Utility of cyano-N-(2-oxo-1,2-dihydroindol-3-ylidene)acetohydrazide in the synthesis of novel heterocycles

Article abstract of DOI:10.3184/174751912X13567100793191

Cyano-N-(2-oxo-1,2-dihydroindol-3-ylidene)acetohydrazide was prepared by condensation of isatin with cyanoacetohydrazide in refluxing 1,4-dioxane. Subsequent reaction with a variety of electrophilic and nucleophilic reagents afforded novel heterocyclic compounds and spirooxoindoles. The IR, ¹H NMR and mass spectra of all the synthesised compounds are discussed.

Full text of DOI:10.3184/174751912X13567100793191

80 RESEARCH PAPER
FEBRUARY, 80–85
JOURNAL OF CHEMICAL RESEARCH 2013
Utility of cyano-N-(2-oxo-1,2-dihydroindol-3-ylidene)acetohydrazide in the
synthesis of novel heterocycles
Mahmoud. R. Mahmouda, Ahmed. K. El-Ziatya, Fatma. S. M. Abu El-Azma,
Mahmoud. F. Ismaila* and Sayed. A. Shibab
aChemistry Department, Faculty of Science, Ain Shams University, 11566 Abbassia, Cairo, Egypt
bChemistry Department, Faculty of Science and Arts, Sajer Shaqra University, Saudia Arabia
Cyano-N-(2-oxo-1,2-dihydroindol-3-ylidene)acetohydrazide was prepared by condensation of isatin with cyanoaceto-
hydrazide in refluxing 1,4-dioxane. Subsequent reaction with a variety of electrophilic and nucleophilic reagents
afforded novel heterocyclic compounds and spirooxoindoles. The IR, 1H NMR and mass spectra of all the synthesised
compounds are discussed.
Keywords: isatin, spirooxoindoles, thiazole and coumarin derivatives
Isatins are synthetically versatile substrates that display diverse
biological and pharmacological properties.1–5 It is an endo-
genous compound and reported to possess a wide range of
central nervous system activities.6,7 It has been reported that
several compounds containing an isatin moiety possess anti-
bacterial, antifungal, anticonvulsant, anti-inflammatory and
anti-HIV activities.8,9 Among several commercially available
substituted hydrazines, cyanoacetohydrazide is a versatile and
convenient intermediate for the synthesis of wide variety of
heterocyclic compounds.10,11
methylene of 2 can take part in condensation and substitution
reactions. Thus, stirring 2 with salicylaldehyde (1:1 molar
ratio) in 1,4-dioxane in the presence of a catalytic amount of
piperidine at room temperature afforded an orange precipitate
with molecular formula C18H11N3O4 (M = 333) which was
identifiedas2-oxo-N′-(2-oxoindolin-3-ylidene)-2H-chromene-
3-carbohydrazide 3 (Scheme 2).
The structure 3 was substantiated from the correct analytical
and spectroscopic data. The IR spectrum of 3 exhibited the
stretching absorption bands for the NH group at 3151 cm−1
(br.), CO at 1736 and 1716 cm−1 and for the C═N group
at 1620 cm−1 and was devoid of the stretching absorption
band for nitrile group. The highest recorded peak in the mass
spectrum of 3 at m/z 333 (1.97%) represents the molecular ion
peak. The fragmentation pattern was in accord with the
assigned structure (see Experimental).
As a continuation of our efforts12–20 to identify new candi-
dates that may be of value in designing new, potent, selective
and less toxic antimicrobial agents, we report here the synthe-
sis of some new heterocycles incorporating an indole moiety
starting from cyanoacetohydrazide and isatin.
Results and discussion
The reaction of compound 2 with 1,3-diphenylpyrazole-4-
carboxaldehyde in refluxing ethanol in the presence of aque-
ous potassium hydroxide (10%) afforded the condensation
product 4, the structure of which was confirmed from its
spectroscopic data. Thus, 1H NMR spectrum of 4 (DMSO-d6)
revealed the signals at δ 11.65 (br.s, 1H, NH, exchangeable
with D2O), 9.92 (s, 1H, NH, exchangeable with D2O), 8.09
(s, 1H, olefinic proton) and 9.10–6.49 (m, 15Harom.), which is in
accord with the assigned structure. Moreover, the highest
recorded peak at m/z 456 represents the radical cation [M-2].
Furthermore, the structure of 4 was chemically supported via
hydrazinolysis in boiling n-butanol which yielded the pyrazole
derivative 5 (Scheme 2).
It was claimed that the reaction of isatin with cyanoacetohy-
drazide in the presence of catalytic amount of triethylamine at
room temperature yielded the corresponding C-condensation
product 1.21
Such a reaction in refluxing 1,4-dioxane afforded the N-
condensation product which identified as 2-cyano-N′-(2-oxo-
1,2-dihydroindol-3-ylidene) acetohydrazide 2 (Scheme 1).
1
The structure of compound 2 was confirmed by IR, H
NMR, MS spectra and correct microanalysis (see Experimen-
tal). The mass spectrum showed the molecular ion at m/z 228
(12.8%).
Oxoindol-3-ylidene acetohydrazide 2 was expected to be a
highly reactive compound. The carbonyl and cyano functions
are suitably situated to enable reactions with common reagents
to form a variety of heterocyclic compounds. Also, the active
The IR spectrum of 5 showed one stretching absorption
band for the carbonyl group at 1705 cm−1 together with νNH at
3200, 3134 cm−1 and devoid of the stretching absorption band
Scheme 1
* Correspondent. E-mail: fawzy2010@sci.asu.edu.eg

JOURNAL OF CHEMICAL RESEARCH 2013 81
Scheme 2
for the nitrile group. The EI-MS fragmentation was consistent
with the proposed structure and revealed the molecular ion
peak at m/z 490 (23%) which upon loss of the isatin moiety,
followed by hydrogen abstraction yielded the radical cation at
m/z 346 (89.6%). The base peak at m/z 77 represents the phenyl
cation.
The reactivity of the hydrazide 2 toward isothiocyanates
was investigated. Thus, when compound 2 was allowed to
react with phenyl isothiocyanate in the presence of potassium
hydroxide in DMF at room temperature followed by in situ
treatment with ethyl iodide, the novel ketene N,S-acetal 6 was
obtained. Subsequent reaction of 6 with hydrazine hydrate in
refluxing ethanol gave the sulfur free compound which was
characterised as the amino pyrazole derivative 7 (Scheme 3).
The structure of 6 was established on the basis of its elemen-
tal analysis and spectral data. The mass spectrum revealed a
molecular ion peak at m/z 391 (12.7%).
IR spectrum of the aminopyrazole derivative 7 was devoid
of a νC≡N absorption and exhibited bands at 3358, 3250, 3158
cm−1 (NH, NH2), 1685 cm−1 (C=O) and 1658 cm−1 (C=N). The
mass spectrum showed a molecular ion peak at m/z 361 (35.5%)
in agreement with its molecular formula C18H15N7O2.
Formation of the aminopyrazole derivative 7 is presumed to
proceed via Michael addition of the hydrazinoamino group
to the ethylenic bond side chain in 6 with elimination of the
ethylthio group followed by intramolecular cyclisation at the
cyano group (Scheme 4).
Upon stirring compound 2 with phenyl isothiocyanate in the
presence of potassium hydroxide in DMF followed by addition
of ethyl chloroacetate cycloalkylation occurred to afford the
1,3-thiazolidinone derivative 8 (Scheme 3).
The structure 8 was confirmed from the microanalytical
and spectroscopic data. The IR spectrum of 8 displayed a νNH
band (broad) centred at 3182 cm−1, with νC≡N at 2205 cm−1, νCO
(thiazolidinone) at 1723 cm−1 and νCO (α,β-unsaturated amide)
1
at 1680 cm−1. The H NMR spectrum (DMSO-d6) exhibited
signals characterstic for three types of protons, in agreement
with the assigned structure. Furthermore, the mass spectrum
revealed the molecular ion peak at m/z 406 (M+3, 35.7%).
Compound 9 was obtained in good yield upon treatment
of 2 with phenyl isothiocyanate in KOH/DMF followed by
acidification with dilute HCl. The microanalytical and spectro-
scopic data were in agreement with the proposed structure 9.
Treatment of compound 2 with elemental sulfur and phenyl
isothiocyanate in refluxing ethanol in the presence of a
catalytic amount of triethylamine afforded the 2-thioxothia-
zolidin-5-carbohydrazide 10 (Scheme 5). The structure 10
was substantiated from the microanalytical and spectroscopic
data.
Refluxing compound 2 with 3,4-dimethoxycinnamonitrile
in boiling 1,4-dioxane in the presence of triethylamine
followed by acidification with dilute acetic acid afforded the
2′,5-dioxo-3,5-dihydro-1H-spiro{[1,2,4]triazolo[1,5-a]pyridine-
2,3′-indoline}-6,8-dicarbonitrile 11. The IR, 1H NMR and mass
spectra of 11 were in consistent with the assigned structure.
The reaction of 2 with an arylidenemalononitrile appeared
to proceed via Michael addition to give the adduct A which
undergoes two cyclisation processes and dehydrogenation to
afford the spiro compound 11 (Scheme 6).
The reaction of compound 2 with nucleophilic reagents such
as hydrazine, carbon nucleophiles and thioglycolic acid have
been investigated. Thus, hydrazinolysis of 2 with hydrazine

82 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 3
Scheme 4
hydrate (80%) in boiling 1,4-dioxane furnished a compound
with molecular formula C9H10N6O2 [M = 234 (33.3%)] which
was identified using the spectral data as the cinnoline deriva-
tive 12 (Scheme 5). The evolution of ammonia during the
course of reaction and the absence of the absorption band for
the nitrile group in the IR spectrum suggests the following
pathway (Scheme 7):
The reaction of 2 with the anion derived from ethyl cyano-
acetate in the presence of piperidine in boiling ethanol afforded
the spiropyrazolo[1,5-a]pyrimidine oxoindole derivative 13
(Scheme 5). The structure 13 was confirmed by the microana-
lytical and spectroscopic data. Thus, the IR spectrum of 13 dis-
played νNH2,NH at 3358, 3260, 3157 cm−1, νCO(ester) at 1685 cm−1
(chelated H-bonding), νCO at 1658 cm−1 and was devoid of
the stretching absorption band for the C≡N group. The mass
spectrum of 13 showed the molecular ion peak at m/z 341
(46.7%).
Furthermore, H NMR spectrum (DMSO-d6) revealed the
presence of five protons attributable to 5NH at δ 10.65 (s, 1H,
exchangeable with D2O), 10.5 (s, 1H, exchangeable with D2O),
1

JOURNAL OF CHEMICAL RESEARCH 2013 83
Scheme 7
Scheme 5
Scheme 6
Scheme 8
9.5–9.4 (d, 2H, exchangeable with D2O), 8.7 (s, 1H, exchange-
able with D2O), 7.36–6.84 (m, 4Harom.), 4.27–4.20 (q, 2H,
J = 6.5 Hz), 2.51 (s, 1H) and 1.057–1.005 (t, 3H, J = 6.5 Hz).
The reaction can be rationalised as shown in Scheme 8.
The reaction of the hydrazide 2 with thioglycolic acid in
refluxing pyridine afforded two isomeric products at (m/z 302)
which were identified as 14 and 15. The structure of com-
pounds 14 and 15 were confirmed by microanalytical and
spectroscopic data.
The formation of 14 and 15 from 2 is summarised in
Scheme 9.
Experimental
Melting points are uncorrected and were measured using an electric
melting point apparatus (G-K). The IR spectra were recorded on a
Pye-Unicam SP1200 spectrophotometer using KBr discs. The 1H
NMR spectra were determined on a Varian GEMINI 300 MHz NMR
spectrophotometer using CDCl3 or DMSO-d6 as solvent with TMS as

84 JOURNAL OF CHEMICAL RESEARCH 2013
5-Amino-3-(1,3-diphenyl-1H-pyrazol-4-yl)-N′-(2-oxoindolin-3-
ylidene)-1H-pyrazole-4-carbohydrazide (5): A mixture of 4 (1.0 g,
2.2 mmol) and hydrazine hydrate 80% (0.01 mol) in n-butanol
(20 mL) was heated under reflux for 3 h. After evaporation of the
solvent in vacuo, the solid obtained was collected by filtration and
recrystallised from petroleum ether (b.p. 60–80 °C) to give 5 as buff
crystals; m.p. 182–183 °C, yield 36%. IR (ν/cm-1): 3200, 3134 (w)
(NH), 1705 (C=O). MS m/z (%): 490 (M.+; 23), 346 (89.6), 77 (100).
Anal. Calcd for C27H22N8O2 (490.52): C, 66.11; H, 4.52; N, 22.84.
Found: C, 66.05; H, 4.35; N, 22.92.
2-Cyano-3-(ethylthio)-N′-(2-oxoindolin-3-ylidene)-3-(phenylamino)
acrylohydrazide (6): To a stirred solution of potassium hydroxide
(0.56 g, 0.01 mol) in N,N-dimethylformamide (20 mL) was added
compound 2 (2.28 g, 0.01 mol). After the mixture was stirred for
30 min., phenyl isothiocyanate (1.2 mL, 0.01 mol) was added. Stirring
was continued at room temperature for 12 h and then ethyl iodide
(0.62 mL, 0.01 mol) was added and stirring was continued for addi-
tional 6 h. The separated product was filtered off, washed several
times with cold water and recrystallised from toluene to give 6 as light
green crystals; m.p. 248–249 °C, yield 48%. IR (ν/cm−1): 3200, 3145
(NH), 2195 (C≡N), 1697 (C=O), 1640 (C=N). MS m/z (%): 391 (M.+;
12.7), 330 (70.2), 231 (43.3), 203 (64.7), 169 (38.6), 161 (58.1), 77
(100). 1H NMR (DMSO-d6) δ (ppm): 13.53 (s, 1H, NH, exchangeable
with D2O), 12.06 (s, 1H, NH, exchangeable with D2O), 11.27 (s, 1H,
NH, exchangeable with D2O), 7.54–6.93 (m, 9Harom.), 2.7–2.6 (q, 2H,
J =7.2 Hz), 1.14–1.10 (t, 3H, J = 7.5 Hz). Anal. Calcd for C20H17N5O2S
(391.45): C, 61.37; H, 4.38; N, 17.89; S, 8.19. Found: C, 61.25; H,
4.14; N, 17.67; S, 8.22%.
5-Amino-N′-(2-oxoindolin-3-ylidene)-3-(phenylamino)-1H-pyr-
azole-4-carbohydrazide (7): A mixture of 6 (1.0 g, 2.56 mmol) and
hydrazine hydrate 80% (5 mmol) in ethanol (20 mL) was heated under
reflux for 4 h. After evaporation of the solvent in vacuo, the solid
obtained was collected and recrystallised from ethanol to give 7 as
brown crystals; m.p. 223–224 °C, yield 77%. IR (ν/cm−1): 3358, 3250,
Scheme 9
an internal standard. The elemental analyses were carried out in
the Faculty of Science, Ain Shams University. MS were recorded
on Shimadzu GC-MS QP1000EX instrument in the Microanalytical
Laboratory, Cairo University. The monitoring of the progress of all
reactions was carried out by TLC.
2-Cyano-N′-(2-oxo-1,2-dihydroindol-3-ylidene)acetohydrazide
(2): A mixture of isatin (1.47 g, 0.01 mol) and cyanoacetohydrazide
(0.99 g, 0.01 mole) in 1,4-dioxane (20 mL) was warmed for 5 min.
The yellow solid which separated after slow evaporation was collected
by filtration and then recrystallised from 1,4-dioxane to give 2
as yellow crystals; m.p. 241–243 °C, yield 97%. IR (ν/cm−1): 3262,
3211, 3135 (NH), 2259 (C≡N), 1735, 1701 (C=O), 1608 (C=N). MS
m/z (%): 228 (M.+; 12.8), 160 (44.8), 132 (83.3), 104 (84.7), 77 (100).
1H NMR (DMSO-d6) δ (ppm): 11.62 (s, 1H, NH, exchangeable with
D2O), 10.8 (s, 1H, NH, exchangeable with D2O), 8.08–6.8 (m, 4Harom.),
4.32 (s, 2H, CH2). Anal. Calcd for C11H8N4O2 (228.21): C, 57.89; H,
3.53; N, 24.55. Found: C, 57.87; H, 3.55; N, 24.52%.
2-Oxo-N′-(2-oxoindolin-3-ylidene)-2H-chromene-3-carbohydrazide
(3): A mixture of 2 (1.0 g, 4.4 mmol) and salicylaldehyde (0.467 mL,
4.4 mmol) in 1,4-dioxane (20 mL) in the presence of piperidine
(0.5 mL) was stirred at room temperature for 3 h. The reaction mixture
was poured onto ice and acidified with dilute acetic acid. The precipi-
tated solid was filtered off, washed several times with cold water and
then recrystallised from toluene to give 3 as orange crystals; m.p.
218–220 °C, yield 65%. IR (ν/cm−1): 3151 (br., NH), 1736, 1716
(C=O), 1620 (C=N). 1H NMR (DMSO-d6) δ (ppm): 10.9 (s, 1H, NH,
exchangeable with D2O), 9.8 (s, 1H, NH, exchangeable with D2O),
8.4–7.0 (m, 8Harom.), 6.7 (s, 1H). MS m/z (%): 333 (M.+; 1.97), 265
(35.29), 237 (91.97), 145 (20.12), 18 (100), 91 (34.99), 90 (38.24),
565 (60.97). Anal. Calcd for C18H11N3O4 (333.3): C, 64.86; H, 3.33; N,
12.61. Found: C, 64.88; H, 3.20; N, 12.43%.
2-Cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)-N′-(2-oxoindolin-3-yli-
dene)acrylohydrazide (4): To a solution of 2 (1.0 g, 4.4 mmol) in 10%
ethanolic KOH (10 mL) and 1,3-diphenylpyrazole-4-carboxaldehyde
(1.09 g, 4.4 mmol) was added. The reaction mixture was heated under
reflux for 1 h and then allowed to cool. The precipitate that formed
was collected by filtration, washed with ethanol, dried and recrystal-
lised from EtOH–DMF (1:1) to give 4 as orange crystals; m.p. 292–
293 °C, yield 97%. IR (ν/cm−1): 3424 (br.), 3164 (w), 2206 (C≡N),
1
3158 (NH, NH2), 1685 (C=O), 1658 (C=N). H NMR (DMSO-d6)
δ (ppm): 11.4 (s, 1H, NH, exchangeable with D2O), 10.1 (s, 1H, NH,
exchangeable with D2O), 9.4 (br.s, 1H, NH, exchangeable with D2O),
8.7 (br.s, 1H, NH, exchangeable with D2O), 8.3–7.0 (m, 9Harom.), 5.7
(br.s, 2H, NH2, exchangeable with D2O). MS m/z (%): 361 (M.+; 35.5),
259(52.9), 231(47.1), 160(23.5), 55(100).Anal. CalcdforC18H15N7O2
(361.36): C, 59.83; H, 4.18; N, 27.13. Found: C, 59.65; H, 4.20; N,
27.36%.
2-Cyano-2-(4-oxo-3-phenylthiazolidin-2-ylidene)-N′-(2-oxoindo-
lin-3-ylidene)acetohydrazide (8): To a stirred solution of potassium
hydroxide (0.56 g, 0.01 mol) in N,N-dimethylformamide (20 mL) was
added compound 2 (2.28 g, 0.01 mol). After the mixture was stirred
for 30 min., phenyl isothiocyanate (1.2 mL, 0.01 mol) was added to
the resulting mixture. Stirring was continued at room temperature for
12 h and then ethyl chloroacetate (1.07 mL, 0.01 mol) was added and
stirring was continued for additional 6 h. The reaction mixture was
acidified with cold dilute acetic acid. The separated solid was filtered
off, washed several times with cold water and recrystallised from
ethanol to give 8 as dark brown crystals; m.p. 204–206 °C, yield 85%.
IR (ν /cm−1): 3182 (br.), 2205 (C≡N), 1723 (C=Othiazolidinone), 1680
(C=Oα,β-unsaturated amide). MS m/z (%): 406 (M+3; 35.7), 322 (64.3), 99
1
(42.9), 55 (100). H NMR (DMSO-d6) δ (ppm): 10.78 (s, 1H, NH,
exchangeable with D2O), 10.37 (s, 1H, NH, exchangeable with D2O),
8.15–6.78 (m, 9Harom.), 3.45 (s, 2H). Anal. Calcd for C20H13N5O3S
(403.41): C, 59.55; H, 3.25; N, 17.36; S, 7.96. Found: C, 59.53; H,
3.27; N, 17.40; S, 7.93%.
2-Cyano-N′-(2-oxoindolin-3-ylidene)-3-(phenylamino)-3-thioxo-
propanehydrazide (9): To a stirred solution of potassium hydroxide
(0.56 g, 0.01 mol) in N,N-dimethylformamide (20 mL) was added
compound 2 (2.28 g, 0.01 mol). After the mixture was stirred for
30 min., phenyl isothiocyanate (1.2 mL, 0.01 mol) was added to the
resulting mixture. Stirring was continued at room temperature for
12 h. The reaction mixture was acidified with cold dilute HCl. The
solid product that separated was filtered, washed with water and
recrystallised from ethanol to give 9 as green crystals; m.p. 226–
228 °C, yield 67%. IR (υ/cm−1): 3218 (br.s) (NH), 2177 (C≡N), 1712
(C=O), 1617 (C=N), 1343 (C=S). 1H NMR (DMSO-d6) δ (ppm): 11.6
(s, 1H, NH, exchangeable with D2O), 10.0 (s, 1H, NH, exchangeable
with D2O), 8.8–7.1 (m, 10Harom.+NH), 3.3 (s, 1H).MS m/z (%): 336
(M.+–HCN, 24.7), 227 (12.6), 160 (31.3), 77 (100). Anal. Calcd for
C18H13N5O2S (363.39): C, 59.49; H, 3.61; N, 19.27; S, 8.82. Found: C,
59.21; H, 3.36; N, 19.45; S, 8.60%.
1
1701 (C=O). MS m/z (%): 456 (M-2; 4). H NMR (DMSO-d6) δ
(ppm): 10.45 (br.s, 1H, NH, exchangeable with D2O), 9.92 (s, 1H,
NH, exchangeable with D2O), 8.09 (s, 1H, olefinic proton), 9.1–6.49
(m, 15Harom.). Anal. Calcd for C27H18N6O2 (458.47): C, 70.73; H, 3.96;
N, 18.33. Found: C, 70.70; H, 3.88; N, 18.15%.

JOURNAL OF CHEMICAL RESEARCH 2013 85
4-Imino-N′-(2-oxoindolin-3-ylidene)-3-phenyl-2-thioxothiazolidin-
5-carbohydrazide (10): To a solution of compound 2 (2.28 g, 0.01 mol)
in ethanol (15 mL) containing triethylamine (0.5 mL), elemental sulfur
(0.32 g, 0.01 mol) and phenyl isothiocyanate (1.35 mL, 0.01 mol)
were added. The reaction mixture was heated at 60 °C for 2 h with
continuous stirring. After cooling, the reaction mixture was acidified
with cold dilute acetic acid. The precipitated solid was filtered off,
washed several times with cold water and recrystallised from toluene
to give 10 as reddish brown crystals; m.p. 208–209 °C, yield 79%.
IR (ν/cm−1): 3413, 3238 (br.s) (NH), 1699 (C=O), 1624 (C=N), 1364
was insoluble in toluene was recrystallised from 1,4-dioxane to give
15.
14:Yellow crystals; m.p. 200–202 °C, yield 19%. IR (ν/cm−1): 3201
(NH), 2262 (C≡N), 1725, 1696, 1619 (C=O). MS m/z (%): 302 (M.+;
1
8.8), 259 (12.5), 230 (48.0), 160 (71.3), 132 (100), 104 (77.5). H
NMR (DMSO-d6) δ (ppm): 12.63 (s, 1H, enolic OH, exchangeable
with D2O), 11.33 (s, 1H, NH, exchangeable with D2O), 7.54 (d, 1H,
J = 7.5 Hz), 7.39 (dd, 1H, J = 6.3 Hz; J = 4.5 Hz), 7.11 (dd, 1H,
J = 7.8 Hz; J = 7.5 Hz), 6.94 (d, 1H, J = 8.4 Hz), 4.41 (s, 2H), 4.21 (s,
1H). Anal. Calcd for C13H10N4O3S (302.31): C, 51.65; H, 3.33; N,
18.53; S, 10.61. Found: C, 51.62; H, 3.32; N, 18.50; S, 10.64%.
15: Brown crystals; m.p. 272–274 °C, yield 58%. IR (ν/cm-1): 3438,
3176 (NH), 1699, 1660 (C=O), 1620 (C=N). MS m/z (%): 302 (M.+;
15.5), 161 (100), 142 (56.7), 132 (10.7), 114 (29.6), 104 (28.4), 86
1
(C=S). H NMR (CDCl3) δ (ppm): 11.2 (s, 1H, NH, exchangeable
with D2O), 9.9 (s, 1H, NH, exchangeable with D2O), 8.6–7.0 (m,
9Harom.), 3.7 (br.s, 2H, exchangeable with D2O). MS m/z (%): 395 (M.+;
35.4), 235 (76.3), 207 (15.7), 161 (70.7), 135 (36.9), 104 (51.1), 77
(100). Anal. Calcd for C18H13N5O2S2 (395.46): C, 54.67; H, 3.31; N,
17.71; S, 16.22. Found: C, 54.47; H, 3.29; N, 17.96; S, 16.25%.
7-(3,4-Dimethoxyphenyl)-2′,5-dioxo-3,5-dihydro-1H-spiro{[1,2,4]
triazolo[1,5-a]pyridine-2,3′-indoline}-6,8-dicarbonitrile (11): A mix-
ture of 2 (1.0 g, 4.4 mmol) and 2-(3,4-dimethoxybenzylidene)malo-
nonitrile (0.94 g, 4.4 mol) in 1,4-dioxane (25 mL) in the presence of
triethylamine (0.5 mL) was heated under reflux for 3 h. the reaction
mixture was concentrated and acidified with cold dilute acetic acid.
The solid which separated out was filtered off, washed several times
with cold water and recrystallised from ethanol to give 11 as brown
crystals; m.p. 188–190 °C, yield 71%. IR (ν/cm−1): 3428 (NH), 2209
1
(28.4). H NMR (DMSO-d6) δ (ppm): 12.44 (br.s, 1H, enolic OH,
exchangeable with D2O), 11.76 (s, 1H, NH, exchangeable with D2O),
11.20 (s, 1H, NH, exchangeable with D2O), 7.46 (d, 1H, J = 7.2 Hz),
7.34 (d, 1H, J = 7.8 Hz), 7.09 (d, 1H, J = 7.8 Hz), 6.93 (d, 1H, J =
7.8 Hz), 3.80 (s, 2H), 3.29 (s, 1H). Anal. Calcd for C13H10N4O3S
(302.31): C, 51.65; H, 3.33; N, 18.53; S, 10.61. Found: C, 51.62; H,
3.31; N, 18.55; S, 10.64%.
Received 16 September 2012; accepted 3 December 2012
Paper 1201426 doi: 10.3184/174751912X13567100793191
Published online: 13 February 2013
1
(C≡N), 1699 (C=O). H NMR (CDCl3) δ (ppm): 11.4 (s, 1H, NH,
exchangeable with D2O), 9.9 (s, 1H, NH, exchangeable with D2O), 8.7
(s, 1H, NH, exchangeable with D2O), 8.2–6.9 (m, 7Harom.), 3.89 (s, 6H,
2OMe). MS m/z (%): 412 (M–CO, 26.1), 252 (17.4), 216 (39.1), 119
(56.5), 92 (52.2), 51 (100). Anal. Calcd for C23H16N6O4 (440.41): C,
62.72; H, 3.66; N, 19.08. Found: C, 62.37; H, 3.46; N, 19.11%.
1-(3-Oxo-2,3-dihydrocinnolin-4(1H)-ylidene)carbonohydrazide
(12): A mixture of 2 (1.0 g, 4.4 mmol) and hydrazine hydrate 80%
(0.01 mol) in 1,4-dioxane (20 mL) was heated under reflux for 2 h. the
solid formed after cooling was collected by filtration and recrystal-
lised from ethanol to give 12 as pale green crystals; m.p. 244–246 °C,
yield 72%. IR (ν/cm−1): 3358 (s), 3154 (br.) (NH), 1686, 1656 (C=O).
MS m/z (%): 234 (M.+; 33.3), 132 (20.5), 105 (43.6), 91 (56.4), 51
(100). Anal. Calcd for C9H10N6O2 (234.21): C, 46.15; H, 4.30; N,
35.88. Found: C, 46.38; H, 4.18; N, 35.68.
Ethyl 5′-amino-2,7′-dioxo-4′,7′-dihydro-1′H-spiro[indoline-3,2′-
pyrazolo[1,5-a]pyrimidine]-3′-carboxylate (13): To a solution of
compound 2 (1.0 g, 4.4 mmol) in ethanol (20 mL) containing piperi-
dine (0.5 mL), ethyl cyanoacetate (0.49 g, 4.4 mmol) was added. The
reaction mixture was heated under reflux for 3 h, then poured on ice
and acidified with dilute acetic acid. The precipitated solid was
filtered off, washed several times with cold water and recrystallised
from ethanol to give 13 as brown crystals; m.p. 212–214 °C, yield
32%. IR (ν/cm−1): 3358, 3260, 3157 (NH2, NH), 1685 (C=Oester, che-
lated H-bonding), 1658 (C=O). MS m/z (%): 341 (M.+; 46.7). 1H NMR
(DMSO-d6) δ (ppm): 10.65 (s, 1H, NH, exchangeable with D2O),
10.5 (s, 1H, NH, exchangeable with D2O), 9.50–9.40 (d, 2H, NH2,
exchangeable with D2O), 8.70 (s, 1H, NH, exchangeable with
D2O),7.36–6.84 (m, 4Harom.), 4.27–4.20 (q, 2H, J = 6.5 Hz), 2.51 (s,
1H), 1.03 (t, 3H, J = 6.5 Hz). Anal. Calcd for C16H15N5O4 (341.32): C,
56.30; H, 4.43; N, 20.52. Found: C, 56.12; H, 4.40; N, 20.45%.
2-Cyano-N-(2,4′-dioxospiro[indoline-3,2′-thiazolidine]-3′-
yl)acetamide (14) and 2-(4-oxo-4,5-dihydrothiazol-2-yl)-N′-(2-oxoin-
dolin-3-ylidene)acetohydrazide (15): A mixture of compound 2
(1.0 g, 4.4 mmol) and thioglycolic acid (0.3 mL, 4.4 mmol) in dry
pyridine (20 mL) was heated under reflux for 3 h. after cooling the
reaction mixture was poured on ice cold acetic acid. The separated
solid was filtered off, washed several times with cold water and recrys-
tallised from toluene to give 14. The remaining solid product which
References
1
2
3
4
5
L. Zhou, Y. Liu, W. Zhang, P. Wei, C. Huang, J. Pei, Y. Yuan and L. Lai,
J. Med. Chem., 2006, 49, 3440.
M.E. Matheus, F.A. Violante, S.J. Garden, A.C. Pinto and P.D. Fernandes,
Eur. J. Pharmacol., 2007, 556, 200.
P.Yogeeswari, D. Sriram, R. Thirumurugan, J.V. Raghavendran, K. Sudhan,
R.K. Pavana and J. Stables, J. Med. Chem., 2005, 48, 6202.
K.L. Ine, J.M. Locke, M. Ranson, S.G. Pyne, and J.B. Bremner, J. Med.
Chem., 2007, 50, 5109.
J.M. Da Silva, S.J. Garden and A.C. Pinto, J. Braz. Chem. Soc., 2001, 12,
273.
6
7
V. Glover, J.M. Halket and P.J. Watkins, J. Neurochem., 1988, 51, 656.
S.K. Bhattacharya, V. Glover and I. McIntyre, Neurosci. Lett., 1982, 92,
218.
8
9
Z.H. Chohan, H. Pervez, and A. Rauf, J. Enz. Inhib. Med. Chem., 2004, 19,
417.
S.N. Pandeya, S. Smitha, M. Jyoti and S.K. Sridhar, Acta Pharm., 2005, 55,
27.
10 S. Bondock, A.E.G. Tarhoni and A.A. Fadda, Arkivoc, 2006, ix, 113.
11 A.P.M. Marcos, N.M. Dayse, P.F. Clarissa, L.N.Z. Kelvis and G.B. Helio,
J. Braz. Chem. Soc., 2008, 19, 1361.
12 M.R. Mahmoud, A.K. E1-Ziaty, M.F. Ismail and S.A. Shiba, Eur. J. Chem.,
2011, 2, 347.
13 M.R. Mahmoud, M.M. El-Shahawi and F.S.M. Abu El-Azm, Eur. J. Chem.,
2011, 2, 404.
14 M.R. Mahmoud, H.M.F. Madkour, E.A.A. El-Bordany and S.A. Soliman,
Eur. J. Chem., 2011, 2, 475.
15 M.R. Mahmoud, M.M. El-Shahawi, F.S.M. Abu El-Azm and S.E. Farahat,
Am. J. Org. Chem., 2011, 1, 14.
16 M.R. Mahmoud, W.S.I. Abou-Elmagd, H.A. Derbala and M.H. Hekal,
Chinese J. Chem., 2011, 29, 1446.
17 M.R. Mahmoud, W.S.I. Abou-Elmagd, S.S. Abd El-Wahab and
S.A. Soliman, J. Chem. Res., 2012, 66.
18 M.R. Mahmoud, W.S.I. Abou-Elmagd, H.A. Derbala and M.H. Hekal,
J. Chem. Res., 2012, 75.
19 M.R. Mahmoud, H.M.F. Madkour, M.M. Habashy and A.M. El-Shwaf,
Am. J. Org. Chem., 2012, 2, 39.
20 M.R. Mahmoud, A.K. E1-Ziaty and A.M. Hussein, World Appl. Sci. J.,
2012, 17, 101.
21 Y.S. Mohammed, H.A.A. Regaila, A.K.M. Gohar, F.F. Abdel-Latif and
E. Kh. Ahmed, Egypt. J. Pharm. Sci., 1988, 29, 419. [Chem. Abstr., 1989,
110, 231374].

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.