4-Methylphenylenediamine 1 was reacted with α-dicarbonylsto give quinoxalines 2a-g, 4a-d and/or 7a-c.Quinoxalines 7a-c were converted into dihydropyridazinoquinoxalines 9a-c, thienoquinoxalines 10a-c and/or dichloroquinoxalines 11a-c. Compounds 11a-c were converted into ethoxyquinoxalines 12a-c, arylaminoquinoxalines13a-f and/or quinazolinoquinoxalines 14a-c. The reaction of 11a-c with semicarbazide and/or sodium azide was also described

Assy, M.G.

Khalil, A.

Sherif, M.H.

Zahran, F.

Revistes Catalanes amb Accés Obert

156 AFINIDAD LXV, 534, Marzo-Abril 2008
Synthesis of some New Quinoxalines with
expected Pharmacological Activities
M.H. Sherif*, M.G. Assy, F. Zahran and A. Khalil
Chemistry Department, Faculty of Science, Zagazig University. Zagazig, Egypt
Síntesis de nuevas quinoxalinas con actividades farmacológicas esperadas
Síntesi de noves quinoxalines amb activitats farmacològiques esperades
Recibido: 9 de mayo de 2007: aceptado: 5 de Septiembre de 2007
RESUMEN
Se hace reaccionar la 4-metilfenilendiamina 1 con com-
puestos α-dicarbonílicos para dar las quinoxalinas 2a-
g, 4a-d y/o 7a-c. Las quinoxalinas 7a-c se transforman
en las dihidropiridazinoquinoxalinas 9a-c, tienoquinoxa-
linas 10a-c y/o dicloroquinoxalinas 11a-c. Los com-
puestos 11a-c se  convierten en las etoxiquinoxalinas
12a-c, arilaminoquinoxalinas 13a-f y/o quinazolinoqui-
noxalinas 14a-c. Se describe también la reacción de 11a-
c con semicarbazida y/o azida sódica. 
Palabras Clave: Quinoxalinas. Dihidropiridazinoquinoxa-
linas. Tienoquinoxalinas. Quinazolinoquinoxalinas.
SUMMARY
4-Methylphenylenediamine 1 was reacted with α-dicar-
bonyls to give quinoxalines 2a-g, 4a-d and/or 7a-c.
Quinoxalines 7a-c were converted into dihydropyridazi-
noquinoxalines 9a-c, thienoquinoxalines 10a-c and/or
dichloroquinoxalines 11a-c. Compounds 11a-c were con-
verted into ethoxyquinoxalines 12a-c, arylaminoquino-
xalines 13a-f and/or quinazolinoquinoxalines 14a-c. The
reaction of 11a-c with semicarbazide and/or sodium azi-
de was also described. 
Key words: Quinoxalines. Dihydropyridazinoquinoxalines.
Thienoquinoxalines, Quinazolinoquinoxalines.
RESUM
Es fa reaccionar la 4-metilfenilendiamina 1 amb com-
postos α-dicarbonílics per donar les quinoxalines 2a-g,
4a-d i/o 7a-c. Les quinoxalines 7a-c es transformen en
les dihidropiridazinoquinoxalines 9a-c, tienoquinoxali-
nes 10a-c i/o dicloroquinoxalines 11a-c. Els compostos
11a-c es converteixen en les etoxiquinoxalines 12a-c,
arilaminoquinoxalines 13a-f i/o quinazolinoquinoxalines
14a-c. Es descriu també la reacció d’11a-c amb semi-
carbazida i/o azida sòdica. 
Mots Clau: Quinoxalines. Dihidropiridazinoquinoxalines.
Tienoquinoxalines. Quinazolinoquinoxalines.
INTRODUCTION
The synthesis of quinoxalines has attracted the atten-
tion of medicinal chemists because of their potential
pharmacodynamic properties(1-5). Numerous publications
describe the synthesis of quinoxalines possessing a
variety of pharmacological activities, such as DNA inte-
ractive behaviour(6-8). Some act as antidiabetic agents(9),
anti-HIV agents(10) and NMDA receptor antagonists(11).
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AFINIDAD LXV, 534, Marzo-Abril 2008 157
RESULTS AND DISCUSSION
Recently, we have reported several new and efficient met-
hods for the synthesis of fused heterocyclic(12-15) from rea-
dily available starting compounds. In the present study we
report the synthesis of new quinazo-lines and condensed
quinazolines. α-Dicarbonyl are versatile building units that
have been extensively utilized in organic synthesis(16-18).The
reaction of 4-methylphenylenediamine 1 with α-diketones
namely benzil, p-dichlorobenzil, tetraketones, 9,10-phe-
nantharenequinone and acenaphthenequinone resulted in
cyclocondensation affording the corresponding quinoxa-
line derivatives 2a-g respectively (Scheme 1).
It was reported that 4-methylphenylenediamine 1 reacted
with asymmetric dicarbonyl to give 6-methylquinoxaline
as major product while 7-isomer as minor product(19). In the
present study it was found that cyclocondensation of ary-
lidenepyruvic acids 3a-d and 4-methyl-phenylenediamine
1 yielded corresponding 6-methylquinoxalines 4a-d res-
pectively not the other isomer(19). (Scheme 2).
When 4-methylphenylenediamine 1 was allowed to react
with aroyl pyruvate 6a-c resulted in cyclocondensation
affording 6-methylquin-oxaline derivatives 7a-c respecti-
vely not 7-methylquinoxaline derivatives 8a-c(19). The qui-
noxalines 7a-c exist in the enol form (no ketonic form can
be detected). Thus for 7a-c, no signal is observed for
–CH2CO- between 3.5 and 4.5 ppm, while a one proton sin-
glet is observed at 6.80 ppm.
Hydrazinolysis of compounds 7a-c using
hydrazine hydrate in ethanolic solution
yielded 1,2-dihydropyridazino[3,4-b]qui-
noxaline 9a-c respectively (Scheme 4).
Upon reacting quinoxalines 7a-c with
P2S5 in dry pyridine resulted in thiation
followed by cyclization affording thie-
noquinoxaline 10a-c (Scheme 4).
Chlorolysis of quinoxaline derivatives 7a-
c using POCl3 afforded the correspon-
ding dichloro-quinoxaline derivatives
11a-c (Scheme 4).
2-Chloroquinoxalines 11a-c appeared to
be versatile starting compound for further
functionlization and annulation of the qui-
noxaline ring. Thus refluxing 2-chloroqui-
noxalines 11a-c with ethoxide resulted in
2-ethoxyquinoxalines 12a-c (Scheme 5).
Chloroquinoxalines 11a-c were now sub-
jected to aminolysis with arylamines
namely; aniline and/or anthranilic acid
by refluxing in ethanol to give arylami-
noquinoxalines 13a-f (Scheme 5).
When compounds 13d-f were allowed
to react with POCl3 resulted heteroan-
nulation affording quinazolinoquinoxali-
nes 14a-c (Scheme 5). The semicarba-
zones 15a-c were achieved by the
reaction of 11a-c with semicarbazide
(Scheme 5). Depending on the reaction
conditions compounds 11a-c were reac-
ted with sodium azide at room temp. yiel-
ded the corresponding azido derivatives
16a-c while upon refluxing compounds
11a-c with sodium azide yielded the
corresponding tetrazoloquinoxaline deri-
vatives 17a-c presumably via the for-
mation of azido derivatives 16a-c. The structures of 17a-
c were proved by the disappearance of azido group in IR
spectrum.
Scheme 1
Scheme 2
TRIPA AFIN 534  13/6/08  12:53  Página 157
158 AFINIDAD LXV, 534, Marzo-Abril 2008
Scheme 3
Scheme 5
Scheme 4
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AFINIDAD LXV, 534, Marzo-Abril 2008 159
EXPERIMENTAL
Melting points are uncorrected and were recorded on
Büchi 510 apparatus. IR spectra were recorded as KBr
disks on a Perkin-Elmer 383 spectrometer and FTIR-
spectrometer Nicolet, impact 400. 1H- and 13C-NMR were
obtained a Bruker Ac 200F and Ac 250, DRX400 instru-
ment at room temperature using TMS as internal stan-
dard. Mass spectra were determined at 70 eV by using
AEI MS 30 mass spectrometer and elemental analyses
were recorded on LECO-Analyser CHNS-932.
Microanalyses were carried out at microanalytical cen-
ter, Cairo University, Egypt and Friedrich-Schiller
University, Jena, Germany.
Quinoxalines 2a-g:
A mixture of 1 (0.01 mole) and appropriate α-diketone (0.01
mole) in acetic acid (20 ml) was refluxed for 3 hours, coo-
led. The precipitate obtained was filtered and crystallized
from ethanol to give crystals of 2a-g respectively (Tables
I and II).
3-Styrylquinoxalines 4a-d:
A mixture of 1 (0.01 mole) and appropriate arylidenepyru-
vic acid (0.01 mole) in acetic acid (20 ml) was refluxed for
2 hours, cooled. The precipitate obtained was filtered and
crystallized from ethanol to give crystals of 4a-d respecti-
vely (Tables I and II).
TABLE I
Spectral analysis data of the synthetic compounds.
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160 AFINIDAD LXV, 534, Marzo-Abril 2008
3-Benzoylmethylquinoxalines 7a-c:
A mixture of 1 (0.01 mole) and appropriate ethylaroylpyru-
vate sodium salt (0.01 mole) in acetic acid (30 ml) was reflu-
xed for 3 hours cooled. The precipitate obtained was filte-
red and crystallized from ethanol to give crystals of 7a-c
respectively (Tables I and II).
1,2-Dihydropyridazino[3,4-b]quinoxalines 9a-c:
A mixture of hydrazine hydrate (0.01 mole) and appropria-
te of compounds 7a-c (0.01 mole) in dimethylformamide
(DMF) was refluxed for 3 hours. The precipitate obtained
upon cooling and pouring into ice cooled water was collec-
ted by filteration and crystallized from ethanol to give crys-
tals of 9a-c respectively (Tables I and II).
Thieno[2,3-b]quinoxalines 10a-c:
A mixture of P2S5 (0.01 mole) and apporopriate quinoxali-
nes 7a-c (0.01 mole) in dry pyridine (30 ml) was refluxed
for 3 hours. The solids obtained upon cooling and acidifi-
cation with HCl (10 ml, 20%) was collected and crystalli-
zed from methanol to give crystals of 10a-c respectively
(Tables I and II).
Dichloroquinoxalines 11a-c:
A mixture of appropriate quinoxalines 7a-c (0.01 mole) and
POCl3 (0.03 mole) was refluxed for 4 hours. The solids that
obtained upon cooling and pouring into ice cooled water
was collected by filteration and crystallized from benzene
to give crystal of 11a-c respectively (Tables I and II).
2-Ethoxyquinoxalines 12a-c:
A mixture of appropriate 11a-c (0.01 mole) and sodium
ethoxide (0.01 mole) was refluxed for 8 hours. The preci-
pitate obtained upon dilution was collected by filteration
and crystallized from ethanol to give crystals of 12a-c res-
pectively (Tables I and II).
2-Arylaminoquinoxalines 13a-f:
A mixture of appropriate 11a-c, appropriate aryl amine
namely aniline and/or anthranilic acid (0.01 mole) and triethy-
lamine (TEA) was refluxed for 8 hours. The precipitate obtai-
ned upon pouring into ice cooled water was collected by
filteration and crystallized from toluene to give crystals of
13a-f respectively (Tables I and II).
TABLE I (continued)
Spectral analysis data of the synthetic compounds.
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AFINIDAD LXV, 534, Marzo-Abril 2008 161
Quinazolinoquinoxalines 14a-c:
A solution of appropriate 13d-f (0.01 mole) in POCl3 (15 ml)
was refluxed for 12 hours. The precipitate obtained upon
pouring into ice cold water was collected by filteration and
crystallized from dichloromethane to give crystals of 14a-
c respectively (Tables I and II).
2-Quinoxalinyl Semicarbazone 15a-c:
A solution of appropriate 11a-c (0.01 mole), semicarbazi-
dehydro-chloride (0.01 mole), TEA (4 drops) in ethanol (30
ml) was refluxed for 8 hours. The precipitate obtained upon
cooling was collected by filteration and crystallized from
benzene to give crystals of 15a-c respectively (Tables I
and II).
2-Azidoquinoxalines 16a-c:
A solution of appropriate 11a-c (0.01 mole) and sodium
azide (0.01 mole) in DMF (20 ml) was stirred for 3 hours.
The precipitate obtained upon pouring into ice cooled
water was collected by filtration and crystallized from
ethanol to give crystals of 16a-c respectively (Tables I
and II).
Tetrazoloquinoxalines 17a-c:
A solution of appropriate 11a-c (0.01 mole) and sodium
azide (0.01 mole) in DMF (20 ml) was refluxed for 6 hours.
The precipitate obtained upon pouring into ice-cooled
water was collected by filteration and crystallized from
ethanol to give crystals of 17a-c respectively (Tables I
and II).
TABLE II
Spectral analysis data of the synthetic compounds.
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162 AFINIDAD LXV, 534, Marzo-Abril 2008
ACKNOWLEDGEMENTS
The authors would like to thank the F.S.U., Jena, Germany
for spectroscopic analysis.
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Synthesis of some new quinoxalines with expected pharmacological activities

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