHz, CDCl3): 308.0699.
15158 | RSC Adv., 2014, 4, 15154–15160
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
Diethyl 7-bromo-4-phenylquinoline-2,3-dicarboxylate.29 (3l)
RSC Advances
7 (a) A. Nayyar, A. Malde, R. Jain and E. Coutinho, Bioorg. Med.
Chem., 2006, 14, 847; (b) A. Nayyar, A. Malde, E. Coutinho
and R. Jain, Bioorg. Med. Chem., 2006, 14, 7302; (c)
A. Nayyar and R. Jain, Curr. Med. Chem., 2005, 12, 1873; (d)
V. Monga, A. Nayyar, B. Vaitilingam, P. B. Palde,
S. S. Jhamb, S. Kaur, P. P. Singh and R. Jain, Bioorg. Med.
Chem., 2004, 12, 6465 (correction: 2005, 13, 1879); (e)
S. Vangapamdu, M. Jain, R. Jain, S. Kaur and P. P. Singh,
Bioorg. Med. Chem., 2004, 12, 2501; (f) R. Jain,
B. Vaitilingam, A. Nayyar and P. B. Palde, Bioorg. Med.
Chem. Lett., 2003, 13, 1051.
(entry 12, Table 2) Yellow solid, m.p. 109–111 ꢀC, 1H NMR (300
MHz, CDCl3): d 8.28 (d, J ¼ 8.1 Hz, 1H), 7.84–7.74 (m, 1H), 7.64
(d, J ¼ 8.3 Hz, 2H), 7.55 (s, 2H), 7.25 (d, J ¼ 8.1 Hz, 2H), 4.50 (q, J
¼ 6.9 Hz, J ¼ 12.2 Hz, 2H), 4.11 (q, J ¼ 7.1 Hz, J ¼ 12.6 Hz, 2H),
1.47 (t, J ¼ 6.9 Hz, J ¼ 7.1 Hz, 3H), 1.06 (t, J ¼ 7.1 Hz, J ¼ 6.9 Hz,
3H). 13C (75 MHz, CDCl3): d 165.9, 164.1, 150.8, 146.0, 145.7,
138.0, 134.1, 132.7, 131.8, 130.6, 129.05, 127.2, 126.8, 126.0,
123.1, 62.1, 61.7, 14.1, 13.8. Mass ESI (m/z) 428 (M + H)+. HRMS
calcd C21H19NO4Br (M + H)+: 428.0497, found 428.0498.
Diethyl
6,7-dimethoxy-4-methylquinoline-2,3-dicarboxy-
late.29 (3m) (entry 13, Table 2) Brown solid, m.p. 114–116 ꢀC, 1H
NMR (400 MHz, CDCl3): d 7.44 (s, 1H), 7.06 (s, 1H), 4.47–4.36 (m,
4H), 3.98 (s, 6H), 2.58 (s, 3H), 1.43 (t, J ¼ 6.7 Hz, J ¼ 7.6 Hz, 3H),
1.36 (t, J ¼ 7.6 Hz, J ¼ 6.7 Hz, 3H). 13C (75 MHz, CDCl3): d 168.0,
165.2, 153.1, 151.5, 143.6, 143.2, 140.7, 126.1, 123.8, 109.1,
101.2, 61.9, 61.5, 56.0, 55.8, 15.5, 14.3, 14.1. Mass ESI (m/z) 348
(M + H)+. HRMS calcd C18H22NO6 (M + H)+: 348.1447, found
348.1449.
8 (a) P. Camps, E. Gomez, D. Munoz-Torrero, A. Badia,
N. M. Vivas, X. Barril, M. Orozco and F. J. Luque, J. Med.
Chem., 2001, 44, 4733; (b) P. Camps, R. El Achb, J. Morral,
D. Munoz-Torrero, A. Badia, J. E. Banos, N. M. Vivas,
X. Barril, M. Orozco and F. J. Luque, J. Med. Chem., 2000,
43, 4657; (c) T. Suzuki, T. Usui, M. Oka, T. Suzuki and
T. Kataoka, Chem. Pharm. Bull., 1998, 46, 1265.
9 (a) X. Franck, A. Fournet, E. Prima, R. Mahieux,
R. Hocquemiller and B. Figadere, Bioorg. Med. Chem. Lett.,
2004, 14, 3635; (b) C. Benard, F. Zouhiri, M. Normand-
Bayle, M. Danet, D. Desmaele, H. Leh, J. F. Mouscadet,
G. Mbemba, C. M. Thomnas, S. Bonnenfant, M. Le Bret
and J. d'Angelo, Bioorg. Med. Chem. Lett., 2004, 14, 2473; (c)
M. A. Fakhfakh, A. Fournet, E. Prina, J. F. Mousvadet,
X. Franck, R. Hocquemiller and B. Figadere, Bioorg. Med.
Chem., 2003, 11, 5013; (d) A. Fournet, R. Mahieux,
M. A. Fakhfakh, X. Franck, R. Hocquemiller and
B. Figadere, Bioorg. Med. Chem. Lett., 2003, 13, 891; (e)
F. Zouhiri, D. Desmaele, J. d'Angelo, M. Ourevitch,
J. F. Mouscadet, H. Leh and M. Le Bret, Tetrahedron Lett.,
2001, 42, 8189.
Diethyl 8-methyl-[1,3]dioxolo[4,5-g]quinoline-6,7-dicarboxy-
1
late.29 (3n) (entry 14, Table 2) Brown solid, m.p. 98–100 C, H
ꢀ
NMR (300 MHz, CDCl3): d 7.53 (s, 1H), 7.25 (s, 1H), 6.17 (s, 2H),
4.53–4.40 (m, 4H), 2.61 (s, 3H), 1.50–1.26 (m, 6H). 13C (75 MHz,
CDCl3): d 167.6, 164.9, 151.2, 149.8, 144.5, 143.0, 141.2, 126.0,
125.2, 113.9, 106.3, 102.1, 99.0, 95.8, 61.8, 61.4, 15.5, 14.0, 13.8.
Mass ESI (m/z) 332 (M + H)+.
Acknowledgements
We are grateful to CSIR, New Delhi for the research fellowships
to AV.
10 (a) A. Tsotinis, M. Vlachou, S. Zouroudis, A. Jeney, F. Timar,
D. E. Thurston and C. Roussakis, Lett. Drug Des. Discovery,
2005, 2, 189; (b) A. R. Martirosyan, R. Rahim-Bata,
A. B. Freeman, C. D. Clarke, R. L. Howard and J. S. Strobl,
Biochem. Pharmacol., 2004, 68, 1729; (c) A. Perzyna,
F. Klupsch, R. Houssin, N. Pommery, A. Lemoine and
J. P. Henichart, Bioorg. Med. Chem. Lett., 2004, 14, 2363; (d)
A. H. Abadi and R. Brun, Arzneim. Forsch., 2003, 53, 655; (e)
J. Charris, P. Martinez, J. Dominguez, S. Lopez, J. Angel
and G. Espinoza, Heterocycl. Commun., 2003, 9, 251; (f)
C. Lamazzi, S. Leonce, B. Pfeiffer, P. Renard,
G. Guillaumet, C. W. Rees and T. Besson, Bioorg. Med.
Chem. Lett., 2000, 10, 2183; (g) J. Osiadacz, L. Kaczmarek,
A. Opolski, J. Wietrzyk, E. Marcinkowska, K. Biernacka,
C. Radzikowski, M. Jon and W. Peczynska-Czoch,
Anticancer Res., 1999, 3333; (h) W. Peczynskaczoch,
F. Pognan, L. Kaczmarek and J. Boratyanski, J. Med. Chem.,
1994, 37, 3503.
Notes and references
1 (a) J. P. Michael, Nat. Prod. Rep., 2007, 24, 223; (b)
J. P. Michael, Nat. Prod. Rep., 2005, 22, 627; (c)
J. P. Michael, Nat. Prod. Rep., 2004, 21, 650; (d) K. Kaur,
M. Jain, R. P. Reddy and R. Jain, Eur. J. Med. Chem., 2010,
45, 3245.
2 (a) R. G. Ridley, Nature, 2002, 415, 686; (b) P. L. Olliaro and
W. R. J. Taylor, J. Exp. Biol., 2003, 206, 3753; (c)
R. Klingenstein, P. Melnyk, S. R. Leliveld, A. Ryckebusch
and C. Korth, J. Med. Chem., 2006, 49, 5300.
3 B. Lal, N. B. Bhise, R. M. Gidwani, A. D. Lakdawala, K. Joshi
and S. Parvardhan, ARKIVOC, 2005, ii, 77.
4 (a) M. Ishiwara, Y. Aoki, H. Takagaki, M. Ui and F. Okajima, J.
Pharmacol. Exp. Ther., 2003, 307, 583; (b) P. Benedetti,
R. Mannhold, G. Cruciani and G. Ottaviani, Bioorg. Med.
Chem., 2004, 12, 3607.
5 (a) P. C. Appelbaum and M. R. Jacobs, Curr. Opin. Microbiol.,
2005, 8, 510; (b) P. Narender, U. Srinivas, M. Ravinder, 11 (a) A. K. Aggarwal and S. A. Jenekhe, Macromolecules, 1991,
B. A. Rao, C. Ramesh, K. Harakishore, B. Gangadasu,
U. S. N. Murthy and V. J. Rao, Bioorg. Med. Chem., 2006, 14, 4600.
6 (a) T. Staalhandske and T. Kalland, Immunopharmacology,
24, 6806; (b) X. Zhang, S. Shetty and S. A. Jenekhe,
Macromolecules, 1999, 32, 7422; (c) S. A. Jenekhe, L. Lu and
M. M. Alam, Macromolecules, 2001, 34, 7315.
1986, 11, 87; (b) T. H. Thatcher, I. Luzina, R. Fishelevich, 12 (a) G. Jones, in Comprehensive Heterocyclic Chemistry II, ed. A.
M. A. Tomai, R. L. Miller and A. A. Gaspari, J. Invest.
Dermatol., 2006, 126, 821.
R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press,
Oxford, UK, 1996, vol. 5, pp. 167–243; (b) C. S. Cho, B. H. Oh,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 15154–15160 | 15159

View Article Online
RSC Advances
Paper
T. J. Kim and S. C. Shim, Chem. Commun., 2000, 1885; (c)
B. Jiang and Y. G. Su, J. Org. Chem., 2002, 67, 9449; (d)
H. Skraup, Ber. Dtsch. Chem. Ges., 1880, 13, 2086; (e)
R. H. Mansake and M. Kulka, Org. React., 1953, 7, 59; (f)
R. J. Linderman and K. S. Kirollos, Tetrahedron Lett., 1990,
31, 2689; (g) M.-E. Theoclitou and L. A. Robinson,
Tetrahedron Lett., 2002, 43, 3907.
L. J. Brando, Org. Biomol. Chem., 2014, 12, 255; (k)
D. Matiadis, V. Stefanou, G. Athanasellis, S. Hamilakis,
V. McKee, O. I. Markopoulou and J. Markopoulos,
Monatsh. Chem., 2013, 144, 1063; (l) O. Mazzoni,
G. Esposito, M. V. Diurno, D. Brancaccion, A. Carotenuto,
P. Grieco, E. Novellino and W. Filippelli, Arch. Pharm.,
2010, 343, 561; (m) N. T. Patil and V. S. Raut, J. Org. Chem.,
2010, 75, 6961.
13 B. Gabriele, R. Mancuso, G. Salerno, G. Ruffolo and
P. Plastina, J. Org. Chem., 2007, 72, 6873.
23 E. C. Taylor and N. D. Heindel, J. Org. Chem., 1967, 32, 1666.
14 V. Francis, H. V. Mierde, P. V. Voort and D. D. Vos, Eur. J. Org. 24 (a) F. Y. Kwong, A. Klapars and S. L. Buchwald, Org. Lett.,
Chem., 2008, 1625.
15 L. Xin-Yuan, P. Ding, H. Jie-Sheng and C. Chi-Ming, Org.
Lett., 2007, 9, 2645.
2002, 4, 581; (b) J. C. Antilla, A. Klapars and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 11684; (c)
J. C. Antilla, J. M. Baskin, T. E. Barder and S. L. Buchwald,
J. Org. Chem., 2004, 69, 5578; (d) L. Liu, M. Frohn, N. Xi,
C. Dominguez, R. Hungate and P. J. Reider, J. Org. Chem.,
2005, 70, 10135; (e) H. Matsumoto, S. Nagashima, T. Kato
and Y. Nagai, Angew. Chem., 1978, 90, 288; (f) C. Faboru,
R. W. Griffiths and A. Pidcock, J. Organomet. Chem., 1982,
225, 331.
16 (a) A. L. Rusanov, L. G. Komarova and M. P. Prigozhina, Russ.
Chem. Rev., 2005, 74, 671; (b) Y. Z. Hu, G. Zhang and
R. P. Thummel, Org. Lett., 2003, 5, 2252; (c)
B. R. McNaughton and B. L. Miller, Org. Lett., 2003, 5,
4257; (d) R. Varala, R. Enugula and S. R. Adapa, Synthesis,
2006, 3825; (e) L. Zhang and J. Wu, Adv. Synth. Catal.,
2007, 349, 1047.
17 (a) M. Narasimhulu, T. S. Reddy, K. C. Mahesh, P. Prabhakar,
C. B. Rao and Y. Venkateswarlu, J. Mol. Catal. A: Chem., 2006,
266, 114; (b) G. C. Muscia, M. Bollini, J. P. Carnevale,
A. M. Bruno and S. E. Asis, Tetrahedron Lett., 2006, 47, 8811.
18 J. Wu, H. G. Xia and K. Gao, Org. Biomol. Chem., 2006, 4, 126.
19 B. Jiang, J. J. Dong, Y. Jin, X. Long Du and M. Xu, Eur. J. Org.
Chem., 2008, 2693.
25 (a) T. Miao and L. Wang, Tetrahedron Lett., 2007, 48, 95; (b)
B. Sreedhar, R. Arundhathi, M. A. Reddy and M. L. Kantam,
Synthesis, 2009, 483; (c) M. Kidwai, N. K. Mishra, V. Bansal,
A. Kumar and S. Mozumdar, Tetrahedron Lett., 2007, 48,
8883; (d) B. Sreedhar, R. Arundhathi, P. L. Reddy and
M. L. Kantam, J. Org. Chem., 2009, 74, 7951; (e) B. C. Ranu,
A. Saha and R. Jana, Adv. Synth. Catal., 2007, 349, 2690; (f)
L. Rout, P. Saha, S. Jammi and T. Punniyamurthy, Eur.
J. Org. Chem., 2008, 640.
20 (a) M. Dabiri, P. Salehi, B. Mostafa and M. S. Nikcheg,
Tetrahedron Lett., 2008, 49, 5366; (b) R. Sarma and 26 (a) G. Pacchioni, Surf. Rev. Lett., 2000, 7, 277; (b)
D. Prajapathi, Synlett, 2008, 19, 3001.
W. D. Knight, K. Clemenger, W. A. de Heer,
W. A. M. Saunders, Y. Chou and M. L. Cohen, Phys. Rev.
Lett., 1984, 52, 2141; (c) A. Kaldor, D. Cox and M. R. Zakin,
Adv. Chem. Phys., 1988, 70, 211.
21 (a) J. Jacob and W. D. Jones, J. Org. Chem., 2003, 68, 3563; (b)
K. Taguchi, S. Sakagucgi and Y. Ishii, Tetrahedron Lett., 2005,
46, 4539; (c) C. S. Cho, B. T. Kim, T. J. Kim and S. C. Shim,
Chem. Commun., 2001, 2576; (d) R. Martinez, D. J. Ramon 27 (a) Nanoparticles and Catalysis, ed. D. Astruc, Wiley-VCH,
and M. Yus, Eur. J. Org. Chem., 2007, 1599; (e) R. Martinez,
D. J. Ramon and M. Yus, Tetrahedron, 2006, 62, 8988; (f)
R. Martinez, D. J. Ramon and M. Yus, Tetrahedron, 2006,
62, 8982; (g) B. Gabriele, R. Mancuso, G. Salerno,
G. Ruffolo and P. Plastina, J. Org. Chem., 2007, 72, 6873; (h)
T. O. Vieira and H. Alper, Chem. Commun., 2007, 2710.
22 (a) M. Sabbaghan, I. Yavari, Z. Hossaini and S. Souri, Helv.
Chim. Acta, 2010, 93, 946; (b) J. Fan, C. Wan, G. Sun and
Weinheim, 2008; (b) M. A. El-Sayed, Acc. Chem. Res., 2001,
34, 257; (c) R. M. Crooks, M. Q. Zhao, L. Sun, V. Chechik
and L. K. Yeung, Acc. Chem. Res., 2001, 34, 181; (d)
A. Roucoux, J. Schulz and H. Patin, Chem. Rev., 2002, 102,
3757; (e) A. T. Bell, Science, 2003, 299, 1688; (f) E. Moreno-
Manas and R. Pleixats, Acc. Chem. Res., 2003, 36, 638; (g)
D. Astruc, F. Lu and J. R. Aranzaes, Angew. Chem., Int. Ed.,
2005, 44, 7852.
Z. Wang, J. Org. Chem., 2008, 73, 8608; (c) J. Horn, 28 A. Venkanna, P. Vinod Kumar Goud and P. V. Rao, Eur.
S. P. Marsden, A. Nelson, D. House and G. G. Weingarten, J. Chem., 2012, 3, 298.
Org. Lett., 2008, 10, 4117; (d) I. Yavari, S. Sey and 29 B. Madhav, S. N. Murthy, K. R. Rao and Y. V. D. Nageswar,
Z. Hossaini, Tetrahedron Lett., 2010, 51, 2193; (e) Helv. Chim. Acta, 2010, 93, 257.
M. Narasimhulu, T. S. Reddy, K. C. Mahesh, P. Prabhakar, 30 H. V. Mierde, P. V. D. Voort, D. D. Vos and F. Verpoort, Eur.
C. B. Rao and Y. Venkateswarlu, J. Mol. Catal. A: Chem., J. Org. Chem., 2008, 1625.
2007, 266, 114; (f) C. S. Cho, B. H. Oh, J. S. Kim, T. J. Kim 31 V. Ravi, E. Ramu and S. R. Adapa, Synthesis, 2006, 3825.
and S. C. Shim, Chem. Commun., 2000, 1885; (g) C. S. Cho, 32 (a) A. W. Chester, J. Org. Chem., 1970, 35, 1797; (b) E. Raee,
B. T. Kim, T. J. Kim and S. C. Shim, Chem. Commun., 2001,
2576; (h) J. M. Contelles, E. P. Mayoral, A. Samadi,
M. C. Carreiras and E. Soriano, Chem. Rev., 2009, 109,
2652; (i) J. M. Nezhad, J. Akbari, A. Heydari and
B. Alirezapour, Bull. Korean Chem. Soc., 2011, 32, 3853; (j)
J. McNulty, R. Vemula, C. Bordon, R. Yolken and
S. Tangestaninejad, M. H. Habibi and V. Mirkhani, Bioorg.
Med. Chem. Lett., 2004, 14, 3611; (c) S. K. Saha, M. Ali and
P. Banerjee, Coord. Chem. Rev., 1993, 122, 41; (d)
I. A. Weinstock, Chem. Rev., 1998, 98, 113; (e) I. M. Baltork,
S. Tangestaninejad, M. Moghadam, V. Mirkhani, S. Anvar
and A. Mirjafari, Synlett, 2010, 3104.
15160 | RSC Adv., 2014, 4, 15154–15160
This journal is © The Royal Society of Chemistry 2014