Synthesis and antimicrobial activity of novel quinoxaline derivatives

Article abstract of DOI:10.1002/jccs.200700066

In this study, certain 3-substituted styrylquinoxalin-2(1H)-ones (2a-d) and their 2-chloro (3a-d) and 2-piperazinyl derivatives (4a-g) were synthesized from 3-methylquinoxalin-2(1H)-one (1). In addition, a series of 1-alkyl-3-substituted styrylquinoxalin-

Full text of DOI:10.1002/jccs.200700066

Journal of the Chinese Chemical Society, 2007, 54, 469-478
469
Synthesis and Antimicrobial Activity of Novel Quinoxaline Derivatives
Mohga M. Badran, Ashraf A. Moneer, Hanan M. Refaat* and Afaf A. El-Malah
Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
In this study, certain 3-substituted styrylquinoxalin-2(1H)-ones (2a-d) and their 2-chloro (3a-d) and
2-piperazinyl derivatives (4a-g) were synthesized from 3-methylquinoxalin-2(1H)-one (1). In addition, a
series of 1-alkyl-3-substituted styrylquinoxalin-2(1H)-ones (5a-d) was also prepared. Moreover, 3-(N2-
arylidenehydrazinocarbonyl)quinoxalin-2(1H)-ones (8a-c) as well as their cyclized oxadiazolinyl deriva-
tives (9a-c) were prepared from 3-hydrazinocarbonylquinoxalin-2(1H)-one (7). Furthermore, 3-(5-substi-
tuted thio-1,3,4-oxadiazol-2-yl)quinoxalin-2(1H)-ones (11a-c) and (12a-c) were obtained from the inter-
mediate compound (10) - previously obtained via cyclization of (7) with CS2. Likewise, 3-(5-oxo-4,5-di-
hydro-(1,3,4-oxadiazol-2-yl)quinoxalin-2(1H)-one (13), 3-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-
quinoxalin-2(1H)-one (14) and its 2-chloro derivative (15) were prepared from 3-hydrazinocarbonyl-
quinoxalin-2(1H)-one (7). Some of these derivatives were evaluated for antimicrobial activity in vitro and
some of the tested compounds showed antibacterial or antifungal activity.
Keywords: 2-Piperazinyl-3-styrylquinoxalines; 3-Oxadiazolylquinoxalin-2(1H)-one; Antimicrobial
activity.
INTRODUCTION
A wide variety of pharmacological properties has
products of 3-substituted styrylquinoxalin-2(1H)-ones
(2a-d). The 1H-NMR spectra of compounds 2a-d showed
two doublet signals at d 7.19-7.71 and d 7.81-8.16 ppm,
corresponding to the two styryl protons. Chlorination of
compounds 2a-d with phosphorus oxychloride gave 2-
chloro-3-substituted styrylquinoxalines (3a-d). The mass
spectrum of compound 3c demonstrated a distinct peak due
to the loss of chlorine radical from the molecular ion peak.
It is worth mentioning that chlorination prior to styryl for-
mation resulted in very poor yield due to the formation of
resinous materials.
been associated with quinoxaline derivatives. These in-
clude antidepressant,1 anticancer,2 antidiabetic,3 antiin-
flammatory,4,5 antimicrobial6,7 and antiviral8,9 activities. Of
particular interest are the styryl,10 N-alkyl,10 arylhydrazi-
nocarbonyl,9-12 oxadiazolyl,12-15 and thioalkyl16,17 quino-
xalines which are reported to possess antibacterial,10,13-16
antifungal11,12,15,17 and antiviral9 activity. In view of these
observations and in continuation of our research in this
field,15,17 it was of interest to synthesize certain new quin-
oxaline analogues to be evaluated for antimicrobial activ-
ity.
Amination of compounds 3a-d with certain substi-
tuted piperazines in n-butanol, gave 2-(4-substituted piper-
azin-1-yl)-3-substituted styrylquinoxalines (4a-g).
It was reported that alkylation of quinoxalin-2-ones
resulted in the formation of N-alkylated quinoxalinone de-
rivatives as the sole product.10,19 Thus the required 1-(alkyl
or allyl)-3-substituted styrylquinoxalin-2(1H)-ones (5a-d)
were prepared by heating a mixture of compounds 2a, 2c or
2d, the halocompound and anhydrous potassium carbon-
ate in dry acetone. The IR spectra of the compounds 5a-d
showed the presence of strong absorption bands at 1660-
1640 characteristic for C=O, while they lacked NH absorp-
tion. In addition, the 1H-NMR proton signals and the mass
RESULTS AND DISCUSSION
The starting material, 3-methylquinoxalin-2(1H)-one
(1), was prepared via the reaction of 1,2-phenylenediamine
and ethyl pyruvate adopting a reported procedure.18 Reac-
tion of 1 with certain aromatic aldehydes using acetic anhy-
dride as a solvent in the presence of a few drops of piperi-
dine, led to the formation of easily separated and high yield
* Corresponding author. Tel: 002 02 3639307; Fax: 002 02 3635140; E-mail: hanan-refaat@hotmail.com

470 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Badran et al.
Scheme I
spectrum of 5b are in agreement with N-alkylation.
It is suggested that compounds 2a-d, 3a-d, 4a-g and
5a-d are of trans configuration, since a strong absorption
band appeared in the region of 980-975 cm-1, in the IR spec-
tra of all the above compounds, characteristic of trans ole-
finic compounds.20-22 Also, the coupling constants of the
styryl protons, in 1H-NMR spectra, are 15-16 Hz, confirm-
ing its trans configuration .10,21,22
other new heterocyclic systems. Thus, treatment of 7 with
certain aromatic aldehydes gave 3-(N2-arylidenehydra-
zinocarbonyl)quinoxalin-2(1H)-ones (8a-c) which upon
cyclization with acetic anhydride yielded the correspond-
ing 3-(4-acetyl-5-aryl-1,3,4-oxadiazolin-2-yl)quinoxalin-
2(1H)-ones (9a-c).
The formation of compounds 9a-c was substantiated
by spectral evidence. Thus, the 1H-NMR spectra revealed
the absence of the two signals corresponding to azomethine
(CH=N) and (CO-NH) protons of its precursors. Moreover,
the appearance of a signal at 2.32 ppm corresponding to an
acetyl group, in addition to a singlet signal at d 7.2 ppm cor-
On the other hand, 3-ethoxycarbonyl-2(1H)-one (6)
was prepared23 and treated with hydrazine hydrate to afford
3-hydrazinocarbonyl quinoxalin-2(1H)-one (7).24 The lat-
ter was used as a versatile compound for the building of

Novel Quinoxaline Derivatives
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 471
responding to the proton at position 5 of oxadiazoline ring,
were indicative of successful formation of the title com-
pounds 9a-c.
EXPERIMENTAL
Melting points were obtained on a Graffin apparatus
and are uncorrected. Microanalyses for C, H and N were
carried out at the Microanalytical Center, Cairo University.
IR spectra were recorded on a Shimadzu 435 Spectrometer,
using KBr discs. 1H-NMR spectra were performed an a Jeol
NMR FXQ-200 MHz Spectrometer, Varian Gemini 300
MHz spectrometer and Jeol 90 MHz spectrometer, using
TMS as internal standard. Mass spectra were recorded on a
GCMS-QP 1000 EX Mass Spectrometer. Progress of the
reactions was monitored by TLC using precoated alumi-
num sheets silica gel MERCK 60 F 254 and was visualized
by UV lamp. Compounds 2b and 3b were reported as pat-
ented.4
Conversely, compound 7 was allowed to react with
carbon disulphide in alcoholic potassium hydroxide to af-
ford 3-(5-mercapto-1,3,4-oxadiazol-2-yl)quinoxalin-2(1H)-
one (10).25
S-Alkylation of 10 with certain alkylhalides fur-
nished the respective 3-(5-substituted thio-1,3,4-oxadi-
1
azol-2-yl)quinoxalin-2(1H)-ones (11a-c). The H-NMR
spectrum of compound 11c showed the appearance of a sin-
glet signal at d 4.5 integrating for two protons of SCH2.
Also, the mass spectrum of compound 11b showed (M-
alkyl) peak, in addition to the molecular ion peak.
The alkylating synthons, 1-(4-substituted piperazin-
1-yl)-2-chloroethan-1-ones, needed for the synthesis of
12a-c were prepared via the reaction of N-substituted
piperazines with chloroacetyl chloride in dry acetone.26
3-[5-(4-Substituted piperazin-1-ylcarbonylmethylthio)-
1,3,4-oxadiazol-2-yl]quinoxalin-2(1H)-ones (12a-c) were
prepared by the reaction of 10 with certain 1-(4-substituted
piperazin-1-yl)-2-chloroethan-1-ones in dry acetone con-
taining anhydrous potassium carbonate. Furthermore, cy-
clization of 7 with 1,1¢-carbonyl diimidazole in the pres-
ence of triethyl amine furnished 3-(5-oxo-4,5-dihydro-
1,3,4-oxadiazol-2-yl)quinoxalin-2(1H)-one (13). The IR
spectrum showed two NH peaks at 3400, 3150 cm-1 and
two carbonyl peaks at 1780, 1670 cm-1 corresponding to the
oxadiazole and the quinoxaline rings, whereas the 1H-NMR
revealed two exchangeable singlet signals at d 9.24 and
10.17 ppm corresponding to two NH groups.
General procedure for the synthesis of 2a-d
A mixture of 3-methyl quinoxaline (1) (0.5 g, 0.003
mol), the appropriate aromatic aldehyde (0.006 mol), ace-
tic anhydride (1 mL) and piperidine (3 drops) was refluxed
for 24 hours. After cooling, the precipitated solid was fil-
tered off, washed with water, dried and crystallized from
dimethylformamide.
3-(2-(2-Fluorophenyl)ethenyl)quinoxalin-2(1H)-one 2a
Yield: 80.0%; mp: 260-262 °C; IR: 3300 (NH), 1660
(C=O), 1620 (C=N), 1590 (CH=CH), 980 (trans CH=CH);
1H-NMR (DMSO-d6) (90 MHz): 7.11-8.17 (m, 10H, 8ArH
and 2 ethenyl-H); Anal. Calcd. for C16H11FN2O: C, 72.17;
H, 4.16; N, 10.52. Found: C, 72.35; H, 4.25; N, 10.40.
Finally, treatment of 7 with 4-nitrobenzoic acid in
phosphorus oxychloride afforded 2-chloro 3-[5-(4-nitro-
phenyl)-1,3,4-oxadiazol-2-yl]quinoxaline (15). In this
one-pot reaction, the acid was first converted to its acid
chloride, which subsequently reacted with the parent hy-
drazinocarbonyl quinoxaline 7 to give the corresponding
N2-acylhydrazinocarbonyl derivative in situ. The latter un-
derwent cyclodehydration followed by chlorination to
yield the oxadiazolyl quinoxaline 15. The progress of the
reaction was monitored by TLC, and it was observed that
after 3 hours, 3-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-
quinoxalin-2(1H)-one (14) was the main separated product
as confirmed by its mass spectrum. The chloro derivative
(15) can also be prepared by chlorination of (14) with phos-
phorus oxychloride.
3-(2-(2-Chlorophenyl)ethenyl)quinoxalin-2(1H)-one 2b
Yield: 70.0%; mp: 242-244 °C; IR: 3450 (NH), 1660
(C=O), 1620 (C=N), 1590 (CH=CH), 975 (trans CH=CH);
1H-NMR (DMSO-d6) (300 MHz): 7.36-7.59 (m, 5H, ArH),
7.68 (d, 1H, J = 15 Hz, ethenyl H), 7.81-7.84 (m, 3H, ArH),
8.10 (d, 1H, J = 15 Hz, ethenyl H), 12.61 (s, 1H, NH, D2O
exchangeable); MS: m/z 284 (M+2, 33.37%), 283 (M+1,
46.58%), 282 (M+, 93.56%), 254 (M + -CO; 21.05%), 253
(100%). Anal. Calcd. for C16H11ClN2O: C, 67.97; H, 3.92;
N, 9.91. Found: C, 67.85; H, 4.25; N, 9.92.
3-(2-(3-Bromophenyl)ethenyl)quinoxalin-2(1H)-one 2c
Yield: 50.0%; mp: 240-242 °C; IR: 3400 (NH), 1660
(C=O), 1620 (C=N), 1590 (CH=CH), 975 (trans CH=CH);
Anal. Calcd. for C16H11BrN2O: C, 58.73; H, 3.39; N, 8.56.

472 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Badran et al.
Scheme II

Novel Quinoxaline Derivatives
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 473
Found: C, 58.36; H, 3.49; N, 8.44.
General procedure for the synthesis of 4a-g
To a solution of the corresponding styrylquinoxalines
(3a-d) (0.002 mol) in n-butanol (10 mL), the respective
N-substituted piperazine (0.004 mol) and triethyl amine (4
drops) were added. The mixture was heated under reflux
for 12-24 hours (monitored by TLC). Upon cooling, the
solid that separated was collected and crystallized from
ethanol.
3-(2-(4-Bromophenyl)ethenyl)quinoxalin-2(1H)-one 2d
Yield: 78.0%; mp: 298-300 °C; IR: 3400 (NH), 1660
(C=O), 1620 (C=N); 1590 (CH=CH), 975 (trans CH=CH);
1H-NMR (DMSO-d6) (90 MHz): 7.19-8.16 (m, 10H, 8ArH
and 2 ethenyl H), 12.40 (s, 1H, NH, D2O exchangeable).
Anal. Calcd. for C16H11BrN2O: C, 58.73; H, 3.39; N, 8.56.
Found: C, 58.33; H, 3.72; N, 8.33.
3-(2-(2-Fluorophenyl)ethenyl)-2-(4-methylpiperazin-1-
yl)quinoxaline 4a
General procedure for the synthesis of 3a-d
Phosphorus oxychloride (15 mL) was added to the
corresponding styrylquinoxaline 2a-d (0.013 mol), and the
mixture was refluxed for 2 hours. Excess phosphorus oxy-
chloride was distilled under reduced pressure, and the re-
sultant residue was treated with cold water (200 mL). The
precipitate formed was filtered off, washed with water, air
dried and crystallized from ethanol.
Yield: 60.0%; mp: 196-198 °C; IR: 2850 (CH aliph.),
1630 (C=N), 1600 (CH=CH), 975 (trans CH=CH); Anal.
Calcd. for C21H21FN4: C, 72.39; H, 6.08; N, 16.08. Found:
C, 72.30; H, 6.10; N, 16.40.
2-(4-(2-Ethoxyphenyl)piperazin-1-yl)-3-(2-(2-fluoro-
phenyl)ethenyl)quinoxaline 4b
Yield: 40.0%; mp: 144-146 °C; IR: 2950 (CH aliph.),
1
1630 (C=N), 1610 (CH=CH), 980 (trans CH=CH); H-
2-Chloro-3-(2-(2-fluorophenyl)ethenyl)quinoxaline 3a
Yield: 70.0%; mp: 170-172 °C; IR: 1620 (C=N), 1570
(CH=CH), 980 (trans CH=CH), 1H-NMR (CDCl3-d1) (90
MHz): 7.09-8.16 (m, 10H, 8ArH and 2 ethenyl H as 2d at
7.21, 8.03, J = 15 Hz); Anal. Calcd. for C16H10ClFN2: C,
67.49; H, 3.54; N, 9.84. Found: C, 67.43; H, 3.77; N, 9.85.
NMR (CDCl3-d1) (300 MHz): 1.46 (t, 3H, OCH2CH3, J =
6.6 Hz), 3.37 (brs, 4H, 2CH2 piperazine), 3.70 (brs, 4H,
2CH2 piperazine), 4.09 (q, 2H, OCH2CH3, J = 6.6 Hz),
7.09-8.26 (m, 14H, 12ArH and 2 ethenyl H as 2d at 7.83,
8.23, J = 15.9 Hz, 2ethenyl H); Anal. Calcd. for C28H27FN4O:
C, 73.98; H, 5.99; N, 12.33. Found: C, 73.88; H, 5.80; N,
12.34.
2-Chloro-3-(2-(2-chlorophenyl)ethenyl)quinoxaline 3b
Yield: 75.0%; mp: 208-210 °C; IR: 1640 (C=N), 1570
(CH=CH), 975 (trans CH=CH); MS: m/z 303 (M+3,
11.6%), 302 (M+2, 38.1%), 301 (M+1, 46.4%), 300 (M+,
59.4%), 265 (M+-Cl, 100%); Anal. Calcd. for C16H10Cl2N2:
C, 63.80; H, 3.35; N, 9.30. Found: C, 63.86; H, 3.34; H,
9.38.
3-(2-(2-Chlorophenyl)ethenyl)-2-(4-(2-methoxyphenyl)-
piperazin-1-yl)quinoxaline 4c
Yield: 70.0%; mp: 190-192 °C; IR: 2850 (CH aliph.),
1630 (C=N), 1590 (CH=CH), 980 (trans CH=CH); MS: m/z
457 (M+1, 3.8%), 456 (M+, 3.1), 247 (100%). Anal. Calcd.
for C27H25ClN4O: C, 70.96; H, 5.51; N, 12.26. Found: C,
70.90; H, 5.80; N, 12.60.
3-(2-(3-Bromophenyl)ethenyl)-2-chloro quinoxaline 3c
Yield: 50.0%; mp: 236-238 °C; IR: 1620 (C=N), 1590
(CH=CH), 980 (trans CH=CH); 1H-NMR (CDCl3-d1) (90
MHz): 7.39-7.79 (m, 10H, 8ArH and 2 ethenyl H); Anal.
Calcd. for C16H10BrClN2: C, 55.60; H, 2.92; N, 8.11.
Found: C, 55.71; H, 3.28; N, 8.25.
3-(2-(2-Clorophenyl)ethenyl)-2-(4-(4-chlorophenyl)-
piperazin-1-yl)quinoxaline 4d
Yield: 70.0%; mp: 222-224 °C; IR: 2900 (CH aliph.),
1
1620 (C=N), 1590 (CH=CH), 975 (trans CH=CH); H-
NMR (CDCl3-d1) (90 MHz): 3.20-3.38 (m, 4H, 2CH2
piperazine), 3.48-3.62 (m, 4H, 2CH2 piperazine), 6.84-8.28
(m, 14H, 12ArH and 2 ethenyl H); Anal. Calcd. for
C26H22Cl2N4: C, 67.68; H, 4.81; N, 12.14. Found: C, 67.70;
H, 4.80; N, 12.50.
3-(2-(4-Bromophenyl)ethenyl)-2-chloro quinoxaline 3d
Yield: 65.0%; mp: 194-196 °C; IR: 1625 (C=N),
1590 (CH=CH), 975 (trans CH=CH); Anal. Calcd. for
C16H10BrClN2: C, 55.60; H, 2.92; N, 8.11. Found: C, 55.42;
H, 2.84; N, 8.09.

474 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Badran et al.
1
3-(2-(3-Bromophenyl)ethenyl)-2-(4-methyl piperazin-
1-yl)quinoxaline 4e
CH=CH); H-NMR (CDCl3-d1) (200 MHz): 3.75 (s, 3H,
CH3), 7.26-8.11 (m, 10H, 8ArH and 2 ethenyl H as 2d at
7.76, 8.07, J = l6 Hz); MS: m/z 298 (M+2, 34.9%), 297
(M+1, 43.5%), 296 (M+, 100%), 283 (62.9%), 281 (M-
CH3, 21.9%); Anal. Calcd. for C17H13ClN2O: C, 68.80; H,
4.41; N, 9.44. Found: C, 68.54; H, 4.68; N, 9.54.
Yield: 50.0%; mp: 246-248 °C; IR: 2800 (CH aliph.),
1620 (C=N), 1590 (CH=CH), 980 (trans CH=CH); Anal.
Calcd. for C21H21BrN4: C, 61.62; H, 5.17; N, 13.69. Found:
C, 61.84; H, 5.20; N, 13.45.
3-(2-(4-Bromophenyl)ethenyl)-2-(4-methylpiperazin-1-
yl)quinoxaline 4f
3-(2-(2-Chlorophenyl)ethenyl)-1-ethylquinoxalin-2(1H)-
one 5c
Yield: 63.0%; mp: 160-162 °C; IR: 2800 (CH aliph.),
1630 (C=N), 1590 (CH=CH), 980 (trans CH=CH); MS: m/z
410 (M+2, 14.9%), 408 (M+, 13.5%), 70 (100%); Anal.
Calcd. for C21H21BrN4: C, 61.62; H, 5.17; N, 13.69. Found:
C, 61.70; H, 5.10; N, 13.80.
Yield: 80.0%, mp: 103-105 °C ; IR: 2950 (CH aliph.),
1660 (C=O), 1600 (C=N), 1575 (CH=CH), 975 (trans
CH=CH); Anal. Calcd. for C18H15ClN2O: C, 69.56; H,
4.86; N, 9.02. Found: C, 69.46; H, 4.91; N, 8.77.
3-(2-(3-Bromophenyl)ethenyl)-1-methylquinoxalin-
2(1H)-one 5d
3-(2-(4-Bromophenyl)ethenyl)-2-(4-(4-chlorophenyl)-
piperazin-1-yl)quinoxaline 4g
Yield: 85.0%; mp: 84-85 °C; IR: 2950 (CH aliph.),
1660 (C=O), 1600 (C=N), 1580 (CH=CH), 980 (trans
1
CH=CH); H-NMR (CDCl3-dl) (300 MHz): 3.83 (s, 3H,
Yield: 70.0%, mp: 210-212 °C; IR: 2850 (CH aliph.),
1
1630 (C=N), 1590 (CH=CH), 980 (trans CH=CH); H-
NMR (CDCl3-d1) (90 MHz): 3.25-3.42 (m, 4H, 2CH2
piperazine), 3.51-3.81 (m, 4H, 2CH2, piperazine), 6.85-
8.21 (m, 14H, 12ArH and 2 ethenyl H); Anal. Calcd. for
C26H22BrClN4: C, 61.73; H, 4.38; N, 11.08. Found: C,
61.77; H, 4.40; N, 11.11.
CH3), 7.33-8.16 (m, 10H, 8ArH and 2 ethenyl H as 2d at
7.83, 8.31, J = 16 Hz), Anal. Cald. for C17H13BrN2O: C,
59.84; H, 3.84; N, 8.21. Found: C, 59.50; H, 4.01; N, 8.49.
General procedure for the synthesis of 8
A mixture of 3-hydrazinocarbonylquinoxalin-2-(1H)-
one (7) (0.6 g, 0.003 mol) and the respective aromatic alde-
hyde (0.003 mol) in ethanol (7 mL) was refluxed for 1 hour.
Upon cooling, the precipitate that formed was filtered off,
dried and crystallized from ethanol.
General procedure for the synthesis of 5
A mixture of compound 2a, 2c or 2d (0.01 mol), alkyl
or allyl halides (0.012 mol) and anhydrous potassium car-
bonate (1.3 g, 0.01 mol) in dry acetone (30 mL) was re-
fluxed for 24 hours. After cooling, the solid that separated
was filtered off and crystallized from ethanol.
3-(N2-4-Chlorobenzylidenehydrazinocarbonyl)quin-
oxalin-2(1H)-one 8a
1-Allyl-3-(2-(2-fluorophenyl)ethenyl)quinoxalin-2(1H)-
one 5a
Yield: 95.0%, mp: > 300 °C; IR: 3600-3400 (2NH),
1
1695, 1640 (2C=O), 1615 (C=N); H-NMR (DMSO-d6)
Yield: 95.0%, mp: 88-90 °C, IR: 2950 (CH aliph.),
1640 (C=O), 1600 (C=N), 1575 (CH=CH), 980 (trans
CH=CH); 1H-NMR (DMSO-d6) (300 MHz): 4.95-4.97 (d,
2H, -NCH2), 5.23-5.31 (m, 2H, CH=CH2), 5.95-6.15 (m,
1H, CH=CH2), 7.18-8.33 (m, 10H, 8ArH and 2 ethenyl H as
2d at 7.83, 8.31, J = 16 Hz); Anal. Calcd. for C19H15FN2O:
C, 74.49; H, 4.93; N, 9.15. Found: C, 74.36; H, 5.26; N,
9.03.
(90 MHz): 7.14-7.87 (m, 8H, ArH), 8.08, 8.39 (2s, 1H, Syn
and anti isomers of benzylidene H), 12.23, 12.36 (2s, 1H,
NH, OH tautomers of –CONH-, D2O exchangeable), 12.50,
12.63 (2s, 1H, NH, OH tautomers of quinoxaline, D2O ex-
changeable); Anal. Calcd. for C16H11ClN4O2: C, 58.81; H,
3.39; N, 17.l5. Found C, 58.62; H, 3.52; N, 16.96.
3-(N2-2-Bromobenzylidenehydrazinocarbonyl)quin-
oxalin-(1H)-one 8b
3-(2-(2-Chlorophenyl)ethenyl)-1-methylquinoxalin-
2(1H)-one 5b
Yield: 83.0%; mp: 294-296 °C; IR: 3500-3400 (2NH),
1
1700, 1640 (2C=O), 1595 (C=N), H-NMR (DMSO-d6)
Yield: 95%; mp: l56-l58 °C; IR: 2900 (CH aliph.),
1660 (C=O), 1600 (C=N), 1580 (CH=CH), 975 (trans
(200 MHz): 7.26-8.01 (m, 8H, ArH), 8.40, 8.68 (2s, 1H,
Syn and anti isomers of benzylidene H) 12.42, 12.47 (2s,

Novel Quinoxaline Derivatives
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 475
1H, NH, OH tautomers of -CONH-D2O exchangeable)
12.79, 12.95 (2s, 1H, NH, OH tautomers of quinoxaline,
D2O exchangeable); Anal. Calcd. for C16H11Br N4O2: C,
5l.77; H, 2.99; N, 15. 09. Found: C, 51.39; H, 2.98; N,
14.93.
Calcd. for C16H12N4O3S: C, 56.46; H, 3.56; N, 16.46.
Found: C, 56.26; H, 4.10; N, 16.49.
3-(5-Ethylthio-1,3,4-oxadiazol-2-yl)quinoxalin-2(1H)-
one 11a
A mixture of ethyliodide (1.6 mL, 0.01 mol) and com-
pound (10) (1.23 g,0.005 mol) in pyridine (10 mL) was
stirred at room temperature for 12 hours, then refluxed for 3
hours, cooled to room temperature and water (20 mL) was
added. The formed precipitate was filtered off and crystal-
lized from n-butanol. Yield: 80.0%; mp: 258-260 °C; IR:
3400 (NH), 2950 (CH aliph.), 1660 (C=O), 1590 (C=N);
Anal. Calcd. for C12H10N4O2S: C, 52.54; H, 3. 67; N, 20.43.
Found: C, 52.55; H, 3.65; N, 20.31.
3-(N2-2-Thenylidenehydrazinocarbonyl)quinoxalin-
2(1H)-one 8c
Yield: 80.0%; mp: 281-283 °C; IR: 3200-3250 (2NH),
1690, 1640 (2C=O), 1595 (C=N); MS: m/z 299 (M+1,
2.3%), 298 (M+, 12.5%), 90 (100%); Anal. Calcd. for
C14H10N4O2S: C, 56.36; H, 3.38; N, 18.78. Found: C, 56.
36; H, 3.75; N, 18.75.
General procedure for the synthesis of 9
The corresponding arylidenehydrazide (8a-c) (0.003
mol) in acetic anhydride (3 mL) was refluxed for 1 hour and
then allowed to cool to room temperature. The mixture was
neutralized with ammonium hydroxide. The solid obtained
was collected by filtration, washed with water and crystal-
lized from ethanol.
General procedure for the synthesis of 11b and 11c
A mixture of compound (10) (3.69 g, 0.915 mol), the
respective halogeno compound (0.018 mol), and sodium
acetate (0.02 mol) in ethanol (30 mL) was heated under re-
flux for 3 hours, then allowed to cool and poured onto cold
water (50 mL). The solid product separated was collected
and crystallized from ethanol.
3-(4-Acetyl-5-(4-chlorophenyl)-1,3,4-oxadiazolin-2-yl)-
quinoxalin-2(1H)-one 9a
3-(5-Propylthio-1,3,4-oxadiazol-2-yl)quinoxalin-2(1H)-
one 11b
Yield: 99.0%, mp 258-260 °C; IR: 3500-3350 (NH),
1
2900 (CH aliph.), 1680, 1660 (2C=O), 1620 (C=N); H-
Yield: 70.0%; mp: 288-290 °C; IR: 3450 (NH), 2900
(CH aliph.), 1685 (C=O); MS: m/z 288 (M+, 17.95%), 246
(42.18%), 213 (29.93%), 145 (100%); Anal. Calcd. for
C13H12N4O2S: C, 54.15; H, 4.20; N, 19.43. Found: C,
53.75; H, 4.20; N, 19.25.
NMR (DMSO-d6) (200 MHz): 2.34 (s, 3H, CH3), 7.18 (s,
1H, oxadiazoline), 7.37-8.02 (m, 8H, ArH), 12.79, 12.95
(2s, 1H, NH, OH tautomers of quinoxaline D2O exchange-
able); Anal. Calcd. for C18H13ClN4O3: C, 58.62; H, 3.55; N,
15.19. Found: C, 58.76; H, 3.59; N, 15.10.
3-(5-Benzylthio-1,3,4-oxadiazol-2-yl)quinoxalin-2(1H)-
one 11c
3-(4-Acetyl-5-(2-bromophenyl)-1,3,4-oxadiazolin-2-yl)-
quinoxalin-2(1H)-one 9b
Yield: 60.0%; mp > 300 °C; IR: 3200 (NH), 2900
1
(CH aliph.), 1660, 1640 (2C=O); H-NMR (DMSO-d6)
Yield: 76.0%; mp: 206-208 °C; IR: 3450-3400 (NH),
1
2900 (CH aliph.), 1740, 1690 (2C=O), 1610 (C=N), H-
(200 MHz): 4.5 (s, 2H, CH2), 7.10-7.67 (m, 9H, ArH),
10.01 (s, 1H, NH, D2O exchangeable). Anal. Calcd. for
C17H12N4O2S: C, 60.70; H, 3.60; N, 16.66. Found: C,
60.60; H, 3.60; N, 16.55.
NMR (DMSO-d6) (300 MHz): 2.32 (s, 3H, CH3), 7.28 (s,
1H, oxadiazoline), 7.33-8.12 (m, 8H, ArH), 12.55, 12.71
(2s, 1H, NH, OH tautomers) of quinoxaline, D2O ex-
changeable); Anal. Calcd. for C18H13BrN4O3: C, 52.32; H,
3.17; N, 13.56. Found: C, 52.21; H, 3.27; N, 13.54.
General procedure for the synthesis of 12
Compound (10) (1.23 g, 0.005 mol), the correspond-
ing substituted piperazinylcarbonylmethyl chloride (0.005
mol) and anhydrous potassium carbonate (1 g, 0.007 mol)
in dry acetone (30 mL) were refluxed on a water bath for 4
hours, then cooled to room temperature and poured onto
crushed ice (50 g). The precipitated product was filtered off
3-(4-Acetyl-5-(2-thienyl)-1,3,4-oxadiazolin-2-yl)quin-
oxalin-2(1H)-one 9c
Yield: 60.0%; mp 204-206 °C; IR: 3500-3400 (NH),
2800 (CH aliph.), 1740, 1670 (2C=O), 1620 (C=N); MS:
m/z 341 (M+1, 0.8%), 340 (M+, 29%), 145 (100%); Anal.

476 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Badran et al.
and crystallized from ethanol.
exchangeable); Anal. Calcd. for C10H6N4O3: C, 52.18; H,
2.63; N, 24.34. Found: C, 51.89; H, 2.35; N, 24.21.
3-[5-(4-Methylpiperazin-1-ylcarbonylmethylthio)-1,3,4-
oxadiazol-2-yl]quinoxalin-2(1H)-one 12a
3-[5-(4-Nitrophenyl)-1,3,4-oxadiazol-2-yl]quinoxalin-
2(1H)-one 14
Yield: 55.0%; mp: > 300 °C; IR: 3400 (NH), 2900
1
(CH aliph.), 1670, 1650 (2C=O), 1610 (C=N), H-NMR
A mixture of the hydrazide (7) (0.4 g, 0.002 mol) and
4-nitrobenzoic acid (0.33 g, 0.002 mol) in phosphorus
oxychloride (10 mL) was refluxed for 3 hours. After cool-
ing, the reaction mixture was poured onto crushed ice (30
g). The formed precipitate was dried and crystallized from
ethanol. Yield: 0.46 g, 70.0%; mp: 277-279 °C; IR: 3450-
3200 (NH), 1665 (C=O), 1600 (C=N), 1520, 1340 (NO2);
MS: m/z 335 (M+, 4.6%), 145 (11.7%), 76 (100%); Anal.
Calcd. for C16H9N5O4: C, 57.31; H, 2.71; N, 20.89. Found:
C, 57.70; H, 2.99; N, 20.70.
(DMSO-d6) (300 MHz): 2.61 (s, 3H, CH3), 3.58-3.82 (m,
4H, 2CH2 piperazine), 4.18-4.38 (m, 4H, 2CH2 piperazine),
4.60 (s, 2H, CH2), 7.40-7.95 (m, 4H, ArH), 12.97 (s, 1H,
NH, D2O exchangeable); Anal. Calcd. for C17H18N6O3S: C,
52.84; H, 4.69; N, 12.75. Found: C, 52.92; H, 4.40; N,
12.73.
3-[5-(4-Benzylpiperazin-1-ylcarbonylmethylthio)-1,3,4-
oxadiazol-2-yl]quinoxalin-2(1H)-one 12b
Yield: 60.0%; mp: 238-240 °C; IR: 3500 (NH), 2900
1
(CH aliph.), 1670, 1650 (2C=O), 1630 (C=N), H-NMR
2-Chloro-3-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)-
quinoxaline 15
(DMSO-d6) (300 MHz): 3.58-3.80 (m, 4H, 2CH2 piper-
azine), 3.83-4.15 (m, 6H, 2CH2 piperazine + CH2), 4.61 (s,
2H, CH2), 6.60-7.46 (m, 9H, ArH), 12.95 (s, 1H, NH, D2O
exchangeable); Anal. Calcd. for C23H22N6O3S: C, 59.72; H,
4.79; N, 18.17. Found: C, 59.50; H, 4.80; N, 18.1.
Method A
Compound (14) (0.33 g, 0.001 mol) was refluxed
with phosphorus oxychloride (10 mL) for 4 hours. After
cooling, the reaction mixture was poured onto crushed ice
(30 g). The formed precipitate was dried and crystallized
from ethanol. Yield: 0.31 g, 90.0%, mp: 225-227 °C; IR:
1600 (C=N), 1520, 1340 (NO2); MS: m/z 353, 355 (M+,
91.6%, 31.4%), 354, 356 (M+1, 18.95%, 6.24%), 163, 165
(C8H4N2Cl, 100%, 33.4). Anal. Calcd. for C16H8ClN5O3: C,
54.31; H, 2.26; N, 19.80. Found: C, 54.29; H, 2.30; N,
19.82.
3-[5-(4-Methoxyphenylpiperazin-1-ylcarbonylmethyl-
thio)-1,3,4-oxadiazol-2-yl]quinoxalin-2(1H)-one 12c
Yield: 63.0%; mp: 94-95 °C; IR: 3400 (NH), 2950
(CH aliph.), 1670, 1650 (2C=O), 1595 (C=N); MS: m/z 478
(M+, 1.9%), 205 (100%), 191 (23.6%); Anal. Calcd. for
C23H22N6O4S: C, 57.72; H, 4.63; N, 17.56. Found: C,
58.09; H, 4.97; N, 17.77.
Method B
The same method described for the synthesis of 14
was used, but the reflux time is 8 hours.
3-(5-Oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)quinoxalin-
2(1H)-one 13
To a 0 °C solution of compound 7 (0.8 g, 0.004 mol)
in tetrahydrofuran (12 mL) was added triethylamine (0.4 g,
0.005 mol) and 1,1¢-carbonyl diimidazole (0.8 g, 0.005
mol). The resulting mixture was stirred for 18 hours at
room temperature. The mixture was then concentrated in
vaccuo and the residue dissolved in ether. The organic layer
was washed successively with 2M HCl, saturated sodium
bicarbonate solution, saturated sodium chloride solution
and dried over magnesium sulphate. The solid produced
was crystallized from dimethyl formamide to afford 0.7 g,
yield: 78.09%; mp > 300 °C; IR: 3450, 3150 (2NH) 1780,
Antimicrobial Activity
Test organisms
The selected compounds were tested for antimicro-
bial activity against various types of bacteria and fungi,
namely:
1. Staphylococcus aureus (Gram positive bacteria).
2. Bacillus subtilis (Gram positive bacteria).
3. Escherichia coli (Gram negative bacteria).
4. Pseudomonas aeruginosa (very resistant Gram
negative bacteria).
5. Candida albicans (a representative of fungi).
Culture media
1
1670 (2C=O), 1640 (C=N); H-NMR (DMSO-d6) (200
MHz): 7.34-7.95 (m, 4H, ArH), 9.24, 10.17 (2s, 2NH, D2O
Nutrient broth, Sabouraud’s broth and nutrient agar

Novel Quinoxaline Derivatives
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 477
Table 1. Results of antimicrobial activity, zones of inhibition (mean ± standard deviation)
Compound
No.
S. aureus
B. subtilis
E. coli
Ps. aeruginosa C. albicans
2c
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
3a
-
-
-
4d
-
-
-
-
4h
-
-
-
-
5a
-
-
-
-
8b
-
-
-
-
9a
11.17 ± 0.764
-
-
-
9b
10.33 ± 1.041
9 ± 1.323
-
-
9c
-
-
-
-
-
-
11a
11b
11c
12a
12b
12c
13
-
8.5 ± 1.0
-
-
-
13.16 ± 1.756
-
-
-
11.33 ± 1.258
-
-
-
10.5 ± 1.323
-
-
-
14.66 ± 1.527
-
-
-
-
-
-
-
-
PRL
AML
N
10
8
-
15
10
-
10
-
-
-
-
26
PRL = Piperacillin standard disc. AML = Amoxicillin standard disc. N = Nystatin standard
disc. - = inactive.
were the products of Oxoid Ltd., England.
Methodology
The agar plate disc diffusion technique27
These compounds exhibited activity comparable to that of
piperacillin against S. aureus, and compound 9b showed
lower activity than amoxicillin against the sporeforming
bacteria B. subtilis.
Sterilized filter paper discs (6 mm in diameter) were
wetted each with 10 mL of a solution of the tested com-
pound containing 10 mg/mL in DMF, and the discs were al-
lowed to air dry. The discs were then placed onto the sur-
face of agar plates (nutrient agar for bacteria and Sabouraud’s
dextrose agar for fungi) seeded with the test organism.
Each plate contained 15 mL of the agar medium, previously
seeded with 0.2 mL of 18 hours broth culture of each organ-
ism. The inoculated plates were incubated at 37 °C for 48
hours, and the inhibition zones were measured in mm.
Discs impregnated with DMF were used as control. The an-
tibacterial references of piperacillin, amoxicillin, and the
antifungal reference nystatin were tested concurrently as
standards.
Of all the tested compounds, compounds 11a-c and
12a,b showed weak activity against Candida species.
ACKNOWLEDGEMENT
The authors wish to express their thanks to Prof. Dr.
Mohammed Abdel-Haleim, Professor of Microbiology and
Immunology, Faculty of Pharmacy, Cairo University, for
his help and for the interpretation of the results of the
antimicrobial screening.
Received April 27, 2006.
RESULTS AND DISCUSSION
REFERENCES
The obtained results are presented in Table 1. The
tests were done in triplicate and the results were given as
mean ± standard deviation. Compounds 9a & 9b showed
remarkable activity against Gram positive bacterial strains.
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