Synthesis of some novel sulfonamide derivatives

Article abstract of DOI:10.1080/10426500701242954

Sulfapyridine (1) was selected as the starting material for the synthesis of some novel thiazolidine, thiosemicarbazide, and quinazoline derivatives. The structures of synthesized compounds were elucidated by elemental analyses and spectral data. Copyrigh

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Phosphorus, Sulfur, and Silicon
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Synthesis of Some Novel
Sulfonamide Derivatives
M. M. Aly a
a Chemistry Department , Faculty of Science, Al-
Azhar University , Nasr City, Cairo, Egypt
Published online: 07 Jun 2007.
To cite this article: M. M. Aly (2007) Synthesis of Some Novel Sulfonamide
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:7,
1497-1506, DOI: 10.1080/10426500701242954
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Phosphorus, Sulfur, and Silicon, 182:1497–1506, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701242954
Synthesis of Some Novel Sulfonamide Derivatives
M. M. Aly
Chemistry Department, Faculty of Science, Al-Azhar University,
Nasr City, Cairo, Egypt
Sulfapyridine (1) was selected as the starting material for the synthesis of some
novel thiazolidine, thiosemicarbazide, and quinazoline derivatives. The structures
of synthesized compounds were elucidated by elemental analyses and spectral
data.
Keywords Quinazoline and sulfonamide derivatives; thiazolidine
INTRODUCTION
Substituted thiazolidines have been demonstrated to possess
antibacterial,1 antifungal,2 anticonvulsant,3 anticancer,4 and
antituberculosis5 activities. Also, thiazolidines have been reported
as novel inhibitors of the bacterial enzyme Mur B, which was the
precursor acting during the biosynthesis of peptidoglycan.6 Fur-
thermore, antibacterial,7 antifungal,8 insulin releasing,9 carbonic
anhydrase inhibitory,10 antiinflammatory,11 and antitumor12 prop-
erties of sulfamoyl moiety were described. As a continuation of our
research program13−15 on the synthesis of heterocyclic compounds,
in this article we report the synthesis of some novel thiazolidine and
quinazoline derivatives containing sulfamoyl moiety from the readily
available sulfapyridine (1).
RESULTS AND DISCUSSION
The non-isolable intermediate 2 was prepared by treatment of sul-
fapyridine (1) with carbon disulfide in dimethylformamide in the
presence of potassium hydroxide at room temperature (Scheme 1).
The non-isolable intermediate 2 was selected as starting material
Received September 11, 2006; accepted December 11, 2006.
Address correspondence to M. M. Aly, Chemistry Department, Faculty of Science, Al-
Azhar University, P.O. Box 11884, Nasr City, Cairo, Egypt. E-mail: m m.aly@hotmail.com
1497

1498
M. M. Aly
SCHEME 1
for the synthesis of some novel thiazolidine and quinazoline deriva-
tives. Thus, the reaction of the non-isolable intermediate 2 with some
halo compounds was investigated. The cycloconden-sation of the non-
isolable intermediate 2 with ethyl chloroacetate at room temperature

Novel Sulfonamide Derivatives
1499
afforded 4-thiazolidinone derivative 3 (Scheme 1). The structure of 4-
thiazolidinone 3 was confirmed by elemental and spectral data. Its in-
frared spectrum showed characteristic absorption bands for NH, CH-
arom., C O, C N, and SO2 functional groups. Also, its 1HNMR (DMSO-
d6) displayed a signal at δ = 4.20 ppm assigned to CH2 in addition to
NH and aromatic protons. The formation of 3 is assumed to proceed via
the initial alkylation by loss of sodium chloride followed by intramolec-
ular cyclization through ethanol elimination. Treatment of the non-
isolated intermediate 2 with α-bromobutyrate furnished thiazolidine
derivatives 5 and structure 6 was ruled out on the basis of analytical
and spectral data. The infrared spectrum of 5 exhibited absorption band
at 3210 cm−1 due to NH group and 1634 cm−1 due to the C N group.
1
The HNMR of (5; DMSO-d6) revealed two ethyl groups in addition to
NH and aromatic protons. The formation of 5 is assumed to proceed
via the initial formation of intermediate 4 followed by elimination of
water (Scheme 1). The non-isolable intermediate 2 was reacted with
phenacyl bromide to yield the thiazolidine derivative 7 on the basis of
analytical and spectral data. Its infrared spectrum showed absorption
band at 3200 cm−1 due to NH and no absorption band between 1600–
1680 cm−1 due to the absence of C O group. The 1HNMR spectrum of
(7; DMSO-d6) displayed the absence of methylene moiety, in addition
to the presence of thiazolidine-H, NH, and aromatic protons. The reac-
tion involves an initial alkylation by loss of sodium chloride followed
by dehydration. Cyclization of the non-isolable intermediate 2 with the
appropriate chloroacetonitrile produced 4-aminothiazolidine derivative
8. The structure of thiazolidine 8 was elucidated by elemental analysis
and spectral data. Its infrared spectrum showed absorption bands at
3450, 3410 cm−1 due to NH2 group, and no absorption band was ob-
served in the spectrum characteristic for C≡N group. The formation of
8 is assumed to proceed via initial alkylation followed by nucleophilic
addition of secondary amino group to the cyano group and tautomer-
ization (Scheme 1).
Alkylation of the non-isolable intermediate 2 with dimethyl sulfate
afforded [4-(pyridin-2-ylsulfamoyl)-phenyl]-dithiocarbamic acid methyl
ester (9) (Scheme 2). The structure of 9 was established on the basis of
1
its elemental analysis and spectral data. The HNMR spectrum of (9;
DMSO-d6) revealed a singlet at δ = 2.94 ppm assigned to SCH3 in addi-
tion to NH and aromatic protons. Reaction of compound 9 with methyl
anthranilate in ethanol in the presence of triethylamine under reflux
gave quinazoline derivative 11. The structure of 11 was confirmed on
the basis of elemental analysis, spectral data and alternative synthesis.
Its infrared spectrum showed absorption band at 3222 cm−1 due to NH
group in addition to the presence of C O (quinazolinone) at 1662 cm−1
.

1500
M. M. Aly
SCHEME 2
1
Also, its H NMR spectrum (DMSO-d6) revealed the absence of SCH3
in addition to the presence of NH and aromatic protons. The formation
of 11 is assumed to proceed via the initial formation of the intermediate
10 by loss of methyl mercaptan followed by intramolecular cyclization
through methanol elimination. Also, quinazoline derivative 11 was ob-
tained via another synthetic route by cyclization of anthranilate with
isothiocyanate derivative 1216 in dioxane under reflux in the presence of
triethylamine. The novel thiosemicarbazide derivative 13 was achieved
by treatment of compound 9 with hydrazine hydrate in ethanol at room
temperature. Mass spectrum of 13 revealed a molecular ion peak at
m/z = 323 (4.5%), and the base peak was found in the spectrum at m/z
= 55.
The reaction of sulfapyridine (1) with chloroacetyl chloride in acetone
containing 10% caustic soda at room temperature afforded the start-
ing material N4-chloroacetylsulfanilamide derivative 1417 (Scheme 2).
Refluxing of compound 14 with potassium thiocyanate in dimethyl-
formamide furnished the novel 4-thiazolidinone derivative 16 in high

Novel Sulfonamide Derivatives
1501
yield. The structure of 16 was established on the basis of analytical
and spectral data. Its infrared spectrum revealed the absence of thio-
cyanate functional group in addition to the presence of NH and C O
functional groups. Also, mass spectrum showed a molecular ion peak
at m/z = 283 [M-64 (SO2); 100%], which is the base peak in the spec-
trum. The formation of 16 is assumed to proceed via the formation of
intermediate 15 followed by intramolecular cyclization of amino group
to the thiocyanate group (Scheme 2). The reactivity of 4-thiazolidinone
16 towards some electrophilic reagents was studied. Condensation of
compo-und 16 with benzylidene-malononitriles (1:1 molar ratio) in
ethanol in the presence of piperidine under reflux yielded the novel
4-thiazolidinone derivatives 17a,b. The structures of compounds 17a,b
were confirmed on the basis of their elemental analysis, spectral data
and alternative synthesis. Infrared spectra of compounds 17a,b showed
the absence of absorption band for the cyano group. Mass spectrum
of compound 17a displayed a molecular ion peak at m/z 410 [M-59
(HSCN); 2.71%], and the base peak was observed in the spectrum at
m/z 405. The formation of 17 is assumed to proceed via Michael addi-
tion of the active methylene functional group to the activated ethylenic
bond followed by the elimination of malononitrile18 to yield 17. Also,
4-thiazolidinone derivatives 17a,b were achieved by treatment of thia-
zolidine 16 with aromatic aldehyde in refluxing ethanol in the presence
of piperidine. In a similar manner, condensation of 16 with tetracya-
noethylene under reflux in ethanol in the presence of triethylamine
afforded the corresponding cyanomethylene derivative 19. The struc-
ture of 19 was established on the basis of analytical and spectral data.
Its infrared spectra showed the presence of cyano and NH functional
groups. The formation of 19 is assumed to proceed via the formation of
intermediate 18 followed by elimination of malononitrile18 to give 19
(Scheme 3).
CONCLUSION
The non-isolable intermediate 2 was used as starting material for
the synthesis of some novel thiazole derivatives 3,5,7, and 8 through
its reaction, with α-halo compounds. Dithiocarbamic acid 9 was con-
verted into the quinazoline derivative 11 by treatment with methyl an-
thranilate. The reaction of 4-thiazolidinone 16 with some electrophilic
reagents was investigated.
EXPERIMENTAL
All melting points are uncorrected. IR spectra (KBr) were measured
1
on Shimadzu 440 spectrometer, H-NMR spectra were determined in

1502
M. M. Aly
SCHEME 3
DMSO-d6 on a Varian Gemini 200 MHz spectrometer using TMS as
internal standard. Chemical shifts are expressed as δ ppm units. Mass
spectra were obtained on GCMS 1000 Ex mass spectrometer at 70 eV.
Elemental analyses were carried out at the Microanalytical Center of
Cairo University. The characteristics data for prepared compounds are
given in Table 1.

Novel Sulfonamide Derivatives
1503
TABLE I Characteristic Data for the Synthesized Compounds
Elemental analyses
calcd./found %
Compd. Yield
Solvent
cryst.
M.p.
(◦C)
Mol. formula
(mol. wt.)
no.
(%)
C%
H% N%
S%
3
78
Acetic acid 145–46
Dioxane 154-56
Acetic acid 160–62
C14H11N3O3S3
(365.45)
C18H19N3O3S3
(421.56)
46.01 3.03 11.50 26.32
46.00 3.00 11.40 26.20
5
7
67
65
60
64
55
57
63
70
72
52
51.28 4.54
51.00 4.50
56.45 3.55
56.30 3.50
9.97 22.82
9.90 22.80
9.87 22.61
9.70 22.50
C
20H15N3O2S3
(425.55)
8
Ethanol
Dioxane
DMF
170–72
140–41
285–87
195–97
240–42
C14H12N4O2S3
(364.47)
C13H13N3O2S3
(339.46)
C19H14N4O3S2
(410.47)
C12H13N5O2S2
(323.39)
46.14 3.32 15.37 26.39
46.00 3.20 15.30 26.30
46.00 3.86 12.38 28.34
45.90 3.90 12.30 28.30
55.60 3.44 13.65 15.62
55.50 3.40 13.50 15.50
44.57 4.05 21.66 19.83
44.50 4.10 21.60 19.80
48.26 3.47 16.08 18.41
48.20 3.40 16.00 18.30
9
11
13
16
17a
17b
19
Dioxane
Dioxane
C
14H12N4O3S2
(348.40)
Acetic Acid 290–92
C21H15ClN4O3S2 53.56 3.21 11.90 13.62
(470.95)
C22H18N4O4S2
(466.53)
53.50 3.10 11.80 13.50
56.64 3.89 12.01 13.75
56.60 3.70 11.90 13.70
49.75 2.46 20.48 15.63
49.70 2.40 20.40 15.50
Acetic Acid
Dioxane
>300
150—51
C
17H10N6O3S2
(410.43)
DMF = dimethylformamide.
Reaction of 1 with Ethyl Chloroacetate, α-Bromobutyrate,
Phenacyl Bromide or Chloroacetonitrile Formation of
Compounds 4-(4-Oxo-2-thioxo-thiazolidin-3-yl)-N-pyri-din-2-
yl-benzenesulfonamide (3), 4-(4-Ethoxy-5-ethyl-
2-thioxo-thiazol-3-yl)-N-pyridin-2-ylbenzenesulfonamide (5),
4-(4-Phenyl-2-thioxo-thia-zol-3-yl)-N-pyridin-2-yl-
benzenesulfonamide (7) and
4-(4-Amino-2-thioxo-thiazol-3-yl)-N-pyridin-2-yl-
benzenesulfonamide (8) (General Procedure)
To a suspension of finely powdered sodium hydroxide (0.04 g, 0.01 mol)
in dry dimethylformamide (10 ml) at 0◦C, the carbon disulfide (0.76
g, 0.01 mol) and sulfapyridine (1) (2.49 g, 0.01 mole) were added in
portions. The reaction mixture was stirred at room temperature for 3 h
and then treated with α-halo compound (0.01 mol) and left at room
temperature for 24 h; then, it was poured into ice/water and acidified
with 0.1 N HCl at pH 3–4. The resulting precipitate was filtered off,

1504
M. M. Aly
TABLE II Spectral Data of the Synthesized Compounds.
Compd. no.
IR/ν
(cm−1
)
1H NMR (DMSO-d6) (δ / ppm)
max
3
3210 (NH), 2932 (CH-aliph), 1634
(C N), 1366, 1140 (SO2)
3210 (NH), 2932 (CH-aliph), 1634
(C N), 1366, 1140 (SO2)
4.20 (s, 2H, CH2), 6.85–8.02 (m,
8H, Ar H), and 10.3 (s, 1H, NH)
1.02 (t, 3H, CH3), 1.99 (t, 3H,
CH3), 3.41 (q, 2H, CH2), 4.5 (q,
2H, CH2), 6.56–7.99 (m, 8H,
Ar H), and 10.42 (s, 1H, NH)
4.59 (s, 1H, NH), 6.3 (s, 1H,
thiazolidine-H) and 6.63–7.78
(m, 13H, Ar H)
5
7
8
3200 (NH), 1558 (C N), 1362,
1136 (SO2)
3450, 3410 (NH2), 2926
—
(CH-aliph.), 1634 (C N), 1390,
1138 (SO2)
9
3264 (NH), 3050 (CH-arom.), 2922
(CH-aliph.)
2.94 (s, 3H, CH3), 6.54-8.11 (m, 8H,
Ar H), 9.32, 11.9 (2s, 2H, 2NH)
6.89–7.99 (m, 14H, Ar H + NH),
13.14 (s, 1H, NH)
11
3222 (NH), 3036 (CH-arom.), 1662
(C O; quinazolinone), 1610
(C N), 1328, 1140 (SO2)
3458, 3330 (NH/NH2), 3060
(CH-arom.), 1338,1150 (SO2)
3252, 3190 (2NH), 1686 (C O),
1628 (C N), 1388, 1136 (SO2)
13
16
—
4.01 (s, 2H, CH2), 6.84–8.01 (m,
8H, Ar H), 10.3, 11.9 (2s, 2H,
2NH)
17a
17b
3280, 3200 (2NH), 1680 (C O),
1608 (C N), 1364, 1140 (SO2)
3320 (NH), 2930 (CH-aliph.), 1602
(C N), 1382, 1138 (SO2)
3.6 (s, 3H, OCH3), 6.67–7.78 (m,
15H, Ar-H + benzylidene-H +
2NH)
19
3250 (NH), 2110 (C N), 1682
(C O), 1624 (C N), 1384, 1128
(SO2)
4.3 (s, 1H, NH), 6.8–7.9 (m, 9H,
Ar H + NH)
dried, and recrystallized from the proper solvent to yield 3, 5, 7, and 8,
respectively.
Synthesis of Compound [4-(Pyridin-2-ylsulfamoyl)-
phenyl]-dithiocar-bamic Acid Methyl Ester (9)
The experimental procedure for 3 was carried out except for the use of
dimethylsulfate instead of the halo compound.
Synthesis of Compound 4-(4-Oxo-2-thioxo-1,4-dihydro-2H-
quinazolin-3-yl)-N-pyridin-2-yl-benzenesulfonamide (11)
Method A
A mixture of compound 9 (3.39 g, 0.01 mol), methyl anthranilate
(1.51 g, 0.01 mol), and triethylamine (1.01 g, 0.01 mol) in ethanol (20

Novel Sulfonamide Derivatives
1505
ml) was heated under reflux for 12 h. The solid product which produced
on heating was collected and recrystallized from the proper solvent.
Method B
A mixture of compound 12 (2.91 g, 0.01 mol), methyl anthranilate
(1.51 g, 0.01 mol), and triethylamine (1.01 g, 0.01 mol) in ethanol (20
ml) was heated under reflux for 1h. The solid product which produced
on heating was collected and recrystallized to give 11.
Synthesis of Thiosemicarbazide Derivative (13)
To a suspension of compound 9 (3.39 g, 0.01 mol) in ethanol (30 ml), the
appropriate hydrazine hydrate (0.5 g, 0.01 mol) was added in portions
with stirring. The reaction mixture was stirred at room temperature for
30 min; the solid that separated out was filtered off and recrystallized
from the proper solvent to give 13.
Synthesis of 4-(2-Imino-4-oxo-thiazolidin-3-yl)-N-pyridin-
2-yl-benzene-sulfonamide (16)
A suspension of compound 14 (3.25 g, 0.01 mol) and potassium thio-
cyanate (0.96 g, 0.01 mol) in dimethylformamide (10 ml) is heated un-
der reflux for 1 h. After cooling the reaction mixture is poured into
water (100 ml), the precipitate is separated by filtration and washed
with water to give 16.
Synthesis of 4-[5-(2-Chlorobenzylidene)-2-imino-4-oxo-
thiazolidin-3-yl]-N-pyridin-2-yl-benzenesulfonamide (17a) and
4-[5-(4-Methoxy-benzylidene)-2-imino-4-oxo-thiazolidin-3-yl]-
N-pyridin-2-yl-benzene-sulfonamide (17b)
Method A
A
mixture of compound 16 (3.48 g, 0.01 mol), benzyli-
denemalononitrile (0.01), and piperidine (0.85 g, 0.01 mol) in ethanol
(20 ml) was heated under reflux for 3h. The solid product which
produced on heating was collected and recrystallized from the proper
solvent to give 17.
Method B
A mixture of compound 16 (3.48 g, 0.01 mol), aromatic aldehyde (0.01
mol), and piperidine (0.85 g, 0.01 mol) in ethanol (20 ml) was heated
under reflux for 1 h. The solid product was collected and recrystallized
to give 17.

1506
M. M. Aly
Synthesis of 4-(5-Dicyanomethylene-2-imino-4-oxo-
thiazolidin-3-yl)-N-pyridin-2-yl-benzenesulfonamide (19)
A mixture of compound 16 (3.48 g, 0.01 mol), tetracyanoethylene (1.28
g, 0.01 mol), and triethylamine (1.01 g, 0.01 mol) in ethanol (20 ml)
was heated under reflux for 0.5h. The solid product which produced on
heating was collected and recrystallized to give 19.
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