Synthesis and antimicrobial activity of novel furothienoquinoxalines, pyranothienoquinoxalines and pyrimidopyranothienoquinoxalines

Article abstract of DOI:10.1002/jccs.200200018

The reaction of ethyl-3-mercaptoquinoxaline-2-carboxylate with phenacyl bromide, ethyl chloroacetate, chloroacetonitrile or chloroacetone furnished the corresponding 3-hydroxy thieno[2,3-b]quinoxaline. 2-Cyano-3-hydroxythieno[2,3-b] quinoxaline and 2-acet

Full text of DOI:10.1002/jccs.200200018

JournaloftheChineseChemicalSociety, 2002, 49, 107-112
107
SynthesisandAntimicrobialActivityofNovelFurothienoquinoxalines,
Pyranothienoquinoxalines and Pyrimidopyranothienoquinoxalines
Osama S. Moustafa* and Yasser A. El-Ossaily
ChemistryDepartment,FacultyofScience,AssiutUniversity,Assiut71516,Egypt
Thereactionofethyl-3-mercaptoquinoxaline-2-carboxylatewithphenacylbromide, ethylchloroacetate,
chloroacetonitrile or chloroacetone furnished the corresponding 3-hydroxy thieno[2,3-b]quinoxaline.
2-Cyano-3-hydroxythieno[2,3-b]quin oxa line and 2-acetyl-3-hydroxythieno[2,3-b]quin oxa line were em-
ployed as precursors in the synthesis of some novel furo[2¢,3¢:4,5]thieno[2,3-b]quin oxa line, pyrano-
[2¢,3¢:4,5]thieno[2,3-b]quin oxa line and other heterocyclic sys tems fused with thieno[2,3-b]quinoxalines.
Theantibacterialandantifungalactivitiesofsomethesynthesisedcompoundswerestudi ed.
INTRODUCTION
Earlierwehavereportedthesynthesisandreactionsof
ac tion of 2 with halocompounds like w-bromoacetophenone
and/or ethyl chloroacetate in the pres ence of fused so dium ac-
etategavethethienoquinoxalinederivatives3 and 4, respec-
tively. Com pound 4 was refluxed in an ethanolic so lu tion of
sodiumhydroxidewhichresultedinhydrolysisfollowedby
spon ta ne ous decarboxylation to give 3-hydroxy-thieno[2,3-
b]quinoxaline6. The cycloaddition re ac tion of6 with ben-
zylidenemalononitrileafforded2-amino-3-cyano-4-phenyl-
4 H-p yrano[2¢,3¢:4,5]thieno[2,3-b]quinoxaline7 in good yield.
The con den sa tion of o-aminonitrile 7 with triethyl ortho-
formate yielded methanimidate 8, while the heat ing of 7 with
aceticanhydrideatrefluxtemperatureledtotheformationof
monoacetylderivative9 (Scheme I).
Thepresentinvistigationwasextendedtothesynthesis
of novel furo[2¢,3¢:4,5]thieno[2,3-b]quinoxalines. The re ac-
tion of2 with chloroacetonitrile in refluxing eth a nol con tain-
ing fused so dium ac e tate gave 2-cyano-3- hydroxythieno-
[2,3-b]quinoxaline 10 which was re acted with ethyl chloro-
acetate in DMF at 100 °C for 3 hr in the pres ence of K2CO3 to
give ethyl-(2-cyano-thieno[2,3-b]quinoxalin-3-yloxy)ace-
tate 11. Upon treat ment with so dium ethoxide in refluxing
ethanol.11 un der went Thorpe-Ziegler cyclyization to fur nish
ethyl-(3-aminofuro[2¢,3¢:4,5]thieno[2,3-b]quinoxaline)-
2-carboxylate 12. Heating of 12 with formamide re sulted in
the for ma tion of the pyrimidofurothienoquinoxaline de riv a-
tive 13. Reaction of o-hydroxycyano com pound 10 with
chloroacetonitrile under the same con di tions af forded 3-
amino-2-cyanofuro[2¢,3¢:4,5]thieno[2,3-b]quinoxaline 14,
which was cyclized to 4-amino-pyrimidofurothieno quin o-
xaline 15 (Scheme II).
somenewquinoxalinederivativesinviewofthesignificant
biologicalactivitesofthecompoundshavingquinoxalinenu-
cleus.1,2 For ex am ple, the 1,2,3,4-tetrahydroquinoxaline ring
systemisanimportantstructuralunitinmanybioactivecom-
pounds:3 1,4-dihydro-6,7-dimethylquinoxaline-2,3-diones
as Flavin me tab o lites and AMBA an tag o nists,4 N-aryl-5-
aminomethylquinoxaline-2,3-diones as both NMDA/glycin
andAMDAreceptorantagonists,5 for anticancer ef forts, and
cytotoxics.6 1H-imidazo-[4,5-g]quinoxaline-4,9-dionesand
other some quin oxa line de riv a tives were used as antivirus
(Hepatits B),7 also, somequinoxalinederivativesareusedas
antibiotics,8 antiherpes,9,10 and antituberculotics.11 Some
quinoxaline derivatives with retinoic acid receptors and
agonisticactivityhavebeensimilarlyevaluated.12 In this re-
spectandalsoforcontinuationofourearlierworkforthesyn-
the sis of many fused heterocyclic sys tems con tain ing quin-
oxalinemoiety,13-17 we were con cerned with the use of ethyl-
3-mercapto-quinoxaline-2-carboxylate15 for the syn the sis of
many fused quin oxa line heterocycles of a new type and it
there fore was tested against bac te ria and fungi.
RESULTSANDDISCUSSION
The thiation of ethyl(quinoxalin-2(1H)-one)-3-carbox-
ylate 1usingP 2S5 in dry pyridine re sulted in the for ma tion of
thioxoderivative2; the lat ter com pound was re ported by an-
other method15 which was used as a po ten tial start ing ma te-
rial for the syn the sis of the tar get heterocycles. Thus, the re-
2-Acetyl-3-hydroxythieno[2,3-b]quinoxaline16 was
pro duced from the re ac tion of 2 with chloroacetone. This
*Correspondingauthor.E-mail:oshmous@aun.eun.eg

108 J. Chin. Chem. Soc., Vol. 49, No. 1, 2002
Moustafa and El-Ossaily
Scheme I
N
N
OH
Scheme I
COC6H4R
S
3a, R = H
b, R = Cl
BrCH COC H -R (P)
2
6 4
N
COOEt
N
N
N
COOEt
SH
N
COOEt
S
OH
P S
2
5
ClCH COOEt
2
Pyr.
N
H
COOEt
O
N
H
N
S
4
1
2
hyd.
NaOH
N
O
NH2
CN
N
N
OH
-CO
2
OH
Ph CH=C(CN)
N
2
N
S
COOH
N
6
S
N
5
S
Ph
7
O
N=CHCOOEt
CN
HC(OEt)
3
N
S
Ph
8
N
O
NHCOCH3
CN
Ac O
2
N
S
Ph
9
Scheme II
N
N
COOEt
N
OH
N
N
O
CN
NH2
ClCH CN
2
ClCH CN
2
2
SCH2 CN
CN
N
S
S
10
14
15
ClCH COOEt
2
HCONH
2
NH2
N
O
N
O
COOEt
OCH2 COOEt
CN
N
N
EtONa
NH2
O
S
N
N
S
S
N
N
11
12
HCONH
2
N
O
NH
N
S
N
13
proved also to be a ver sa tile synthon for the preperation of
other new thienoquinoxalines; thus, its con den sa tion with
hydroxylaminegavethecorrespondingoxime 17. An at tempt
to cyclize 17 to the isoxazolothienoquinoxaline 18 by heat ing
with ace tic an hy dride failed, and the biacetyl de riv a tive 19
wasisolatedinstead.Ringclosureof16 throughreactionwith
diethyloxalategaveethyl-(3-H-pyrano[2¢,3¢:4,5]thieno [2,3-
b]quinoxalin-4-one)-2-carboxylate 20 (Scheme III).
Screening for Antimicrobial Activities
Mostsynthesizedcompounds( 2, 3a, 6 , 8, 10, 11, 12, 14
and 20) were tested for their antimicrobial ac tiv i ties in vi tro
against three strains of bac te ria: Gram postive Bacillussubtillus,
Micrococcus luteusand Gram neg a tive Serrationrhodenil

SynthesisandAntimicrobialActivityofFusedThienoquinoxalines
J. Chin. Chem. Soc., Vol. 49, No. 1, 2002 109
Scheme III
N
N
N
N
ClC H CO C H
N
OH
2
3
O
OH
Ac O
2
NH OH
2
N
X
2
C=NOH
COCH
CH
3
3
S
S
N
S
16
CH
3
17
18
(COOEt)
N
2
N
O
O
COOEt
OCOCH
3
C=NOCOCH
3
N
S
S
N
CH
3
20
19
and three spe cies of fungi:Aspergillus fumigatus, Penicllum
chrysogen, and Fusarium equisetiusingthefilterpapertech-
nique18,19 by mea sur ing the zone of in hi bi tion in mm at 25mg
con cen tra tion. The screen ing re sults given in Ta ble 1 in di-
cated that among the tested com pounds, 3a, 6, 8, 10, 12, 14
and 20showed good growth in hi bi tion against Gram postive
bac te ria, but only two com pounds,6 and 14, showed good
growthinhibitionagainstGramnegativebacteria.However,
con cern ing the antifungal ac tiv i ties, only com pound 6 was
ac tive against all types of fungi that were used but com pound
11was ac tive against Fusarium equisetionly (Ta ble 1).
Elementalanalysisgaveacceptableresultsunlessotherwise
stated. Melting Points, Yields and Spec tro scopic data are
listed in Ta bles 2 and 3.
Ethyl(3-mercaptoquinoxaline)-2-carboxylate (2)
Compound 2waspreparedaccordingtotheliterature,15
m.p. 210 °C.
3-Hydroxy-2-benzoylthieno[2,3-b]quinoxaline (3a)
3-Hydroxy-2-p-chlorobenzoylthieno[2,3-b]quinoxaline
(3b)
Ethyl(3-hydroxythieno[2,3-b]quinoxaline)-2-carboxylate
(4)
EXPERIMENTAL
General Procedure
Melting points were determined on a Gallen-Kamp
meltingpointapparatusandareuncorrected.IRspectrawere
re corded on a Pye-Unicam SP3-100 spectrophotometer us ing
KBr wa fer tech nique.1H NMR spec tra were mea sured on a
Varian390-90MHzNMRspectrometerinasuitabledeutreated
solvent,usingTMSastheinternalstandard.Elementalanaly-
ses were per formed on a Perkin-Elmer 240 C microanalyzer.
A mix ture of 2 (0.01 mol), fused so dium ac e tate (0.02
mol), and halocompounds (0.01 mol) in abs. eth a nol (20 mL)
washeatedunderrefluxfor3hr.Thereactionmixturewasdi-
luted with (50 mL) H2O. The solid pre cip i tate was col lected
and recrystallized from the proper sol vent.
3a was ob tained by re ac tion of 2 with phenacyl bro-
mide.
Table 1. Antimicrobial Activities of the Select Compounds [zone of inhibiton in mm]
Antibacterial activity
Antifungal activity
Comp. No.
Bacillus
subtillus
Micrococcus Serration
Aspergillus
fumigatus
Penicllum
chrysogen
Fusarium
equiseti
luteus
rhodenil
2
3a
6
-
9
14
8
-
24
14
-
-
-
9
-
-
-
18
-
-
-
17
-
-
-
11
-
8
10
11
12
14
20
8
-
8
12
9
-
-
20
-
-
-
-
9
-
-
8
-
-
-
-
-
-
-
-
-
-
-
19
-
-

110 J. Chin. Chem. Soc., Vol. 49, No. 1, 2002
Table 2. Physical Data of Compounds 3-20
Moustafa and El-Ossaily
The solid which pre cip i tated while hot was fil tered off and
recrystallized from eth a nol as pale red crys tals.
Comp.
No.
M.P. °C
Yield%
Formula
Mol.Wt
3-Cyano-4-phenyl-(4H)-pyrano[2¢,3¢:4,5]thieno[2,3-b]-
quinoxaline-2-methaimidate (8)
3a
3b
4
300
285
75
71
75
65
70
77
70
80
90
80
72
75
90
77
73
85
C17H10N2O2S
306
C17H9N2O2SCl
340.5
C13H10N2O3S
274
C10H6N2OS
202
C20H12N4OS
356
C24H16N4O3S
440
C22H14N4O2S
398
C15H11N3O3S
313
C15H11N3O3S
313
C14H6N4O2S
294
C13H6N4OS
266
C14H7N5OS
293
A sus pen sion of7 (0.01 mol) in (15 mL) triethyl ortho-
formate was heated un der re flux for 3 hr; and al lowed to cool.
The pre cip i tated solid was fil tered off and crys tal lized from
ethanolasredcrystals.
198-200
223
6
7
288
3-Cyano-2-acetylamino-4-phenyl-(4H)-pyrano[2¢,3¢:4,5]-
thieno[2,3-b]quinoxaline (9)
8
256-57
>300
112
A so lu tion of7 (0.02 mol) in ace tic an hy dride (35 mL)
was refluxed for 3 hr; the re ac tion mix ture was cooled, then
di luted with wa ter (10 mL). The solid formed was fil tered off
andrecrystallizedfromethanolasyellowcrystals.
9
11
12
13
14
15
16
17
19
20
224
2-Cyano-3-hydroxythieno[2,3-b]quinoxaline (10)
A mix ture of2 (0.01 mol) and chloroacetonitrile (0.01
mol) so dium ac e tate (0.025 mol) in abs.eth a nol (40 mL) was
refluxed for 2 hr. The solid ob tained upon di lu tion with wa ter
was fil tered off and recrystallized from eth a nol as red crys-
tals.
>360
290
>360
245-46
280
C12H8N2O2 S
244
C12H9N3O2 S
259
C16H13N3O4S
343
Ethyl(2-cyano-thieno[2,3-b]quinoxalin-3-yloxy)acetate
(11)
A mix ture of 10 (0.01 mol) and ethyl chloroacetate
(0.01 mol) so dium ac e tate (0.02 mol) in abs.eth a nol (35 mL)
was refluxed for 2 hr; then poured onto cold wa ter. The solid
ob tained was fil tered off and recrystallized from eth a nol as
browncrystals.
240
236-37
C16H10N2O4S
326
Ethyl(3-aminofuro[2¢,3¢:4,5]thieno[2,3-b]quinoxaline)-2-
carboxylate (12)
3b wasobtainedbyreactionof2 withp-chlorophenacyl
bromide.
4 was ob tained by re ac tion of 2 with ethyl chloro-
acetate.
A sus pen sion of11 (0.015 mol) in so dium ethoxide so-
lution(1.0gsodiumin100mLabs.ethanol)washeatedunder
re flux for 30 min. The solid prod uct sep a rat ing on cool ing
was col lected and recrystallized from eth a nol as deep red
crystals.
3-Hydroxy-(2H)-thieno[2,3-b]quinoxaline(6)
A so lu tion of4 (0.01 mol) in (30 mL) ethanolic sod.hy-
drox ide 10% was heated un der re flux for 3 hr; and left to cool.
Thereactionmixturewasdilutedwith(40mL)H2O and acid-
i fied with di lute HCl. The solid ob tained was fil tered off and
recrystallized from ace tic acid as brown crys tals.
2,3-Dihydropyrimido[4²,5²:4¢,5¢]furo[2¢,3¢:4,5]thieno[2,3-
b]quinoxalin-4-one (13)
A so lu tion of 12 (0.5 g) in formamide (15 mL) was
heatedunderrefluxfor4hr.Theprecipitateseparatingafter
cool ing was col lected and recrystallized from ace tic acid.
2-Amino-3-cyano-4-phenyl-(4H)-pyrano[2¢,3¢:4,5]thieno-
[2,3-b]quinoxaline (7)
3-Amino-2-cyanofuro[2¢,3¢:4,5]thieno[2,3-b]quinoxaline
(14)
To a mix ture of 6 (0.01 mol) and benzylidene malono-
nitrile in (20 mL) eth a nol, a few drops of piperidine were
added. Thereactionmixturewasheatedunderrefluxfor3hr.
Thetitlecompoundwaspreparedbyreactionof10 with

SynthesisandAntimicrobialActivityofFusedThienoquinoxalines
J. Chin. Chem. Soc., Vol. 49, No. 1, 2002 111
Table 3. Spectral Data of Compounds 3-20
1
Comp.
IR (n cm-1) / H NMR d (ppm)
3a
3b
4
3450 (OH), 1710 (CO), 1610 (C=N); (DMSO-d6): d 7.3-7.8 (m, 9H, Ar-H), d 12.7 (s, 1H, OH).
3500 (OH), 1700 (CO), (DMSO-d6): d 7.3-7.8 (m, 9H, Ar-H, OH).
3530 (OH), 2900 (CH aliph.), 1720 (CO), 1620 (C=N); (CDCl3): d 1.1-1.4 (t, 3H, CH3), d 3.2-3.6 (q,
2H, CH2), d 7.3-8.0 (m, 4H, Ar-H). d 11.1 (s, 1H, OH).
6
7
8
3550-3320 (br. OH), (CDCl3): d 7.5-8.0 (m, 4H, Ar-H), d 9.1 (s, 1H, CH).
3450 (NH2), 2220 (CN), 1620 (C=N); (DMSO-d6): d 6.1 (s, 2H, NH2), d 7.5-8.3 (m, 9H, Ar-H).
2970 (CH aliph.), 2220 (CN), 1695 (CO), 1610 (C=N); (DMSO-d6): d 1.2-1.5 (t, 3H, CH3), d 3.2-3.6
(q, 2H, CH2), d 5.4 (s, 1H, CH pyran), d 7.5-7.8 (m, 9H, Ar-H), d 6.7 (s, 1H, N=CH).
3180 (NH), 2220 (CN), 1660 (C=O); (DMSO-d6): d 2.4 (s, 3H, CH3), d 5.7 (s, 1H, CH pyran), d 7.3-7.8
(m, 9H, Ar-H), 9.8 (s, 1H, NH).
9
11
12
2220 (CN), 1720 (C=O); (DMSO-d6): d 1.15-1.40 (t, 3H, CH3), d 3.2-3.5 (q, 2H, CH2), d 4.2 (s, 2H,
CH2), d 7.4-8.1 (m, 4H, Ar-H).
d
d
d
d
3300 (NH2), 1670 (CO); (CDCl3): 1.2-1.5 (t, 3H, CH3), 3.1-3.6 (q, 2H, CH2), 5.8 (s, 2H, NH2),
7.5-8.0 (m, 4H, Ar-H).
13
14
15
16
17
19
3220 (NH), 1680 (CO); (CF3COOD): d 7.5-8.2 (m, 4H, Ar-H), d 9.3 (s, H, CH).
d
d
3320 (NH2), 2220 (CN),1620 (C=N); (DMSO-d6): 6.1 (s, 2H, NH2), 7.6-8.1 (m, 4H, Ar-H).
3320 (NH2), 1615 (C=N); (CF3COOD): d 7.5-8.15 (m, 4H, Ar-H), d 9.5 (s, 1H, CH).
3550 (OH), 1700 (C=O), 1620 (C=N); (CDCl3): d 2.4 (s, 3H, CH3), d 7.2-7.8 (m, 5H, Ar-H and OH).
3580-3200 (br-OH), 1620 (C=N).
1760, 1700 (2C=O), 2990 (CH, aliph.); (CF3COOD): d 1.5 (s, 3H, CH3), d 2.5, 3.1 (2s, 6H, 2CH3), d
7.5-8.10 (m, 4H, Ar-H).
d
d
d
20
2950 (CH, aliph.), 1720, 1680 (2C=O); (CDCl3): 1.25-1.6 (t, 3H, CH3), 3.1-3.4 (q, 2H, CH2),
7.5-7.9 (m, 4H, Ar-H), d 9.2 (s, 1H, CH).
chloroacetonitrile (0.01 mol) in (20 mL) DMF, pot.car bon ate
(0.02 mol), the re ac tion mix ture was heated on a wa ter bath
for 2 hr, cooled, and di luted with wa ter (20 mL). The pre cip i-
tate was col lected and recrystallized from ace tic acid.
formed af ter cool ing was col lected and recrystallized from
ethanolascolourlesscrystals.
Synthesis of diacetyl derivative (19)
Asolutionof17(0.01mol)inaceticanhydride(25mL)
was refluxed for 3 hr; then cooled and poured onto ice/wa ter.
The pre cip i tate thus formed was col lected and recrystallized
fromethanolaspaleyellowcrystals.
4-Amino-(2H)-pyrimido[4¢,5¢:4,5]furo[2¢,3¢:4,5]thieno[2,3-
b]quinoxaline (15)
A so lu tion of 14 (0.5 g) in formamide (15 mL) was
heated un der re flux for 5 hr. The pre cip i tate sep a rat ing on
heat ing was col lected and recrystallized from eth a nol as yel-
lowishcrystals.
Ethyl(pyrano[2¢,3¢:4,5]thieno[2,3-b]quinoxalin-(3H)-4-one)-
2-carboxylate (20)
A mix ture of o-acetyl com pound16 (0.01 mol) and di-
ethyloxalate(0.01mol)inethanol(20mL)wasrefluxedfor3
hr; the solid prod uct sep a rated from the hot mix ture was fil-
tered off and recrystallized from eth a nol as goldish yel low
crystals.
2-Acetyl-3-hydroxythieno[2,3-b]quinoxaline (16)
The ti tle com pound was pre pared by re ac tion of2 with
chloroacetone (0.01 mol) in (20 mL) DMF, pot.car bon ate
(0.03 mol), the re ac tion mix ture was heated on a wa ter bath
for 2 hr; cooled, and di luted with wa ter (20 mL). The pre cip i-
tate was collected and recrystallized from acetic acid as
brownishcrystals.
Received July 18, 2001.
3-Acetyloxime-3-hydroxythieno[2,3-b]quinoxaline (17)
Amixtureof16 (0.005 mol), (0.005 mol) hyroxylamine
hyrochloride and (0.005 mol) sod.ac e tate trihydrate in (30
mL) eth a nol was heated un der re flux for 5 hr. The solid
Key Words
Synthesis; Antimicrobial; Furothienoquinoxalines;
Pyranothienoquinoxalines and
pyrimidopyranothienoquinoxalines.

112 J. Chin. Chem. Soc., Vol. 49, No. 1, 2002
Moustafa and El-Ossaily
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