Synthesis and antibacterial activities of some quinoline substituted quinoxaline derivatives

Article abstract of DOI:10.14233/ajchem.2015.18261

p-Anisidine (1) on treatment with ethyl acetoacetate gave 1-(ethyl-3-[(4-methoxyphenyl)imino]butanoate) (2), which on cyclization in hot Dowtherm oil gave 4-hydroxy-6-methoxy-2-methylquinoline (3). The latter, on chlorination with SO₂Cl₂

Full text of DOI:10.14233/ajchem.2015.18261

Asian Journal of Chemistry; Vol. 27, No. 8 (2015), 3129-3130
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SIAN
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OURNAL OF HEMISTRY
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http://dx.doi.org/10.14233/ajchem.2015.18261
NOTE
Synthesis and Antibacterial Activities of Some Quinoline Substituted Quinoxaline Derivatives
1,*
1
2
G. ANUKUMARI , M. ANAND RAO and P.K. DUBEY
1Department of Chemistry, Osmania University, Hyderabad-500 007, India
2Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India
*Corresponding author: E-mail: anukumari.g@gmail.com
Received: 6 June 2014;
Accepted: 26 August 2014;
Published online: 27 April 2015;
AJC-17207
p-Anisidine (1) on treatment with ethyl acetoacetate gave 1-(ethyl-3-[(4-methoxyphenyl)imino]butanoate) (2), which on cyclization in
hot Dowtherm oil gave 4-hydroxy-6-methoxy-2-methylquinoline (3). The latter, on chlorination with SO2Cl2, gave 3-chloro-4-hydroxy-
6-methoxy-2-methylquinoline (4) which with POCl3 was transformed into 3,4-dichloro-6-methoxy-2-methylquinoline (5). Treatment of
compound 5 with o-phenylenediamine gave the novel product 2-methoxy-6-methyl-7,7a,11a,12-tetrahydroquinolino[3,4-b]quinoxaline
(6) whose structure was assigned based on spectral data.
Keywords: Quinoxilines, Quinolines, Diamines, Chlorination.
Quinoxaline derivatives are an important class of hetero-
cycles that display a wide range of biological properties1.
Quinoline ring system is present as a basic structure in a wide
variety of heterocyclic synthetic and natural bioactive com-
pounds2. Quinoline derivatives have been explored for the
diverse types of pharmacological activities such as antimicro-
bial3, antiinflamatory4, antiamoebic5, antiseptic/antiinfective6,
anticancer7, antineurodegenarative8 etc. Having many bene-
ficial biological activities, quinoline derivatives have become
the synthetic goals of many organic and medicinal chemists1.
Quinoxalines are omnipresent in many heterocyclic structural
units in pharmaceuticals and bioactive natural products9. They
are the core constituents of various antibiotics such as echino-
mycin, levomycin and actinoleutin10,11. In view of these consi-
derations, it was considered worthwhile to synthesize quinoline
based quinoxaline type of compounds as new chemical entities
and as potentially biologically active compounds.
Melting points were determined in open capillary tubes
using Buchi melting point apparatus and are uncorrected. IR
spectra (in KBr pellets) were recorded on a Shimadzu FTIR
157 spectrometer. All 1H and 13C NMR spectra were recorded
on a Bruker instrument, using TMS as an internal standard,
operating at 400 MHz and 100 MHz, respectively. The mass
spectra were recorded either on single quadrupole mass or
XCT ion trap spectrometers. Completion of the reaction was
monitored by TLC and plates which were visualized by UV
light and/ or iodine vapours.
mmol), ethyl acetoacetate (13 g, 100 mmol) and ethanol (150
mL) was refluxed for 4 h. At the end of this period, the reaction
mixture was distilled to half its volume to remove ethanol and
the residue cooled to room temperature. The separated solid
was filtered, washed with cold ethanol (2 × 20 mL) and dried.
Yield = 21 g (75 %), m.p.: 35 °C (Lit13. m.p. 38 °C).
Preparation of 4-hydroxy-6-methoxy-2-methylquin-
oline (3): Ethyl 3-[(4-methoxyphenyl)imino]butanoate (2)
(17 g, 80 mmol) was added slowly to pre-heated Dowtherm
oil (50 mL) at 250 °C in small lots. After the completion of
addition, the reaction mixture was cooled to room temperature
and diluted with hexane. The separated solid was filtered,
washed with hexane (30 mL) and dried. The solid obtained
was dissolved in 10 % NaOH (100 mL), filtered and neutralized
with dil. HCl (20 %, 20 mL). The separated, off-white, solid
was filtered, washed with water (2 × 20 mL) and dried. Yield
= 10 g (68 %), m.p. 270 °C (Lit.11 m.p.: 267-269 °C).
Preparation of 3-chloro-4-hydroxy-6-methoxy-2-
methylquinoline (4): A mixture of compound 3 (14.15 g, 7.5
mmol), SO2Cl2 (8 mL, 8 mmol) and chloroform (50 mL) was
stirred at room temperature. The reaction was monitored by
TLC. After the completion of the reaction, the solvent was
evaporated under reduced pressure. The residual solid obtained
was washed with water (2 × 20 mL) and dried. The crude
product was purified by recrystallisation from methanol to
obtain compound 4 as off-white solid. Yield = 10 g (70 %),
m.p. 269-271 °C.
Preparation of ethyl-3-[(4-methoxyphenyl)imino]
butanoate (2): A mixture of p-anisidine (1) (12.3 g, 100
Preparation of 3, 4-dichloro-4-hydroxy-6-methoxy-2-
methylquinoline (5): A mixture of 4 (4.15 g, 1.5 mmol) and

3130 Anukumari et al.
Asian J. Chem.
O
OH
O
OH
N
O
Cl
O
O
O
c
a
b
N
NH
2
2
3
4
1
d
Cl
HN
N
O
Cl
O
NH
e
N
6
5
Scheme-1: (a) Ethyl acetoacetate, ethanol, heat, 90 °C, 4 h (b) dowtherm oil, 250 °C, 0.5 h (c) SO2Cl2, CHCl3, 6 h, r.t., (d) POCl3, 100 °C, 1h, (e) OPDA,
DMF, 90 °C, Pd(PPh3)4, 4 h
phosphorus oxychloride (4.5 mmol, 10 mL) was heated on a
hot water bath at 100 °C for 1 h. The reaction was monitored
by TLC. After the completion of reaction, the mixture was
cooled to room temperature and diluted with ice-cold water
(20 mL). It was then neutralised with sodium bicarbonate (5 %,
50 mL). The separated solid was filtered, washed with water
(2 × 20 mL) and dried to obtain compound 5. Yield = 3 g
(70 %), m.p. 91-93 °C. For spectral data.
Preparation of 2-methoxy-6-methyl-7,7a,11a,12-tetra-
hydroquinolino[3,4-]quinoxaline (6a): A mixture of com-
pound 5 (0.61 g, 0.25 mmol ), o-phenylenediamine (0.27 g,
0.25 mmol), triphenylphosphine palladium (0.1 g) and DMF
(25 mL) was heated for 4 h on a hot water bath at 100 °C. The
reaction mixture was cooled to room temperature, diluted with
water (15 mL) and filtered to remove triphenylphosphine
palladium. The filtrate was washed with distilled water (2 ×
20 mL), organic layer was extracted with ethyl acetate (3 × 30
mL) and the organic layer evaporated under reduced pressure
to obtain a crude residue. The latter was recrystallised from
ethanol to obtain compound 6. Yield = 0.3 g (49 %), m.p.:
142-143 °C. For spectral data.
spectrum showed signals at δ 2.62 (s, 3H, CH3), 3.83 (s, 3H,
OCH3), 7.56-8.01 (m, 3H, aromatic). Its LC/MS (ESI- MS)
showed m/z = 243 (M+ + 2) and 245 (M+ + 4) as twin peaks
corresponding to a molecular mass of 241. Compound 5 on
treatment with o-phenylenediamine in the presence of
Pd(PPh3)4 catalyst in DMF on a hot water bath at 100 °C for
4 h gave 2-methoxy-6-methyl-7,7a,11a,12-tetrahydroquino-
lino[3,4b]quinoxaline (6) whose structure was assigned based
on its spectral data. Thus, it's IR (KBr, νmax, cm-1) showed an
1
absorption at ≈3000 (N-H, broad). Its H NMR (400 MHz,
CDCl3) spectrum showed signals at δ 2.62 (s, 3H, CH3), 3.83
(s, 3H, OCH3), 5.56-8.01 (m, 7H aromatic), 3.34 (s, two-NH
protons). Its LC/MS showed the molecular ion peak (M+ + 1)
at (ESI-MS) m/z = 271 corresponding to a molecular mass of
270 when recorded in the Q + 1 mode.
ACKNOWLEDGEMENTS
The authors are thankful to the authorities of Osmania
University, Hyderabad, India for providing laboratory facilities
and to the authorities of Jawaharlal Nehru Technological
University, Hyderabad, India for encouragement.
Condensation of p-anisidine (1) with ethyl acetoacetate
in refluxing ethanol gave the previously reported12 ethyl-3-
[(4-methoxyphenyl)imino]butanoate (2) as shown in Scheme-I.
The latter was thermally cyclized by heating at 250 °C using
Dowtherm oil for 0.5 h to obtain 4-hydroxy-6-methoxy-2-
methylquinoline (3), which is also known in literature13. Com-
pound 3 on treatment with sulphuryl chloride in chloroform
at room temperature gave 3-chloro-4-hydroxy-6-methoxy-2-
methylquinoline (4), which was characterized based on its
spectral data. Thus, its IR showed a diagnostic absorption at a
3275 cm-1 as a medium and broad peak assignable to a -OH
stretching vibration and 1635 cm-1 assignable to -C=O func-
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