Click chemistry approach: Regioselective one-pot synthesis of some new 8-trifluoromethylquinoline based 1,2,3-triazoles as potent antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2014.01.008

Three series of 8-trifluoromethylquinoline based 1,2,3-triazoles derivatives (5a-c, 6a-d and 7a-c) were synthesized by multi-step reactions by click chemistry approach. Synthesized compounds were characterized by spectral studies and X-ray analysis. The final compounds were screened for their in-vitro antimicrobial activity by well plate method (zone of inhibition). Compounds 5c, 6b, 8b, 11 and 12 were found to be active against tested microbial strains. The results are summarized in Tables 5 and 6.

Full text of DOI:10.1016/j.ejmech.2014.01.008

European Journal of Medicinal Chemistry 74 (2014) 324e332
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Click chemistry approach: Regioselective one-pot synthesis of some
new 8-trifluoromethylquinoline based 1,2,3-triazoles as potent
antimicrobial agents
,
b
c
B. Garudachari a, Arun M. Isloor a , M.N. Satyanarayana , Hoong-Kun Fun ,
*
Gurumurthy Hegde d
a Medicinal Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, India
b Department of Physics, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, India
c Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
d Faculty of Industrial Science and Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Gambang, Kuantan, Pahang Darul Makmur,
Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Three series of 8-trifluoromethylquinoline based 1,2,3-triazoles derivatives (5aec, 6aed and 7aec) were
synthesized by multi-step reactions by click chemistry approach. Synthesized compounds were char-
acterized by spectral studies and X-ray analysis. The final compounds were screened for their in-vitro
antimicrobial activity by well plate method (zone of inhibition). Compounds 5c, 6b, 8b, 11 and 12 were
found to be active against tested microbial strains. The results are summarized in Tables 5 and 6.
Ó 2014 Elsevier Masson SAS. All rights reserved.
Received 7 August 2013
Received in revised form
2 January 2014
Accepted 2 January 2014
Available online 11 January 2014
Keywords:
8-Trifluoromethylquinoline
1,2,3-Triazole
Click chemistry
Suzuki coupling
Antimicrobial activity
1. Introduction
Ciprofloxacin, Grepafloxacin). A large variety of quinoline de-
rivatives are found in plant alkaloids, which are used in the treat-
In recent years, the mounting threat of bacterial resistance has
heightened the urgency to discover and develop new anti-infective
agents with novel mechanism of action and enhanced activity
profile [1e3]. The fluorinated compounds have been very impor-
tant in the pharmaceutical field because of their multiple phar-
macological action. Incorporation of trifluoromethyl group instead
of hydrogen atom can alter the biological activities [4,5]. Intro-
duction of trifluoromethyl group provides better electronic effect at
neighboring carbon centers, as well as having a substantial effect on
the molecule’s dipole moment, acidity and basicity of neighboring
groups [6]. Fluorine is much more lipophilic than hydrogen, so
incorporation of fluorine atoms in a molecule will make it more fat
soluble and as a hydrogen bond acceptor [7].
ment of Malaria, bacterial infection and tuberculosis [8e11]. Recent
observations suggested that, substitution of trifluoromethyl group
at C-8 position of the quinoline have a profound effect on biological
activity [12,13]. Trifluoromethyl quinolines and its derivatives have
wide range of applications in the field of pharmaceuticals as anti-
malarial [14], antibacterial, antifungal [12], antituberculosis [15],
anticancer agents [16]. Mefloquine and Tafenoquine are some of the
drugs which contain trifluoromethyl group and quinoline as a core
moiety (Figs. 1 and 2).
Synthesis of 1,2,3-triazoles and their derivatives form
an important class of heterocycles with various pharmacological
activities. 1,2,3-Triazole derivatives have been reported as anti-
bacterial, antifungal, antitubercular, anticancer, antiviral, antihy-
pertensive, anticholinergic and anti-inflammatory agents [17e20].
Literature review revealed that, insertion of pharmacophore at
position four of quinoline with heterocyclic derivatives enhances
its antimicrobial [21] and antituberculosis activity [15]. The sub-
stitution of trifluoromethyl functional group at eighth position
showed good pharmacological properties like antimicrobial,
Quinoline derivatives are well-known heterocycles, play an
important role in developing new antimicrobial agents (Eg.
* Corresponding author. Tel.: þ91 824 2474000; fax: þ91 824 2474033.
E-mail address: isloor@yahoo.com (A.M. Isloor).
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2014.01.008

B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
325
Suzuki reaction was employed to synthesize 4-ethoxy-3-(1-methyl-
1H-indol-5-yl)-8-trifluoromethyl-quinoline (12) in satisfactory
good yields by reacting N-methylindole-5-boronic acid with 11
(Scheme 4). The crude products were purified by column chroma-
tography. The reaction pathway has been summarized in Schemes
1e4. Newly synthesized compounds were characterized by IR,
NMR, mass spectral and C, H, N elemental analyses.
The formation of 4-prop-2-ynyloxy-8-trifluoromethyl-quino-
line-3-carboxylic acid ethyl ester (4) was conformed by the peaks at
3261 cmꢀ1, 2120 cmꢀ1 in IR spectrum which is due to the (C^CeH-
str) stretching of propargyl chain. Bands at 1700 cmꢀ1 and
1103 cmꢀ1 are due to C]O stretch of carboxylic ester and phenolic
ether respectively. The 1H NMR spectrum of 4 showed triplet and a
NH
HO
N
CF3
CF3
Fig. 1. Structure of Mefloquine.
CF3
quartet at
acetylene CH proton appeared as singlet at
appeared as a singlet at 5.08. The triplet at
proton of quinoline ring. Doublets appeared at
due to quinoline fifth and seventh protons respectively. The quin-
oline third proton appeared as a singlet at 9.24.
Formation of 1,2,3-triazol-8-trifluoromethyl-quinoline-3-
carboxylic acid ethyl ester derivatives (5aec, 6aed and 7aec)
were confirmed by the presence of absorption peak at 1724e
1582 cmꢀ1 in IR spectra which are due to (C]O) stretching of
carboxylic esters. Absorption band at 1254e1131 cmꢀ1 are due to
N]N of the 1,2,3-triazoles. The 1H NMR spectra of compounds 5ae
d
1.35,
d
4.38 corresponding to carboxylic ethyl ester. The
3.66. The CH2 proton
7.82 is due to sixth
8.28 and 8.55 are
O
O
d
d
d
O
N
d
d
HN
d
NH2
Fig. 2. Structure of Tafenoquine.
antifungal and antitumor activities [12,22]. In recent years,
regioselective click chemistry has wide application in the syn-
thetic organic chemistry and biomedicinal chemistry. Click
chemistry has been explored as a new approach to synthesis
regioselective 1,2,3-triazole derivatives for the new drugs devel-
opment. Prompted by these observations and in continuation of
our research on biologically active heterocycles [23e26], we
hereby report the synthesis of some new 1,2,3-triazole derivatives
containing 8-trifluoromethyquinoline nucleus by the click chem-
istry approach. The synthesized compounds were screened for
their antimicrobial properties.
c, 6aed and 7aec showed triplet at
d
1.36e1.40 and a quartet at
d
4.40e4.49 are due to the carboxylic ethyl esters. CH2 protons
appeared as singlets at d 31e5.54 and 4.42e6.19. A singlet at d 8.19e
8.27 are due to proton of 1,2,3-triazole moiety. All other aromatic
protons appeared in 7.06 to 9.26 regions. The mass spectra of all
d
the final derivatives showed comparable molecular ion peak with
respect to molecular formula. Three dimensional structures of 5c,
6c and 8a were evidenced by X-ray crystallographic study. Similarly
the spectral values for all the compounds and C, H, N analyses are
presented in the experimental part and the characterization data
are provided in Table 1.
2.2. X-ray crystallographic study of compound 5c, 6c and 8a
2. Results and discussion
The X-ray crystallographic analysis of the compounds 5c, 6c and
8a were carried out by fine-focus sealed tube graphite. The crystal
structure solution was worked out by Bruker SMART APEXII DUO
CCD diffractometer. All the atoms were located in different Fourier
maps and refined isotropically, using a riding model and all the
projections were generated using ORTEP. The details of the crystal
data and refinement are shown in Tables 2e4. Also the single
crystal image for compounds 5c, 6c and 8a are given in Figs. 3e5
[30e32].
2.1. Chemistry
Gould-Jacobs method was utilized to synthesize the intermedi-
ate (3). The selective O-alkylation of 3 was carried out by treating it
with propargylbromide in acetone media [27e29] (Scheme 1). The
targeted regioselective 1,4 substituted 1,2,3-triazole derivatives
(5aec, 6aed and 7aec) were synthesized by multicomponent one
pot click chemistry approach, reacting 4-prop-2-ynyloxy-8-
trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (4) with
various benzyl bromides, phenacyl bromides and alkyl bromides
(Scheme 2). 6-Trifluoromethyl-furo[3,2-c]quinoline derivatives
(8a,b) were synthesized by treating ethyl chloroacetate and 4-
hydroxy-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester
(3) in dimethylformamide using potassium carbonate base followed
by the hydrolysis of ester using LiOH (Scheme 3). The versatile
2.3. Antimicrobial studies
The newly synthesized compounds (5aec, 6aed, 7aec, 8a,b, 11
and 12) were screened for their in-vitro antibacterial activity
against Escherichia coli, Bacillus subtilis and Pseudomonas aeruginosa
O
O
OH
N
O
O
N
O
O
i
ii
NH
O
iii
O
O
NH2
CF3
CF3
CF3
CF3
1
3
2
4
Scheme 1. Synthetic route for 4-prop-2-ynyloxy-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (4): (i) diethyl ethoxymethylene malonate, 110 ꢁC, 6 h; (ii) Dowtherm,
250 ꢁC, 5 h; (iii) propargylbromide, K2CO3, acetone, 50 ꢁC, 12 h.

326
B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
R1
R
O
N
N
N
N
N
N
O
O
O
O
O
O
O
iv
O
v
O
N
N
CF3
N
CF3
5a-c
4
F3C
6a-d
vi
R2
N
N
N
O
O
O
N
CF3
7a-c
Scheme 2. Synthetic route for 1,2,3-triazol-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester derivatives (5aec, 6aed and 7aec): (iv, v and vi) alkyl bromide (aromatic,
phenacyl and aliphatic), NaN3, aqueous PEG 400 (5 mL, 1:1, v/v), sodium ascorbate, 10 mol % of Copper sulfate.
R3
strength on the 1,2,3-triazole (alkyl chain and methoxy substitu-
tion) decreases antibacterial activity. On the other hand, intro-
ducing halogen or electron withdrawing phenyl ring on 1,2,3-
triazole with trifluromethyl quinoline increases the antibacterial
activity. The activity exhibited by the synthesized compounds were
due to both 1,2,3-triazole and quinoline core rings. Since the
presence of active functional group on both the rings (quinoline
and 1,2,3-triazole), no definite SAR could be established in this
series of compounds. General structure of final derivatives are
given in Fig 6.
O
OH
N
O
O
O
O
viia
b
O
N
O
CF3
F3C
3
8a,b
Scheme 3. Synthetic route for 3-ethoxycarbonylmethoxy-6-trifluoromethyl-furo[3,2-
c]quinoline-2-carboxylic acid ethyl ester (8a) and 3-ethoxycarbonylmethoxy-6-
trifluoromethyl-furo[3,2-c]quinoline-2-carboxylic acid (8b): (vii) a: ethyl chlor-
oacetate, K2CO3, DMF, RT, 6 h; (vii) b: LiOH, MeOH, 2 h.
OH
N
O
OH
N
O
OH
O
OH
Br
viii
using Ciprofloxacin as standard by well plate method (zone of in-
hibition) [33,34]. The test compounds were dissolved in dime-
thylsulfoxide (DMSO) at concentrations of 0.5 mg/mL and 1.0 mg/
mL.
ix
CF3
N
x
CF3
CF3
10
3
9
The antibacterial screening revealed that, all the tested com-
pounds showed good inhibition against various tested microbial
strains compared to the standard drug. Among the synthesized
compounds 5c, 6b, 8b, 11 and 12 were found to be more active
against tested bacterial strains as compared to the standard. The
enhanced antibacterial activity of 5c and 6b were due to presence
of chlorine in the 4-benzyl-[1,2,3]-triazole at the fourth position of
8-trifluoromethylquinoline-3-carboxylic ester. The compounds 8b,
11 and 12 contains furan ring (8b), bromo (11) and N-methylindole
(12) groups at third position of 8-trifluoromethylquinoline ring
which accounts for the enhanced antibacterial activity. Compounds
5b, 6c and 8a exhibited moderate antibacterial activity against all
tested bacterial stains. In general, increase of electron donating
N
O
O
Br
xi
N
CF3
11
N
CF3
12
Scheme 4. Synthetic route for 4-ethoxy-3-(1-methyl-1H-indol-5-yl)-8-trifluorometh
yl-quinoline (12): (vii) LiOH, MeOH, 2 h; (ix) NBS, THF, RT, 12 h; (x) EtI, K2CO3, DMF,
RT, 2 h; (xi) N-methylindole-5-boronic acid, toluene, EtOH, K2CO3, palladium acetate,
80 ꢁC, 2 h.

B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
327
Table 1
Characterization data of the compounds (5aec, 6aed, 7aec, 8a,b, 11 and 12).
Table 4
Crystal data and measurement details for compound 8a.
Compounds R/R1/R2/R3
Molecular formula
(mol. wt.)
M.p.
(ꢁC)
Yield
(%)
Crystal data
Empirical formula
Formula weight
Crystal system
Crystal dimension
Space group
C19H16F3NO6
411.33
Triclinic
5a
5b
5c
6a
6b
6c
6d
7a
7b
7c
8a
8b
11
12
H
4-NO2
2,4-Cl2
F
Cl
Br
OCH3
CH2CH3
CH2CH2CH3
CH2CH2CH2CH3
OCH2CH3
OH
e
C23H19F3N4O3 (456.4) 93e95
76
C23H18F3N5O5 (501.4) 152e154 89
C23H17Cl2F3N4O3 (525.3) 150e152 79
C24H18F4N4O4 (502.4) 125e127 80
0.56 mm ꢂ 0.38 mm ꢂ 0.15 mm
P1
ꢀ
C
24H18ClF3N4O4 (518.8) 120e122 72
a (A)
8.9167 (3)
8.9223 (3)
13.4125 (5)
904.22 (5)
102.895, 97.098, 16.035
2
424
0.13
200 K
0.71073
ꢀ
C
24H18BrF3N4O4 (563.3) 105e107 72
C25H21F3N4O5 (514.4) 134e136 53
C18H17F3N4O3 (394.3) 100e102 55
b (A)
ꢀ
c (A)
Volume (A )
3
ꢀ
C19H19F3N4O3 (408.3) 71e73
C20H21F3N4O3 (422.4) 63e65
49
42
Angle
Z
a,
b,
g
C19H16F3NO6 (411.3) 125e127 92
17H12F3NO6 (383.2) 133e135 90
12H9BrF3NO (320.1) 106e108 85
21H17F3N2O (370.3) 60e62 67
F000
C
C
C
m
(mmꢀ1
)
Temperature (T)
Radiation wavelength (A)
Radiation type
ꢀ
e
Mo K
a
Radiation source
Radiation monochromator
Fine-focus sealed tube
Graphite
The in-vitro antifungal activities of newly synthesized com-
pounds (5aec, 6aed, 7aec, 8a,b, 11 and 12) were determined by
well plate method [35,36]. The results indicate that, among the
tested compounds 8b and 12 were active against all tested fungal
strains. The enhanced activities of compounds are due to hetero-
cyclic moieties (furan, N-methylindole) attached to the 8-
trifluoromethylquinoline ring. All other compounds such as, 1,2,3-
triazole with alkyl, aryl and phenacyl substitution with tri-
fluoromethylquinoline showed lesser antifungal activity as
compared with that of trifluoromethylquinoline core moiety with
heterocyclic attachment at third position. Probably in this case,
direct substitution of heterocyclic moieties at third position of tri-
fluoromethylquinoline is more suited compared with 1,2,3-triazole
with ether linkage to enhance the antifungal activity. Tables 5 and 6
depict the antimicrobial screening results of the final compounds.
Table 2
Crystal data and measurement details for compound 5c.
Crystal data
Empirical formula
Formula weight
Crystal system
Crystal dimension
Space group
C23H17Cl2F3N4O3
525.31
Monoclinic
3. Conclusion
0.32 mm ꢂ 0.31 mm ꢂ 0.17 mm
Three series of 8-trifluoromethylquinoline based 1,2,3-triazoles
derivatives (5aec, 6aed, 7aec, 8a,b,11 and 12) were synthesized by
multi-step reactions. Compounds with an electron withdrawing
group in 1,2,3-triazole ring are shown better yield compared with
an electron donating group. The synthesized compounds were
characterized by spectral studies, single crystal X-ray analysis and
screened for their antimicrobial activities.
Among the screened samples 5c, 6b, 8b, 11 and 12 showed
moderate to good inhibition against all tested bacterial strains. The
enhanced antibacterial activity of 5c and 6b are due to chlorine
P21/c
ꢀ
a (A)
10.0414 (6)
18.3997 (11)
15.5456 (7)
2246.0 (2)
90, 128.559, 90
4
ꢀ
b (A)
ꢀ
c (A)
Volume (A )
3
ꢀ
Angle
Z
a, b, g
F000
m
1072
0.35
(mmꢀ1
)
Temperature (T)
Radiation wavelength (A)
Radiation type
100 K
0.71073
ꢀ
Mo K
a
Radiation source
Radiation monochromator
Fine-focus sealed tube
Graphite
Table 3
Crystal data and measurement details for compound 6c.
Crystal data
Empirical formula
Formula weight
Crystal system
Crystal dimension
Space group
C24H18BrF3N4O4
563.33
Monoclinic
0.58 mm ꢂ 0.16 mm ꢂ 0.07 mm
P21/c
ꢀ
a (A)
5.2809 (2)
24.5131 (10)
18.3517 (7)
2342.08 (16)
90, 99.643, 90
4
ꢀ
b (A)
ꢀ
c (A)
Volume (A )
3
ꢀ
Angle
Z
a, b, g
F000
m
1136
1.82
(mmꢀ1
)
Temperature (T)
Radiation wavelength (A)
Radiation type
200 K
0.71073
ꢀ
Mo K
a
Radiation source
Radiation monochromator
Fine-focus sealed tube
Graphite
Fig. 3. ORTEP diagram showing the X-ray crystal structure of compound 5c.

328
B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
Fig. 4. ORTEP diagram showing the X-ray crystal structure of compound 6c.
substitution on the phenyl ring of 1,2,3-triazole and ethyl 8-(tri-
fluoromethyl)quinoline-3-carboxylate. Substitution of heterocyclic
fused rings (8b) at 3rd position and derivatization at 3rd position of
8-trifluoromethylquinoline may be the reasons for the enhanced
activity of compounds 11 and 12. Compound 8b and 11 showed
significant inhibition against fungal strains as compared with
standard drugs, this may be due to the substitution of oxygen de-
rivative at 4th position of 8-trifluoromethylquinoline. On the other
hand, heterocyclic (furan, N-methylindole) substituted 8-
trifluoromethylquinoline derivatives were found to good antimi-
crobial agents compared with the standard drugs. In conclusion,
electron donating character or increase of alkyl chain in the 1,2,3-
triazole ring at 4th position of 8-trifluoromethylquinoline reduces
antimicrobial activity. The presence of electron withdrawing
group (NO2) and halogen (chloro and dichloro) substitution on the
phenyl ring of 1,2,3-triazole at 4th position of the 8-
trifluoromethylquinoline derivatives increase the antimicrobial
activity of the final derivatives.
properties, it showed that benzyl-[1,2,3]-triazole with electron
withdrawing group at the 4th position of the 8-
trifluoromethylquinoline and heterocyclic (furan, N-methylindole)
at 3rd position of 8-trifluoromethyl ring are ideally suited for
obtaining more efficient antimicrobial compounds.
4. Experimental
4.1. Analysis and instruments
All the chemicals were purchased from Sigma Aldrich, Merck
and S. D. Fine chemicals-India. Commercial grade solvents were
used and were distilled before use. Melting points were determined
by open capillary method and were uncorrected. The IR spectra
(neat) were recorded on a Nicolet Avatar 5700 FTIR spectropho-
tometer and Bruker, Varian (400 MHz) spectrometer was used to
R
R1
In our study we have incorporated 1,2,3-triazole at fourth po-
sition of quinoline ring with ether linkage. Probably in this case
1,2,3-triazole is not so important for antimicrobial activity. More-
over, the presence of active pharmacophore on phenyl ring cause
certain change of activity. As regards the relationships between the
structure of the heterocyclic scaffold and detected antimicrobial
O
N
N
O
N
O
O
O
N
O
N
O
O
F3C
CF3
O
N
O
N
Br
N
CF3
CF3
Fig. 5. ORTEP diagram showing the X-ray crystal structure of compound 8a.
Fig. 6. Structure of final derivatives.

B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
329
Table 5
Antibacterial activity of the compounds (5aec, 6aed, 7aec, 8a,b, 11 and 12).
Compound no.
Zone of inhibition in mm (mean ꢃ S.D.) n ¼ 3
Escherichia coli
Bacillus subtilis
Pseudomonas aeruginosa
Concentration mg/mL
Standard
0.5
1
0.5
1
0.5
1
Ciprofloxacin
Control
5a
5b
5c
6a
6b
6c
6d
7a
7b
7c
8a
22 ꢃ 0.5
24 ꢃ 0.9
22 ꢃ 0.5
25 ꢃ 0.7
24 ꢃ 0.4
28 ꢃ 0.5
00
00
00
00
00
00
02 ꢃ 0.1
08 ꢃ 0.9
13 ꢃ 0.6
02 ꢃ 0.1
14 ꢃ 0.6
07 ꢃ 0.6
04 ꢃ 0.2
08 ꢃ 0.4
05 ꢃ 0.8
04 ꢃ 0.4
08 ꢃ 0.7
10 ꢃ 0.8
04 ꢃ 0.8
17 ꢃ 0.4
04 ꢃ 0.2
10 ꢃ 0.3
15 ꢃ 0.7
04 ꢃ 0.2
15 ꢃ 0.4
10 ꢃ 0.8
06 ꢃ 0.3
12 ꢃ 0.7
08 ꢃ 0.6
07 ꢃ 0.6
10 ꢃ 0.8
12 ꢃ 0.9
16 ꢃ 0.4
18 ꢃ 0.2
03 ꢃ 0.4
07 ꢃ 0.3
11 ꢃ 0.4
03 ꢃ 0.2
08 ꢃ 0.7
04 ꢃ 0.3
03 ꢃ 0.4
06 ꢃ 0.7
07 ꢃ 0.7
06 ꢃ 0.4
04 ꢃ 0.2
07 ꢃ 0.5
13 ꢃ 0.5
15 ꢃ 0.8
05 ꢃ 0.6
10 ꢃ 0.4
13 ꢃ 0.1
06 ꢃ 0.4
11 ꢃ 0.3
06 ꢃ 0.8
05 ꢃ 0.7
08 ꢃ 0.4
08 ꢃ 0.6
09 ꢃ 0.3
06 ꢃ 0.3
10 ꢃ 0.7
15 ꢃ 0.4
16 ꢃ 0.5
04 ꢃ 0.2
06 ꢃ 0.7
13 ꢃ 0.9
04 ꢃ 0.4
10 ꢃ 0.3
06 ꢃ 0.3
05 ꢃ 0.7
05 ꢃ 0.3
04 ꢃ 0.3
06 ꢃ 0.5
08 ꢃ 0.3
09 ꢃ 0.4
15 ꢃ 0.6
15 ꢃ 0.9
06 ꢃ 0.3
09 ꢃ 0.5
16 ꢃ 0.8
05 ꢃ 0.8
13 ꢃ 0.6
08 ꢃ 0.7
06 ꢃ 0.3
08 ꢃ 0.3
06 ꢃ 0.2
07 ꢃ 0.7
11 ꢃ 0.9
12 ꢃ 0.9
17 ꢃ 0.7
17 ꢃ 0.5
8b
11
12
record 1H NMR and 13C NMR spectra (DMSO-d6, CDCl3) using TMS
as internal standard. Chemical shift values were given in (ppm)
Anal. calcd. for C15H16F3NO4; Calcd: C, 54.38; H, 4.80; N, 4.23;
found: C, 54.38; H, 4.80; N, 4.20 [27].
d
scales. The mass spectra were recorded on LC-MS-Agilent 1100
series and elemental analysis was performed on a Flash EA 1112
series CHNS-O Analyzer. The completion of the reactions was
monitored by silica gel coated aluminum sheets (silica gel 60 F254).
The names of the structures were given as per chemdraw and
chemsketch.
4.3. Syntheses of 4-hydroxy-8-trifluoromethyl-quinoline-3-
carboxylic acid ethyl ester (3)
Diethyl
2-[(2-trifluoromethyl-phenylamino)-methylene]-
malonic acid diethyl ester (2) (10.0 g, 0.030 mol) and Dowtherm
(100 mL) were heated to 250 ꢁC for 5 h. The reaction mixture was
then cooled to 25 ꢁC and stirred in 150 mL of hexane for 10 min. The
solid product obtained was filtered and dried. The crude product
was purified by column chromatography using pet ether and ethyl
acetate (5:5) as the eluent to get white solids.
4.2. Syntheses of diethyl 2-[(2-trifluoromethyl-phenylamino)-
methylene]-malonic acid diethyl ester (2)
2-(Trifluoromethyl)aniline (1) (10.0 g, 0.062 mol) and diethyl
ethoxymethylene malonate (20.10 g, 0.093 mol) were heated to
110 ꢁC for 6 h. The reaction mixture was cooled to room tempera-
ture, the solid thus formed was taken in pet ether and stirred for
20 min. Further it was filtered to get white crystalline solid.
Yield: (8.1 g, 94.1%). M.p: 295e297 ꢁC. IR (neat nmax/cmꢀ1): 3352
(eOH), 3118, 2979 (CeH-str), 1708 (C]O). 1H NMR (400 MHz,
DMSO-d6):
d
ppm 1.23 (t. 3H, J ¼ 8.0 Hz, eCH3), 4.16 (q, 2H, eCH2),
7.53 (t, 1H, ArH, J ¼ 8.0 Hz), 8.07 (d, 1H, ArH, 7.8 Hz), 8.41 (d, 2H,
Yield: (19.1 g, 92.8%). M.p: 84e86 ꢁC (84e86). IR (neat nmax
/
ArH, J ¼ 8.0 Hz), 11.62 (s, 1H, eOH, D2O-exchangeble). 13C NMR:
cmꢀ1): 3278 (NeH), 3176, 2986 (CeH-str), 1706 and 1654 (C]O).
d ppm 14.70, 60.49, 111.39, 119.07, 122.60, 124.00, 124.61, 125.35,
Table 6
Antifungal activity of the compounds (5aec, 6aed, 7aec, 8a,b, 11 and 12).
Compound no.
Zone of inhibition in mm (mean ꢃ S.D.) n ¼ 3
Aspergillus flavus
Chrysosporium keratinophilum
Candida albicans
Concentration mg/mL
Standard
0.5
1
0.5
1
0.5
1
Fluconazole
Control
5a
13 ꢃ 0.2
10 ꢃ 0.1
17 ꢃ 0.2
15 ꢃ 0.2
22 ꢃ 0.2
20 ꢃ 0.2
00
00
00
00
00
00
*
*
*
*
*
*
5b
5c
6a
02 ꢃ 0.1
05 ꢃ 0.3
e
04 ꢃ 0.2
07 ꢃ 0.4
e
03 ꢃ 0.5
04 ꢃ 0.5
e
04 ꢃ 0.6
06 ꢃ 0.5
e
04 ꢃ 0.1
04 ꢃ 0.6
e
06 ꢃ 0.3
06 ꢃ 0.4
e
6b
6c
04 ꢃ 0.2
06 ꢃ 0.7
04 ꢃ 0.4
05 ꢃ 0.2
04 ꢃ 0.3
06 ꢃ 0.3
*
*
*
*
*
*
6d
7a
*
*
*
*
*
*
*
*
*
*
*
*
7b
7c
8a
8b
11
12
*
03 ꢃ 0.3
04 ꢃ 0.2
08 ꢃ 0.5
10 ꢃ 0.4
06 ꢃ 0.6
12 ꢃ 0.6
02 ꢃ 0.3
03 ꢃ 0.5
06 ꢃ 0.7
08 ꢃ 0.6
02 ꢃ 0.3
08 ꢃ 0.5
04 ꢃ 0.2
05 ꢃ 0.3
09 ꢃ 0.6
10 ꢃ 0.6
04 ꢃ 0.3
11 ꢃ 0.5
02 ꢃ 0.4
04 ꢃ 0.4
05 ꢃ 0.7
07 ꢃ 0.8
03 ꢃ 0.3
09 ꢃ 0.5
05 ꢃ 0.3
05 ꢃ 0.2
07 ꢃ 0.3
10 ꢃ 0.4
05 ꢃ 0.2
11 ꢃ 0.7
02 ꢃ 0.3
06 ꢃ 0.3
07 ꢃ 0.5
04 ꢃ 0.7
09 ꢃ 0.7
*Not detected inhibition.

330
B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
130.99, 131.04, 131.55, 146.43, 164.50. MS: m/z ¼ 286 (M þ 1). Anal.
calcd. for C13H10F3NO3; Calcd: C, 54.74; H, 3.53; N, 4.91; found: C,
54.75; H, 3.54; N, 4.95.
4.5.3. 4-[1-(2,4-Dichloro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-
8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5c)
IR (neat nmax/cmꢀ1): 3078, 2977 (CeH-str), 1690 (C]O), 1218
(N]N); 1H NMR (400 MHz, DMSO-d6):
d 1.37 (t, 3H, CH3,
J ¼ 7.10 Hz), 4.41 (q, 2H, CH2, J ¼ 14.2 Hz, J ¼ 7.12 Hz), 5.45 (s, 2H,
CH2), 5.66 (s, 2H, CH2), 7.11 (d, 1H, ArH, J ¼ 8.32 Hz), 7.40 (dd, 1H,
ArH, J ¼ 8.32 Hz, J ¼ 2.12 Hz), 7.65e7.72 (m, 2H, ArH), 8.23 (s, 1H,
ArH), 8.25 (d, 1H, ArH, J ¼ 7.16 Hz), 8.35 (d, 1H, ArH, J ¼ 7.80 Hz),
9.24 (s,1H, ArH); 13C NMR: 14.43, 50.55, 62.16, 69.05, 116.28,124.72,
126.22, 126.70, 128.27, 129.03, 129.61, 130.85, 132.19, 132.76, 134.16,
134.46, 142.39, 146.86, 153.13, 162.86, 164.54. MS: m/z ¼ 525. Anal.
calcd. for C23H17Cl2F3N4O3; Calcd: C, 52.59; H, 3.26; N, 10.67; found:
C, 52.58; H, 3.26; N, 10.66 [30].
4.4. Syntheses of 4-prop-2-ynyloxy-8-trifluoromethyl-quinoline-3-
carboxylic acid ethyl ester (4)
A
mixture of
4-hydroxy-8-trifluoromethyl-quinoline-3-
carboxylic acid ethyl ester (3) (5.0 g, 0.017 mol), potassium car-
bonate (2.66 g, 0.019 mol) and propargylbromide (2.02 g, 0.17 mol)
in dry acetone (25 mL) was stirred at 50 ꢁC for 12 h. The completion
of reaction was monitored by TLC. After completion of reaction,
reaction mixture was concentrated under vacuum and poured into
ice-cold water. The solid product obtained was purified by column
chromatography using pet ether and ethyl acetate as eluent to get
white solids.
4.5.4. 4-{1-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-1H-[1,2,3]triazol-4-
ylmethoxy}-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl
ester (6a)
Yield: (3.89 g, 68.72%). M.p: 50e52 ꢁC. IR (neat nmax/cmꢀ1): 3261
(C^CeH-str), 2990, 2948 (CeH-str), 2120 (C^C), 1700 (C]O), 1103
IR (neat nmax/cmꢀ1): 3069, 2976 (CeH-str), 1710, 1590 (C]O),
1222 (N]N); 1H NMR (400 MHz, DMSO-d6):
d 1.40 (t, 3H, CH3,
(CeO); 1H NMR (400 MHz, DMSO-d6):
d
1.35 (t, 3H, CH3, J ¼ 7.10 Hz),
J ¼ 7.10 Hz), 4.45 (q, 2H, CH2, J ¼ 14.22 Hz, J ¼ 7.10 Hz), 5.49 (s, 2H,
CH2), 6.19 (s, 2H, CH2), 7.44 (t, 2H, ArH, J ¼ 8.84 Hz), 7.78 (t, 1H, ArH,
J ¼ 7.88 Hz), 8.13e8.16 (m, 2H, ArH), 8.24 (s, 1H, ArH), 8.28 (d, 1H,
ArH, J ¼ 7.60 Hz), 8.43 (d, 1H, ArH, J ¼ 7.76 Hz), 9.26 (s, 1H, ArH).
Anal. calcd. for C24H18F4N4O4; Calcd: C, 57.37; H, 3.61; N, 11.15;
found: C, 57.39; H, 3.62; N, 11.14.
3.66 (s, 1H, CH), 4.38 (q, 2H, CH2, J ¼ 14.22 Hz, J ¼ 7.10 Hz), 5.08 (s,
2H, CH2), 7.82 (t, 1H, ArH, J ¼ 7.88 Hz), 8.28 (d, 1H, ArH, J ¼ 7.20 Hz),
8.55 (d, 1H, ArH, J ¼ 7.80), 9.24 (s, 1H, ArH). Anal. calcd. for
C
16H12F3NO3; Calcd: C, 59.45; H, 3.74; N, 4.33; found: C, 59.47; H,
3.73; N, 4.34.
4.5. General procedure for the syntheses of 1,2,3-triazol-8-
trifluoromethyl-quinoline-3-carboxylic acid ethyl ester derivatives
(5aec, 6aed and 7aec)
4.5.5. 4-{1-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-1H-[1,2,3]triazol-4-
ylmethoxy}-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl
ester (6b)
IR (neat nmax/cmꢀ1): 3040, 2990 (CeH-str), 1710, 1582 (C]O),
To a stirred solution of alkyl bromide (aromatic, phenacyl and
aliphatic) (0.50 g, 0.0017 mol), sodium azide (0.117 g, 0.0018 mol) in
aqueous PEG 400 (polyethylene glycol) (5 mL, 1:1, v/v), 4-prop-2-
ynyloxy-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester
(0.58 g, 0.0018 mol), sodium ascorbate (0.356 g, 0.0018 mol),10 mol
% of Copper sulfate were added. The heterogeneous mixture was
stirred vigorously overnight (12 h). Completion of the reaction was
monitored by the TLC. The product was then extracted in ethyl
acetate and concentrated. The crude product was purified by col-
umn chromatography using pet ether and ethyl acetate as the
eluent.
1212 (N]N); 1H NMR (400 MHz, DMSO-d6):
d 1.36 (t, 3H, CH3,
J ¼ 8.00 Hz), 4.40 (q, 2H, CH2, J ¼ 12.00 Hz, J ¼ 4.00 Hz), 5.44 (s, 2H,
CH2), 6.15 (s, 2H, CH2), 7.63 (d, 2H, ArH, J ¼ 8.00 Hz), 7.74 (t, 1H, ArH,
J ¼ 8.00 Hz), 8.02 (d, 2H, ArH, J ¼ 8.00 Hz), 8.21 (s, 1H, ArH), 8.24 (d,
1H, ArH, J ¼ 8.00 Hz), 8.39 (d,1H, ArH, J ¼ 8.00 Hz), 9.22 (s,1H, ArH);
13C NMR: 14.48, 56.40, 62.22, 69.30, 115.98, 124.65, 126.85, 127.34,
129.06,129.59,130.58,133.30,139.62,142.35, 146.92, 153.14,163.03,
164.65, 191.66. Anal. calcd. for C24H18ClF3N4O4; Calcd: C, 55.55; H,
3.50; N, 10.80; found: C, 55.58; H, 3.51; N, 10.75.
4.5.6. 4-{1-[2-(4-Bromo-phenyl)-2-oxo-ethyl]-1H-[1,2,3]triazol-4-
ylmethoxy}-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl
ester (6c)
4.5.1. 4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethoxy)-8-
IR (neat nmax/cmꢀ1): 3085, 2974 (CeH-str), 1706, 1582 (C]O),
trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5a)
IR (neat nmax/cmꢀ1): 3031, 2974 (CeH-str), 1724 (C]O), 1206
1132 (N]N); 1H NMR (400 MHz, DMSO-d6):
d 1.36 (t, 3H, CH3,
(N]N); 1H NMR (400 MHz, DMSO-d6):
d 1.36 (t, 3H, CH3,
J ¼ 8.00 Hz), 4.40 (q, 2H, CH2, J ¼ 8.00 Hz), 5.44 (s, 2H, CH2), 6.15 (s,
2H, CH2), 7.74e7.79 (m, 3H, ArH), 7.93 (d, 2H, ArH, J ¼ 8.00 Hz), 8.21
(s, 1H, ArH), 8.24 (d, 1H, ArH, J ¼ 8.00 Hz), 8.39 (d, 1H, ArH,
J ¼ 8.00 Hz), 9.22 (s, 1H, ArH); 13C NMR: 14.48, 56.38, 62.22, 69.30,
115.97, 124.65, 126.85, 127.33, 128.87, 129.06, 130.63, 130.95, 132.54,
133.62, 142.34, 146.93, 153.15, 163.04, 164.65. MS: m/z ¼ 563. Anal.
calcd. for C24H18BrF3N4O4; Calcd: C, 51.17; H, 3.22; N, 9.95; found: C,
51.17; H, 3.21; N, 9.94 [31].
J ¼ 7.10 Hz), 4.40 (q, 2H, CH2, J ¼ 14.2 Hz, J ¼ 7.12 Hz), 5.44 (s, 2H,
CH2), 5.58 (s, 2H, CH2), 7.16e7.18 (m, 2H, ArH), 7.31e7.32 (m, 3H,
ArH), 7.70 (t,1H, ArH, J ¼ 7.88 Hz), 8.25 (s,1H, ArH), 8.27 (s,1H, ArH),
8.35 (d, 1H, ArH, J ¼ 8.24 Hz), 9.24 (s, 1H, ArH). Anal. calcd. for
C
23H19F3N4O3; Calcd: C, 60.52; H, 4.20; N, 12.28; found: C, 60.55; H,
4.21; N, 12.24.
4.5.2. 4-[1-(4-Nitro-benzyl)-1H-[1,2,3]triazol-4-ylmethoxy]-8-
trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5b)
IR (neat nmax/cmꢀ1): 3082, 2976 (CeH-str), 1705 (C]O), 1525
4.5.7. 4-{1-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-1H-[1,2,3]triazol-
4-ylmethoxy}-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl
ester (6d)
(NO2), 1220 (N]N); 1H NMR (400 MHz, DMSO-d6):
d 1.37 (t, 3H,
CH3, J ¼ 7.10 Hz), 4.41 (q, 2H, CH2, J ¼ 14.2 Hz, J ¼ 7.10 Hz), 5.46 (s,
2H, CH2), 5.76 (s, 2H, CH2), 7.38 (d, 2H, ArH, J ¼ 8.76 Hz), 7.72 (t, 1H,
ArH, J ¼ 7.88 Hz), 8.17 (d, 2H, ArH, J ¼ 8.80 Hz), 8.24 (d, 1H, ArH,
J ¼ 7.48 Hz), 8.33 (s, 1H, ArH), 8.36 (d, 1H, ArH, J ¼ 7.64 Hz), 9.24 (s,
1H, ArH); 13C NMR: 14.44, 52.35, 62.17, 69.08, 116.17, 124.30, 124.71,
126.25, 126.76,129.02,129.30,130.86, 142.66,143.72,146.85,147.69,
153.13, 162.78, 164.44. Anal. calcd. for C23H18F3N5O5; Calcd: C,
55.09; H, 3.62; N, 13.97; found: C, 55.10; H, 3.60; N, 13.98.
IR (neat nmax/cmꢀ1): 2979, 2937 (CeH-str), 1707, 1588 (C]O),
1231 (N]N), 1130 (CeO); 1H NMR (400 MHz, DMSO-d6):
d 1.36 (t,
3H, CH3, J ¼ 8.00 Hz), 4.00 (s, 3H, CH3), 4.49 (q, 2H, CH2,
J ¼ 12.00 Hz, J ¼ 4.00 Hz), 65.44 (s, 2H, CH2), 6.09 (s, 2H, CH2), 7.06
(d, 2H, ArH, J ¼ 8.00 Hz), 7.74 (t, 1H, ArH, J ¼ 8.00 Hz), 7.99 (d, 2H,
ArH, J ¼ 8.00 Hz), 8.22 (s, 1H, ArH), 8.24 (d, 1H, ArH, J ¼ 8.00 Hz),
8.39 (d, 1H, ArH, J ¼ 8.00 Hz), 9.22 (s, 1H, ArH); 13C NMR: 14.49,
56.04, 56.18, 62.23, 69.32, 114.71, 126.86, 127.39, 129.08, 131.06,

B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
331
142.24, 153.15, 163.04, 164.41. Anal. calcd. for C25H21F3N4O5; Calcd:
C, 58.37; H, 4.11; N, 10.89; found: C, 58.39; H, 4.21; N, 10.88.
0.0024 mol) in methanol (10 mL) at 0 ꢁC was added lithium hy-
droxide (0.06 g, 0.0026 mol) for 5 min. The mixture was allowed to
stir for 2 h and was quenched by the slow addition water (25 mL),
acidified using dilute HCl. The precipitated solids were collected by
filtration and recrystallized by ethanol.
4.5.8. 4-(1-Ethyl-1H-[1,2,3]triazol-4-ylmethoxy)-8-
trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (7a)
IR (neat nmax/cmꢀ1): 2984, 2940 (CeH-str), 1699 (C]O), 1251
IR (neat nmax/cmꢀ1): 3236 (eOH), 3095, 2981 (CeH-str), 1736
(N]N); 1H NMR (400 MHz, DMSO-d6):
d
1.33e1.41 (m, 6H, 2CH3),
(C]O), 1130 (CeO); 1H NMR (400 MHz, DMSO-d6):
d 1.17 (t, 3H,
4.31e4.45 (m, 4H, 2CH2), 5.39 (s, 2H, CH2), 7.74 (t, 1H, ArH,
J ¼ 7.86 Hz), 8.23 (s, 1H, ArH), 8.24 (d, 1H, ArH, J ¼ 7.44 Hz), 8.38 (d,
1H, ArH, J ¼ 8.32), 9.21 (s, 1H, ArH); 13C NMR: 14.44, 15.86, 45.08,
62.18, 69.30, 116.11, 124.62, 125.01, 126.78, 129.03, 130.86, 142.25,
146.89, 153.09, 162.89, 164.63. Anal. calcd. for C18H17F3N4O3; Calcd:
C, 54.82; H, 4.35; N, 14.21; found: C, 54.82; H, 4.36; N, 14.20.
CH3, J ¼ 8.0 Hz), 4.10 (q, 2H, CH2, J ¼ 8.0 Hz), 5.02 (s, 2H, CH2), 7.54
(t, 1H, ArH, J ¼ 8.0 Hz), 8.09 (d, 1H, ArH, J ¼ 8.0 Hz), 8.43 (d, 1H, ArH,
J ¼ 8.0 Hz), 8.49 (s, 1H, ArH), 11.72 (s, 1H, OH, D2O-exchangeble).
Anal. calcd. for C17H12F3NO6; Calcd: C, 53.27; H, 3.16; N, 3.65; found:
C 53.26; H, 3.19; N, 3.65.
4.8. Synthesis of 4-hydroxy-8-trifluoromethyl-quinoline-3-
carboxylic acid (9)
4.5.9. 4-(1-Propyl-1H-[1,2,3]triazol-4-ylmethoxy)-8-
trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (7b)
IR (neat nmax/cmꢀ1): 2975, 2939 (CeH-str), 1704 (C]O), 1252
(N]N); 1H NMR (400 MHz, DMSO-d6):
d 0.71 (t, 3H, CH3,
To a suspension of 4-hydroxy-8-trifluoromethyl-quinoline-3-
carboxylic acid ethyl ester (3) (5 g, 0.017 mol) in methanol
(50 mL) at 0 ꢁC was added lithium hydroxide (0.45 g, 0.019 mol) for
10 min. The mixture was allowed to stir for 2 h and was quenched
by the slow addition water (100 mL), acidified using dilute HCl. The
precipitated solids were collected by filtration and recrystallized by
ethanol.
J ¼ 7.38 Hz), 1.38 (t, 3H, CH3, J ¼ 7.10 Hz), 1.70e1.79 (m, 2H, CH2),
2.48e2.49 (m, 2H, CH2), 4.42 (q, 2H, CH2, J ¼ 14.22 Hz, J ¼ 7.10 Hz),
5.43 (s, 2H, CH2), 7.75 (t, 1H, ArH, J ¼ 7.86 Hz), 8.21 (s, 1H, ArH), 8.26
(d, 1H, ArH, J ¼ 7.16 Hz), 8.38 (d, 1H, ArH, J ¼ 7.76), 9.24 (s, 1H, ArH);
13C NMR: 11.04, 14.57, 23.57, 51.38, 62.11, 69.24, 116.14, 124.65,
125.52, 126.75, 129.06, 130.91, 142.10, 146.82, 153.11, 162.85, 164.54.
Anal. calcd. for C19H19F3N4O3; Calcd: C, 55.88; H, 4.69; N, 13.72;
found: C55.87; H, 4.69; N, 13.73.
Yield: (4.3 g, 95.5%). M.p: 258e260 ꢁC. IR (neat nmax/cmꢀ1): 3440
(eOH), 3113, 3061 (CeH-str), 1720 (C]O). Anal. calcd. for
C11H6F3NO3; Calcd: C, 51.37; H, 2.35; N, 5.45; found: C, 51.39; H,
2.33; N, 5.46.
4.5.10. 4-(1-Butyl-1H-[1,2,3]triazol-4-ylmethoxy)-8-
trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (7c)
IR (neat nmax/cmꢀ1): 2964, 2930 (CeH-str), 1702 (C]O), 1254
4.9. Synthesis of 3-bromo-8-trifluoromethyl-quinolin-4-ol (10)
(N]N); 1H NMR (400 MHz, DMSO-d6):
d
0.80 (t, 3H, CH3, J ¼ 7.36 Hz),
1.02e1.12 (m, 2H, CH2),1.38 (t, 3H, CH3, J ¼ 7.10 Hz),1.65e1.72 (m, 2H,
CH2), 4.31 (t, 2H, CH2, J ¼ 6.94 Hz), 4.42 (q, 2H, CH2, J ¼ 14.22 Hz,
J ¼ 7.10 Hz), 5.43 (s, 2H, CH2), 7.73 (t,1H, ArH, J ¼ 7.88 Hz), 8.19 (s,1H,
ArH), 8.25 (d,1H, ArH, J ¼ 7.08 Hz), 8.37 (d,1H, ArH, J ¼ 8.44 Hz), 9.24
(s, 1H, ArH). 13C NMR: 13.65, 14.43, 19.32, 31.99, 49.50, 62.16, 69.21,
116.14, 123.00, 124.75,125.49, 126.69, 129.06, 130.88, 142.06, 146.87,
153.10,162.87,164.57. Anal. calcd. for C20H21F3N4O3; Calcd: C, 56.87;
H, 5.01; N, 13.26; found: C, 56.88; H, 5.00; N, 13.24.
The 4-hydroxy-8-trifluoromethyl-quinoline-3-carboxylic acid
(5.0 g, 0.019 mol) was taken up in THF (50 mL). NBS (3.73 g,
0.021 mol) was added, and the reaction mixture was allowed to
stir at room temperature overnight. After completion of the re-
action, the reaction mixture was concentrated under vacuum,
poured into ice-cold water. The solid product obtained was
filtered, washed with water and recrystallized from ethanol to get
white solids.
IR (neat nmax/cmꢀ1): 3165, 3015 (CeH-str), 1607 (C]C); 1H NMR
4.6. Synthesis of 3-ethoxycarbonylmethoxy-6-trifluoromethyl-furo
[3,2-c]quinoline-2-carboxylic acid ethyl ester (8a)
(400 MHz, DMSO-d6):
d
7.28 (t, 1H, ArH, J ¼ 8.00 Hz), 7.86 (d, 1H,
ArH, J ¼ 8.00 Hz), 8.19 (s, 1H, ArH), 8.61 (d, 1H, ArH, J ¼ 8.00 Hz),
11.73 (s, 1H, OH, D2O-exchangeble); 13C NMR: 105.83, 122.67,
125.38, 130.94, 131.54, 135.49, 141.38, 171.46, 194.17. Anal. calcd. for
To a suspension of 4-hydroxy-8-trifluoromethyl-quinoline-3-
carboxylic acid ethyl ester (2.0 g, 0.0070 mol), potassium carbon-
ate (1.06 g, 0.0077 mol) in dimethylformamide (20 mL) was added
ethyl 4-chloroacetoacetate (2.53 g, 0.0154 mol). The mixture was
allowed to stir for 6 h at 80 ꢁC and was quenched by the slow
addition water (25 mL), The precipitated solids were collected by
filtration and recrystallized from ethanol.
C10H5BrF3NO; Calcd: C, 41.13; H, 1.73; N, 4.80; found: C 41.13; H,
1.71; N, 4.82.
4.10. Synthesis of 3-bromo-4-ethoxy-8-trifluoromethyl-quinoline
(11)
IR (neat nmax/cmꢀ1): 2989, 2958 (CeH-str), 1748, 1711 (C]O),
1134 (CeO); 1H NMR (400 MHz, DMSO-d6):
d
1.14 (t, 3H, CH3,
The mixture of 3-Bromo-8-trifluoromethyl-quinolin-4-ol (3.0 g,
0.010 mol) potassium carbonate (1.52 g, 0.011 mol) and ethyliodide
(2.40 g, 0.015 mol) in dimethylformamide (30 mL) was stirred at
room temperature for 2 h. After completion of reaction, the reaction
mixture was poured into ice-cold water. The solid product obtained
was filtered. The crude product obtained was purified by column
chromatography using pet ether and ethyl acetate (9:1) as the
eluent to get white solids.
J ¼ 8.0 Hz), 1.32 (t, 3H, CH3, J ¼ 8.0 Hz), 4.12 (q, 2H, CH2, J ¼ 8.0 Hz),
4.30 (q, 2H, CH2, J ¼ 8.0 Hz), 4.98 (s, 2H, CH2), 7.80 (t, 1H, ArH,
J ¼ 8.0 Hz), 8.26 (d, 1H, ArH, J ¼ 8.0 Hz), 8.72 (d, 1H, ArH, J ¼ 8.0 Hz),
9.19 (s, 1H, ArH); 13C NMR: 14.42, 61.46, 62.23, 70.68, 71.95, 114.71,
116.11, 124.23, 126.76, 127.80, 129.43, 131.06, 132.08, 146.79, 153.14,
162.94,164.37,168.47,168.86. Anal. calcd. for C19H16F3NO6; Calcd: C,
55.48; H, 3.92; N, 3.41; found: C 55.51; H, 3.92; N, 3.40 [32].
IR (neat nmax/cmꢀ1): 3015, 2954 (CeH-str),1573 (C]C),1128 (Ce
4.7. Synthesis of 3-ethoxycarbonylmethoxy-6-trifluoromethyl-furo
[3,2-c]quinoline-2-carboxylic acid (8b)
O); 1H NMR (400 MHz, DMSO-d6):
d
1.50 (t, 3H, CH3, J ¼ 7.0 Hz), 4.33
(q, 2H, CH2, J ¼ 7.0 Hz, J ¼ 13.8 Hz), 7.82 (t, 1H, ArH, J ¼ 7.8 Hz), 8.25
(d, 1H, ArH, J ¼ 7.2 Hz), 8.45 (d, 1H, J ¼ 8.8 Hz), 9.14 (s, 1H, ArH). MS:
m/z ¼ 320.1 (M þ 1). Anal. calcd. for C12H9BrF3NO; Calcd: C, 45.03;
H, 2.83; N, 4.38; found: C 45.05; H, 2.83; N, 4.37.
To a suspension of 3-ethoxycarbonylmethoxy-6-trifluoromet
hyl-furo[3,2-c]quinoline-2-carboxylic acid ethyl ester (1.0 g,

332
B. Garudachari et al. / European Journal of Medicinal Chemistry 74 (2014) 324e332
4.11. Synthesis of 4-ethoxy-3-(1-methyl-1H-indol-5-yl)-8-
trifluoromethyl-quinoline (12)
thank Director, NITK Surathkal, India for the encouragements. Au-
thors thank Mr. S.K Peethambar, Department of Bio-Chemistry,
Jnanasahyadri, Kuvempu University, Karnataka, Shankaraghatta-
577 451, India for the technical assistance in biological screening.
The authors extend their appreciation to The Deanship of Scientific
Research at King Saud University for funding the work through
research group project no. RGP-VPP-207.
3-Bromo-4-ethoxy-8-(trifluoromethyl)quinoline
(0.5
g,
0.0015 mol), N-methylindole-5-boronic acid (0.29 g, 0.0017 mol)
were dissolved in a mixture of toluene and ethanol (5:5,10 mL). The
solution was subsequently stirred for 10 min under nitrogen at-
mosphere. Potassium carbonate (0.234 g, 0.0017 mol) and palla-
dium acetate (0.050 g, 0.00022 mol) were then added to the
reaction mass and refluxed for 2 h under nitrogen atmosphere.
After completion of the reaction, the reaction mixture was filtered
through celite bed. The crude product obtained was purified by
column chromatography using pet ether and ethyl acetate (9:1) as
the eluent.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.01.008.
References
IR (neat nmax/cmꢀ1): 2975, 2942 (CeH-str); 1H NMR (400 MHz,
DMSO-d6):
d
1.13 (t, 3H, CH3, J ¼ 7.00 Hz), 3.73 (q, 2H, CH2,
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Acknowledgments
AMI and SMN thank Department of Information & Technology,
Government of India, New Delhi for the financial support. AMI also