Alumina-supported synthesis of antibacterial quinolines using microwaves

Article abstract of DOI:10.1016/S0968-0896(99)00256-4

7-(5'-Alkyl-1',3',4'-thiadiazol/oxadiazol-2'-ylthio)-6-fluoro-2,4- dimethylquinolines and 3-formyl-2-(2'-hydroxy-1',4'-naphthoquinon-3'-yl)-4- methyl/6-methyl/7-methyl/8-methylquinolines have been synthesised by the reaction of 5-alkyl-1,3,4-thiadiazol/oxadiazol-2-thiols with 7-chloro-6- fluoro-2,4-dimethylquinoline and by the reaction of 2-hydroxy-1,4- naphthoquinone with 2-chloro-3-formyl-4-methyl/6-methyl/7-methyl/8- methylquinolines respectively on basic alumina using microwaves, the reaction time has been brought down from hours to seconds with improved yield as compared to conventional heating. The compounds were tested for their in vitro antibacterial activity. All compounds showed promising antibacterial activity. The best activity was observed by compounds 3a and 3f. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00256-4

Bioorganic & Medicinal Chemistry 8 (2000) 69±72
Alumina-Supported Synthesis of Antibacterial Quinolines using
Microwaves
M. Kidwai,a,* K. R. Bhushan,a P. Sapra,a R. K. Saxenab and R. Gupta b
aDepartment of Chemistry, University of Delhi, Delhi 110007, India
bDepartment of Microbiology, University of Delhi, South Campus, Delhi 110021, India
Received 19 July 1999; accepted 25 August 1999
AbstractÐ7-(50-Alkyl-10,30,40-thiadiazol/oxadiazol-20-ylthio)-6-¯uoro-2,4-dimethylquinolines and 3-formyl-2-(20-hydroxy-10,40-
naphthoquinon-30-yl)-4-methyl/6-methyl/7-methyl/8-methylquinolines have been synthesised by the reaction of 5-alkyl-1,3,4-thia-
diazol/oxadiazol-2-thiols with 7-chloro-6-¯uoro-2,4-dimethylquinoline and by the reaction of 2-hydroxy-1,4-naphthoquinone with
2-chloro-3-formyl-4-methyl/6-methyl/7-methyl/8-methylquinolines respectively on basic alumina using microwaves, the reaction
time has been brought down from hours to seconds with improved yield as compared to conventional heating. The compounds
were tested for their in vitro antibacterial activity. All compounds showed promising antibacterial activity. The best activity was
observed by compounds 3a and 3f. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
Chemistry
Quinolines and their derivatives have been associated
with various biological activities. Compounds con-
taining quinoline moiety have shown good amoebici-
dal,1 bactericidal,2 fungicidal3 and antimalarial4
activities. Highly active antimalarial drugs plasmaquin,5
chloroquin and primaquin6 are well known in the
market. 1,3,4-Thiadiazoles/oxadiazoles are pharmaco-
logically7 important. 1,4-Naphthoquinone is also
associated with diverse biological activities.8,9 Reac-
tions on solid support10,11 without using solvent in a
domestic microwave oven12,13 are currently in use for
synthetic chemists to develop an eco-friendly techni-
que.14 Keeping in view the utility of microwave irradia-
tion (MWI) and pharmacological importance of the
above-mentioned heterocycles, we report herein the
synthesis of quinoline derivatives in dry media using
MWI in order to develop an economical, rapid and safe
method devoid of solvent usage and to screen them for
bactericidal activity.
7-Chloro-6-¯uoro-2,4-dimethylquinoline 2 was synthe-
sised via cyclisation of 4-(3-chloro-4-¯uoroanilino)pent-
3-en-2-one 1 (mixture) by adsorption on acidic alumina
using MWI for 210 s as evidenced by the disappearance
of the CˆO band at 1685 cm in IR spectra. Substitu-
1
tion of chlorine in 7-chloro-6-¯uoro-2,4-dimethylquino-
line (2-chloro-3-formyl methylquinolines)15 with
mercapto substituted-1,3,4-thiadiazoles/oxadiazoles (2-
hydroxy-1,4-naphthoquinone) was achieved by adsorp-
tion of 7-chloro-6-¯uoro-2,4-dimethylquinoline (2-chlo-
ro-3-formyl methylquinolines) and thiadiazoles/
oxadiazoles16 (2-hydroxy-1,4-naphthoquinone) on basic
alumina using MWI for 120±180 s furnishing 7-(50-
alkyl-10,30,40-thiadiazol/oxadiazol-20-ylthio)-6-¯uoro-2,4-
dimethylquinolines [3-formyl- 2-(20-hydroxy-10,40-naph-
thoquinon-30-yl)-4-methyl/6-methyl/7-methyl/8-methyl-
quinolines]. The structure of compounds 3a±f (Scheme 1)
were evidenced by the disappearance of signal for SH
1
proton in H NMR spectrum at d 11±12, band in IR
spectrum at 2570 cm 1 and appearance of band at 1525±
1
1580 cm due to CˆN. The structure of compounds
5a±e (Scheme 2) were con®rmed by disappearance of
signal in H NMR spectrum at d 7.0 due to C3 proton
Keywords: quinoline; drymedia; basic alumina; microwaves; solid
support.
1
and appearance of multiplet at d 7.25±8.32 due to
aromatic protons.
*Corresponding author. Tel.: +91-11-7257336; fax: +91-11-7257206;
e-mail: vpasmar.duchem@axcess.net.in
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00256-4

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M. Kidwai et al. / Bioorg. Med. Chem. 8 (2000) 69±72
Antibacterial Activity
mineral acids which make it a clean, ecient and cheap
technology to obtain various useful heterocyclic com-
pounds for organic synthesis. The results shown in
Table 1 demonstrate the versatility of the process as
considerable reaction rate enhancement has been
observed by bringing down the reaction time from
hours to seconds with improved yield as compared to
conventional heating.18
Compounds 3a±f and 5a±e were tested (Table 2) for
their in vitro antibacterial activity against ®ve bacterial
strains by the cup-plate agar di€usion method.17
Compounds were dissolved in phosphate bu€er at con-
centration of 50 mg/mL. Among all synthesised quino-
lines, 3a and 3f provided the best antibacterial activity
and compared well with the activities of nor¯oxacin.
Compounds 3c, 3d, 5a, 5b and 5d also possess promising
antibacterial activity. All compounds were found active
against Klebsiella aerogens and Escherichia coli.
Experimental
Melting points (mp) were determined using a Thomas
Hoover melting point apparatus and are uncorrected.
IR (KBr, cm 1) spectra were obtained on a Perkin±
Elmer FTIR-1710 spectrophotometer. 1H NMR spectra
were recorded at 90 MHz on a Perkin±Elmer R-32
spectrometer using TMS as internal standard (chemical
shifts in d, ppm). Elemental analyses were performed on
a Heraeus CHN-Rapid Analyser. EI mass spectra were
This is the ®rst report on the reactions of quinolines on
a solid support using MWI in which thiadiazole/oxa-
diazole/1,4-naphthoquinone rings are incorporated. In
short, the salient feature of our approach is coupling
microwaves with solvent free technique keeping mod-
ernisation and simpli®cation of classical procedure,
avoiding volatile and toxic organic solvents, corrosive
Scheme 1.
Scheme 2.

M. Kidwai et al. / Bioorg. Med. Chem. 8 (2000) 69±72
71
Table 1. Physical data of compounds 3a±f and 5a±e
(%) 207/(209). Anal. calcd for C11H9NFCl: C, 63.15; H,
4.30; N, 6.69. Found: C, 63.12; H, 4.28; N, 6.70.
Compound
no.
Conventional heating
Time (h)/yield (%)
MWI
Time (s)/yield (%)
General procedure for the preparation of 7-(50 -alkyl-10,30,
40 -thiadiazol/oxadiazol-20 -ylthio)-6-¯uoro-2,4-dimethyl-
quinolines (3a±f)
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
4/79
6/76
4/78
5/80
6/75
7/76
4/80
5/77
6/70
5/71
4/82
150/94
150/96
135/95
180/98
165/94
180/96
120/95
135/95
165/96
120/94
150/98
Basic alumina (40 g) was added to the solution of thia-
diazole/oxadiazole (10 mmol) and quinoline 2 (2.09 g,
10 mmol) in CH2Cl2 (10 mL) at room temperature. The
reaction mixture was mixed and the adsorbed material
was dried, placed in an alumina bath inside the microwave
oven and then irradiated for 120±180 s. On completion of
the reaction, the mixture was worked up as described
above and crystallised from EtOH:CHCl3 (3:1).
Table 2. Antibacterial activitya of quinoline derivativesa
3a. Mp 79±81 ꢀC. 1H NMR (CDCl3) d 0.90 (t, 3H,
J=8 Hz, 70-CH3), 1.28 (m, 8H, 4ÂCH2), 1.62 (m, 2H,
20-CH2), 2.36 (t, 2H, J=7 Hz, 10-CH2) 2.52 (s, 3H, 4-
CH3), 2.62 (s, 3H, 2-CH3), 6.99 (s, 1H, 3-H), 7.91 (d,
IH, J=9 Hz, 5-H), 8.10 (d, 1H, J=5 Hz, 8-H). IR (KBr
cm 1) 1526 (CˆN). Anal. calcd for C20H24N3SOF: C,
64.31; H, 4.28; N, 6.70. Found: C, 64.34; H, 4.30; N,
6.69.
Compound
no.
BLb
KAc
ECd
EHe
CRf
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
++
g
+++
++
+++
++++
+
++
++++
+++
+++j
+++
+
+++
+++
+++
++
h
+
++i
+
++++
++
++++
++++
+++
++
+++
++
+++
+
++
++
+++
++
+++
++
+++k
+++
++
+
+++
++
3b. Mp 55±57 ꢀC. 1H NMR (CDCl3) d 0.88 (t, 3H,
J=8 Hz, 70-CH3), 1.28 (m, 8H, 4ÂCH2), 1.61 (m, 2H,
20-CH2), 2.37 (t, 2H, J=7 Hz, 10-CH2), 2.49 (s, 3H, 4-
CH3), 2.60 (s, 3H, 2-CH3). 6.97 (s, 1H, 3-H), 7.71 (d,
1H, J=9 Hz, 5-H), 8.11 (d, 1H, J=5 Hz, 8-H). IR (KBr
cm 1) 1575 (C ˆ N). Anal. calcd for C20H24N3S2F: C,
61.69; H, 6.16; N, 10.77. Found: C, 61.67; H, 6.18; N,
10.81.
+++
Nor¯oxacin ++++ ++++ ++++ ++++ ++++
aData are zones of inhibition (mm).
bBL, Bacillus lichenformis-2715.
cKA, Klebsiella aerogens-2281.
dEC, Escherichia coli-K12
.
eEH, Erwinia herbicola-2491.
3c. Mp 48±50 ꢀC. 1H NMR (CDCl3) d 0.92 (t, 3H,
J=8 Hz, 90-CH3), 1.29 (m, 12H, 6ÂCH2), 1.62 (m, 2H,
20-CH2), 2.41 (t, 2H, J=7 Hz, 10-CH2), 2.46 (s, 3H, 4-
CH3), 2.59 (s, 3H, 2-CH3), 6.98 (s, 1H, 3-H), 7.80 (d,
1H, J=9 Hz, 5-H), 8.10 (d, 1H, J=5 Hz, 8-H). IR (KBr
cm 1) 1528 (CˆN). Anal. calcd for C22H28N3SOF: C,
65.83; H, 6.98; N, 10.47. Found: C, 65.85; H, 6.95; N,
10.50.
fCR, Corynbacterium rubrum-2253.
g
=No measurable activity.
h+=3±9 mm.
i++=10±12 mm.
j+++=13±16 mm.
k++++=17±21 mm.
recorded on a JEOLJHS-DX 303 mass spectrometer.
For microwave irradiation a Padmini Essentia domestic
microwave oven, Model Brownie (2450 MHz) was used.
3d. Mp 50±52 ꢀC. 1H NMR (CDCl3) d 0.88 (t, 3H,
J=8 Hz, 90-CH3), 1.25 (m, 12H, 6ÂCH2), 1.62 (m, 2H,
20-CH2), 2.35 (t, 2H, J=7 Hz, 10-CH2), 2.47 (s, 3H, 4-
CH3), 2.58 (s, 3H, 2-CH3), 6.98 (s, 1H, 3-H), 7.61 (d,
1H, J=9 Hz, 5-H), 8.15 (d, IH, J=5 Hz, 8-H). IR (KBr
cm 1) 1573 (C ˆ N). Anal. calcd for C22H28N3S2F: C,
63.30; H, 6.71; N, 10.07. Found: C, 63.27; H, 6.73; N,
10.09.
General procedure for the preparation of 7-chloro-6-¯uoro-
2,4-dimethylquinoline (2)
Acidic alumina (20 g) was added to the solution of
compound 1 (2.27 g, 10 mmol) dissolved in CH2Cl2
(10 mL) at room temperature. The reaction mixture was
thoroughly mixed and the adsorbed material was dried
in air (beaker) and placed in an alumina bath19 inside
the microwave oven for 210 s. Upon completion of the
reaction, the mixture was cooled and then product was
extracted into CH2Cl2 (3Â15 mL). The solvent was
removed under reduced pressure and the residue was
puri®ed by crystallisation from CH3OH to give product
identi®ed as 2 (1.95 g, 94%).
3e. Mp 86±88 ꢀC. 1H NMR (CDCl3) d 0.89 (t, 3H,
J=8 Hz, 110-CH3), 1.27 (m, 16H, 8ÂCH2), 1.73 (m, 2H,
20-CH2), 2.51 (t, 2H, J=7 Hz, 10-CH2), 2.45 (s, 3H, 4-
CH3), 2.60 (s, 3H, 2-CH3), 6.99 (s, 1H, 3-H), 7.81 (d,
1H, J=9 Hz, 5-H), 8.14 (d, 1H, J=5 Hz, 8-H). IR (KBr
cm 1) 1530 (CˆN). Anal. calcd for C24H32N3SOF: C,
67.13; H, 7.45; N, 9.79. Found: C, 67.11; H, 7.40; N,
9.75.
2. Mp 66±68 ꢀC. H NMR (CDCl3) d 2.30 (s, 3H, 4-
1
CH3), 2.43 (s, 3H, 2-CH3), 6.91 (s, 1H, 3-H), 7.50 (d,
1H, J=9 Hz, 5-H), 8.12 (d, IH, J=5 Hz, 8-H). MS m/z
3f. Mp 73±75 ꢀC. 1H NMR (CDCl3) d 0.90 (t, 3H,
J=8 Hz, 110-CH3), 1.26 (m, 16H, 8ÂCH2), 1.65 (m, 2H,

72
M. Kidwai et al. / Bioorg. Med. Chem. 8 (2000) 69±72
20-CH2), 2.43 (t, 2H, J=7 Hz, 10-CH2), 2.45 (s, 3H, 4-
CH3), 2.60 (s, 3H, 6-CH3), 7.10 (s, 1H, 3-H), 8.02 (d,
1H, J=9 Hz, 5-H), 8.20 (d, 1H, J=5 Hz, 8-H). IR (KBr
cm 1) 1580 (C ˆ N). Anal. calcd for C24H32N3S2F: C,
64.71, H, 7.19; N, 9.43. Found: C, 64.69; H, 7.21; N,
9.45.
Anal. calcd for C21H13NO4: C, 73.48; H, 3.79; N, 4.08.
Found: C, 73.46; H, 3.77; N, 4.06.
5e. Mp 73±75 ꢀC. 1H NMR (DMSO-d6+ CDC13) d 2.62
(s, 3H 4-CH3), 5.15 (s, 1H OH), 7.25±8.37 (m, 9H, Ar-H),
10.40 (s, 1H, CHO). MS m/z (%) 344/(343). Anal. calcd
for C21H13NO4: C, 73.48; H, 3.79; N, 4.08. Found: C,
73.45; H, 3.77; N, 4.05.
General procedure for the preparation of 3-formyl-2-(20-
hydroxy-10,40-naphthoquinon-30-yl)-4-methyl/6-methyl/7-
methyl/8-methylquinolines (5a±e)
References
Basic alumina (40 g) was added to the solution of 2-hy-
droxy-1,4-naphthoquinone (1.68 g, 10 mmol) and quin-
oline 4a±e (10 mmol) in CH2Cl2 (10 mL) at room
temperature. The reaction mixture was mixed and the
adsorbed material was dried, placed in an alumina bath
inside the microwave oven and then irradiated for 2±
3 min. On completion of the reaction, the mixture was
worked up as described above and crystallised from
C2H5OH.
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1
5.10 (s, 1H, OH), 7.25±8.32 (m, 10H, Ar-H), 10.45 (s,
1H, CHO). MS m/z (%) 331/(329). Anal. calcd for
C20H11NO4: C, 72.94; H, 3.34, N, 4.25. Found: C,
72.91; H, 3.31; N, 4.22.
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1
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C, 73.45, H, 3.77; N, 4.05.
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1
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1