Synthesis of some new 2-substituted-4-sulfamoylphenylazo-thiophene and/or thiazole derivatives as antibacterial agents

Article abstract of DOI:10.1080/10426507.2015.1100183

Benzoylacetone has been reacted with phenyl isothiocyanate to afford two different thiocarbamoyl derivatives (α-phenylthiocarbamoyl benzoylacetone and benzoyl thioacetanilide) depending upon the base used to perform the reaction. Several new 2-substituted

Full text of DOI:10.1080/10426507.2015.1100183

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis Of Some New 2-Substituted-4-
Sulfamoylphenylazo-Thiophene And/Or Thiazole
Derivatives As Antibacterial Agents
Ahmed A. Fadda, Afnan M. El-badrawy, Hala M. Refat & Ehab Abdel-Latif
To cite this article: Ahmed A. Fadda, Afnan M. El-badrawy, Hala M. Refat & Ehab Abdel-Latif
(2016): Synthesis Of Some New 2-Substituted-4-Sulfamoylphenylazo-Thiophene And/Or
Thiazole Derivatives As Antibacterial Agents, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2015.1100183
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1100183
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Jan 2016.
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SYNTHESIS OF SOME NEW 2-SUBSTITUTED-4-SULFAMOYLPHENYLAZO-
THIOPHENE AND/OR THIAZOLE DERIVATIVES AS ANTIBACTERIAL AGENTS
1
,*
1
2
1
Ahmed A. Fadda , Afnan M. El-badrawy , Hala M. Refat , and Ehab Abdel-Latif
1
Department of Chemistry, Faculty of Science, Mansoura University, ET-35516, Mansoura,
Egypt
2
Department of Chemistry, Faculty of Education, Suez Canal University, Al-Arish, Egypt
*
Address correspondence to Ahmed A. Fadda, Department of Chemistry, Faculty of Science,
Mansoura University, ET-35516, Mansoura, Egypt. E-mail: afadda50@yahoo.com
Abstract
Benzoylacetone has been reacted with phenyl isothiocyanate to afford two different
thiocarbamoyl derivatives (α-phenylthiocarbamoyl benzoylacetone and benzoyl thioacetanilide)
depending upon the base used to perform the reaction. Several new 2-substituted-4-
sulfamoylphenylazo-thiophene and/or thiazole derivatives were synthesized by heterocyclization
of the thiocarbamoyl derivatives with various halogenated reagents. The synthesized compounds
were screened for their antibacterial activities; they showed accepted activities with respect to
the control drugs.
1
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Keywords
Benzoylacetone; sulfanilamide; thiocarbamoyl; thiophene; thiazolodin-5-one; antibacterial
activities
2
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INTRODUCTION
Apart from commercialized applications as antibacterial/antibiotic agents, various
sulfonamides are known to inhibit several enzymes such as carbonic anhydrase, cysteine
protease, HIV protease and cyclooxygenase [1]. Moreover, the widespread potential value of
sulfonamides, have led to the discovery of various other therapeutic applications, in cancer
chemotherapy, diuretics, hypoglycemia and the anti-impotence agent Viagra [2].
In addition, five membered heterocyclic compounds containing sulfur are essentially
utilized in medicine for the treatment of different kinds of fungal and bacterial infections and
gastric ulcers and cancer [3]. Among the antimicrobial and antifungal agents, thiophene
containing heterocycles are known to have a promising activity [4]. Thiazole derivatives have
considerable interest from therapeutic point of view because of their utility as antibacterial and
antifungal [5,6], anti-inflammatory [7], anti-tubercular [8], potent central nervous system (CNS)
[
9], anti-HIV [10] and antimalarial agents [11]. A growing number of semi-synthetic penicillin
analogues and other antibiotics known to have the chemical structure of classic antimicrobial
drugs (such as sulfanilamides), as well as an increasingly pressing problem of bacterial resistance
urged us to investigate new sulfanilamide derivatives.
The aim of our work was to study the influence of sulfanilamides on the antibacterial
activity of thiophene and/or thiazole derivatives. Therefore, it is of therapeutic interest to design
and produce compounds containing sulfonamide and thiophene or thiazole pharmacophores in
one molecule.
RESULTS AND DISCUSSION
3
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The base-prompted reaction of benzoylacetone, which is an acidic methylene compound,
with phenyl isothiocyanate in dry DMF containing KOH at room temperature led to the
formation of the non-isolable intermediate 1 which gave α-phenylthiocarbamoyl benzoylacetone
(2) upon treatment with dilute HCl [12] (Scheme 1). On the other hand, heating of benzoyl
acetone with phenyl isothiocyanate in ethanolic sodium ethoxide solution (EtOH/NaOEt) affects
the acetyl cleavage with the formation of benzoyl thioacetanilide (3).
Diazotization of sulfanilamide by a reaction with nitrous acid (HCl/ NaNO ) at 0-5°C
2
yielded the corresponding diazonium chloride 4 which underwent a coupling reaction with α-
phenylthiocarbamoyl benzoylacetone (2) in ethanol containing sodium acetate affected one
group (acetyl or benzoyl) cleavage through the intermediate 5 to form the corresponding benzoyl
derivative 7. The formation of 2-benzoyl-2-[(4-sulfamoyl-phenyl)-hydrazono]-thioacetanilide (7)
through an acetyl cleavage finds support from the literature, Japp-Klingemann reaction type
[
13,14], and spectral data rather than the benzoyl cleavage which lead to the non-isolated product
(Scheme 2).
Heterocyclization of compound 7 with different α-bromoketone compounds such as
6
bromoacetone, phenacyl bromide and p-bromophenacyl bromide furnished the corresponding
thiophene derivatives 9a, 9b and 9c; the reaction proceeded in good yields by refluxing the
reactants in ethanol containing drops of triethylamine as a catalyst (Scheme 3). The formation of
thiophene derivatives 9 from the reaction of 7 with the appropriate alkylating agent (such as
bromoacetone, phenacyl bromide and p-bromophenacyl bromide) starts through nucleophilic
attack of the thiolate group to form the non-isolable S-alkylated intermediate 8 which via
nucleophilic addition and intramolecular cyclocondensation by water elimination [12] gave the
4
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corresponding
5-anilino-3-phenyl-2-substituted-4-[(4-sulfamoyl-phenyl)-azo]-thiophene
derivatives 9a-c.
In a similar manner, treatment of 2-benzoyl-2-[(4-sulfamoyl-phenyl)-hydrazono]-
thioacetanilide (7) with ethyl bromoacetate by reflux in ethanol containing drops of triethylamine
led to the formation of the corresponding thiophene derivative, 5-anilino-2-ethoxycarbonyl-3-
phenyl-4-[(4-sulfamoyl-phenyl)-azo]-thiophene (10) (Scheme 3). In addition, 5-anilino-2-cyano-
3
-phenyl-4-[(4-sulfamoyl-phenyl)-azo]-thiophene (11) was prepared by the reaction of
thioacetanilide derivative 7 with chloroacetonitrile by reflux in ethanol containing a catalytic
amount of triethylamine. The structure of thiophene compound 11 was verified by elemental
analysis and by spectroscopic methods.
Heterocyclization of compound 7 with chloroacetanilide to give the corresponding
thiophene 13 and/or thiazole 14 did not proceed under the conditions of hot ethanol catalyzed by
triethylamine. The reaction proceeded only in ethanolic sodium ethoxide solution under reflux to
afford the corresponding thiophene derivatives 13 through nucleophilic attack of the thiolate
group followed by ring closure and water elimination (Scheme 4). Based on its elemental
analysis and spectral data, the product was assigned as the thiophene structure 13 not the thiazole
structure 14. Thus, the IR spectrum showed three absorption bands at 3397, 3317, 3246 due to
-1
1
NH and NH) functions besides one carbonyl absorption band at 1647 cm . The H NMR
2
spectrum revealed multiplet signal in the region δ 7.14-7.82 corresponding to the protons of
phenyl and amino groups, in addition to two singlet signals at δ 11.16 and 13.62 due to the
protons of two NH groups. Stirring of 2-benzoyl-2-[(4-sulfamoyl-phenyl)-hydrazono]-
thioacetanilide (7) with chloroacetyl chloride in dioxane containing drops of triethylamine as a
5
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catalyst at room temperature afforded the corresponding arylazo-thiazole derivative 16 through
heterocyclization of the non-isolable intermediate 15. The product 16 that analyzed for
1
C H N O S was isolated in moderate yield. Its H NMR spectrum showed singlet signal at
23
18
4
4 2
4
.16 of the cyclic methylene protons and multiplet signal in the region 7.05-7.80 due to the
aromatic and amino protons.
Heterocyclization of the thiocarbamoyl derivatives 2 and/or 3 with chloroacetyl chloride
in dioxane containing drops of triethylamine furnished the corresponding thiazolidin-5-one
derivatives 17 and/or 18 respectively (Scheme 5). The reactivity of the methylene group of these
thiazolidin-5-one derivatives was tested towards the electrophilic coupling reaction. Thus, diazo-
coupling of 17 and/or 18 with diazotized sulfanilamide proceeds in ethanol containing sodium
acetate to afford the corresponding 4-arylazo-thiazolidin-5-one derivatives 19 and/or 20
respectively (Scheme 5). The chemical structures of the synthesized thiazolidin-5-one derivatives
1
7-20 were elucidated based on their elemental analyses and spectral data (experimental section).
Diazo-coupling reaction of the diazotized sulfanilamide 4 with phenacyl bromide
proceeds in pyridine at 0-5 °C to give the corresponding hydrazonoyl bromide compound 21
Scheme 6). Refluxing of 21 with thiosemicarbazone derivative in ethanol containing drops of
(
triethylamine as a basic catalyst afforded the corresponding 5-arylazothiazole derivative 22. The
chemical structures of compounds 21 and 22 were secured by correct elemental analyses and
spectral data.
Antibacterial Screening
The synthesized compounds 7-11, 13, 16-20 and 22 were screened for their antibacterial
activities at 100 g/mL concentration against two Gram positive bacteria (Bacillus subtilis
6
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ATCC6633; Staphylococcus aureus ATCC 29213), two Gram negative bacteria (Pseudomonas
aeruginosa ATCC 27953; Escherichia coli ATCC 25922). Ampicillin was used as standard
antibacterial reference. The results of antibacterial activities were shown in Table S 1
(
Supplemental Materials).
EXPERIMENTAL
All melting points (uncorrected) were determined on an electrothermal Gallenkamp
melting point apparatus. The IR spectra were recorded in KBr disks on a Thermo Scientific
Nicolet iS 50 FT-IR spectrometer (not all frequencies are reported). The NMR spectra were
acquired using a Bruker WP 300 spectrometer at 300 MHz using TMS as an internal standard and
DMSO-d or CF COOD as solvent. The mass spectra were performed using a Varian MAT 311
6
3
mass spectrometer at 70 eV. The progress of the reactions was monitored by TLC using
aluminum silica gel plates 60 F245. Elemental analyses were carried out at the Micro Analytical
Center, Cairo University, Giza, Egypt; the results were in satisfactory agreement with the
calculated values. Antimicrobial tests were carried out by the agar well diffusion method [15] at
the Micro Analytical Center, Cairo University, Giza, Egypt. The synthesized compounds were
individually tested against a panel of gram positive and gram negative bacterial pathogens. The
1
13
Supplemental Materials contains sample H and C NMR spectra for selected products (Figures
S 1 – S 14).
Synthesis of α-phenyl thiocarbamoyl-benzoylacetone (2):
To a cold suspension of potassium hydroxide (0.56 g, 0.01 mol) in DMF (20 mL),
benzoylacetone (1.62 g, 0.01 mol) and phenyl isothiocyanate (1.2 mL, 0.01 mol) were added.
The mixture was stirred overnight at room temperature and then poured onto ice-cold water (95-
7
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1
00 mL). Acidification using dilute HCl until the medium becomes acidic gave the solid product
which was filtered off, washed with water, dried and crystallized from ethanol.
2
-1
Yellow crystals, m.p. = 139-140°C, lit. m. p. = 140°C [12], yield = 91%. IR (ν / cm ): 3229
(
NH), 1665 (broad, C=O). Analysis for C H NO S (297.08): Calcd.: C, 68.66; H, 5.08; N,
17 15 2
4
.71%; Found: C, 68.58; H, 5.10; N, 4.76%.
Synthesis of benzoyl thioacetanilide (3):
A mixture of benzoylacetone (1.62 g, 0.01 mol) and phenyl isothiocyanate (1.2 mL, 0.01
mol) in NaOEt solution (prepared from 0.23 g Na metal and 20 mL absolute ethanol) was
refluxed for 2 h. The reaction mixture was allowed to cool at room temperature, and then poured
onto ice-cold water (75-80 mL). The solid precipitate, which formed upon neutralization with
dilute HCl, was filtered off, washed with water, dried and recrystallized from ethanol to give
benzoyl thioacetanilide (3).
-1

Yellow crystals, m.p. = 110-111°C, yield = 72%. IR ( /cm ): 3190 (NH), 1677 (C=O), 1278
1
(
C=S). H NMR (DMSO-d ): /ppm = 4.65 (s, 2H, CH ), 7.25-8.05 (m. 10H, Ar-H), 12.13 (s,
6
2
1
3
1
H, NH). C NMR (CDCl /CF COOD): /ppm = 37.40, 123.63 (2C), 126.33, 129.50 (2C),
3
3
1
29.66 (4C), 132.06, 133.18, 138.74, 173.78, 195.53. Analysis for C H NOS (255.07): Calcd.:
15 13
C, 70.56; H, 5.13; N, 5.49%; Found: C, 70.67; H, 5.08; N, 5.56%.
Synthesis of 2-benzoyl-2-[(4-sufamoyl-phenyl)-hydrazo]-thioacetanilide (7):
A well stirred solution of sulfanilamide (1.72 g, 0.01 mol) in concentrated HCl (3 mL)
was cooled in an ice bath and diazotized with a solution of sodium nitrite (0.7 g, 0.01 mol) in
water (10 mL). The freshly prepared cold diazonium solution was added dropwise to a well
stirred cold solution of 2 (2.97 g, 0.01 mol) in ethanol (25 mL) containing 3 g sodium acetate.
8
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The reaction mixture was stirred for 2 h at 0-5ºC. The crude product 7 was filtered off, dried well
and recrystallized from ethanol.
-1
Orange crystals, m.p. = 165-166°C, yield = 68%. IR (

/cm ): 3335, 3254 (NH ), 1631
2
1
(
(
(
conjugated C=O), 1592 (C=N), 1520 (N=N), 1269 (C=S). H NMR (DMSO-d ): /ppm = 7.18
6
1
3
s, 2H, NH ), 7.25-8.16 (m. 14H, Ar-H), 10.91 (s, 1H, =NNH), 12.34 (s, 1H, NH). C NMR
2
CF COOD): /ppm = 110.42, 121.54, 121.77 (2C), 128.68 (4C), 130.88 (4C), 131.39, 131.52,
3
1
32.50. 133.60, 143.13, 144.37, 152.84, 157.52, 159.78. MS (EI): m/z (%) = 438 (molecular ion
peak, 28), 105 (base peak, 100). Analysis for C H N O S (438.08): Calcd.: C, 57.52; H, 4.14;
2
1
18
4
3 2
N, 12.78%; Found: C, 57.64; H, 4.09; N, 12.71%.
Synthesis of 5-anilino-2-substituted-3-phenyl-4-[(4-sulfamoyl-phenyl)azo]-thiophene
derivatives 9-11:
General procedure: A mixture of thiocarbamoyl compound 7 (0.876 g, 0.002 mol) and
different α-halogenated compounds (namely; bromoacetone, phenacyl bromide, p-
bromophenacyl bromide, ethyl bromoacetate and chloroacetonitrile) (0.002 mol) was refluxed
for 4 h in absolute ethanol (20 ml) and catalytic amount of triethylamine (5 drops). The reaction
mixture was allowed to cool and the solid product that formed was filtered off, dried and
recrystallized from ethanol to give the corresponding thiophene derivatives 9a-c, 10 and/or 11,
respectively.
2
-Acetyl -5-anilino-3-phenyl-4-[(4-sulfamoyl-phenyl)azo]-thiophene (9a):
-1

2
Orange crystals, m.p. = 216-217°C, yield = 88%. IR ( /cm ): 3305, 3234 (NH and NH), 1641
1
(
C=O), 1541 (N=N). H NMR (DMSO-d ): /ppm = 1.89 (s, 3H, CH ), 7.31 (s, 2H, NH ), 7.48-
6
3
2
13
7
.80 (m, 14H, Ar-H), 13.97 (s, 1H, NH). C NMR (CDCl ): /ppm = 21.40, 119.93 (2C), 122.51
3
9
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(2C), 124.49 (2C), 128.31 (2C), 129.32 (2C), 129.50 (2C), 129.74 (2C), 130.24 (2C), 133.86,
1
7
38.83, 140.01, 141.11, 150.85, 152.89, 165.52. MS (EI): m/z (%) = 476 (molecular ion peak, 5),
7 (base peak, 100). Analysis for C H N O S (476.10): Calcd.: C, 60.49; H, 4.23; N, 11.76%;
2
4
20
4
3 2
Found: C, 60.67; H, 4.16; N, 11.84%.
-Anilino-2-benzoyl- 3-phenyl-4-[(4-sulfamoyl-phenyl)azo]-thiophene (9b):
5
-1
Red crystals, m.p. = 235-236°C, yield = 80%. IR (ν / cm ): 3446, 3297, 3230 (NH and NH),
2
1
1
596 (broad, conjugated C=O and C=C), 1544 (N=N). H NMR (DMSO-d ): /ppm = 7.13-7.83
6
(
m, 21H, Ar-H and NH ), 14.23 (s, 1H, NH). Analysis for C H N O S (538.11): Calcd.: C,
2 29 22 4 3 2
6
4.66; H, 4.12; N, 10.40%; Found: C, 64.84; H, 4.03; N, 10.51%.
-Anilino-2-(4-bromobenzoyl)-3-phenyl-4-[(4-sulfamoyl-phenyl)azo]-thiophene (9c):
5
-1

2
Red crystals, m.p. = 272-273°C, yield = 77%. IR ( /cm ): 3372, 3242 (NH and NH), 1608
(
(
(
conjugated C=O), 1590 (C=C), 1557 (N=N). MS (EI): m/z (%) = 616 (20.77), 618 (22.42)
molecular ion peaks), 183 (100), 185 (96.87) (base peaks). Analysis for C H BrN O S
2
9
21
4
3
2
616.02): Calcd.: C, 56.40; H, 3.43; N, 9.07%; Found: C, 56.18; H, 3.33; N, 9.18%.
5
-Anilino-2-ethoxycarbonyl-3-phenyl-4-[(4-sulfamoyl-phenyl)-azo]-thiophene (10):
-1

2
Orange crystals, 167-169°C, yield = 88%. IR ( /cm ): 3340, 3243, 3105 (NH and NH), 1669
1
(
C=O), 1595 (C=C), 1545 (N=N). H NMR (DMSO-d ): /ppm = 1.21 (t, 3H, CH ), 4.08 (q, 2H,
6
3
CH ), 7.22-7.78 (m, 16H, Ar-H and NH ), 14.13 (s, 1H, NH). MS (EI): m/z (%) = 506
2
2
(
molecular ion peak and base peak, 100). Analysis for C H N O S (506.11): Calcd.: C, 59.27;
25 22 4 4 2
H, 4.38; N, 11.06%; Found: C, 59.11; H, 4.44; N, 11.14%.
5
-Anilino-2-cyano-3-phenyl-4-[(4-sulfamoyl-phenyl)-azo]-thiophene (11):
-1

2
Reddish brown crystals, m.p. = 268-270°C, yield = 82%. IR ( /cm ): 3328, 3248 (NH and
1
0
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1
NH), 2202 (C≡N), 1594 (C=C), 1546 (N=N). H NMR (DMSO-d ): /ppm = 7.17-7.84 (m, 16H,
6
Ar-H and NH ), 13.96 (s, 1H, NH). MS (EI): m/z (%) = 459 (molecular ion peak, 69.05), 77
2
(
base peak, 100). Analysis for C H N O S (459.08): Calcd.: C, 60.11; H, 3.73; N, 15.24%;
23 17 5 2 2
Found: C, 60.22; H, 3.70; N, 15.29%.
Synthesis of 5-anilino-3-phenyl-2-phenylcarbamoyl-4-[(4-sulfamoyl-phenyl)-azo]-thiophene
13):
(
A mixture of thiocarbamoyl compound 7 (0.88 g, 0.002 mol) and chloroacetanilide (0.34
g, 0.002 mol) in 0.003 mol NaOEt solution (prepared from 0.07 g Na metal and 15 mL absolute
ethanol) was refluxed for 2 h. The reaction mixture was allowed to cool at room temperature,
poured onto ice-cold water (45-50 mL) and neutralized by dilute HCl. The solid product that
formed was filtered off, washed with water, dried and recrystallized from ethanol to give the
thiophene compound 13.
-1

2
Orange crystals, m.p. = 135-136°C, yield = 68%. IR ( /cm ): 3397, 3317, 3246 (NH and NH),
1
1
647 (C=O), 1596 (C=C), 1523 (N=N). H NMR (DMSO-d ): /ppm = 7.14-7.82 (m, 21H, Ar-H
6
and NH ), 11.16 (s, 1H, NH), 13.62 (s, 1H, NH). MS (EI): m/z (%) = 553 (molecular ion peak,
2
4
1
1.47), 77 (base peak, 100). Analysis for C H N O S (553.12): Calcd.: C, 62.91; H, 4.19; N,
29 23 5 3 2
2.65%; Found: C, 62.75; H, 4.27; N, 12.54%.
Synthesis of 2-[benzoyl-(4-sulfamoyl-phenylazo)methylene]-3-phenyl-1,3-thiazolidin-5-one
16):
(
To a solution of 7 (2.19 g, 0.005 mol) in dioxane (20 mL) containing drops of
triethylamine, chloroacetyl chloride (0.8 mL, 0.01 mol) was added dropwise with stirring at 0-
°C. After complete addition, the reaction mixture was stirred for 2 h and then poured into ice-
5
1
1
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cooled water (45-50 mL). The solid product that formed was collected by filtration and
recrystallized from ethanol.
-1

2
Red crystals, m.p. = 175-177 °C, yield = 66%. IR ( /cm ): 3377, 3261 (NH ), 1711 (C=O,
1
ring), 1663 (C=O), 1594 (C=C), 1510 (N=N). H NMR (CDCl ): /ppm = 4.16 (s, 2H, CH ),
3
2
1
3
7
1
1
.05-7.80 (m, 16H, Ar-H and NH2). C NMR (CDCl /CF COOD): /ppm = 33.73, 95.59,
3
3
22.28 (2C), 123.02 (2C), 128.60 (2C), 129.55, 129.73 (2C), 130.66 (2C), 130.73 (2C), 132.28,
32.38, 135.55, 136.56, 149.00, 149.45, 159.60, 168.74. Analysis for C H N O S (478.08):
2
3
18
4
4 2
Calcd.: C, 57.73; H, 3.79; N, 11.71%; Found: C, 57.91; H, 3.87; N, 11.59%.
Synthesis of 3-phenyl-2-substituted-thiazolidin-5-ones 17 and 18:
To a solution of thiocarbamoyl derivatives 2 and/or 3 (0.005 mol) in dioxane (20 mL)
containing drops of triethylamine, chloroacetyl chloride (0.8 mL, 0.01 mol) was added dropwise
with stirring at 0-5°C. After complete addition, the reaction mixture was stirred for 2 h and then
poured onto ice-cooled water (75-80 mL). The solid product that formed was collected by
filtration and recrystallized from ethanol to give 17 and/or 18.
2
-(1,3-Dioxo-1-phenylbutan-2-ylidene)-3-phenylthiazolidin-5-one (17):
-1

Yellow crystals, m.p. = 152-153°C, yield = 72%. IR ( /cm ): 1729 (C=O, broad), 1638 (C=O),
1
1
1
6
2
593 (C=C). H NMR (DMSO-d ): /ppm = 2.00 (s, 3H, CH ), 4.00 (s, 2H, CH ), 6.95-7.55 (m,
6
3
2
0H, Ar-H). Analysis for C H NO S (337.08): Calcd.: C, 67.64; H, 4.48; N, 4.15%; Found: C,
19
15
3
7.72; H, 4.50; N, 4.10%.
-[Benzoyl-methylene]-3-phenyl-thiazolidin-5-one (18):
-1

Yellow crystals, m.p. = 224-225°C, yield = 58%. IR ( /cm ): 1758 (C=O, ring), 1674 (C=O,
1
benzoyl), 1591 (C=C). H NMR (DMSO-d ): /ppm = 4.31 (s, 2H, CH ), 7.29-7.60 (m, 11H, Ar-
6
2
1
2
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H and olefinic CH=C). Analysis for C H NO S (295.07): Calcd.: C, 69.13; H, 4.44; N, 4.74%;
1
7
13
2
Found: C, 69.02; H, 4.50; N, 4.81%.
Synthesis of 2-[benzoyl-methylene]-3-phenyl-4-(4-sulfamoyl-phenylazo)-1,3-thiazolidin-5-
one 19 and 20:
A well-stirred solution of sulfanilamide (0.86 g, 0.005 mol) in concentrated HCl (1.5 mL)
was cooled in an ice bath and diazotized with a solution of sodium nitrite (0.35 g, 0.005 mol) in
water (10 mL). The freshly prepared cold diazonium solution was added dropwise to a well
stirred cold solution (0-5°C) of the thiazolidin-5-one derivatives 17 and/or 18 (0.005 mol) in
pyridine (20 mL). The reaction mixture was stirred for 2 h at 0-5°C. The crude products 19
and/or 20 were filtered off, dried well and recrystallized from ethanol.
2
-(1,3-Dioxo-1-phenylbutan-2-ylidene)-3-phenyl-4-(4-sulfamoyl-phenyl-hydrazono)-
thiazolidin-5-one (19):
-1

2
Yellow crystals, m.p. = 234-235°C, yield = 58%. IR ( /cm ): 3442, 3335 (NH and NH), 1731
1
(
C=O, ring), 1639 (C=O). H NMR (DMSO-d ): /ppm = 1.80 (s, 3H, CH ), 6.75 (s, 2H, NH ),
6
3
2
1
3
6
1
1
.95-7.60 (m, 14H, Ar-H), 11.15 (s, 1H, NH). C NMR (CDCl /DMSO): /ppm = 26.57,
3
09.53, 124.31 (2C), 127.12 (2C), 128.31, 130.32 (2C), 132.33, 134.26 (2C), 134.43 (2C),
34.91 (2C), 140.33, 144.43, 145.43, 145.77, 153.16, 156.06, 159.94, 168.42, 169.87. Analysis
for C H N O S (520.09): Calcd.: C, 57.68; H, 3.87; N, 10.76%; Found: C, 57.77; H, 3.90; N,
2
5
20
4
5 2
1
0.71%.
-[Benzoyl-methylene]-3-phenyl-4-(4-sulfamoyl-phenylhydrazono)-thiazolidin-5-one (20):
2
-1

2
Yellow crystals, m.p. = 256-258°C, yield = 64%. IR ( /cm ): 3420, 3342 (NH and NH), 1713
1
(
C=O, ring), 1628 (C=O, conjugated). H NMR (DMSO-d ): /ppm = 6.85 (s, 2H, NH ), 7.25-
6
2
1
3
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.80 (m, 15H, Ar-H and olefinic CH=C), 11.35 (s, 1H, NH). MS (EI): m/z (%) = 478 (molecular
ion peak, 20.0), 77 (base peak, 100). Analysis for C H N O S (478.08): Calcd.: C, 57.73; H,
23
18
4
4 2
3
.79; N, 11.71%; Found: C, 57.58; H, 3.71; N, 11.64%.
Synthesis of (4-sulfamoyl-phenylhydrazono) phenacyl bromide (21):
A well-stirred solution of sulfanilamide (0.86 g, 0.005 mol) in concentrated HCl (1.5 mL)
was cooled in an ice bath and diazotized with a solution of sodium nitrite (0.35 g, 0.005 mol) in
water (10 mL). The freshly prepared cold diazonium solution was added dropwise to a well
stirred cold solution (0-5°C) of phenacyl bromide (1.0 g, 0.005 mol) in pyridine (20 mL). The
reaction mixture was stirred for 2 h at 0-5°C. The solid product was filtered off, dried well and
recrystallized from ethanol to give orange crystals of 21.
-1

2
Orange crystals, m.p. = 190-191°C, yield = 78%. IR ( /cm ): 3307, 3236 (NH and NH), 1674
1
(
C=O). H NMR (DMSO-d ): /ppm = 7.10 (s, 2H, NH ), 7.40-7.80 (m, 9H, Ar-H), 12.25 (s, 1H,
6
2
NH). Analysis for C H BrN O S (380.98): Calcd.: C, 43.99; H, 3.16; N, 10.99%; Found: C,
1
4
12
3
3
4
3.82; H, 3.23; N, 11.12%.
Synthesis
of
2-(benzylidenehydrazino)-4-phenyl-5-(4-sulfamoyl-phenylazo)-thiazole
derivatives 22:
A mixture of hydrazonoyl bromide 21 (0.76 g, 002 mol) and the appropriate
thiosemicarbazone derivative (0.002 mol) in absolute ethanol (20 mL) and triethylamine (0.2
mL) was refluxed for 2 h. The precipitate formed on cooling was filtered off, dried, and finally
recrystallized from EtOH/DMF mixture (2:1) to afford the corresponding thiazole 22.
2
-(Benzylidenehydrazino)-4-phenyl-5-(4-sulfamoyl-phenylazo)-thiazole (22a):
-1

2
Reddish brown crystals, m.p. = 241-242°C, yield = 72%. IR ( /cm ): 3323, 3224 (NH and
1
4
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NH), 1658 (C=N), 1554 (N=N). H NMR (DMSO-d ): /ppm = 7.20 (s, 2H, NH ), 7.35-7.80 (m,
6
2
1
3
1
1
1
5
2
4H, Ar-H), 8.10 (s, 1H, CH=N), 11.65 (s, 1H, NH). C NMR (CDCl /CF COOD): /ppm =
3
3
23.76 (2C), 126.39, 128.67 (2C), 129.45 (2C), 129.53 (3C), 129.57 (4C), 131.87, 133.09,
35.08, 139.79, 142.34, 151.47, 163.14, 166.53. Analysis for C H N O S (462.55): Calcd.: C,
2
2
18
6
2 2
7.13; H, 3.92; N, 18.17%; Found: C, 57.27; H, 3.85; N, 18.25%.
-(4-Methylbenzylidenehydrazino)-4-phenyl-5-(4-sulfamoyl-phenylazo)-thiazole (22b):
-1

2
Brown crystals, m.p. = 255-256°C, yield = 82%. IR ( /cm ): 3315, 3214 (NH and NH), 1655
1
(
C=N), 1548 (N=N). H NMR (DMSO-d ): /ppm = 2.40 (s, 3H, CH ), 7.15 (s, 2H, NH ), 7.30-
6
3
2
7
.80 (m, 13H, Ar-H), 8.15 (s, 1H, CH=N), 11.55 (s, 1H, NH). MS (EI): m/z (%) = 281
(
molecular ion peak – C H , – 4-MeC H CH=N, 100). Analysis for C H N O S (476.11):
6 5 6 4 23 20 6 2 2
Calcd.: C, 57.97; H, 4.23; N, 17.63%; Found: C, 57.85; H, 4.27; N, 17.71%.
1
5
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REFERENCES
1
2
4
3
. Supuran, C. T.; Casini, A.; Scozzafava, A. Med. Res. Rev. 2003, 23, 535-558.
. Supuran, C. T.; Innocenti, A.; Mastrolorenzo, A.; Scozzafava, A. Mini-Rev. Med. Chem. 2004,
, 189-200.
. Altıntop, M. D; Ozdemir, A.; Turan-Zitouni, G.; Ilgın, S.; Atlı, O.; Demirel, R.; Kaplancıklı,
Z. A. Eur. J. Med. Chem. 2015, 92, 342-352.
4
2
5
. Kumar, P. S.; Junapudi, S.; Gurrala, S.;.Bathini, R. Int. J. Pharm. Pharm. Sci. 2011, 3, 273-
77.
. Pattan, S. R.; Dighe, N. S.; Nirmal, S. A.; Merekar, A. N.; Laware, R. B.; Shinde, H. V.;
Musmade, D. S. Asian J. Res. Chem. 2009, 2, 196-201.
6
7
. Argyropoulou, I.; Geronikaki, A.; Vicini, P.; Zanib, F. Arkivoc 2009, VI, 89-102.
. Sharma, R. N.; Xavier, F. P.; Vasu, K. K.; Chaturvedi, S. C.; Pancholi, S. S. J. Enzyme Inhib.
Med. Chem. 2009, 24, 890-897.
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9
1
1
1
2
1
1
4
. Bairwa V. K.; Telvekar, V. N. Comb. Chem. High. Throughput Screen. 2013, 16, 244-247.
. Mishra, C. B; Kumari, S.; Tiwari, M. Eur. J. Med. Chem. 2015, 92, 1-34.
0. Bhattacharya, P.; Leonard, J. T.; Roy, K.; Bioorg. Med. Chem. 2005, 13, 1159-1165.
1. Karade, H. N.; Acharya, B. N.; Sathe, M.; Kaushik, M. P. Med. Chem. Res. 2008, 17, 19-29.
2. Fadda, A. A.; Abdel-Latif, E.; El-Mekawy, R. E. Phosphorus Sulfur Silicon Relat. Elem.
008, 183, 1940–1953.
3. Japp, F. R.; Klingemann, F. Ann. Chem. 1888, 247, 190-225.
4. Abdellah, S. O.; Metwally, N. H.; Anwar, H. F.; Elnagdi, M. H. J. Heterocycl. Chem. 2005,
2, 781-786.
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1
5. Scott, A. C. Laboratory Control of Antimicrobial Therapy, in: 13 ed., in: Collee, J. G.;
Duguid, J. P.; Fraser, A. G.; Marmion, B. P. (Eds.), Mackie and Mac-Cartney Practical Medical
Microbiology, 2 Churchill, Livingstone, 1989, pp. 161-181.
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S
cheme 1:
1
8
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O
O
S
H
H N S
N N
O
2
CH3
O
H N S
NH2
2
O
PhHN
6
HCl/NaNO2
N N Cl
O
O
S
O
COCH3
N N C COPh
H C
Ph
+
3
EtOH
NaOAc
H N S
2
O
PhHN
PhHN
S
SO NH
2
2
2
5
4
O
O
O
O
H
H N S
N N
H N S
N N
2
2
Ph
SH
Ph
O
O
PhHN
PhHN
S
7B
7A
Scheme 2:
1
9
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Scheme 3:
2
0
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Scheme 4:
2
1
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O
O
S
COPh
R
R
Dioxane / TEA
Ph
+
ClCOCH Cl
2
N
PhHN
SH
Ph
2
: R = COCH3
17: R = COCH3
8: R = H
3: R = H
1
N=N Cl
O
S
COPh
R
SO NH2
2
O
4
H
N
H N S
N N
2
Ph
O
1
9: R = COCH3
0: R = H
2
Scheme 5:
2
2
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Scheme 6:
2
3
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