Synthesis of some new heterocycles of pharmaceutical interest: Pyridinyl and isoxazolyl quinoxaline derivatives

Article abstract of DOI:10.1002/jccs.200300172

3-(p-Acetyl-anilinomethyl)quinoxalin-2(1H)-one (3) was prepared by the reaction of 3-bromomethyl-quinoxalin-2(1H)-one(1) with p-aminoacetophenone (2) in pyridine. Reaction of p-acetylcompound (3) with aromatic aldehydes yield the corresponding chalcones (4a-c). Condensation of latter chalcones with malononitrile afforded cyanopyridines (5a-c). Also, the reaction of chalcones (4a-c) with hydroxylamine hydrochloride furnished isoxazoles (6a-c). The reaction of bromo compound (1) with p-aminobenzophenone yield (8) which was condenced with hydrazine hydrate to get the corresponding hydrazone derivatives (9). Some of the synthesized compounds have been screened for their antimicrobial activity against various strains of bacteria and fungi.

Full text of DOI:10.1002/jccs.200300172

Journal of the Chinese Chemical Society, 2003, 50, 1205-1208
1205
Synthesis of Some New Heterocycles of Pharmaceutical Interest: Pyridinyl
and Isoxazolyl Quinoxaline Derivatives
Osama S. Moustafa
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
3-(p-Acetyl-anilinomethyl)quinoxalin-2(1H)-one (3) was prepared by the reaction of 3-bromomethyl-
quinoxalin-2(1H)-one (1) with p-aminoacetophenone (2) in pyridine. Reaction of p-acetylcompound (3) with
aromatic aldehydes yield the corresponding chalcones (4a-c). Condensation of latter chalcones with
malononitrile afforded cyanopyridines (5a-c). Also, the reaction of chalcones (4a-c) with hydroxylamine hy-
drochloride furnished isoxazoles (6a-c). The reaction of bromo compound (1) with p-aminobenzophenone
yield (8) which was condenced with hydrazine hydrate to get the corresponding hydrazone derivatives (9).
Some of the synthesized compounds have been screened for their antimicrobial activity against various
strains of bacteria and fungi .
Keywords: Quinoxaline; Isoxazoles; Antimicrobial activity.
INTRODUCTION
Quinoxaline derivatives are known to possess interest-
presence of pyridine as a basic catalyst to get 3-(p-acetyl-
anilinomethyl)quinoxalin-2(1H)-one 3 which was treated
with virous aromatic aldehydes to give chalcones 4a-c (the IR
spectra of these compounds showed two absorption bands at
970 , 730 cm-1 duo to the presence of these compounds as a
mixture their trans and cis forms, respeceivally;21 the latter
compounds on treatment with malononitrile in the presence
of ammonium acetate gave cyanopyridinylquinoxalinones
5a-c through Michael reaction22 with the elimination of water
and hydrogen (Scheme I).
ing biological properties which show antibacterial, fungi-
cidal, insecticidal, anthelmic and cytotoxic activities.1 Re-
cently, that some quinoxaline derivatives inhibit selectively
the platelet-derived growth factor (PDGF) receptor kinase,
PDGF-dependent DNA synthesis in cells2 and its unique in-
hibitory activity against a panel of human cancer cell lines.3
On the other hand, a quinonimine system (napthooxazino-
quinoxalinone derivative)4 is of interest because this system
constitutes the structure of several antitumor antibiotics such
as actionmycin D,5 questiomycin A,6 and glycosylquestio-
mycin.7 Also, among the wide variety of heterocycles that
have been explored for the viral and antifungal activities of
developing pharmaceutically important molecules, cyano-
pyridines,8-10 isoxazoles11-13 have been similarly investigated.
The present investigation, and in continuation of our work on
quinoxaline moiety;14-18 is concerned with the use of 3-bro-
momethylquinoxalin-2(1H)-one for the synthesis of many
heterocycles systems of a new type with the aim of investigat-
ing their antimicrobial properties.
Reaction of chalcones 4a-c with hydroxylamine hydro-
chloride in the presence of sodium acetate in acetic acid fur-
nished isoxazolylquinoxalinone derivatives 6a-c (Scheme
II).18b,23
Also the bromo compound 1 was reacted with p-amino-
benzophenone 7 in basic medium to afford 3-(4-benzoyl-
anilinomethyl)quinoxalin-2(1H)-one 8; hydrazinolysis of the
latter compound with hydrazine hydrate afforded the corre-
sponding hydrazone 9 (Scheme III).
ANTIMICROBIAL ACTIVITY
The newly synthesized compounds were screened for
their antibacterial activity aganist three species of different
bacteria: Gram postive, Bacillus subtillus, Micrococcus
luteus and Gram negative; Serration rhodenil and three spe-
cies of fungi: Aspergillus fumigatus, Penicllum chrysogen,
RESULTS AND DISCUSSION
The starting compound 3-bromomethylquinoxalin-
2(1H)-one 1 was reacted with p-aminoacetophenone 2 in the
* Corresponding author. E-mail: oshmous@acc.aun.eun.eg

1206 J. Chin. Chem. Soc., Vol. 50, No. 6, 2003
Moustafa et al.
Scheme I
H
N
H
H N
COCH3
N
2
O
N
N
O
OH
H
2
Pyr.
CH -N-
COCH3
CH2Br
2
, reflux
CH2Br
N
N
3
1
Y
CHO
Y
N
NaOH
H
N
H
N
CH (CN)
2
2
O
O
H
CH COONH
3
4
H
CN
Y
CH -N-
COCH=CH
2
CH -N-
2
N
EtOH, reflux
NH2
N
4 a, Y = H
b, Y = NO
5 a, Y = H
b, Y = NO
2
2
c, Y = OCH
3
c, Y = OCH
3
EXPERIMENTAL
Scheme II
H
N
Melting points were determined on a Gallen Kamp
melting point apparatus and are uncorrected. IR spectra were
recorded on a Pye-Unicam SP3-100 spectrophotometer using
KBr wafer technique.1H NMR spectra were measured on a
Varian 390-90 MHz NMR spectrometer in the suitable deu-
terated solvent, using TMS as internal standard. Elemental
analyses were performed on a Perkin-Elmer 240 C micro-
analyzer and all compounds gave results in an acceptable
range. Spectroscopic data are listed in Table 2.
O
H
CH -N
NH OH
2
Y
4a-c
2
N
NaOAc
HOAc , reflux
N
O
6 a, Y= H
b, Y = NO
2
c, Y= OCH
3
and Fusarium equiseti using the filter paper technique19,20
measuring the zone of inhibition in mm at 25 mg concentra-
tion. The screening results summerized in Table 1 indicated
that among of tested compounds, the new compounds showed
good growth inhibition against Gram postive bacteria, but
only two compounds 3 and 5a showed good growth inhibition
against Gram negative bacteria. However, concerning the
antifungal activities only two compounds 3 and 6a were ac-
tive against fungi. The results of the antimicrobial activity
tests are summarized in Table 1.
3-Bromomethylquinoxalin-2(1H)-one (1) was prepared ac-
cording to the literature14 mp. 245 °C.
3-(p-Acetylanilinomethyl)quinoxalin-2(1H)-one (3)
Method A:
To a mixture of p-aminoacetophenone 2 (1.35 g, 0.01
mol) in pyridine (2.3 mL, 0.025 mol), 3-bromomethylquino-
Scheme III
H
N
O
O
H
O
C
Pyr.
1
+
H2N
C
CH -N-
2
N
7
8
NH NH .H O
2
2
2
H
N
O
H
NNH2
CH -N-
C
2
N
9

Chemistry and Antimicrobial Activity of Quinoxalines
J. Chin. Chem. Soc., Vol. 50, No. 6, 2003 1207
Table 1. Antimicrobial Activity of Some Synthesized Compounds [zone of inhibition in mm]
Antibacterial activity
Antifungal activity
Comp. No.
Bacillus Micrococcus Serration Aspergillus Penicillium Fusarium
subtillus
luteus
rhodenil
fumigatus chrysogen
equiseti
3
7
-
7
-
7
11
-
7
-
-
-
-
-
-
-
-
16
-
19
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
12
-
-
-
13
-
4b
5a
5b
6a
6b
8
-
-
-
-
9
Table 2. Spectroscopic Data of Compounds 3-9
Comp. No
IR (n cm-1) / 1H NMR d (ppm)
3
3400, 3200 (2NH), 1710, 1670 (2CO), 1610 (C=N); (DMSO-d6): d 2.4 (s, 3H, CH3), 4.2 (s,
2H, CH2), 7.2-7.9 (m, 8H, Ar-H), 10.5, 11.4 (2s, 2H, 2NH).
4a
4b
4c
5a
5b
5c
6a
6b
6c
8
3300, 3150 (2NH), 2960 (CH-alph.), 1700, 1670 (2CO), 1600 (C=N); (CF3COOD): d 4.3 (s,
2H, CH2), 7.4-8.2 (m, 15H, Ar-H and CH=CH).
3350-3100 (2NH), 2950 (CH-alph.), 1700, 1670 (2CO), 1610 (C=N); (CF3COOD): d 4.2 (s,
2H, CH2), 7.4-8.1 (m, 14H, Ar-H and CH=CH).
3400-3180 (2NH), 2960 (CH-alph.), 1705, 1670 (2CO), 1620 (C=N); (CDCl3): d 3.58 (s, 3H,
OCH3), 4.35 (s, 2H, CH2), 7.5-8.0 (m, 14H, Ar-H and CH=CH), 10.5, 11.1 (2s, 2H, 2NH).
3450, 3200 (NH, NH2), 2220 (CN), 1670 (CO), (DMSO-d6): d 2.6 (s, 2H, NH2), 4.35 (s, 2H,
CH2), 7.5-8.2 (m, 14H, Ar-H and CH, pyr.), 10.4, 11.0 (2s, 2H, 2NH).
3330 (NH, NH2), 2220 (CN), 1670 (CO); (DMSO-d6): d 2.45 (s, 2H, NH2), d 4.2 (s, 2H, CH2),
7.2-8.1 (m, 13H, Ar-H and CH, pyr ), 10.5, 11.2 (s, 2H, 2NH).
3180-3420 (NH, NH2), 2220 (CN); 1670 (CO), (DMSO-d6): d 2.6 (s, 2H, NH2), 3.58 (s, 3H,
OCH3), 4.25 (s, 2H, CH2), 7.3-7.9 (m, 13H, Ar-H), 11.3 (s, 1H, NH).
3200 (NH), 1670 (CO), 1620 (C=N); (DMSO-d6): d 4.4 (s, 2H, CH2), 7.4 -8.2 (m, 14H, Ar-H),
10.5, 11.3 (s, 2H, 2NH).
3200-3300 (NH), 1670 (CO), (DMSO-d6): d 4.45 (s, 2H, CH2), 7.3-8.1 (m, 13H, Ar-H ), 10.7
(s, 1H, NH).
3240 (NH), 1670 (CO), 1620 (C=N); (DMSO-d6): d 4.50 (s, 2H, CH2), 7.4-8.2 (m, 13H, Ar-
H), 10.85 (s, 1H, NH).
3220, 3500 (NH), 1720, 1670 (2CO); (CDCl3): d 4.3 (s, 2H, CH2), 7.4-8.0 (m, 13H, Ar-H).
11.2 (s, 1H, NH).
9
3250-3420 (NH, NH2), 1670 (CO); 1600 (C=N); (CF3COOD): d 4.4 (s, 2H, CH2), 7.6-8.2 (m,
13H, Ar-H).
xalin-2(1H)-one 1 (2.39 g, 0.01 mol) was added portionwise
with constant stirring. The mixture was refluxed for 3 h in 20
mL of ethanol; the contents were poured into a crushed ice
(60 g) and conc. HCl (5 mL) mixture. The product thus sepa-
rated was filtered and crystallized from ethanol, 67% yield,
as yellow crystals mp: 261-262 °C, [C17H15N3O2; 293].
Method B:
tents were poured into a crushed ice (60 g) and conc. HCl (5
mL) was added. The product thus separated was filtered and
crystallized from ethanol, 71% yield.
Condensation of (3) with aromatic aldehydes
A mixture of acetyl compound 3 (3.25 g, 0.01 mol) and
aromatic aldehydes (0.01 mol) in ethanol (20 mL), and NaOH
(40%, 5 mL) was stirred for 5 h. The contents were poured
into a crushed ice; the product was isolated by acidifaction
(HCl, 5 mL) and crystallized from ethanol.
To a solution of p-aminoacetophenone 2 (1.35 g, 0.01
mol) in 10 mL of pyridine, 3-bromomethylquinoxalin-2(1H)-
one 1 (2.39 g, 0.01 mol) was added portionwise with constast
stirring. The mixture was stirred for 30 min. at 0 °C; the con-
4a: 72% yield, as reddish crystals mp: 251-252 °C

1208 J. Chin. Chem. Soc., Vol. 50, No. 6, 2003
Moustafa et al.
[C24H19N3O2; 381].
[C22H19N5O; 369].
4b: 65% yield; as red crystals mp: 280-281 °C
[C24H18N4O4; 426].
Received December 3, 2002.
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4c: 69% yield, as pale brown crystals mp: 272-274 °C
[C25H21N3O3; 411].
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cooled contents were then poured into crushed ice with con-
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and the residue was crystallized from ethanol to give 5a-c.
5a: 72% yield, as yellowish crystals mp: 222-224 °C
[C27H20N6O; 444].
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A solution of ketone compound 8 (3.55 g, 0.01 mol) and
hydrazine hydrate (0.01 mol) in ethanol (30 mL) was heated
under reflux for one h; the reaction mixture was cooled, the
solid separated was filtered and crystallized from ethanol to
give 65% yield of 9, as yellowish crystals mp: 154-155 °C