Ethyl {4-[2-(saccharin-2-yl)acetylsulfamoyl]phenylazo}cyanoacetate in the synthesis of polyfunctionally heteroaromatic derivatives

Article abstract of DOI:10.1002/jhet.176

(Chemical Equation Presented) An efficient and direct one-pot reaction of ethyl saccharinylcyanoacetate derivative 3 with a variety of active methylene reagents and nitrogen nucleophiles afforded novel series of polyfunctionally substituted heteroaromatic

Full text of DOI:10.1002/jhet.176

September 2009
Ethyl {4-[2-(Saccharin-2-yl)acetylsulfamoyl]phenylazo}cyanoacetate
in the Synthesis of Polyfunctionally Heteroaromatic Derivatives
895
A. A. Aly*
Faculty of Science, Chemistry Department, Benha University, Benha, Egypt
*E-mail: alymaboud@yahoo.com
Received July 9, 2008
DOI 10.1002/jhet.176
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
An efficient and direct one-pot reaction of ethyl saccharinylcyanoacetate derivative 3 with a variety
of active methylene reagents and nitrogen nucleophiles afforded novel series of polyfunctionally substi-
tuted heteroaromatic derivatives 5–13, respectively. The pyrazole derivative 13 was seemed to be the
excellent precursors for the synthesis of pyrazolo[1,5-a]pyrimidine derivatives 14–24. The antimicrobial
screening of some synthesized products was evaluated against some selected bacteria and fungi. The
structures of the synthesized derivatives were established by elemental and spectral data.
J. Heterocyclic Chem., 46, 895 (2009).
INTRODUCTION
by diazotization of the sulfanilamide derivative 1 followed
by coupling the resulting intermediate 2 with ethyl cyanoa-
cetate in ethanolic sodium acetate solution at 0–5ꢀC. The
structure of compound 3 was established on the basis of its
elemental analysis and spectral data. Thus, its IR spectrum
showed bands at 3320 and 3290 cmꢁ1 for mNH groups,
2220 cmꢁ1 for mCN, and at 1725, 1680 cmꢁ1 for carbonyl
The increasing medicinal potential of both saccharine
and sulfonamide derivatives as intermediate to biologi-
cally active compounds [1–5] and in continuation of our
efforts [6,7] in the synthesis of heterocyclic systems
incorporating saccharinyl and sulfonamide moieties as
potential pharmaceuticals. We reported here on the util-
ity of ethyl saccharinylcyanoacetate 3 as building blocks
for synthesis of new polyfunctionally substituted hetero-
aromatic derivatives of pyran, pyridine, pyridazine, tria-
zine, pyrimidine, and their analogues of sulfonamido
moiety of promising therapeutic applications [8–13].
1
groups. The H NMR spectrum showed signals as triplet at
d ¼ 1.53 for methyl proton, quartet at 4.50, singlet at d ¼
4.85 for two methylene protons, multiplets at d ¼ 7.21–
8.35 for aromatic protons and two singlet at d ¼ 8.53, 9.01
for 2NH protons, which disappeared upon addition of D2O
to the NMR sample (Scheme 1).
The reactivity of compound 3 toward 1,3-dicarbonyl
compounds was investigated with respect to the synthe-
sis of highly substituted pyran and pyridine. Thus, the
reaction of equimolar amounts of compound 3 and ace-
tylacetone and/or acetoacetanilide derivative in refluxing
RESULTS AND DISCUSSION
The key starting material ethyl {4-[2-(saccharin-2-yl)-
acetylsulfamoyl]phenylazo}cyanoacetate (3) was prepared
C
V
2009 HeteroCorporation

896
A. A. Aly
Vol 46
Scheme 1. (i) NaNO2/AcOH/HCl; (ii) NCCH2COOEt, AcONa; (iii) CH3COCH2COCH3 or CH3COCH2CONHPh, dioxane, Et3N.
1,4-dioxane containing a few drops of triethylamine
afforded 4-(5-acetyl-4-amino-6-methyl-2-oxo-2H-pyran-
3-ylazo)-N-[2-(saccharin-2-yl)acetyl]benzenesulfonamide
(5) and 4-(5-acetyl-4-amino-6-hydroxy-2-oxo-1-phenyl-
1,2-dihydropyridin-3-ylazo)-N-[2-(saccharin-2-yl)acetyl]-
benzenesulfonamide (6), respectively. In a similar man-
ner, the treatment of compound 3 with malononitrile or
ethyl cyanoacetate and/or ethyl acetoacetate afforded the
pyridazine derivatives 7a–c, respectively (Scheme 2).
Moreover, the reaction of compound 3 with 2-benzylide-
nemalononitrile and/or ethyl 2-cyano-3-phenylacrylate in
refluxing 1,4-dioxane containing a few drops of triethyl-
amine yielded the pyridazine derivatives 9a,b.
The formation of compounds 9a,b are assumed to
proceed via Michael-type addition of the NH of the hy-
drazone moiety in 3 to the activated a,b-unsaturated
center of substituted cinnamonitriles, yielding a cyclic
Michael adducts 8a,b, which are cyclized followed by
the aromatization to the final products 9a,b via elimina-
tion of an ethanol molecule and subsequent dehydrocya-
nation. The reaction of compound 3 with phenyl isothio-
cyanate afforded 4-(6-cyano-5-oxo-4-phenyl-3-thioxo-
4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(saccharin-2-yl)-
acetyl]benzenesulfonamide(11). Compound 11 was
assumed to be formed via an initial nucleophilic attack
of NH group of compound 3 on the isothiocyanate moi-
ety giving the adduct 10, which cyclized via the elimi-
nation of ethanol molecule to give compound 11. The
structure of compound 11 was assigned on the basis of
their elemental analysis and spectral data. Its IR spec-
trum showed bands at 3290 cmꢁ1 for mNH, 2215 cmꢁ1
for mCN, and 1685–1675 cmꢁ1 for mCO.
As an extension of such synthetic route, the behavior
of hydrazonoester 3 toward some nitrogen nucleophiles
was investigated with the aim of synthesizing a biologi-
cally active substituted pyrimidine and pyrazole deriva-
tives. Thus, the reaction of compound 3 with equimolar
amounts of urea or thiourea, in refluxing ethanolic so-
dium ethoxide solution gave the corresponding pyrimi-
dine derivatives 12a,b. While the reaction of compound
3 with hydrazine hydrate in refluxing absolute ethanol
yielded, 4-(5-amino-3-hydroxy-1H-pyrazol-4-ylazo)-N-
[2-(saccharin-2-yl)acetyl]benzenesulfonamide (13). The
structure of compound 13 was assigned on the basis of
elemental analysis and spectral data which agree with the
proposed structure (Scheme 2). 5-Aminopyrazole 13 has
been emphasized as a new synthetic auxiliary used for the
preparation of pyrazolo[1,5-a]pyrimidine derivatives
[14,15], which associated with a great applications in
pharmaceutical fields [16–19] and dyestuff industry
[20,21]. Thus, the reaction of compound 13 with acetylac-
etone in refluxing glacial acetic acid afforded 4-(5,7-di-
methyl-2-hydroxypyrazolo[1,5-a]pyrimidin-3-ylazo)-N-[2-
(saccharin-2-yl)acetyl]benzenesulfonamide (14). Reaction
of compound 13 with aromatic aldehydes viz benzalde-
hyde and 4-methoxybenzaldehyde in absolute ethanol
yielded Schiff bases 15a,b, respectively (Scheme 3).
The study was extended to investigate the behavior of
Schiff bases toward some active methylene compounds.
Thus, the treatment of 15a,b with malononitrile afforded
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Ethyl {4-[2-(Saccharin-2-yl)acetylsulfamoyl]phenylazo}cyanoacetate
in the Synthesis of Polyfunctionally Heteroaromatic Derivatives
897
Scheme 2. (i) NCCH2CN or NCCH2CO2Et or CH3COCH2CO2Et, dioxane, Et3N; (ii) PhCH¼C(CN)2 or PhCH¼C(CN)CO2Et, dioxane, Et3N; (iii)
PhNCS, dioxane, Et3N; (iv) H2NCONH2 or H2NCSNH2, NaOEt; (v) N2H4ꢂH2O, EtOH.
the pyrazolo[1,5-a]pyrimidines 16a,b, which also
obtained authentically, from the reaction of compound
13 with b-aryl-a-cyanoacrylonitrile derivatives in reflux-
ing 1,4-dioxane, which are identical in all respects
(m.p., m.m.p., and spectral data). The formation of com-
pounds 16a,b are assumed to proceed via initial addition
of the active methylene of malononitrile to the double
bond of the Schiff bases 15a,b to form the non-isolable
Michael adduct, which also formed via the initial attack
of the exocyclic amino group of compound 13 on the
activated double bond of acrylonitrile derivatives. This
Michael adduct undergoes intramolecular cyclization to
give compounds 16a,b. Additionally, the reaction of
Schiff bases 15a,b with ethyl cyanoacetate yielded pyra-
zolo[1,5-a]pyrimidines 17a,b which also obtained via in-
dependent synthesis from the reaction of compound 13
with b-aryl-a-cyanoacrylate derivatives, which are iden-
tical in all respects (m.p., m.m.p., and spectral data)
(Scheme 3). Also, the treatment of compound 13
with ethoxymethylenemalononitrile and/or ethyl ethoxy-
methylenecyanoacetate in refluxing dimethylformamide
containing a few drops of piperidine afforded the
pyrazolopyrimidine derivatives 19 and 20, respectively
(Scheme 4).
The reaction of compound 13 with 2-phenylhydrazono-
malononitrile [22] in refluxing absolute ethanol contain-
ing a few drops of pyridine afforded 4-(5,7-diamino-2-
hydroxy-6-phenylazopyrazolo[1,5-a]pyrimidin-3-ylazo)-N-
0
`
Scheme 3. (i) CH3COCH2COCH3, AcOH; (ii) Ar CHO, EtOH; (iii) CH2(CN)2, EtOH, piperidine; (iv) ArCH¼C(CN)2, 1,4-dioxane; (v)
`
NCCH2CO2Et, EtOH, piperidine; (vi) ArCH¼C(CN)CO2Et, 1,4-dioxane.
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898
A. A. Aly
Vol 46
Scheme 4. (i) EtOCH¼C(X)CN, DMF, piperidine; (ii) PhNHN¼C(CN)2, EtOH, pyridine; (iii) PhNHN¼C(CN)CO2Et, EtOH, pyridine.
[2-(saccharin-2-yl)acetyl]benzenesulfonamide (22). The
formation of compound 22 was assumed via the conden-
sation of the 5-NH2 group of the pyrazole ring with the
cyano group of malononitrile derivative to yield the
intermediate 21, in which internal nucleophilic attack of
1-NH group of the pyrazole ring on the other cyano
group followed by a migration of 5-NH proton of the
pyrazole ring to the nitrogen atom of imino group to
yield the nonisolable adduct, which tautomerized forming
the isolable product 22. While, the reaction of compound
13 with ethyl 2-phenylhydrazonocyanoacetate [23]
gave nonisolable intermediate 23, which cyclized to
afford 4-(7-amino-2-hydroxy-5-oxo-6-phenylazo-4,5-di-
hydropyrazolo[1,5-a]pyrimidin-3-ylazo)-N-[2-(saccharin-
2-yl)acetyl]benzenesulfonamide (24) (Scheme 4). The
structures of the synthesized compounds were assigned
on the basis of elemental analysis and spectral data
(c.f., experimental).
The antimicrobial activity. The antimicrobial activ-
ities of some synthesized compounds were screened in
vitro using the hole plate and filter paper methods [24]
for their antibacterial activity against Escherichia coli
and Pseudomonas aeruginosa as gram-negative bacteria
and Staphylococcus aureus as gram-positive bacteria.
Whereas the antifungal activity was tested against As-
pergillus niger and Fusarium oxysporium. Ampicillin as
an antibacterial agent and Clotrimazole as an antifungal
were used as a reference drugs to evaluate the potency
of the tested compounds under the same conditions. The
minimal inhibitory concentration (MIC) values listed in
Table 1 show that all the tested compounds have a
similar or highest degree of inhibition area against the
organisms relative to the reference drugs used.
EXPERIMENTAL
Melting points are uncorrected. IR spectra in KBr were
recorded on a Perkin–Elmer 298 spectrophotometer.1H and
13C NMR spectra were obtained on an Varian Gemini 200
MHz instrument using TMS as internal reference with chemi-
cal shifts expressed as d ppm. Mass spectra were recorded on
a Shimadzu GCMS-QP 1000 instrument (70 eV EI mode).
13C NMR values of saccharinylsulfonamide moiety for com-
pounds 5–24 are the same as in compound 3 with d ꢃ 0.1–0.5
ppm.
Ethyl {4-[2-(saccharin-2-yl)acetylsulfamoyl]phenylazo}-
cyanoacetate (3). A cold solution of diazonium chloride 2 (30
mmol) [prepared from the addition of a cold solution of so-
dium nitrite (0.69 g, 10 mmol) in H2O (5 mL) to a cold solu-
tion of compound 1 (3.95 g, 10 mmol) in concentrated hydro-
chloric acid (10 mL) and glacial acetic acid (10 mL) at 0–
5ꢀC] was added dropwise to a solution of ethyl cyanoacetate
(30 mmol) in ethanol (30 mL) containing sodium acetate (5.0
g). After the complete addition of the diazonium chloride, the
reaction mixture was stirred at room temperature overnight.
The precipitated product which separated upon dilution with
cold water (40 mL) was filtered off, washed with water (3 ꢄ
30 mL), dried and recrystallized from n-butanol to give 3.
Yield, 3.79 g (73%); m.p. 141–143ꢀC; IR: m ¼ 3320, 3290
(NH), 2220 (CN), 1725, 1680 (CO), 1350, 1130 cmꢁ1 (SO2);
1H NMR (CDCl3): d ¼ 1.53 (t, 3H, CH3), 4.50 (q, 2H, CH2),
4.85 (s, 2H, CH2), 7.21–8.35 (m, 8H, ArH), 8.53, 9.01 (2s,
2H, 2NH, exchangeable); 13C NMR: d ¼ 14.5 (CH3), 36.3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Ethyl {4-[2-(Saccharin-2-yl)acetylsulfamoyl]phenylazo}cyanoacetate
in the Synthesis of Polyfunctionally Heteroaromatic Derivatives
899
Table 1
In vitro antimicrobial activity of the tested compounds.
E. coli
P. aeruginosa
S. aureus
A. niger
F. oxysporium
Compound No
A
MIC
A
MIC
A
MIC
A
MIC
A
MIC
5
6
7a
9b
11
þþ
þþ
þþþ
þþþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
ꢁ
125
250
500
125
125
125
250
125
125
250
250
125
125
ꢁꢁ
þþ
þ
125
125
250
250
125
250
125
250
250
500
125
250
250
ꢁ
þþ
þþþ
þþ
þþþ
þ
250
250
125
500
125
250
125
250
125
250
125
250
125
ꢁ
þþ
þ
250
250
250
500
250
125
125
125
250
125
125
250
ꢁ
þþ
þþ
þ
125
500
125
125
125
250
250
250
250
500
250
250
ꢁ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþþ
þþþ
þ
þþ
þþ
þþ
þþ
þþ
þ
þþ
þþþ
þþ
þ
12b
13
þþþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
ꢁ
16a
17b
þþ
þþ
þþ
þ
þþ
þ
19
22
þ
24
Ampicillin
Clotrimazole
þ
þ
þþþ
ꢁ
ꢁ
ꢁ
þþþ
125
þþþ
250
A, antimicrobial activity of tested compounds; MIC, minimum inhibitory concentration; ꢁ, inactive; þ, > 5 mm, slightly active; þþ, > 7 mm,
moderately active; þþþ, > 9 mm, highly active.
(CH2), 52.6 (CH2CH3), 65.3 (C-CN),108.2 (CN), 150.4 (CO),
118.3, 118.9, 120.3, 120.6, 129.2, 141.3 (phenyl ring), 125.3,
126.3, 127.1, 129.5, 130.1, 131.5 (phenyl ring), 146.5, 155.4
(2CO) (saccharinylsulfonamide moiety); Anal. Calcd. for
C20H17N5O8S2 (519.51): C, 46.24; H, 3.30; N, 13.48%. Found:
C, 46.51; H, 3.50; N, 13.10%.
ethyl acetoacetate (2 mmol) in 1,4-dioxane (25 mL) containing a
catalytic amount of Et3N (0.4 mL) was heated under reflux for
10 h. The reaction mixture was cooled to room temperature,
poured into crushed ice (20 g), and neutralized with diluted HCl.
The resulting solid product was filtered off and recrystallized
from proper solvent to give the compounds 7a–c.
4-(5-Acetyl-4-amino-6-methyl-2-oxo-2H-pyran-3-ylazo)-N-
[2-(saccharin-2-yl)acetyl]benzenesulfonamide (5). A mixture
of compound 3 (1.04 g, 2 mmol) and acetylacetone (2 mmol) in
1,4-dioxane (25 mL) containing a catalytic amount of Et3N (0.4
mL) was heated under reflux for 8 h. The reaction mixture was
concentrated in vacuo and the formed solid product was collected
by filtration and recrystallized from ethanol to give 5. Yield, 0.70
g (61%); m.p. 166–168ꢀC; IR: m ¼ 3405–3240 (multiple bands,
Ethyl 4-amino-5-cyano-6-imino-1-{4-[2-(saccharin-2-yl)a-
cetylsulfamoyl]phenyl}-1,6-dihydropyridazine-3-carboxylate
(7a). Yield, 0.69 g (59%) (DMF-H2O); m.p. 173–175ꢀC; IR: m
¼ 3310–3200 (NH2, NH), 2215 (CN), 1730, 1680 cmꢁ1 (CO);
1H NMR (DMSO-d6): d ¼ 1.65 (t, 3H, CH3), 4.60 (q, 2H,
CH2), 4.80 (s, 2H, CH2), 5.95 (s, 2H, NH2), 7.18–8.15 (m, 8H,
ArH), 8.20, 8.95 (2s, 2H, 2NH, exchangeable); Anal. Calcd.
for C23H19N7O8S2 (585.57): C, 47.18; H, 3.27; N, 16.74%.
Found: C, 47.37; H, 3.51; N, 16.41%.
Ethyl 4-amino-5-cyano-6-oxo-1-{4-[2-(saccharin-2-yl)acetylsul-
famoyl]phenyl}-1,6-dihydropyridazine-3-carboxylate (7b). Yield,
0.71 g (61%) (n-butanol); m.p. 220–222ꢀC; IR: m ¼ 3340–
3210 (NH2, NH), 2220 (CN), 1725, 1680 cmꢁ1 (CO); 1H
NMR (CDCl3): d ¼ 1.45 (t, 3H, CH3), 4.45 (q, 2H, CH2), 4.75
(s, 2H, CH2), 5.90 (br s, 2H, NH2), 7.30–8.41 (m, 8H, ArH),
8.75 (s, 1H, NH, exchangeable); 13C NMR: d ¼ 12.3 (CH3),
50.3 (CH2), 80.1 (C-5), 112.3 (CN), 140.2 (C-3), 150.2 (CO),
152.5 (C-6), 156.7 (C-4); Anal. Calcd. for C23H18N6O9S2
(586.56): C, 47.10; H, 3.09; N, 14.33%. Found: C, 47.39; H,
3.34; N, 14.10%.
Ethyl 5-acetyl-4-amino-6-oxo-1-{4-[2-(saccharin-2-yl)acetylsul-
famoyl]phenyl}-1,6-dihydropyridazine-3-carboxylate (7c). Yield,
0.86 g (71%) (1,4-dioxane); m.p. 212–214ꢀC; IR: m ¼ 3230
(NH), 2225–2220 (CN), 1680–1675 cmꢁ1 (CO); MS: m/z ¼
603 (Mþ); Anal. Calcd. for C24H21N5O10S2 (603.58): C,
47.76; H, 3.51; N, 11.60%. Found: C, 47.93; H, 3.75; N,
11.85%.
General procedure for the preparation of compounds
9a,b. A mixture of compound 3 (1.04 g, 2 mmol) and benzyli-
denemalononitrile or ethyl a-cyanocinnamate (2 mmol) in 1,4-
dioxane (20 mL) containing a catalytic amount of triethylamine
(0.4 mL) was heated under reflux for 9 h. The reaction mixture
1
NH2, NH), 1710, 1690, 1680 cmꢁ1 (CO); H NMR (CDCl3): d ¼
1.95 (s, 3H, CH3), 2.10 (s, 3H, CH3CO), 4.75 (s, 2H, CH2), 5.85
(br s, 2H, NH2), 7.25–8.12 (m, 8H, ArH), 8.30 (s, 1H, NH,
exchangeable); 13C NMR: d ¼ 16.2 (CH3), 20.1 (CH3CO), 81.3
(C-5), 89.5 (C-3), 136.3 (C-4), 141.4 (C-6), 161.2 (CO), 165.7 (C-
2); Anal. Calcd. for C23H19N5O9S2 (573.56): C, 48.16; H, 3.34;
N, 12.21%. Found: C, 48.32; H, 3.50; N, 12.01%.
4-(5-Acetyl-4-amino-6-hydroxy-2-oxo-1-phenyl-1,2-dihydro-
pyridin-3-ylazo)-N-[2-(saccharin-2-yl)acetyl]benzenesulfona-
mide (6). A mixture of compound 3 (1.04 g, 2 mmol) and ace-
toacetanilide (2 mmol) in 1,4-dioxane (25 mL) containing a
catalytic amount of Et3N (0.4 mL) was heated under reflux for 8
h. The reaction mixture was concentrated in vacuo and the
formed solid was collected by filtration and recrystallized from
1,4-dioxane to give 6. Yield, 0.87 g (67%); m.p. 183–185ꢀC; IR:
m ¼ 3495–3200 (multiple bands, OH, NH2, NH), 1705, 1680,
1675 cmꢁ1 (CO); 1H NMR (CDCl3): d ¼ 1.95 (s, 3H, CH3),
4.10 (s, 2H, CH2), 5.95 (br s, 2H, NH2), 7.30–8.3 (m, 13H,
ArH), 8.35, 8.50 (2s, 2H, NH, and OH, exchangeable); Anal.
Calcd. for C28H22N6O9S2 (650.64): C, 51.69; H, 3.41; N,
12.92%. Found: C, 51.41; H, 3.19; N, 12.75%.
General procedure for the preparation of compounds
7a–c. A mixture of compound 3 (1.04 g, 2 mmol) and active
methylene compounds viz malononitrile, ethyl cyanoacetate, and
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900
A. A. Aly
Vol 46
was cooled at room temperature, poured onto ice (20 g), and
neutralized with diluted HCl. The formed solid product was fil-
tered off and recrystallized from proper solvent to give 9a,b.
4-(3,5-Dicyano-4-oxo-6-phenyl-4H-pyridazin-1-yl)-N-[2-(saccha-
rin-2-yl)acetyl]benzenesulfonamide (9a). Yield, 0.88 g (73%)
(benzene); m.p. 241–243ꢀC; IR: m ¼ 3310 (NH), 2220–2215
for 2 h. The solid product which formed after cooling was fil-
tered off and recrystallized from 1,4-dioxane to give 13. Yield,
3.94 g (78%); m.p. 207–209ꢀC; IR: m ¼ 3450–3200 (OH,
1
NH2, NH), 1675 cmꢁ1 (CO); H NMR (CDCl3): d ¼ 4.50 (s,
2H, CH2), 5.80 (br s, 2H, NH2), 7.15–8.25 (m, 8H, ArH),
8.30–9.10 (br s, 3H, 2NH, and OH, exchangeable); 13C NMR:
d 62.3 (C-4), 153.3 (C-5), 156.2 (C-3); Anal. Calcd. for
C18H15N7O7S2 (505.49): C, 42.77; H, 2.99; N, 19.40%. Found:
C, 42.50; H, 2.71; N, 19.67%.
4-(5,7-Dimethyl-2-hydroxypyrazolo[1,5-a]pyrimidin-3-ylazo)-
N-[2-(saccharin-2-yl)acetyl]benzenesulfonamide (14). A mix-
ture of compound 13 (1.01 g, 2 mmol) and acetylacetone (3
mmol) in glacial acetic acid (20 mL) was refluxed for 5 h. The
reaction mixture was cooled, the separated solid was filtered
off, washed with water and recrystallized from 1,4-dioxane to
give 14. Yield, 0.83 g (73%); m.p. 196–198ꢀC; IR: m ¼ 3420–
3290 (OH, NH), 1675 cmꢁ1 (CO); 1H NMR (CDCl3): d ¼
1.2–1.4 (br s, 6H, 2CH3), 4.55 (s, 2H, CH2), 7.13–8.10 (m,
9H, ArH), 8.30–8.50 (br s, 2H, NH, and OH, exchangeable);
Anal. Calcd. for C23H19N7O7S2 (569.57): C, 48.50; H, 3.36;
N, 17.21%. Found: C, 48.28; H, 3.12; N, 17.36%.
General procedure for the preparation of compounds
15a,b. A mixture of compound 13 (1.01 g, 2 mmol), benzalde-
hyde and/or 4-methoxybenzaldehyde (2 mmol) in absolute
ethanol (25 mL) was heated under reflux for 5 h. The reaction
mixture was cooled and the formed solid was filtered off and
recrystallized to give 15a,b.
4-[5-(Benzylideneamino)-3-hydroxy-1H-pyrazol-4-ylazo]-N-[2-
(saccharin-2-yl)acetyl]benzenesulfonamide (15a). Yield, 0.80 g
(67%) (ethanol); m.p. 174–176ꢀC; IR: m ¼ 3490–3290 (OH,
NH), 1670 cmꢁ1 (CO); 1H NMR (CDCl3): d ¼ 4.60 (s, 2H,
CH2), 7.25–8.30 (m, 14H, ArH, and benzylic proton), 8.40,
8.60, 9.10 (3s, 3H, 2NH, and OH, exchangeable); Anal. Calcd.
for C25H19N7O7S2 (593.59): C, 50.58; H, 3.23; N, 16.52%.
Found: C, 50.74; H, 3.49; N, 16.23%.
4-{3-Hydroxy-5[(4-methoxybenzylidene)amino]-1H-pyra-
zolo-4-ylazo}-N-[2-(saccharin-2-yl)acetyl]benzenesulfona-
mide (15b). Yield–0.79 g (63%) (ethanol); m.p. 213–215ꢀC;
IR: m ¼ 3480–3210 (OH, NH), 1675 cmꢁ1 (CO); Anal. Calcd.
for C26H21N7O8S2 (623.62): C, 50.08; H, 3.39; N, 15.72%.
Found: C, 50.30; H, 3.63; N, 15.42%.
General procedure for the preparation of compounds
16a,b. Method A: A mixture of compounds 15a or 15b (2
mmol) and malononitrile (0.13 g, 2 mmol) in absolute ethanol
(20 mL) containing piperidine (0.4 mL) was heated under
reflux for 8 h. The separated solid was filtered off and recrys-
tallized from 1,4-dioxane to give 16a,b. Yield, 0.73 g (61%
for 16a) and 0.86 g (62% for 16b).
1
(CN), 1705, 1680–1670, cmꢁ1 (CO); H NMR (DMSO-d6): d
¼ 4.60 (s, 2H, CH2), 7.40–8.31 (m, 13H, ArH), 8.45 (s, 1H,
NH, exchangeable); Anal. Calcd. for C27H16N6O7S2 (600.58):
C, 54.00; H, 2.69; N, 13.99%. Found: C, 54.26; H, 2.81; N,
13.79%.
Ethyl 6-cyano-5-oxo-3-phenyl-2-{4-[2-(saccharin-2-yl)acetylsul-
famoyl]phenyl}-2,5-dihydropyridazine-4-carboxylate (9b). Yield,
0.90 g (69%) (ethanol); m.p. 193–195ꢀC; IR: m ¼ 3290 (NH),
1
2215 (CN), 1725, 1705, 1680 cmꢁ1 (CO); H NMR (CDCl3):
d ¼ 1.55 (t, 3H, CH3), 4.30 (q, 2H, CH2), 4.50 (s, 2H, CH2),
7.20–8.35 (m, 13H, ArH), 8.40 (s, 1H, NH, exchangeable);
Anal. Calcd. for C29H21N5O9S2 (647.64): C, 53.78; H, 3.27;
N, 10.81%. Found: C, 53.95; H, 3.51; N, 10.59%.
4-(6-Cyano-5-oxo-4-phenyl-3-thioxo-4,5-dihydro-3H-[1,2,4]tri-
azin-2-yl)-N-[2-saccharin-2-yl]acetyl]benzenesulfonamide (11). A
mixture of compound 3 (1.04 g, 2 mmol) and phenyl isothio-
cyanate (2 mmol) in 1,4-dioxane (20 mL) containing triethyl-
amine (0.4 mL) was heated under reflux for 6 h. The reaction
mixture was cooled at room temperature, poured onto cold
water (40 mL) and neutralized with dilute HCl. The solid
product that formed was collected by filtration and recrystal-
lized from ethanol to give 11. Yield, 0.93 g (76%); m.p. 211–
213ꢀC; IR: m ¼ 3290 (NH), 2215 (CN), 1685–1675 cmꢁ1
(CO); 1H NMR (CDCl3): d ¼ 4.55 (s, 2H, CH2), 7.12–8.25
(m, 13H, ArH), 8.35 (s, 1H, NH, exchangeable); Anal. Calcd.
for C25H16N6O7S3 (608.63): C, 49.34; H, 2.65; N, 13.81%.
Found: C, 49.10; H, 2.31; N, 13.96%.
General procedure for the preparation of compounds
12a,b. To a solution of compound 3 (1.04 g, 2 mmol) in ethanolic
sodium ethoxide solution (25 mL) [prepared by dissolving sodium
metal (2.0 g) in absolute ethanol (20 mL)], urea or thiourea (2
mmol) was added. The reaction mixture was heated under reflux
for 8 h. The solvent was evaporated in vacuo and the residue was
triturated with cold water. The solid formed was collected by filtra-
tion and recrystallized from proper solvent to give 12a,b.
4-(6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylazo)-N-[2-
(saccharin-2-yl)acetyl]benzenesulfonamide (12a). Yield, 0.73 g
(68%) (DMF); m.p. 251–253ꢀC; IR: m ¼ 3400–3230 (NH2,
1
NH), 1680–1675 cmꢁ1 (CO); H NMR (CDCl3): d ¼ 4.61 (s,
2H, CH2), 5.85 (br s, 2H, NH2), 7.25–8.05 (m, 8H, ArH),
8.10–8.50 (br s, 3H, 3NH, exchangeable); Anal. Calcd. for
C19H15N7O8S2 (533.50): C, 42.78; H, 2.83; N, 18.38%. Found:
C, 42.96; H, 2.98; N, 18.10%.
4-(6-Amino-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-ylazo)-
N-[2-(saccharin-2-yl)acetyl]benzenesulfonamide (12b). Yield, 0.80
g (73%); (1,4-dioxane); m.p. 230–232ꢀC; IR: m ¼ 3395–3200
(NH2, NH), 1685–1680 cmꢁ1 (CO), 1260 cmꢁ1 (CS); 1H
NMR (CDCl3): d ¼ 4.65 (s, 2H, CH2), 5.90 (br s, 2H, NH2),
7.30–8.20 (m, 8H, ArH), 8.30–9.00 (br s, 3H, 3NH, exchange-
able); Anal. Calcd. for C19H15N7O7S3 (549.56): C, 41.52; H,
2.75; N, 17.84%. Found: C, 41.20; H, 2.49; N, 17.98%.
4-(5-Amino-3-hydroxy-1H-pyrazol-4-ylazo)-N-[2-(saccha-
rin-2-yl)acetyl]benzenesulfonamide (13). A mixture of com-
pound 3 (5.19 g, 10 mmol) and hydrazine hydrate (0.6 g, 12
mmol) in absolute ethanol (25 mL) was heated under reflux
Method B: A mixture of compound 13 (1.01 g, 2 mmol)
and arylidene malononitriles (2 mmol) in 1,4-dioxane (25 mL)
containing a few drops of piperidine (0.4 mL) was refluxed for
10 h. The obtained solid after cooling was recrystallized from
1,4-dioxane to give 16a,b. Yield, 0.82 g (69% for 16a) and
0.98 g (71% for 16b).
4-(7-Amino-6-cyano-2-hydroxy-5-phenyl-4,5-dihydropyra-
zolo[1,5-a]pyrimidin-3-ylazo)-N-[2-(saccharin-2-yl)acetyl]ben-
zenesulfonamide (16a). m.p. 165–167ꢀC, IR: m ¼ 3505–3200
(OH, NH2, NH), 2215 (CN), 1680 cmꢁ1 (CO); 1H NMR
(CDCl3): d ¼ 4.50 (s, 2H, CH2), 5.10 (s, 1H, CH), 5.70 (br s,
2H, NH2), 7.21–8.11 (m, 13H, ArH), 8.20–9.10 (br s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Ethyl {4-[2-(Saccharin-2-yl)acetylsulfamoyl]phenylazo}cyanoacetate
in the Synthesis of Polyfunctionally Heteroaromatic Derivatives
901
2NH, OH, exchangeable); 13C NMR: d ¼ 36.3 (C-5), 47.8 (C-
6), 60.1 (C-3), 110.3 (CN), 150.1 (C-3a), 151.2 (C-7), 156.3
(C-2), 120.1, 120.4, 123.2, 123.6, 124.2, 129.3 (phenyl ring);
Anal. Calcd. for C28H21N9O7S2 (659.65): C, 50.98; H, 3.21;
N, 19.11%. Found: C, 50.63; H, 3.08; N, 19.37%.
4-(6-Cyano-2-hydroxy-7-oxo-4,7-dihydropyrazolo[1,5-a]pyr-
imidin-3-ylazo)-N-[2-(saccharin-2-yl)acetyl]benzenesulfonamide
(20). A mixture of 13 (1.01 g, 2 mmol) and ethyl ethoxyme-
thylenecyanoacetate (0.34 g, 2 mmol) in DMF (20 mL) con-
taining a few drops of piperidine (0.4 mL) was refluxed for 4
h. The reaction mixture was cooled and the formed solid was
filtered off and recrystallized from DMF to give 20. Yield,
0.65 g (56%); m.p. 196–198ꢀC; IR: m ¼ 3490–3180 (OH,
NH), 2210 (CN), 1680–1675 cmꢁ1 (CO); 1H NMR (DMSO-
d6): d ¼ 4.55 (s, 2H, CH2), 7.15–8.10 (m, 9H, ArH), 8.60–
9.10 (br s, 3H, 2NH, and OH, exchangeable); Anal. Calcd. for
C22H14N8O8S2 (582.53): C, 45.36; H, 2.42; N, 19.24%. Found:
C, 45.53; H, 2.61; N, 19.41%.
4-(5,7-Diamino-2-hydroxy-6-phenylazopyrazolo[1,5-a]pyrimi-
din-3-ylazo)-N-[2-(saccharin-2-yl)acetyl]benzenesulfonamide
(22). A mixture of 13 (1.01 g, 2 mmol) and 2-phenylhydrazo-
nomalononitrile (0.34 g, 2 mmol) in absolute ethanol (20 mL)
containing a few drops of pyridine (0.4 mL) was heated under
reflux for 6 h, then allowed to cool at room temperature. The
precipitated solid was filtered off, washed with water (3 ꢄ 30
mL) and recrystallized from n-butanol to give 22. Yield, 0.85
g (63%); m.p. 186–188ꢀC; IR: m ¼ 3495–3180 (OH, NH2,
NH), 1670 cmꢁ1 (CO); 1H NMR (CDCl3): d ¼ 4.61 (s, 2H,
CH2), 5.85–6.10 (br s, 4H, 2NH2), 7.10–8.15 (m, 13H, ArH),
8.50–8.75 (br s, 2H, NH, and OH, exchangeable); Anal. Calcd.
for C27H21N11O7S2 (675.66): C, 48.00; H, 3.13; N, 22.80%.
Found: C, 48.26; H, 3.36; N, 22.51%.
4-[7-Amino-6-cyano-2-hydroxy-5-(4-methoxyphenyl)-4,5-dihy-
dropyrazolo[1,5-a]pyrimidin-3-ylazo]-N-[2–(saccharin-2-yl)ace-
tyl]benzenesulfonamide (16b). m.p. 190–192ꢀC, IR: m ¼
1
3490–3210 (OH, NH2, NH), 2220 (CN), 1675 cmꢁ1 (CO); H
NMR (CDCl3): d ¼ 3.90 (s, 3H, OCH3), 4.55 (s, 2H, CH2),
4.95 (s, 1H, CH), 5.75 (br s, 2H, NH2), 7.20–8.15 (m, 12H,
ArH), 8.30–9.10 (br s, 3H, 2NH, OH, exchangeable); Anal.
Calcd. for C29H23N9O8S2 (689.68): C, 50.50; H, 3.36; N,
18.28%. Found: C, 50.76; H, 3.60; N, 18.10%.
General procedure for the preparation of compounds
17a,b. Method A: A mixture of compounds 15a or 15b (2
mmol) and ethyl cyanoacetate (2 mmol) in absolute ethanol
(20 mL) containing piperidine (0.4 mL) was heated under
reflux for 8 h. The formed solid was filtered off and recrystal-
lized from n-butanol to give 17a,b. Yield, 0.91 g (64% for
17a) and 0.89 g (60% for 17b).
Method B: A mixture of compound 13 (1.01 g, 2 mmol) and b-
aryl-a-cyanoacrylate derivatives (2 mmol) in 1,4-dioxane (20 mL)
containing piperidine (0.3 mL) was refluxed for 10 h. The resulting
solid was filtered off and recrystalized from n-butanol to give 17a,b.
Yield, 1.02 g (72% for 17a) and 1.08 g (73% for 17b).
4-(7-Amino-2-hydroxy-5-oxo-6-phenylazo-4,5-dihydropyr-
azolo[1,5-a]pyrimidin-3-ylazo)-N-[2-(saccharin-2-yl)acetyl]ben-
zenesulfonamide (24). A mixture of 13 (1.01 g, 2 mmol) and
ethyl 2-phenylhydrazonocyanoacetate (0.43 g, 2 mmol) in
absolute ethanol (20 mL) containing a few drops of pyridine
(0.5 mL) was heated under reflux for 6 h, then allowed to cool
at room temperature. The formed solid was filtered off, washed
with water (3 ꢄ 30 mL) and recrystallization from DMF to
give 24. Yield, 0.82 g (61%); m.p. 201–203ꢀC; IR: m ¼ 3490–
Ethyl 7-amino-2-hydroxy-5-phenyl-3-{4-[2-(saccharin-2-
yl)acetylsulfamoyl]phenylazo}-4,5-dihydropyrazolo[1,5-a]py-
rimidine-6-carboxylate (17a). m.p. 236–238ꢀC, IR:
m
¼
3490–3180 (OH, NH2, NH), 1730, 1675 cmꢁ1 (CO); H NMR
(CDCl3): d ¼ 1.60 (t, 3H, CH3), 4.45 (q, 2H, CH2), 4.65 (s,
2H, CH2), 5.20 (s, 1H, CH), 5.70 (br s, 2H, NH2), 7.20–8.15
(m, 13H, ArH), 8.50–9.55 (br s, 3H, 2NH, and OH, exchange-
able); Anal. Calcd. for C30H26N8O9S2 (706.71): C, 50.99; H,
3.71; N, 15.86%. Found: C, 50.81; H, 3.50; N, 15.97%.
1
1
3200 (OH, NH2), 1680–1675 cmꢁ1 (CO); H NMR (DMSO ¼
Ethyl
7-amino-2-hydroxy-5-(4-methoxyphenyl)-3-{4-[2-
d6): d ¼ 4.50 (s, 2H, CH2), 5.85 (br s, 2H, NH2), 7.26–8.20
(m, 13H, ArH), 8.40–9.10 (br s, 3H, 2NH, and OH, exchange-
able); 13C NMR: d ¼ 67.1 (C-6), 68.5 (C-3), 131.5 (C-3a),
148.5 (C-7), 152.1 (C-2), 154.2 (C-5), 120.1, 120.9, 121.2,
121.8, 122.5, 123.1 (phenyl ring); Anal. Calcd. for
C27H20N10O8S2 (676.64): C, 47.93; H, 2.98; N, 20.70%.
Found: C, 47.75; H, 2.71; N, 20.50%.
(saccharin-2-yl)acetylsulfamoyl]phenylazo}-4,5-dihydropyr-
azolo[1,5-a]pyrimidine-6-carboxylate (17b). m.p. 203–205ꢀC,
IR: m ¼ 3490–3190 (OH, NH2, NH), 1725, 1670 cmꢁ1 (CO);
1H NMR (DMSO-d6): d ¼ 1.70 (t, 3H, CH3), 3.95 (s, 1H,
OCH3), 4.40 (q, 2H, CH2), 4.60 (s, 2H, CH2), 5.15 (s, 1H,
CH), 5.75 (br s, 2H, NH2), 7.15–8.20 (m, 12H, ArH), 8.25–
9.50 (br s, 3H, 2NH, and OH, exchangeable); Anal. Calcd. for
C31H28N8O10S2 (736.73): C, 50.54; H, 3.83; N, 15.21%.
Found: C, 50.35; H, 3.60; N, 15.36%.
Acknowledgment. The author is grateful to the Botany Depart-
ment, Benha University, for biological screening.
4-(7-Amino-6-cyano-2-hydroxypyrazolo[1,5-a]pyrimidin-3-
ylazo)-N-[2-(saccharin-2-yl)acetyl]benzenesulfonamide (19). A
mixture of 13 (1.01 g, 2 mmol) and ethoxymethylenemalononi-
trile (0.22 g, 2 mmol) in DMF (25 mL) containing a few drops
of piperidine (0.3 mL) was heated under reflux for 4 h. The reac-
tion mixture was cooled and the formed solid was filtered off and
recrystallized from 1,4-dioxane to give 19. Yield, 0.67 g (58%);
m.p. 211–213ꢀC; IR: m ¼ 3480–3190 (OH, NH2, NH), 2215
(CN), 1675 cmꢁ1 (CO); 1H NMR (CDCl3): d ¼ 4.60 (s, 2H,
CH2), 5.95 (br s, 2H, NH2), 7.15–8.20 (m, 9H, ArH), 8.60–
9.10 (br s, 2H, NH, and OH, exchangeable); 13C NMR: d ¼
35.6 (C-6), 82.1 (C-3), 111.2 (CN), 140.2 (C-3a), 150.3 (C-5),
153.1 (C-7), 156.3 (C-2); Anal. Calcd. for C22H15N9O7S2
(581.54): C, 45.44; H, 2.60; N, 21.68%. Found: C, 45.65; H,
2.81; N, 21.45%.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet