Green approach for the efficient synthesis of quinolines promoted by citric acid

Article abstract of DOI:10.3987/COM-08-11405

Citric acid promoted Friedlander synthesis of a mini-library of poly substituted quinolines (30 examples) at 100 °C under solvent-free conditions was achieved in moderate to excellent yields (54-99%). The method is simple, cost-effective and environmental

Full text of DOI:10.3987/COM-08-11405

HETEROCYCLES, Vol. 75, No. 10, 2008
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HETEROCYCLES, Vol. 75, No. 10, 2008, pp. 2523 - 2533. © The Japan Institute of Heterocyclic Chemistry
Received, 6th April, 2008, Accepted, 9th June, 2008, Published online, 12th May, 2008. COM-08-11405
GREEN APPROACH FOR THE EFFICIENT SYNTHESIS OF
QUINOLINES PROMOTED BY CITRIC ACID
Ramu Enugala,a Sreelatha Nuvvula,a Vijay Kotra,a Ravi Varala,b and
Srinivas R. Adapaa,*
aI&PC Division, Indian Institute of Chemical Technology, Hyderabad, India-500
007
bPresent address: Lab no: 202, Dept. of Quimica, Universidade Nova de Lisboa,
Caparica, 2829-516-Portugal (FCT/UNL)
Tel: 9140-27193169; Fax: 9140-27160921; Email: dradapaiict@yahoo.com
Abstract – Citric acid promoted Friedlander synthesis of a mini-library of poly
o
substituted quinolines (30 examples) at 100 C under solvent-free conditions was
achieved in moderate to excellent yields (54-99%). The method is simple,
cost-effective and environmentally benign.
INTRODUCTION
Quinolines are privileged scaffolds possessing wide applications in medicinal chemistry,1 being used as
antimalarial, anti-inflammatory, anti-asthametic, antibacterial, antihypertensive and tyrosine kinase
PDGF-RTK inhibiting agents.2 In addition, quinolines are valuable synthons, used for the nano and
mesostructures with enhanced electronic and photonic properties.3 Although other methods such as
Skraup, Doebner von Miller, and Combes procedures have been reported4 for the preparation of
quinolines, the Friedlander annulation is one of the most simple and straightforward methods for the
synthesis of substituted quinolines.
The Friedlander synthesis is an acid or base catalyzed condensation followed by a cyclodehydration
between 2-aminoaryl ketone and a second carbonyl compound containing a reactive α-methylene group.
Generally, this reaction is carried out by refluxing an aqueous or alcoholic solution of reactants in the
presence of base at high temperature.5 Under thermal or base catalysis conditions, o-aminobenzophenone

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HETEROCYCLES, Vol. 75, No. 10, 2008
fails to react with simple ketones such as cyclohexanone and β-keto esters.6 Recently, notable Bronsted
and Lewis acids7 such as H2SO4, HCl, ZnCl2, NaAuCl4⋅2H2O, Y(OTf)3, SnCl2⋅2H2O, FeCl3, ionic liquids,
molecular iodine, Nd(NO3)3⋅6H2O, p-TsOH, TCT (2,4,6-trichloro-1,3,5-triazine or cyanuric chloride),
CeCl3⋅7H2O, [Sc(O3SOC12H25)3], silver phosphotungstate, zirconium tetra(dodecyl sulfate) (Zr(DS)4),
amberlyst-15, and sulfonated cellulose and starch have been shown to be effective for the synthesis of
quinolines. However, most of the methods have significant drawbacks such as low yields of the products,
harsh reaction conditions, difficulties in work-up and often use of expensive acid and base catalysts.
Furthermore, the synthesis of quinolines in general have been carried out in polar solvents such as
acetonitrile, THF, DMF, and DMSO leading to complex isolation and recovery procedures. Since
quinoline derivatives are increasingly useful and important in drugs and pharmaceuticals, the
development of a simple, efficient and environmentally benign protocol is still desirable.
Another promising synthetic approach to environmentally friendly chemistry is to minimize or eliminate
the use of harmful organic solvents. Organic reactions under solvent-free conditions are advantageous
because of their enhanced selectivity and efficiency, ease of manipulation, cleaner product formation, and
toxic or often volatile solvents are avoided.8 In recent years, a lot of attention has been paid to
organocatalysts owing to their eco-friendliness and can proceed under aerobic atmosphere, other notable
advantages are: usually less expensive and commercially available.9
RESULTS AND DISCUSSION
Based on our recent expertise and following related literature reports on utilization of organoacids as
promoters in construction of various heterocycles,10 and also our continued efforts in developing novel
synthetic routes for carbon-carbon, carbon-heterobond formations,11 we at first began our study for the
model reaction using 2-aminobenzophenone (1 mmol) and ethyl acetoacetate (EAA, 1.1 mmol) at 100 oC
for a period of 5 h under neat conditions promoted by 4-nitrobenzoic acid (1 equiv.). As we expected, the
corresponding quinoline was isolated in good yield (entry 2, Table 1).
Table 1. Model reaction 2-aminobenzophenone with EAA
Ph
O
CO2Et
Me
O
O
organoacid
Ph
+
100 oC, neat, 5 h
OEt
Me
NH2
N

HETEROCYCLES, Vol. 75, No. 10, 2008
2525
Entry
Organoacid
malonic acid
4 -nitrobenzoic acid
p-anisic acid
tartaric acid
p-TsOH
Isolated Yield (%)
1
2
78
88
69
80
90
58
94
79
65
70
74
86
42
3
4
5
6
anthranilic acid
citric acid
7
8
benzoic acid
cinnamic acid
proline
9
10
11
12
13
mandelic acid
2-picric acid
no catalyst
Inspired by this result, we surveyed the efficacy of various organoacids chosen (Table 1) under the above
reaction conditions for the model reaction. Among the catalysts screened, citric acid (entry 7, Table 1)
showed the best result with a 94% isolated yield. Citric acid is a tricarboxylic weak organoacid which
serves as an environmentally benign cleaning agent,12 relatively inexpensive reagent. In the absence of
any catalyst, 42% of the isolated yield was observed (entry 13, Table 1).
The optimum yields of the product were obtained when a ratio of substrate to EAA (1:1.1). Further, 0.5
equiv. of promoter was sufficient to give the optimum yield whereas the reaction was sluggish when
carried out decreasing the amount of catalyst loadings further. The desired product could not be obtained
in the same yield (94%) at the temperature lower than 100 oC. To the best of our knowledge, there are no
earlier reports on the preparation of quinolines using citric acid as an organo promoter.
Then, we studied the effect of various solvents on the model reaction and the results are summarized in
Table 2. As can be seen from Table 2, good yield was obtained using water (entry 1, Table 2) as reaction
medium, thus opening the scope for green chemistry as well. Compared to the organic solvents tested
(entries 2-4 and 6-7, Table 2), solvent free conditions afforded excellent isolated yields (94%, entry 5,
Table 2) under the optimized conditions.

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HETEROCYCLES, Vol. 75, No. 10, 2008
Table 2. Effect of solvents on the model reaction
Entry
Solvent
H2O
Yield (%)a
1
2
3
4
5
6
7
76
73
80
58
94
21
0
THF
CHCl3
MeCN
neat
toluene
DMF
aIsolated yields.
To determine the scope of the methodology, the reaction was performed with model reaction on a 20
mmol scale using citric acid (0.5 equiv.). And to our utmost satisfaction, the reaction was complete in 5 h
affording the corresponding product in 92% isolated yield, thus confirming the possibility of being scaled
up.
Intrigued by the results obtained under optimized conditions, we then examined various structurally
divergent 2-aminoaryl ketones such as 2-aminobenzophenone, 2-aminoacetophenone, and 2-amino-
5-chlorobenzophenone for the condensation to take place; and β-keto esters could also be extended to
other α-methylene ketones such as cyclopentanone, cyclohexanone, 5,5-dimethylcyclohexanedione
(dimedone) and the results are summarized in Table 3. The present protocol is equally effective for both
cyclic and acyclic ketones. In all cases reactions were clean and devoid of self-condensation of ketones,
which are normally observed under basic conditions. Furthermore, most of the products (solids) were
isolated by simple filtration as described in experimental procedure.

HETEROCYCLES, Vol. 75, No. 10, 2008
2527
Table 3. Synthesis of polysubstituted quinolines promoted by citric acid
Mp (oC)
Lit.ref.
Found
Time (h) Yield (%)a
α-aminoaryl ketone α-methylene ketone
Entry
Product
Me
Me
CO2Et
O
O
93
oil7
oil7
oil7
oil7
O
1
2
3
5
oil
Me
OEt
N
Me
NH2
Me
Me
CO2Me
O
O
O
oil
95
5
Me
Me
Ph
OMe
N
Me
NH2
Me
O
Me
O
O
O
O
NH2
Me
oil
oil
Me
Me
5
93
82
Me
N
Me
O
CO2Et
Ph
5.5
4
5
O
OEt
N
NH2
Me
Me
O
58-607
75-777
O
60
76
92
86
2
4
N
Me
NH2
Me
O
O
6
7
N
NH2
Me
O
O
O
Me
105-1077
O
108
4
98
Me
Me
Me
Me
NH2
Ph
N
Ph
O
O
O
O
NH2
Ph
Me
Me
65-667
Me
8
9
5
5
69
75
65
N
Ph
Me
O
O
Cl
208-2107
210
Cl
O
Me
Me
Me
Me
N
Ph
O
O
NH2
Ph
CO2Et
Me
O
92b
98-997
99-1007
114-1167
100
O
5
94
10
Me
N
OEt
NH2
Ph
Ph
O
O
O
CO2Me
Me
99
11
12
83
88
5.5
5
Me
Me
OMe
NH2
Ph
N
O
Ph
O
O
O
NH2
Ph
114-116
Me
Me
Me
N
Me
O
Ph
O
O
O
Me
Ph
105-1077
139-1417
88
13
14
15
Ph
5
2
78
95
NH2
Ph
N
Ph
O
O
140-141
N
NH2
Ph
O
Ph
140-1427
O
4
141-142
99
NH2
N
a Isolated yields. bReaction on 20 mmol scale.

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HETEROCYCLES, Vol. 75, No. 10, 2008
Table 3. Synthesis of polysubstituted quinolines promoted by citric acid
Mp (oC)
Found
Entry
α-methylene ketone
α-aminoaryl ketone
Product
Yield (%)a
Time (h)
Lit.ref.
Ph
Ph
O
O
O
O
CO2Et
Me
Cl
Cl
Cl
O
16
1087
108
135
5
5
84
96
Me
OEt
NH2
Ph
N
Ph
O
Cl
Cl
O
133-1357
OMe
Me
17
Me
OMe
NH2
N
Ph
Ph
O
O
O
O
O
O
Cl
Cl
Me
149-1507
105-1077
149
106
5
5
92
78
18
19
Me
Ph
Me
NH2
Ph
N
Ph
Me
Cl
CO2Et
Ph
O
OEt
NH2
Ph
N
Ph
O
O
Cl
Cl
Cl
O
20
21
5
5
3
87
84
93
104-1057
104
NH2
Ph
N
Ph
Cl
Cl
O
131-1327 131-132
NH2
Ph
N
Ph
Me
Me
Me
Me
O
O
NH2
Ph
799
22
23
98-99
Me
Me
Me
Me
N
Ph
O
Cl
O
1277
127
88
3
N
NH2
Ph
Ph
Me
O
NH2
Ph
O
24
25
79
70
65
106
161
126
6
6
105-1077
N
Ph
Ph
Me
O
NH2
Ph
O
-
-
N
O2N
NO2
Me
Ph
O
O
26
6
N
Br
NH2
Ph
Me
Br
Ph
O
O
27
28
8
6
-
-
137
54
72
HO
N
NH2
Ph
Me
OH
OMe
Ph
O
O
162-163
MeO
N
Ph
NH2
Ph
O
Me
Cl
Cl
Cl
Cl
1027
1957
O
8
8
74
58
29
30
101-103
194-196
N
NH2
Ph
Ph
Me
O
O
N
NH2
Br
Br
a Isolated yields. bReaction on 20 mmol scale.
The proposed mechanism for the citric acid-promoted synthesis of substituted quinolines may tentatively
be visualized to occur via a tandem sequence of reactions involving initially the formation of

HETEROCYCLES, Vol. 75, No. 10, 2008
2529
amino-ketone condensation, thereafter activation of carbonyl oxygen of second carbonyl compound
containing active methylene group by carboxylic hydrogen of citric acid through intermolecular hydrogen
bonding, and subsequent cyclocondensation to produce a quinoline derivative.
The efficiency and generality of the present citric acid-promoted protocol can be realized at a glance by
comparing our results for the chosen model substrate (entry 7, Table 1) with those of some recently
reported procedures (as shown in Table 4). The reaction has been compared to with respect to the
reaction times and isolated yields.
Table 4. Comparision of the catalytic efficiency of citric
acid with some recently reported catalysts for the model reaction
Entry
Catalyst ref
Time (h) Isolated yield (%)
2H2O7
NaAuCl4
6
83
92
1
2
10
7
Nd(NO )
3 3 6H2O
3a
24
16
bmimCl:ZnCl2
92
96
7
I2
4
5
5
citric acid
94
7
6
7
Y(OTf)3
4
12
3
89
94
7
Sc(O3SOCl2H25)3
7
8
9
Zr(DS)4
Amberlyst-157
72
89
2.5
1.5
10
7H2O7
CeCl3
95
abmim=1-butyl-3-methyl imidazolium chloride
In conclusion, we have demonstrated a mild and efficient eco-friendly Friedlander synthesis of quinolines,
using citric acid as a novel organoacid green promoter, that uses neither harsh conditions nor the use of
hazardous acids or bases. Notable advantages of our protocol includes: (a) operational simplicity, (b)
good substrate scope, (c) the relatively non-toxic, inexpensive, water soluble organocatalyst (d) high
yields of products (e) no transition metal contamination.
EXPERIMENTAL
Experimental protocols
Melting points were recorded a Buchi R-535 apparatus. IR spectra were determined on a Bruker
1
Vector-22 spectrometer. H NMR spectra of CDCl3 solutions were recorded on Bruker Avance-300
spectrometer. The chemical shifts are reported as parts per million downfield from tetramethylsilane. 13C
NMR spectra (75.5 MHz) were recorded on a Bruker Avance-300 spectrometer with complete proton

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HETEROCYCLES, Vol. 75, No. 10, 2008
decoupling; chemical shifts are reported in ppm relative to the solvent resonance as the internal solvent
(CDCl3, δ = 77.16). Mass spectra were recorded on a VG7070H micromass spectrometer. Elemental
analysis was performed on a Vario EL analyzer. The purity of the compounds was checked by TLC on
precoated SiO2 gel (HF254, 100-200 mesh) aluminum plates (E. Merck) using n-hexane: EtOAc (9:1) as
mobile phase and visualized by iodine vapors.
General procedure
A mixture of o-amino-aryl ketone (1.0 mmol), α-methylene ketone (1.1 mmol) and citric acid (0.5 mmol),
0
was stirred at 100 C under solvent-free conditions for appropriate time (Table 3). After completion of
the reaction as indicated by TLC, the reaction mixture was diluted with water (2 mL) and the solid
quinoline product which separated out was filtered, washed with water and dried. The crude solid was
then recrystallized from a mixture of Et2O and hexane. For liquid quinolines, the reaction mixture was
extracted in Et2O (2×5 mL), dried over MgSO4 and concentrated in vacuo to give the crude product which
was further purified either by a short column chromatography (silica gel, EtOAc-hexane, 1:9) to afford
the corresponding pure quinoline derivative.
All the compounds were known and characterized by IR, NMR, mass spectrometry and also by
comparing their physical characteristics with those in the literature.4-7
Please see supporting information for spectral data for selected compounds.
Spectral data for representative compounds:
Entry 3, Table 3: Oil; IR (NaCl): ν 3068, 2959, 1703, 1614, 1585, 1208, 758 cm-1; 1H NMR (300 MHz,
CDCl3): δ 2.57 (s, 3H), 2.58 (s, 3H), 2.62 (s, 3H), 7.53-8.01 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 15,
23.3, 32.4, 123.5, 126.2, 129, 129.6, 135.6, 138.4, 146.7, 152.4, 206.3; MS (EI, 70 eV): m/z= 199 (M+),
158, 125; Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.32; H, 6.51; N, 7.07.
o
1
Entry 5, Table 3: Solid; mp 60 C; IR (KBr): ν 3065, 2957, 1613, 908, 751 cm−1; H NMR (300 MHz,
CDCl3): δ 2.2 (m, 2H), 2.49 (s, 3H), 2.99 (t, J =7.55 Hz, 2H), 3.3 (t, J =6.9 Hz, 2H), 7.46-8.01 (m, 4H);
13C NMR (75 MHz, CDCl3): δ 14.6, 22.7, 29.4, 34.8, 123.1, 125.0, 126.9, 127.8, 128.9, 133.7, 137.8,
147.2, 166.7; MS (EI, 70 eV): m/z= 183 (M+), 168, 154, 140, 127, 115, 102, 90, 77, 63, 57; Anal. Calcd
for C13H13N: C, 85.21; H, 7.15; N, 7.64. Found: C, 85.17; H, 7.07; N, 7.72. Entry 9, Table 3: Yellow
o
solid; mp 210 C; IR (KBr): ν 3074, 2952, 2866, 1696, 1554, 1477, 1384, 1297, 1198, 1079, 837, 699
1
cm−1; H NMR (300 MHz, CDCl3): δ 1.15 (s, 6H), 2.56 (s, 2H), 3.25 (s, 2H), 7.14-7.17 (m, 2H),
7.43-7.97 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 28.3, 32.1, 48.3, 54.2, 123.3, 126.7, 127.8, 128.1,
128.3, 130.2, 132.4, 136.8, 147.4, 150.0, 161.4, 197.5; MS (EI, 70 eV): m/z= 335 (M+); Anal. Calcd for
C21H18ClNO: C, 75.11; H, 5.40; N, 4.17. Found: C, 75.07; H, 5.43; N, 4.21. Entry 16, Table 3: Yellow

HETEROCYCLES, Vol. 75, No. 10, 2008
2531
o
1
solid; mp 108 C; IR (KBr): ν 3064, 2983, 1725, 1605, 1224, 907, 732 cm-1; H NMR (300 MHz,
CDCl3):0.92-0.95 (t, J = Hz, 3H), 2.73 (s, 3H), 4.03-4.07 (q, J = 7 Hz 2H), 7.32-8 (m, 8H); 13C NMR (75
MHz, CDCl3): δ 13.5, 23.6, 61.4, 125.1, 125.9, 128.4, 128.7, 129.2, 130.5, 131, 132.3, 135, 145.3, 146,
154, 168; MS (EI, 70 eV): m/z= 325 (M+), 296, 280, 252, 217, 189, 176, 149, 123, 109, 88, 71, 57; Anal.
Calcd for C20H19ClNO2: C, 70.05; H, 4.95; N, 4.30. Found: C, 70.09; H, 4.90; N, 4.36. Entry 21, Table
o
3: Yellow solid; mp 165 C; IR (KBr): ν 3059, 2945, 2858, 1599, 1570, 1477, 1440, 1349, 1266, 1165,
1075, 937, 831, 818, 757, 708, 617 cm−1; 1H NMR (300 MHz, CDCl3): δ 1.55 (m, 2H), 1.59 (m, 2H), 2.56
13
(t, J =6.5 Hz, 2H), 3.3 (t, J=7 Hz, 2H), 7.2-8.02 (m, 8H); C NMR (75 MHz, CDCl3): δ 23, 28.2, 34.3,
124.6, 127.5, 128.2, 128.9, 129.1, 129.3, 129.5, 130.2, 131.3, 136.5, 144.8, 145.8, 159.6; MS (EI, 70 eV):
m/z= 293 (M+), 278, 258, 242, 230, 201, 189, 176, 150, 89, 77. Anal. Calcd for C19H16ClN: C, 77.68; H,
5.49; N, 4.77. Found: C, 77.59; H, 5.34; N, 4.68. Entry 29, Table 3: Solid; mp 101-103 oC; IR (KBr): ν
3055, 1684, 1483, 907, 729 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.4-8.02 (m, 14H); 13C NMR (75 MHz,
CDCl3): δ 120, 124.4, 126.4, 127.5, 128.7, 128.8, 129.4, 130.4, 131.6, 132.7, 137.7, 139.1, 147.2, 148.4,
157; MS (EI, 70 eV): m/z= 316 (M+), 288, 125; Anal. Calcd for C21H14ClN: C, 79.87; H, 4.47; N, 4.44.
Found: C, 79.81; H, 4.52; N, 4.41.
ACKNOWLEDGEMENTS
Dr. Enugala and Dr. Varala thank DIICT, Dr. J. S. Yadav and Council of Scientific Industrial Research
(CSIR, India) for financial support.
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