An environmentally benign one pot synthesis of substituted quinolines catalysed by fluoroboric acid based ionic liquid

Article abstract of DOI:10.1007/s12039-012-0272-y

Organic synthesis generally required large amount of solvent, avoiding the use of organic solvents in synthesis is a paradigm shift directed at developing more benign chemistry, and with ionic liquids surprisingly can lead to access to new compounds. An elegant one-pot synthesis of quinoline derivatives has been achieved by reaction of substituted anilines with β-ketoester at 60°C in ethanol using an ionic liquid [Et₃NH]⁺[BF ₄]^- as catalyst. All the reactions gave products with high degree of purity and excellent yield (78.93%) within the shorter span of time (20.65 min) than those reactions with conventional methods. The screening of solvents as well as the reuse of ionic liquid has been evaluated. The structure of the products has been elucidated by spectral and analytical data. The present scope and potential economic impact of the reaction are demonstrated by the synthesis of substituted quinolines. Remaining challenges and future perspectives of the new transformation are discussed.

Full text of DOI:10.1007/s12039-012-0272-y

c
J. Chem. Sci. Vol. 124, No. 4, July 2012, pp. 877–881. ꢀ Indian Academy of Sciences.
An environmentally benign one pot synthesis of substituted quinolines
catalysed by fluoroboric acid based ionic liquid
A RAJENDRANa,∗, C KARTHIKEYANb, K RAJATHIb and D RAGUPATHYc
aDepartment of Chemistry, Sir Theagaraya College, Chennai 600 021, India
bResearch and Development Centre, Bharathiar University, Coimbatore 641 046, India
cDepartment of Applied Chemistry, Kyungpook National University, 1370, Sangyuk 3 Dong, BUk GU,
Daegu 701-702, South Korea
e-mail: annamalai_rajendran2000@yahoo.com
MS received 23 September 2011; revised 13 January 2012; accepted 7 February 2012
Abstract. Organic synthesis generally required large amount of solvent, avoiding the use of organic sol-
vents in synthesis is a paradigm shift directed at developing more benign chemistry, and with ionic liquids
surprisingly can lead to access to new compounds. An elegant one-pot synthesis of quinoline derivatives has
been achieved by reaction of substituted anilines with β-ketoester at 60◦C in ethanol using an ionic liquid
[Et3NH]+[BF4]−as catalyst. All the reactions gave products with high degree of purity and excellent yield
(78–93%) within the shorter span of time (20–65 min) than those reactions with conventional methods. The
screening of solvents as well as the reuse of ionic liquid has been evaluated. The structure of the products has
been elucidated by spectral and analytical data. The present scope and potential economic impact of the reac-
tion are demonstrated by the synthesis of substituted quinolines. Remaining challenges and future perspectives
of the new transformation are discussed.
Keywords. One-pot synthesis; benign synthesis; ionic liquids; fluoroboric acid; quinolines.
1. Introduction
with melting points below the boiling point of water
have gained intensive attention in nearly all fields of
chemistry.7 Furthermore, through the incorporation of
functional groups, the synthesis of task specific ionic
liquids (TSILs) has been a focus of research, leading to
tailor-made substances for desired applications. Tradi-
tional chemical synthesis focused on optimizing yields,
with little regard to a chemical’s impact on the environ-
ment and its long term viability. There is now a realiza-
tion that more benign chemical synthesis is required, as
an integral part of developing sustainable technologies.
Optimizing the yield is important but other issues need
to be addressed, including minimizing the number of
steps, simplicity, waste, atom efficiency, energy usage,
safety and eco-friendliness.8
Lewis acidic ionic liquids have been receiving exten-
sive interest as green substitute for H2SO4, HF and
AlCl3 catalysts in chemical processes. Lewis acids
are increasingly used in organic synthesis and have
received considerable attention as non-toxic, recyclable
and readily available catalysts for various organic trans-
formations, affording the corresponding products in
excellent yields with high selectivity. For many years,
the synthesis of quinoline and its derivatives has been
of considerable interest in organic and medicinal chem-
istry since a large number of natural products and drugs
In recent years, environment-friendly reaction pro-
cesses have extensively been studied from the stand
point of green chemistry. For example, oxidation reac-
tions with the air, or reaction in water, supercritical
fluids, and fluorous solvents are cited.1 Most recently,
ionic liquids have gained much attention as green sol-
vents for organic synthesis. The development of envi-
ronmentally improved new synthetic routes, which are
as much direct as possible and make use of safe
and non-toxic starting materials, is a major target of
the modern chemistry of organic synthesis.2 In recent
years, the interest in room temperature ionic liquids is
increasing as green reaction media for synthetic organic
chemistry. Researchers have recently found that such
ionic liquids are very useful as solvents as well as cata-
lysts for several organic and inorganic syntheses.3 Ionic
liquids are good candidates for replacement of toxic
and volatile organic compounds because of their lower
vapour pressures and lack of flammability.4–6 The syn-
thesis of these ionic liquids (ILs), their characterization
and possible applications have been developing pro-
gressively as the properties of this class of organic salts
∗For correspondence
877

878
A. Rajendran et al.
contain this heterocyclic moiety. In addition, quino- TMS as an internal standard.24 Mass spectra were
lines are valuable synthons, used for the preparation of recorded on a JEOL SX 102/DA-6000 mass spectro-
nano and meso structures with enhanced electronic and meter. All reactants were purchased from Sigma-
photonic properties.9 As part of the continuing effort Aldrich and Lancaster and used as received. Solvents
towards the expeditious synthesis of biodynamic hete- used in the reaction are double distilled by vacuum
rocycles, the possibility of developing a novel and effi- distillation.25–27
cient method to construct the quinoline scaffold became
the focus of interest.10 This is inspite of some meth-
ods such as the Skraup, Doebner-von Miller, Combes
2.1 General procedure for the synthesis of substituted
quinolines, 3a-h
reaction and Friedlander being valuable for the synthe-
sis of quinolines.11–13 Bronsted acids and several Lewis
In a 50 ml round bottom flask, substituted anilines 1a-
h (1 mmol), ethyl acetoacetate 2 (1 mmol) and 5 mol%
acids have been reported to be effective for the synthe-
[Et3NH]+[BF4]−in ethanol (15 ml) were mixed and the
resulting solution was stirred at 60◦C. After completion
of the reaction as monitored by TLC, the reaction mix-
ture was filtered and the crude product was subjected to
purification by flash chromatography using a mixture of
20% ethyl acetate and 80% n-hexane as eluent to yield
the quinolines 3a-h. The purified product was recrystal-
lized using appropriate solvent. The structure of all the
products was unambiguously established on the basis of
their spectral analysis.
sis of quinolines. However, many of these procedures
also suffered from harsh reaction conditions (such as
high temperature >100◦C, use of litres of corrosive sol-
vents even for milligram scale reactions and catalysts,
time consumption, inability to recover the solvent and
catalysts after use) low yields, difficult work-up and in
some cases high catalyst loading had to be employed
in order to obtain a respectable yield.14 The aforemen-
tioned drawbacks of conventional methods can be over-
come when we use the ionic liquid [Et3NH]+[BF4]−.
Thus, simple, eco-benign and efficient procedures for
the synthesis of these important heterocycles are still
in demand.15 Inspired by reports on catalytic appli-
cations of fluoroboric acid for organic transformation
and the endeavour of this research group toward the
development of new synthetic methods, we report here
a novel and efficient procedure for the synthesis of
quinolines.16–18
3. Results and discussion
An initial study was performed by the treatment of ani-
line 1a with ethyl acetoacetate 2 in methanol in the pres-
ence of catalytic amounts of [Et3NH]+[BF4]− (10 mol
%) at RT (scheme 1).
To our delight, the formation of 2-hydroxy-4-me-
thylquinoline 3a was observed. Complete conversion
and 93% isolated yields were obtained after 30 min.
Further studies established that 5 mol% of catalyst was
equally efficient to perform the reaction (table 1).
Moreover, it is noteworthy that this reaction could be
run under normal condition without loss in efficiency.
Among the solvent screened, ethanol and methanol
were demonstrated as the best solvent. Further proce-
dures were developed with ethanol as it is more envi-
ronmentally benign as compared to methanol. This is
because of high solubility of [Et3NH]+[BF4]− in polar
solvents. Under solvent-free conditions, the reaction
2. Experimental
The melting points were determined in open capil-
lary tubes in infra tech melting point apparatus and
are uncorrected.19 The homogeneity of the products
was checked on TLC plates coated with silica gel-
G and visualized by exposure to iodine vapours.20–23
The IR spectra were recorded on Perkin-Elmer Infrared
model S99-B and on Shimadzu IR-435 spectropho-
tometer (νmax in cm−1). 1H NMR spectra were recorded
on a Varian unity 250 MHz NMR spectrometer using
NH2
O
O
HBF4, Ethanol
OEt
+
o
60 C
OH
N
R
R
1a-h
3a-h
Scheme 1. Synthesis of substituted quinolines.

Efficiency of catalytic activity of the proposed ionic liquid
879
Table 1. Evaluation of catalytic activity of [Et3NH]+[BF4]− Table 3. Effect of temperature on the synthesis of various
on the synthesis of various substituted-4-methyl quinoline- substituted-4-methylquinoline-2-ol.
2-ol.
Entry
Temperature (◦C)
Time (min)
bYield(%)
[Et3NH]+[BF4]−
(X mol%)
Time
(min)
Entry
bYield(%)
1
2
3
4
RT
45
60
≥80
35
30
25
20
86
90
93
94
1
2
3
4
5
0
5
60
45
30
25
20
0
88
93
93
95
10
15
20
bIsolated yield based upon the starting amine
Reactions conditions: aniline (1a, 1 mmol); ethylacetoace-
tate (2, 1 mmol); [Et3NH]+[BF4]− (X mol%); solvent
ethanol; RT; 1 atm. bIsolated yields
3.1 Spectral data
Compound 3a: M.F.C10H9NO; 1H NMR - 2.14 δ
(s, 3H, CH3), 6.15 δ (s, 1H, CH), 7.33-7.4 δ (m,
4H), 8.43 δ (s, 1H, NH); IR- 3400 cm−1(O-H, str),
1650 cm−1(C=N, str), 3030 cm−1(C-H, str, aromatic),
1100 cm−1(C-C, str); 1650 cm−1(C=C, str); Mass- MS:
m/z [M+] 159
also proceeded smoothly to afford the corresponding
product, although the yield was slightly lower (table 2).
In order to examine the effect of temperature, con-
centration of [Et3NH]+[BF4]− was kept constant at
5 mol% and the reaction was monitored at different
temperatures as compiled in table 3. At elevated tem-
peratures using 5 mol% of [Et3NH]+[BF4]− gave bet-
ter results in terms of yield and reaction times. To
demonstrate the generality of this method, the scope
of this reaction under optimized conditions was inves-
tigated and it was found that structurally diverse aro-
matic amines with different substitution (both electron
withdrawing and electron donating group) reacted with
equal ease to produce a range quinolines derivatives in
excellent yields (table 4).
1
Compound 3b: M.F. C10H8FNO; H NMR - 2.28 δ
(s, 3H, CH3), 6.17 δ (s, 1H, CH), 7.22 δ (s,1H, CH),
7.53 δ (d, 1H, J = 7.7 Hz, CH), 7.66 δ (d,1H, J =
7.6Hz, CH), 9.12 δ (s,1H,NH); IR- 3400 cm−1(O-H,
str), 1650 cm−1(C=N, str), 3030 cm−1(C-H, str, aro-
matic), 1100 cm−1(C-C, str); 1650 cm−1(C=C, str),
1300 cm−1(C-F, str); Mass- MS: m/z [M+] 175
Compound 3c: C11H11NO; 1H NMR - 2.28 δ (s,
3H, CH3), 2.43 δ (S, 3H, CH3), 7.25 δ (s,1H,CH),
7.27 δ (s,1H, CH), 7.51 δ (d, 1H, J = 7.7 Hz,
CH), 7.54 δ (d,1H, J = 7.6Hz, CH), 9.10 δ (s, 1H,
NH); IR- 3400 cm−1(O-H, str), 1650 cm−1(C=N, str),
3030 cm−1(C-H, str, aromatic), 1100 cm−1(C-C, str);
1650 cm−1(C=C, str), 3100 cm−1(C-H, str, aliphatic);
Mass- MS: m/z [M+] 173
It is important to stress that the catalyst was recycled
by solvent (water) extraction method and reused for five
runs with only slight drop in activity (table 5).
An additional starting material was added into the
reaction mixture and reaction was continued for an
additional 10 h which resulted in the formation of 3a
in excellent yields. The structure of the products (3a–h)
1
obtained was elucidated by H NMR, FT-IR and Mass
1
Compound 3d: C11H11NO2; H NMR - 2.38 δ (S,
spectral studies.26
3H,CH3), 3.82 δ (S, 3H,CH3), 6.43 δ (s,1H,CH), 7.52
δ (s,1H, CH), 7.51 δ (d, 1H, J = 7.7 Hz, CH), 7.63
δ ( d,1H, J = 7.6Hz, CH), 7.81 δ ( d,1H, J = 7.6Hz,
CH), 8.82 δ (s, 1H, NH); IR- 3400 cm−1(O-H, str),
1650 cm−1(C=N, str), 3030 cm−1(C-H, str, aromatic),
1100 cm−1(C-C, str), 1650 cm−1(C=C, str), 3100 cm−1,
1250 cm−1(-O-C, str), 3100 cm−1(C-H, str, aliphatic);
MS: m/z [M+] 189
Table 2. Screening of solvents for the synthesis of various
substituted 4-methylquinoline-2-ol.
Entry
Solvent
Time (min) bYield(%)
1
2
3
4
5
Methanol
Ethanol
Dichloromethane
Acetonitrile
45
35
70
55
40
88
86
64
72
70
1
Compound 3e: C10H8N2O3; H NMR - 2.25 δ (s,
Solvent free condition
3H, CH3), 3.82 δ (S, 3H,CH3), 6.14 δ (s,1H,CH),
7.41 δ (s,1H, CH), 7.65 δ (d, 1H, J = 7.4 Hz, CH),
7.78 δ ( d,1H, J = 7.6Hz, CH), 8.42 δ (s, 1H,
NH); IR- 3400 cm−1(O-H, str), 1650 cm−1(C=N, str),
Reactions conditions: aniline (1a, 1 mmol); ethylacetoac-
etate (2, 1 mmol); [Et3NH]+[BF4]− (X mol%); solvent
ethanol; RT; 1 atm. bIsolated yields

880
A. Rajendran et al.
Table 4. [Et3NH]+[BF4]− promoted synthesis of various substituted 4-methyl-
quinoline-2-ol.
Entry Aniline
R
Time (min) Product bYield (%) m.p.(◦C)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
4-F
4-CH3
20
25
35
30
65
40
30
45
3a
3b
3c
3d
3e
3f
93
78
84
91
76
76
80
87
218
261
249
257
300
300
181
271
4-OCH3
4-NO2
4-COOH
2-pyridinyl
2-napthylamine
1g
1h
3g
3h
Reactions conditions: aniline (1a, 1 mmol); ethylacetoacetate (2, 1 mmol);
[Et3NH]+[BF4]− (5 mol%); solvent ethanol; temperature 60◦C; 1 atm. bIsolated yields
H, CH), 3.76 δ (s, 2H, NH2); IR- 3400 cm−1(O-H,
Table 5. Reuse of [Et3NH]+[BF4]− in
the synthesis of 3a using ethanol at 60◦C
for 20 min.
str), 1650 cm−1(C=N, str), 3030 cm−1(C-H, str, aro-
matic), 1100 cm−1(C-C, str); 1650 cm−1(C=C, str),
3400 cm−1(N-H, str); MS: m/z [M+] 300
Entry
Yield (%)
1
2
3
4
5
91
90
90
88
87
4. Conclusion
In conclusion, we have described a simple, efficient
and a facile tandem protocol for an elegant one-pot
synthesis of quinoline derivatives by reaction of sub-
stituted anilines with β-ketoester at 60◦C in ethanol
using fluoroboric acid / [Et3NH]+[HSO4]− as catalyst.
The major advantages of the present method are much
faster reaction, easy work up procedure and good to
excellent yields and avoiding the usage of hazardous
organic solvent and toxic catalyst. In addition to this,
the fluoroboric acid / [Et3NH]+[HSO4]− catalyst was
successfully reused for five runs without potential loss
of activity. This proves that this method is much more
convenient than those with conventional catalysts.
bIsolated yield based upon the starting
amine
3030 cm−1(C-H, str, aromatic), 1100 cm−1(C-C, str);
1650 cm−1(C=C, str), 3100 cm−1, 1560 cm−1(C-N, str,
aromatic); MS: m/z [M+] 204
Compound 3f: C11H9NO3; 1H NMR - 2.41 δ (s,
3H, CH3), 6.44 δ (s, 1H, CH), 7.88-8.96 δ (m, 3H,
CH), 7.83 δ (d, 1H, J = 7.3Hz, CH), 9.46 δ (s, 1H,
NH), 11.36 δ (s, 1H, COOH); IR- 3400 cm−1(O-H,
str), 1650 cm−1(C=N, str), 3030 cm−1(C-H, str, aro-
matic), 1100 cm−1(C-C, str); 1650 cm−1(C=C, str),
1750 cm−1(C=O, str of –COOH group); MS: m/z [M+]
203
Acknowledgements
AR acknowledges the funding support given by the
University Grants Commission, New Delhi for his
major research project [F.No 35-147/2009(SR)]. He
thanks the principal and the management of Sir
Theagaraya College, Chennai for the constant encour-
agement. His thanks are also due to Mr. P Sakthivel,
Sastra University, Tanjore for the spectral recording.
1
Compound 3g: C12H12N2O; H NMR - 2.41 δ (s,
3H, CH3), 6.44 δ (s, 1H, CH), 7.88-8.96 δ (m, 3H,
CH), 7.83 δ (d, 1H, J = 7.3Hz, CH), 9.46 δ (s, 1H,
NH), 11.36 δ (s, 1H, COOH); IR- 3400 cm−1(O-H,
str), 1650 cm−1(C=N, str), 3030 cm−1(C-H, str, aro-
matic), 1100 cm−1(C-C, str); 1650 cm−1(C=C, str),
1300 cm−1(C-N, str of pyridinyl); MS: m/z [M+] 236
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