Synthesis and microbiological activity of some newly synthesized derivatives of 2-Oxo-2H-chromen-2-one

Article abstract of DOI:10.1155/2011/402975

By the action of 2-amino-5-methylthio-1,3,4-thiadiazole, 3-amino-5- methylisoxazole, 2-amino-6-fluorobenzothiazole, 2-amino-5-chloropyridine, respectively, on 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride, the corresponding 9-methylthio-7,7-dioxo-7,7a-dihydro-5-oxo-7λ⁶, 10-dithia-8,11- diaza-cyclopenta[b] phenantren-6-one, 9-methyl-7,7-dioxo-7H-5,8- dioxa-7λ⁶- thia-7a,11-diaza-cyclopenta[b] phenantren-6-one, 9-fluoro-7,7-dioxo-7H-5- oxa-7λ⁶,12-dithia-7a,13-diaza- indeno[1,2-b] phenantren-6-one and 9-Chloro- 7,7-dioxo-7H-5-oxa- 7λ⁶-thia-7a,12-diaza-benzo[α]anthracen -6-one were formed and they have been isolated in satisfying yields. Based on the biological activity of chromene-2-ones and heterocyclic compounds condensed in position 3 and 4, we also studied microbiological activity of these new compounds (5-8), against Staphylococcus aureus ATCC 25923, Streptococcus pneumoniae, Aeromonas Salmonicida, Bacillus spp and some of them exhibited significant activity. Copyright E-Journal of Chemistry 2004-2011.

Full text of DOI:10.1155/2011/402975

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(4), 1522-1527
http://www.e-journals.net
Synthesis and Microbiological Activity of Some Newly
Synthesized Derivatives of 2-Oxo-2H-chromen-2-one
MAJLINDA DACI-AJVAZI§, SEVDIJE GOVORI§* and SHUHRETA OMERAGIQ
§University of Prishtina
Faculty of Natural and Mathematical Sciences
Department of Chemistry, 10000 Prishtina, Republic of Kosovo
Microbiological Laboratory of Regional Water Company
s_govori@yahoo.com
Received 28 September 2010; Accepted 27 November 2010
Abstract: By the action of 2-amino-5-methylthio-1,3,4-thiadiazole, 3-amino-5-
methylisoxazole, 2-amino-6-fluorobenzothiazole, 2-amino-5-chloropyridine,
respectively, on 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride, the
corresponding 9-methylthio-7,7-dioxo-7,7a-dihydro-5-oxo-7λ6,10-dithia-8,11-
diaza-cyclopenta[b] phenantren-6-one, 9-methyl-7,7-dioxo-7H-5,8-dioxa-7λ6-
thia-7a,11-diaza-cyclopenta[b] phenantren-6-one, 9-fluoro-7,7-dioxo-7H-5-
oxa-7λ6,12-dithia-7a,13-diaza-indeno[1,2-b] phenantren-6-one and 9-Chloro-
7,7-dioxo-7H-5-oxa-7λ6-thia-7a,12-diaza-benzo[α]anthracen
-6-one
were
formed and they have been isolated in satisfying yields. Based on the biological
activity of chromene-2-ones and heterocyclic compounds condensed in position
3 and 4, we also studied microbiological activity of these new compounds
(5-8), against Staphylococcus aureus ATCC 25923, Streptococcus
pneumoniae, Aeromonas Salmonicida, Bacillus spp and some of them
exhibited significant activity.
Keywords: 2-Oxo-2H-chromen-2-one, Heterocyclic amines, Synthesis, Microbiological activity
Introduction
4-Hydroxy-2H-chromen-2-one has evoked a great deal of interest due to their biological
properties and characteristic conjugated molecular architecture. In continuation of our work1,2 on
the chemistry of 3,4-disubstituted-2-oxo-2H-chromene and the derived coumarins annelated
in the 3,4-position, we decided to prepare some new 2-oxo-2H-chromene derivatives with a
variety of nucleophiles, where we produced a number of novel cyclised coumarins. Hard
and borderline nucleophiles exclusively substituted chlorine in position 4, while soft
nucleophiles substituted the group in position 3. Chromene-2-one derivatives have been
reported for anticoagulant3-5, antibacterial6-7, antiinflamatory8, antimicrobial9, antiHIV10-13
,

1523
S. GOVORI et al.
antioxidant14, anticancer15 and antiproliferative and antiviral16 activities. It was found that
when one biodynamic heterocyclic system was coupled with another heterocyclic system,
enhanced biological activity was produced.
These newly synthesized polycyclic compounds (5-8), have similar structure with lots
of chromene-2-one compounds that are well known for their physiological activity17-19
.
From all chromene-2-ones, 4-hydroxychromene-2-one differs for its chemical reactivity, as
it contains the enolysed β-ketoesteryc system. The molecule of 4-hydroxychromene-2-one
contains two cycles: the benzene and the α-pyrone one-which has the –OH group attached in
the -4 position. This α-pyrone nucleus, reacts faster than benzene one, with either
electrophylic or nucleophylic reagents.
Therefore, 4-hydroxychromene-2-one, enable possibilities for synthesis of new
condensed and cyclisized derivatives, enabling transition from bicyclic to heteropolycyclic
compounds.
Experimental
Melting points of synthesized compounds (5-8) were determined with a Buechi apparatus
and are uncorrected. IR spectra (KBr in cm-1) were recorded on Perkin Elmer Spectrum BX
FTIR spectrophotometer, 1H NMR were recorded on Bruker Avance DPX 300
spectrophotometer at 300 MHz for 1H, using DMSO-d6 and CDCl3 as solvent, with TMS as
the internal standard (chemical shifts in δ ppm). The purity of the compounds was monitored
by TLC using precoated HF 254 (60) silica gel plates.
General methods of synthesis
4-Hydroxychromene-2-one (1, 16 g) was added in one portion to monochlorosulfonic acid
(40 mL). Mixture was refluxed in water bath in 70 ºC for 2.5 hours, then 125 mL dry
benzene was added drop wise to the mixture and after short vigorous mixing (20 min),
solution was left for short period in a room temperature and very voluminous precipitate was
formed. Precipitate (2) was filtered on a glass funnel and washed first with dioxane (20 mL)
then with ethylacetate (20 mL) and then with ether (20 mL). After washing we obtained a
white powder (93% yield). Ammonium salt of 4-hydroxychromene-2-one-3-sulfonic acid
(2, 14 g) was dissolved in small quantity of water and with vigorous mixing KOH (4%, 100 mL)
was added. Rapidly formed white crystals (3, yield 86%) were filtered and washed off with
ethanol (95%). 8 g of 3 was added to POCl3 (60 mL) and refluxed in a hot oily bath for 4 h.
Hot mixture was filtered off in a vacuum filter, filtrate was evaporated and obtained yellow
crystal precipitate (4, yield 30%).
1 g, (0.0038 mol) of 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride (4) was dissolved
in 20 mL of dry benzene and an appropriate equivalent portion of heterocyclic amino
derivatives was added, in presence of triethylamine (2 mL), as catalyst and the mixture was
refluxed for 4-10 h. After cooling, the precipitate was filtered off, washed with hot benzene
and dried.
9-Methylthio-7,7-dioxo-7,7a-dihydro-5-oxo-7λ6,10-dithia-8,11-diaza-cyclopenta[b]
phenantren-6-one (5)
A mixture of 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride (1 g, 0.0036 mol), 20 mL of
dry benzene, 0.53 g, (0.0036 mol) of 2-amino-5-methylthio-1,3,4-thiadiazole and a portion
of thriethylamine were refluxed for 4 h. The solution was filtered, washed off with benzene
then crystallized from ethanol. The obtained product was white color.

Synthesis and Microbiological Activity
1524
Yield 35,62% M.P. 135 ˚C, IR (KBr) (υ cm-1): 3800-3153(OH,NH); 2920(C-H al);
1703(C=O, α-pir); 1621(C=N); 1562-1356(C=Car); 1207-1161(SO2); 751(C-Car); 648(C-S-C);
1H-NMR (DMSO-d6) (ppm): 14.1 s (1H, OH); 7.88-5.75 m (4Har); 4.2 s (1H, NH); 3.14-2.49 s
(3H, CH3) C13H11O5N3S3: C 40.51, H 2.87, N 10.90, Exp: C 39.50, H 2.90, N 10.40 M+teo:
385,43; M+exp: 385.43. M(
385 (7.2), 368 (21.5), 242 (88.7), 162 (93),
13 11
C H
3 3
5 ):
O N S
120 (100), 74 (46).
9-Metil-7,7-dioxo-7H-5,8-dioxo-7λ6-tia-7a,11-diaza-ciklopenta[b]phenantren-6-one (6)
A mixture of 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride (1 g, 0.0036 mol), 20 mL of
dry benzene, 0.34 g (0.0036 mol) of 3-amino-5-methyl-izoxazole and a portion of
thriethylamine were refluxed for 10 h. The solution was filtered, washed off with benzene
than crystallized from ethanol. The obtained product was yellowish color.
Yield 29.1% M.P. 242.3 ˚C, IR (KBr) (υ cm-1): 3030(C-Har); 2950(C-Hal); 1715(C=O, α-pir);
1609(C=N); 1551-1433(C=Car); 1270-1178(SO2); 762(C-Car); 1H-NMR (DMSO-d6) (ppm):
8.33-7.15 m (4H, ar); 1.7 s (3H, CH3). C13H8O5N2S: C 51.32, H 2.65, N 9.21, Exp: C 51.14,
H 2.88, N 9.05 M+teo: 304,28 M+exp: 305.0, M(
137 (72), 71 (90.2), 55 (80).
) :305 (67), 289 (8.2), 154 (100),
8
H O N S
5
2
13
C
9-Fluoro-7,7-dioxo-7H-5-oxa-7λ6,12-dithia-7a,13-diaza-indeno[1,2-b]phenantren-
6-one (7)
A mixture of 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride (1 g, 0.0036 mol), 20 mL of
dry benzene, 0.62 g (0.0036 mol) of 2-amino-6-fluorobenzothiazole and a portion of
thriethylamine were refluxed for 10 h. The solution was filtered, washed off with benzene
than crystallized from ethanol. The obtained product was white color.
Yield (31.34%), M.P. 254-256 ˚C, IR (KBr) (υ cm-1): 3070(C-Har); 1710(C=O, α-pir);
1608(C=N); 1570-1469(C=Car); 1269-1170(SO2); 759(C-Car); H-NMR (DMSO-d6) (ppm):
1
8.36-7.30 m (7H, arom). C16H7O4N2S2F: C 51.33, H 1.88, N 7.48, Exp: C 51.00, H 2.26, N
7.43 M+teo: 374.36, M+exp: 375.0, M(
) : 375 (23), 307 (25.4), 289 (12), 154 (100),
7 4 2 2
16
C H O N S F
137 (72), 71 (40), 55 (47).
9-Chloro-7,7-dioxo-7H-5-oxa-7λ6-thia-7a,12-diaza-benzo[α]anthracen-6-one (8)
A mixture of 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride (1 g, 0.0036 mol), 20 mL of
dry benzene, 0.46 g (0.0036 mol) of 2-amino-5-chloropyridine and a portion of
thriethylamine were refluxed for 10 h. The solution was filtered, washed off with benzene
than crystallized from ethanol. The obtained product was intensive yellow color.
Yield (28,0%), M.P. >270 ˚C, IR (KBr) (υ cm-1): 1715(C=O, α-pir); 1627(C=N);1547-
1447(C=Car); 1263-1122(SO2); 755(C-Car); 1H-RBM (DMSO-d6) (ppm): 8.17-7.06 m
(7H, arom). 13C-RBM (DMSO-d6) (40.33-41.24) 153.67 (C=N); 138.11 (Car); 116.72
(C-Cl);115.4 (C-SO2). C14H7O4N2SCl: C 50.23, H 2.108, N 8.37, Exp: C 49.95, H 2.24, N
8.15. M+teo: 334,72; M+exp: 335.0; M(
335 (82.9), 307 (23), 289 (11), 154
) :
C H O N SCl
14
7
4
2
(100), 137 (75.8), 71 (71), 55 (61).
Results and Discussion
4-Chloro-2-oxo-2H-chromene-3-sulfonyl chloride (4) was prepared by the series of
reactions of 4-hydroxy-chromene-2-one with ClSO3H, with NH3, then with 4% KOH
solution, and with POCl3. New compounds (5-8) were obtained in reaction of (4) with amino
derivatives of heterocyclic compounds in presence of triethylamine.

1525
S. GOVORI et al.
OH
OH
OH
SO3
O
K
SO3 NH4
O
a
b
O
O
O
O
(3)
(2)
(1)
c
Cl
SO2Cl
O
O
(4)
Figure 1. Synthesis of 4-chloro-2-oxo-2H-chromene-3-sulfonyl chloride (4) Reagents:
(a) ClSO3H, NH3 (b) 4% KOH, (c) POCl3, DMF
Y
Z
X
N
N
Cl
SO2
SO2Cl
O
Het-NH2
C6H6, Et3N
O
O
O
(4)
(5-8)
Y
Z
X
N
HN
SO2Cl
O
O
- H
Y
Y
Z
Y
Z
Z
X
X
X
N
N
O
N
N
O
N
N
O
SO2Cl
O
SO2Cl
O
SO2
O
-HCl
(5-8)
Figure 2. Reaction mechanism
CH3
SCH3
S
O
N
N
N
N
N
SO2
SO2
O
O
O
O
(5)
(6)

Synthesis and Microbiological Activity
1526
F
Cl
S
N
O
N
N
O
N
SO2
SO2
O
O
(7)
(8)
Figure 3. Structure of synthesized compounds (5-8)
Structure from obtained compounds (5-8) was determined from spectral analysis IR,
1H-NMR, mass spectroscopy and elementary analysis. In IR spectra of (5-8) analyzed compounds
we can see characteristic bands in region 1710-1727 cm-1 corresponding to C=O stretching,
1608-1627 cm-1 there is another band from C=N stretching, 1570-1433 cm-1 there is characteristic
-1
band for aromatic double bond C=C and SO2 vibration are visible in 1270-1122 cm .
In 1H-NMR spectra of gained compounds there are signals in expected positions, signals
as multiplets that come from aromatic protons, are in 8.36-7.06 ppm. Among the compounds
tested for anti bacterial activity, compound 7 showed highest zone of inhibition against
S.aureus in higher concentrations and in lower concentration, the inhibition zone was higher
against Aeromonas Salmonicida and Bacillus spp.
Biological activity
The antimicrobial activity of synthesized compounds (5-8) was determined by cup plate,
Kirby-Bauer method. Antimicrobial activity was carried out against 24 h old cultures of
Staphylococcus aureus beta lactamase positive ATCC 25923, collection of WRC (Water
Regional Company) from regional hospital, Staphylococcus aureus collection of WRC
outside the regional hospital, Streptococcus pneumoniae, Aeromonas salmonicida collection
of WRC, Bacillus spp, collection of WRC. The compounds were tested at three
concentrations, 0.1 mg/mL, 0.3 mg/mL and 0.5 mg/mL in dimethylformamide against all
organisms. Novobiocin was used as standard drug for antibacterial activity.
Table 1. Microbiological activity of newly synthesized compound
0.1
0.3
0.5
0.1
0.3
0.5
7
11
13
2
8
8
4
3
-
4
4
3
2
-
7
8
10
3
-
5
9
6
10
3
12
15
7
13
9
3
-
-
6
-
-
29
29
29
29
29
29
5
6
0.1
0.3
0.5
0.1
0.3
0.5
7
8
12
7
11
13
1
3
9
4
3
-
7
9
14
3
2
-
1
3
1
3
-
14
-
-
3
12
15
9
10
-
3
-
10
10
10
29
29
29
7
8
5
-

1527
S. GOVORI et al.
35
30
25
20
15
10
5
0
0.1
0.3
5
0.5
0.1
0.3
6
0.5
0.1
0.3
7
0.5
0.1
0.3
8
0.5
Staph.aureus ATCC
Staph.AureusHospital
Strept.Pneum.
BacillusSpp.
Staph.Aureus(outside of hospital)
Aeromonas.Salmon.Salmonicida
Novobiocine
Figure 4. Graphs of microbiological activity results for compounds 5-8
Conclusion
The present study was aimed at synthesis of some novel chromene-2-one derivatives. The
compounds were screened for anti bacterial activities and were found to posse’s
considerable activity.
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