Action of Hydrazines on 2-(2-Oxindolin-3-ylidene)malononitrile, (E,Z)-Ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate and Isatin-β-thiosemicarbazone as a Source of Spiro Indoline-pyrazole Systems

Article abstract of DOI:10.1002/jhet.2163

2-(2-Oxindolin-3-ylidene)malononitrile (1a) or (E,Z)-ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate (1b) or isatin-β-thiosemicarbazone (1c) undergoes reactions with prototype hydrazine hydrate itself and some of its simple congeners to give hydrazone derivatives bearing indoline-2-one moiety (2). The hydrazone derivatives (2) when heated with acetyl acetone or ethyl acetoacetate in dry pyridine afforded the spiro indoline derivatives (3a, 3b). Also, cinnoline derivative (9) is obtained by action of hydrazine hydrate on the N-acetyl derivative of (6a). The structures of the newly synthesized compounds were evaluated by IR, ¹H-NMR spectroscopy, mass spectra and elemental analyses.

Full text of DOI:10.1002/jhet.2163

Month 2014
Action of Hydrazines on 2-(2-Oxindolin-3-ylidene)malononitrile, (E,Z)-
Ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate and Isatin-
β-thiosemicarbazone as a Source of Spiro Indoline-pyrazole Systems
*
Ahmed S. A. Youssef, Magdy M. Hemdan, Samir A. Emara, and Rabaa M. Kamel
Department of Chemistry, Faculty of Science, Ain Shams University, P. O. Box 11566, Abbassia, Cairo, Egypt
*
E-mail: ahmedy84@hotmail.com
Received October 2, 2013
DOI 10.1002/jhet.2163
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
2-(2-Oxindolin-3-ylidene)malononitrile (1a) or (E,Z)-ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate (1b)
or isatin-β-thiosemicarbazone (1c) undergoes reactions with prototype hydrazine hydrate itself and some of
its simple congeners to give hydrazone derivatives bearing indoline-2-one moiety (2). The hydrazone
derivatives (2) when heated with acetyl acetone or ethyl acetoacetate in dry pyridine afforded the spiro
indoline derivatives (3a, b). Also, cinnoline derivative (9) is obtained by action of hydrazine hydrate on
the N-acetyl derivative of (6a). The structures of the newly synthesized compounds were evaluated by IR,
1H-NMR spectroscopy, mass spectra and elemental analyses.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
hydrate such as phenylhydrazine, 2-pyridylhydrazine, and
benzoyl hydrazine in ethanol afforded the hydrazide deriva-
tives 2b–d in good yields. Moreover, the reaction of 1b with
hydroxyl amine hydrochloride yielded the oxime derivative
2e as shown.
The interest in isatin derivatives stems from their pharmaco-
logical [1,2] and industrial application [3,4]. Substituted isatins
are found in plants: melosatin alkaloids can be obtained from
the caribbean tumorigenic plant Melochia tomentosa [5–7] as
well as in fungi; 6-(3′-methylbuten-2′-yl)isatin was isolated
from Streptomyces albus [8,9]. N-substituted isatins [10] are
reported to show a wide range of biological activities such as
antibacterial [11], anti-fungal [12,13], antiviral [14], anti-HIV
[15,16] and anti-leukemia [17]. These compounds were also
reported to have effects on central nervous system [18,19].
Isatin and a number of its derivatives posses a reactive
carbonyl group that readily undergoes condensation reactions
under mild conditions [20]. It was therefore suitable as a
precursor for the synthesis of heterocycles incorporating spiro
indolines [21,22] for pharmacological evaluation [23], medic-
inal application as muscle relaxants, and anti-inflammatory
agents [24,25].
In view of these observations, we have now investigated the
reaction of 2-(2-oxindolin-3-ylidene)malononitrile (1a) or (E,
Z)-ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate (1b) or
isatin-β-thiosemicarbazone (1c) with hydrazine derivatives to
explore the possibility of the formation of novel spiro system
incorporating indole and pyrazole moieties.
Treatments of 2-(2-oxindolin-3-ylidene)malononitrile
(1a), (E,Z)-ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate
(1b), or isatin-β-thiosemicarbazone (1c) in ethanol under
heating with the prototype hydrazine hydrate itself afforded
the hydrazone derivative 2a in one-pot reaction. In addition,
the reactions of 1a, b with the congeners of hydrazine
The structures of compounds 2a–e were substantiated
from their microanalytical and spectral data. Thus, their
IR spectra show bands corresponding to NH and CO, as
well as a band for OH in case of 2e. Further support for
the assigned structures of compounds 2a–e was gained
from 1H-NMR spectra, which exhibit signals characteristic
for aromatic protons in addition to NH and OH protons in
the downfield region exchangeable with D2O. The
configurational assignment of compounds 2a–e as the Z-
configurated isomers was based on the higher δ values
for the signals of NH or OH protons and the lower
frequency of absorption for carbonyl group, which
suggests their existence as their chelated forms shown.
1
Inspection of H-NMR spectrum of compound 2a shows
its existence as a mixture of syn and anti in a ratio of
74 : 26 (see Experimental section). Moreover, the mass
spectral data are in accord with their proposed structures
as they show the molecular ion peaks as well as some of
important peaks.
© 2014 HeteroCorporation

A. S. A. Youssef, M. M. Hemdan, S. A. Emara, and R. M. Kamel
Vol 000
malononitrile (4) and ethyl 2-(2-benzamidophenyl)-3,3-
dicyanoacrylate 5 (cf. Equation 1). Compound 5 is formed
during crystallization with ethanol.
The formation of compounds 2a–e can be rationalized
on the basis of expulsion of the dicyanomethylene, cyanoc
arboethoxymethylene, or thiosemicarbazonyl groups with
the formation of imine derivatives as depicted in Schemes 1
and 2. H2S Gas was evolved during the reaction progress
of 1c with hydrazine hydrate, which was detected by black-
ening of a paper wet with lead acetate solution.
The structures of compounds 4 and 5 are evidenced from
their IR spectrum that displayed bands corresponding to NH,
CN, CO (ester), and CO (amide). Their 1H-NMR spectrum
is in accord with the proposed structures as it showed
signals for NH, ethyl, and aromatic protons. Another
support for the existence of this adduct as a mixture of the
two compounds 4 and 5 is gained from mass spectrum. This
is evidenced from GCMS diagram, which exhibits two
bands, one corresponding to the compound 4 and the other
to compound 5. The mass spectrum of 4 does not show the
molecular ion peak, instead it shows [M+ – (CO + HCN)]
peak. However, the MS for compound 5 shows the correct
molecular ion peak beside some of important peaks. On do-
ing crystallization of the previous adduct using benzene in-
stead of ethanol, we get the compound 4 as the sole product.
This is a good proof for the incorporation of ethanol in the
formation of compound 5.
The hydrazone derivative 2a when heated with ace-
tyl acetone or ethyl acetoacetate in dry pyridine afforded
the spiro derivatives 3a, b. The IR spectra of compounds
3a, b show absorption bands correlated with NH, C═O
1
and C═N groups. Their H-NMR spectra exhibit signals
corresponding to NH, OH, CH3, and aromatic protons,
as well as signals for CH3CH2 protons in case of 3b.
The appearance of a signal in the downfield region at δ
14 corresponding to OH proton suggests the existence of
compounds 3a, b in solution as their chelated lactim
forms shown.
Heating of compounds 1a, b in acetic anhydride
furnished a mixture of N-acetyl and O-acetyl derivatives
6a, b as well as the quinoline derivative 7 in case of 1a
(cf. Equation 2). All Attempts to separate the isomeric
components 6a, b by fractional crystallization or column
chromatography failed because of the low percentage of
O-acetyl derivative and the small difference in the RF for
the two isomers. On the other hand, compound 7 was obtained
on heating of 1a with glacial acetic acid then crystallization of
the adduct with ethanol. The existence of compounds 6a, b as
mixtures of N-acetyl and O-acetyl isomers in the ratios of
The authors aimed to undergo benzoylation or acyla-
tion to compounds 1a, b hoping to prevent the removal
of dicyanomethylene or cyanocarboethoxymethylene
moiety by the action of hydrazine derivatives. Thus,
refluxing of 1a with benzoyl chloride in dry acetone in
the presence of anhydrous potassium carbonate as a base
yielded an adduct that was proved to be a mixture of two
compounds, the 2-(1-benzoyl-2-oxindolin-3-ylidene)
1
71 : 29 and 62 : 38% were evidenced from their H-NMR
spectra that show also two singlet signals corresponding to
N-methyl and O-methyl protons at δ 2.61, 2.58, and 2.63,
2.56 ppm for 6a, b, respectively.
Scheme 2
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Action of Hydrazines on 2-(2-Oxindolin-3-ylidene)malononitrile, (E,Z)-Ethyl
2-cyano-2-(2-oxindolin-3-ylidene)acetate and Isatin-β-thiosemicarbazone
Month 2014
Treating an ethanolic solution of 6a with hydrazine
hydrate yielded the cinnoline derivative 9 as well as the
hydrazone derivative 2a in minor amounts. However,
similar treatment of 6b with hydrazine hydrate gave the
N-acetyl hydrazone 10 and small amounts of the hydrazone
derivative 2a. The structure of 9 is deduced from microan-
alytical and spectral data. Its IR spectrum shows bands
characteristic for NH, CN, CO (ester), and CO (amide).
1
The structures of 6a, b were deduced from their micro-
analytical and spectral data. Thus, their IR spectra show
bands correlated with CN and CO groups. Further evidence
was gained from their 1H-NMR spectra that displayed
signals corresponding to aliphatic and aromatic protons.
The H-NMR spectrum is in accord with the suggested
structure.The higher δ value for the signal of NH proton
suggests the existence of 9 as its chelated form shown. Its
MS shows the molecular ion peak, beside some of impor-
tant peaks, which is in accord with the proposed structure.
Compound 9 is formed from the N-acetyl isomer as
depicted in Scheme 4. However, compound 2a is formed
from the O-acetyl isomer through the attack of hydrazine
at the carbonyl function of O-acetyl group with concomi-
tant removal of the dicyanomethylene group by the attack
with another molecule of hydrazine hydrate (cf. Scheme 1).
The structure of compound 10 is substantiated from its
microanalytical and spectral data. Its IR spectrum shows
1
The appearance of two singlet signals in H-NMR spectra
of 6a, b corresponding to two methyl protons is in accord
with their existence as a mixture of N-acetyl and O-acetyl
derivatives. The mass spectrum of 6a exhibits the correct
molecular ion peak in addition to other important peaks.
The structure of quinoline derivative 7 was ascertained
from its spectral data, which were in accord with the
suggested structure. The formation of compounds 6a and
7 can be rationalized as shown in Scheme 3.
1
bands attributable to NH2, NH, and CO groups. The H-
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. A. Youssef, M. M. Hemdan, S. A. Emara, and R. M. Kamel
Vol 000
Scheme 4
3-ylidene)acetate proceeds through attack at β carbon of 2-
oxindoline moiety with extrusion of the dicyanomethylene
group or cyanocarboethoxymethylene group.
EXPERIMENTAL
Melting points were measured on an electrothermal melting
point apparatus and were uncorrected. The elemental analyses
were done on a Perkin-Elemer 2400 CHN elemental analyzer.
The IR spectra were recorded on FTIR Maltson (infinity series)
spectrophotometer as KBr discs. The 1H-NMR spectra were
measured on Varian Gemini 300 MHz spectrometer, with chemi-
cal shift (δ) expressed in ppm downfield from TMS as internal
standard, in DMSO-d6. Mass spectra were determined on
Shimadzu GC-MSQP 1000 EX instrument operating at 70 eV.
TLC was run using TLC aluminum sheets silica gel F254 (Merck).
It was carried out the monitoring of the progress of all reactions
and homogeneity of the synthesized compounds.
NMR spectrum displays two broad doublet signals for 2
NH protons, singlet signal for CH3 protons and multiplet
signals for aromatic protons. The appearance of two signals
for protons of NH2 group as two broad doublets instead of
one broad singlet signal equivalent to two protons is a good
evidence for the magnetic non-equivalence of the two
protons, which was produced because of chelation. This
suggests the existence of 10 in the syn conformation.
Recalling 10 is formed from the N-acetyl isomer; however,
2a is formed from O-acetyl isomer (cf. Scheme 1).
2-(2-Oxindolin-3-ylidene)malononitrile (1a) or (E,Z)-ethyl 2-cyano-
2-(2-oxindolin-3-ylidene)acetate (1b) or isatin-β-thiosemicarbazone
(1c) were synthesized as mentioned in the literatures [26,27].
Reactions of 1a–c with hydrazine hydrate and its derivatives.
A
mixture of 1a–c 1.5 g (0.007 mol) and hydrazine hydrate 1.5 ml,
phenylhydrazine 0.76 g, 2-pyridyl hydrazine 0.76 g, or benzoyl
hydrazine 0.95 g in 30 ml ethanol was refluxed for 7 h. The
reaction mixture was concentrated and left to cool. The
precipitated solid was filtered and recrystallized from suitable
solvent to give.
(Z,E)-3-Hydrazonoindolin-2-one (2a). This compound was
obtained as yellow crystals (ethanol), (78–98%), mp 228–230°C;
IR: 3356, 3152 NH, 3050 aryl-H, 1686 CO 1659 C═N, 1589,
1
1551 C═C, 748 cmÀ1; H-NMR (dimethylsulphoxide-d6): δ 6.86
Similar treatment of 6a, b with phenylhydrazine yielded
an adduct that could have one of the two possible struc-
tures 11 or 12 beside compound 2b in minor amounts. The
IR and 1H-NMR spectra of this adduct are in agreement with
the two suggested structures and cannot differentiate
between them. The appearance of a peak at m/z 279 that
corresponds to the molecular ion of compound 11 is a good
evidence for the existence of this adduct as structure 11 and
not 12. It is worth to mention that compound 11 is formed
from the N-acetyl isomer through extrusion of dicyan
omethylene or cyanocarboethoxymethylene moiety. How-
ever, 2b is formed from the O-acetyl isomer by the same
route in addition to the removal of acetyl group by the attack
with another molecule of phenylhydrazine.
(d, 1H, Hd, Jo = 6.9 Hz), 6.98 (t, 1H, Hc, Jo = 6.9, 7.8Hz), 7.15
(t, 1H, Hb, Jo = 6.9, 7.8 Hz), 7.36 (d, 1H, Ha, Jo = 7.5 Hz), 10.09
(br.s, 1H, NHCO, exchangeable); For anti isomer (E-isomer): 8.78
(d, 1H, NHb’, exchangeable), 10.37 (d, 1H, NHa′, exchangeable);
For syn isomer (Z-isomer): 9.58 (d, 1H, NHb, exchangeable),
10.52 (d, 1H, NHa, exchangeable); ms: m/z 161 (M+.), 160
(M+ À 1), 144 (M+ À OH), 133 (M+ À CO), 104, 91, 75, 62. Anal.
Calcd. for C8H7N3O: C, 59.62; H, 4.38; N, 26.07. Found: C, 59.
23; H, 4.12; N, 25.87.
(Z)-3-(2-Phenylhydrazono)indolin-2-one (2b). This compound
was obtained as yellow crystals (ethanol), (64%), mp 208–210°C; IR:
3165, 3121 NH, 3056, 3024 aryl-H, 1684 C═O, 1617 C═N, 1595,
1555 C═C, 746, 688 cmÀ1 1H-NMR (dimethylsulphoxide-d6): δ
;
6.89–7.51 (m, 9H, Ar-H), 11.20 (br.s, 1H, NHCO, exchangeable),
12.70 (br.s, 1H, NH-N, exchangeable); Anal. Calcd. for
C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.73; H, 4.34;
N, 17.82.
(Z)-3-(2-(Pyridin-2-yl)hydrazono)indolin-2-one (2c).
This
compound was obtained as yellow crystals (ethanol/dioxan),
(56%), mp 282–284°C; IR: 3186, 3138 NH, 3063, 3019 aryl-H,
1693 CO 1620 C═N, 1600, 1569 C═C, 732 cmÀ1 1H-NMR
;
(dimethylsulphoxide-d6): δ 6.91–8.24 (m, 8H, Ar-H), 11.10,
12.76 (two br.s, 2H, 2NH, exchangeable); ms: m/z 238 (M+.),
210 (M+ À CO), 209 (M+ À (CO + H)), 208, 104, 79. Anal.
Calcd. for C13H10N4O: C, 65.54; H, 4.23; N, 23.52. Found: C,
65. 66; H, 4.11; N, 23.33.
CONCLUSION
The action of nitrogen nucleophiles on 2-(2-oxindolin-3-
(Z)-N′-(2-Oxindolin-3-ylidene)benzohydrazide (2d).
This
ylidene)malononitrile, (E,Z)-ethyl 2-cyano-2-(2-oxindolin-
compound was obtained as orange crystals (ethanol), (93 %), mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Action of Hydrazines on 2-(2-Oxindolin-3-ylidene)malononitrile, (E,Z)-Ethyl
2-cyano-2-(2-oxindolin-3-ylidene)acetate and Isatin-β-thiosemicarbazone
Month 2014
278–280°C; IR: 3235, 3167 NH, 3063 aryl-H, 1689 CO
1621C═N, 1600, 1538 C═C, 753, 689 cmÀ1 1H-NMR
2-(1-Benzoyl-2-oxindolin-3-ylidene)malononitrile (4) and ethyl
2-(2-benzamidophenyl)-3,3-dicyanoacrylate (5). This compound
was obtained as white crystals (ethanol), (29%), mp 168–170°C;
IR: 3234 NH, 3059 aryl-H, 2981, 2931, 2874 alkyl-H, 2231 CN,
;
(dimethylsulphoxide-d6): δ 6.94 (d, 1H, J = 5.0 Hz), 7.09 (t, 1H,
J = 4.6 Hz), 7.37 (t, 1H, J = 4.6 Hz), 7.59 (t, 3H, J = 4.0 Hz),
7.66 (d, 1H, J = 4.1 Hz 7.87 (d, 2H, J = 4.6 Hz), 12.37 (br.s, 1H,
NH indolo exchangeable), 13.92 (br.s, 1H, NHCO,
exchangeable); ms: m/z 265 (M+), 237 (M+ À CO), 179, 160
(M+ À PhCO), 119, 117, 105 (PhCO), 77 (Ph). Anal. Calcd. for
C15H11N3O2: C, 67.92; H, 4.18; N, 15.84. Found: C, 67.78; H,
4.02; N, 15.66.
1
1728 CO ester, 1660 CO amide, 1576 C═C, 695, 770cmÀ1; H-
NMR (dimethylsulphoxide-d6): δ 1.45 (t, 3H, CH3CH2O–, J = 7.2,
7.5 Hz), 4.58 (q, 2H, CH3CH2O–, J = 7.2 Hz), 7.57–8.14 (m, 9H,
Ar-H), 11.87 (br.s, 1H, NH, exchangeable); ms: m/z for
compound 4: 245 (M+ À (CO+ HCN)), 169, 142, 141, 122, 114,
105 (PhCO), 77 (Ph); for compound 5: 345 (M+), 344 (M+ À H),
317 (M+ À CO), 316, 140, 105 (PhCO), 77 (Ph).
Reaction of 1b with hydroxylamine hydrochloride.
A
solution of 1b 0.5 g (0.0021 mol) in ethanol (15 mL), hydroxylamine
hydrochloride 0.14g (0.0023 mol), and ammonium acetate 0.14 g
(0.0018 mol) was refluxed for 4 h. The precipitated solid was
filtered off and recrystallized to afford.
Reactions of 1a, b with acetic anhydride. A solution of 1a
or b 1 g in 10mL acetic anhydride was refluxed for 7 h. Concentrate
the reaction mixture, filter the solid precipitated and then
fractionally crystallize the compounds 6a and 7 produced in case
of 1a.
(Z)-3-(Hydroxyimino)indolin-2-one (2e).
This compound
was obtained as orange crystals (ethanol), (80%), mp 206–208°C;
IR: 3400–2600 br. OH, 3181 NH, 3089 aryl-H, 1713 CO, 1662
2-(1-Acetyl-2-oxindolin-3-ylidene)malononitrile and 3-(dicyano-
methylene)-3H-indol-2-yl acetate (6a).
This compound was
1
C═N, 1618 C═C, 751cmÀ1; H-NMR (dimethylsulphoxide-d6):
obtained as red crystals (pet. ether 60–80), (20%), mp 162–164°C;
δ 6.83 (d, 1H, J = 4.6 Hz), 6.97 (t, 1H, J = 4.6 Hz), 7.30 (t, 1H,
J = 4.6 Hz), 7.89 (d, 1H, J = 4.6 Hz), 10.67 (br.s, 1H, NH,
exchangeable), 13.26 (br.s, 1H, OH, exchangeable); ms: m/z 162
(M+), 145 (M+ À OH), 134 (M+ À CO), 117, 116, 102. Anal.
Calcd. for C8H6N2O2: C, 59.26; H, 3.73; N, 17.28. Found: C,
58.98; H, 3.68; N, 17.56.
IR: 3077, 3019 aryl-H, 2934, 2827 alkyl-H, 2223 CN, 1760, 1712
CO, 1587 C═C, 760 cmÀ1 1H-NMR (dimethylsulphoxide-d6): δ
;
2.49 (s, 3H, OCOCH3), 2.58 (s, 3H, NCOCH3), 7.37–8.27 (m, 4H,
Ar-H); ms: m/z 237 (M+), 196, 195 (M+ À CH2═C═O), 168, 167.
Anal. Calcd. For C13H7N3O2: C, 65.82; H, 2.97; N, 17.71. Found:
C, 65.63; H, 3.13; N, 17.52.
Reactions of 2a with acetyl acetone and ethyl acetoacetate.
A
Ethyl 2-amino-3-cyanoquinoline-4-carboxylate (7).
This
solution of 2a 0.5 g (0.0031 mol) and acetyl acetone 0.32 g or ethyl
acetoacetate 0.57 g in pyridine (15 mL) was refluxed for 7 h, then
poured onto cold dilute HCl. The precipitated solid was filtered and
recrystallized from a suitable solvent to give.
compound was obtained as yellow crystals (ethanol), (10 %),
mp 175–178°C; IR: 3409, 3322, 3149 NH2, 3087 aryl-H, 2980,
2932 alkyl-H, 2223 CN, 1726 CO ester, 1658 C═N, 1613
C═C, 762 cmÀ1 1H-NMR (dimethylsulphoxide-d6): δ 1.40 (t,
;
4′-Acetyl-5′-methyl-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one
(3a). This compound was obtained as red crystals (ethanol), (54%),
mp 206–208°C; IR: 3118 NH, 3065 aryl-H, 2987 alkyl-H, 1701 CO
1616 C═N, 1550 C═C, 739cmÀ1; 1H-NMR (dimethylsulphoxide-
d6): δ 2.10 (s, 3H, CH3CO), 2.24 (s, 3H, CH3-pyrazole), 5.54 (s, 1H,
CH-pyrazole), 6.89 (d, 1H, Jo = 7.8 Hz), 7.02 (t, 1H, Jo = 7.8 Hz,
Jm = 1.2 Hz), 7.29 (d, 1H, Jo = 7.5Hz, Jm = 1.2 Hz), 7.47 (d, 1H,
Jo = 7.5 Hz), 10.97 (br.s, 1H, NH, exchangeable),14.80 (br.s, 1H,
OH, exchangeable); ms: m/z 244 (M+ + 1), 243 (M+), 228, 215
(M+ À CO), 200 (M+ À CH3CO), 199, 184, 174, 149, 147, 146,
132, 131, 118, 117, 104, 102, 98, 97, 96, 77, 76. Anal. Calcd. for
C13H13N3O2: C, 64.19; H, 5.39; N, 17.27. Found: C, 63. 93; H,
5.16; N, 17.06.
3H, CH3CH2O–, J = 6.9, 7.2 Hz), 4.58 (q, 2H, CH3CH2O–,
J = 6.9, 7.5 Hz), 7.31–8.04 (m, 4H, Ar-H), 7.19 (br.s, 2H, NH2,
exchangeable); ms: m/z 242 (M+. + 1), 241 (M+), 213
(M+ À CO), 196, 184, 169, 168, 142, 141, 114, 76, 75. Anal.
Calcd. For C13H11N3O2: C, 64.72; H, 4.60; N, 17.42. Found: C,
64.33; H, 4.93; N, 17.22.
Ethyl 2-cyano-2-(1acetyl-2-oxindolin-3-ylidene)acetate and ethyl
2-cyano-2-(2-acetoxyindolin-3-ylidene)acetate (6b). This compound
was obtained as yellow crystals (ethanol), (90 %), mp 97–100°C; IR:
3124, 3095 aryl-H, 2992, 2940, 2909 alkyl-H, 2213 CN, 1756, 1731
C═O, 1623 C═N, 1594 C═C, 755 cmÀ1
;
1H-NMR
(dimethylsulphoxide-d6): For N-acetyl isomer
δ 1.32 (t, 3H,
COOCH2CH3, J= 6.9, 7.2 Hz), 2.63 (s, 3H, COCH3), 4.45 (q, 2H,
COOCH2CH3, J= 6.9, 7.2 Hz), 7.29 (t, 1H, Jo =7.2, 7.8Hz,
Jm = 1.5 Hz), 7.62 (t, 1H, Jo = 8.1 Hz), 8.08 (dd, 1H, Jo = 7.5 Hz), 8.16
(t, 1H, Jo = 7.5, 7.8 Hz). For O-acetyl isomer δ 1.36 (t, 3H,
COOCH2CH3, J= 6.9, 7.2 Hz), 2.56 (s, 3H, COCH3), 4.47 (q, 2H,
COOCH2CH3, J= 6.9, 7.2 Hz), 7.39 (t, 1H, Jo =7.8Hz, Jm =0.9Hz),
7.66 (m, 1H, Jo = 8.1 Hz), 8.08 (dd, 1H, Jo = 7.5 Hz), 8.16 (t, 1H,
Jo = 7.8 Hz). Anal. Calcd. For C15H12N2O4: C, 63.38; H, 4.25; N,
9.85. Found: C, 63.62; H, 4.04; N, 9.71.
Reaction of 6a, b with hydrazine hydrate. A solution of
6a or b 0.5 g (0.0018–0.0021 mol) in ethanol (20 mL) and
hydrazine hydrate (1 mL) was refluxed for 6 h. The precipitated
solid was filtered off and recrystallized from a suitable solvent
to give.
Ethyl 5′-methyl-2-oxo-2′,4′-dihydrospiro[indoline-3,3′-pyrazole]-
4′-carboxylate (3b). This compound was obtained as yellow
crystals (light petroleum 60–80/benzene), (85%), mp 156–158°C;
IR: 3238 NH, 3102 aryl-H, 2959, 2933, 2896, 2869 alkyl-H,
1703, 1654 CO, 1616 C═N, 1566 C═C, 740 cmÀ1 1H-NMR
;
(dimethylsulphoxide-d6): δ 0.90 (t, 3H, CH3CH2O–), 2.24 (s, 3H,
CH3 pyrazolo), 4.13 (q, 2H, CH3CH2O–), 5.06 (s, 1H, CH
pyrazolo), 6.90 (d, 1H, Jo = 7.8 Hz), 7.03 (t, 1H, Jo = 7.5 Hz), 7.29
(d, 1H, Jo = 7.8 Hz, Jm =1.2Hz), 7.46 (d, 1H, Jo = 7.5 Hz), 10.98
(br.s, 1H, NH, exchangeable), 14.17 (br.s, 1H, OH,
exchangeable); ms: m/z 273 (M+), 228, 227 (M+ À C2H5OH), 200
(M+ À CO2C2H5), 184, 159, 149, 141, 132, 118, 115, 102, 98, 76,
75. Anal. Calcd. for C14H15N3O3: C, 61.53; H, 5.53; N, 15.38.
Found: C, 61.58; H, 5.41; N, 15.12.
Ethyl 1-acetyl-3-cyano-1,2-dihydrocinnoline-4-carboxylate (9). This
compound was obtained as yellow crystals (ethanol), (52%), mp
154–156°C; IR: 3258 NH, 3092, 3066 aryl-H, 2983, 2931 alkyl-H,
1727 CO ester, 1680 C═O amide, 1619 C═N, 1575 C═C,
Reaction of 1a with benzoyl chloride.
A mixture of 1a
0.5 g (0.0026 mol) and benzoyl chloride 0.3 mL in 20 mL dry
acetone and dry potassium carbonate 0.5 g was refluxed for 6 h.
The reaction mixture was poured onto ice cold water. The
precipitated solid was filtered off and recrystallized to give.
771 cmÀ1
;
1H-NMR (dimethylsulphoxide-d6):
δ
1.41 (t, 3H,
CH3CH2O–, J= 6.9, 7.5 Hz), 2.18 (s, 3H, CH3CO), 4.62 (q, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. A. Youssef, M. M. Hemdan, S. A. Emara, and R. M. Kamel
Vol 000
[5] Kapadia, G. J.; Shukla, Y. N.; Choudhury, B. K.; Basak, S. P.;
Fales, H. M.; Sokoloski, E. A. J Chem Soc Chem Commun 1977, 535.
[6] Kapadia, G. J.; Shukla, Y. N.; Basak, S. P.; Sokoloski, E. A.;
Fales, H. M. Tetrahedron 1980, 36, 2441.
[7] Kapadia, G. J.; Shukla, Y. N. Planta Med 1993, 59, 568.
[8] Grafe, U.; Radics, L. J. Antibiotics 1986, 39, 162.
[9] Grafe, U.; Schade, W.; Fleck, W. Ger East Patent DD 241,
749, 24 Dec1986; Chem Abstr 1986, 107, 216174 k.
[10] Mesropyan, E. G.; Ambartsumyan, G. S. Russ J Org Chem
2001, 37, 1476.
[11] Buhfid, R.; Joly, N.; Ohmani, F.; Essassi, E. M.; Massoui, M.;
Martin, P. Lett Org Chem 2008, 3.
[12] Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Sci Pharm
1999, 67, 103.
[13] Ravichandran, V.; Mohan, S.; Kumar, K. S. Arkivoc 2007, xiv, 51.
[14] Terzioglu, N.; Karali, N.; Gursoy, A.; Pannecouque, C.;
Leysen, P.; Paeshuyse, J.; Neyts, J.; De Clercq, E. Arkivoc 2006, i, 109.
[15] Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Eur J Med
Chem 2000, 35, 249.
CH3CH2O–, J= 6.9, 7.2 Hz), 7.77–8.04 (m, 4H, Ar-H), 11.14 (br.s,
1H, NH, exchangeable); ms: m/z 271 (M+), 270 (M+ À 1), 242, 241,
240, 213, 212, 141, 106, 77 (Ph). Anal. Calcd. For C14H13N3O3: C,
61.99; H, 4.83; N, 15.49. Found C, 61.72; H, 4.29; N, 15.18.
(Z)-1-acetyl -3-hydrazonoindolin-2-one (10). This compound
was obtained as buff crystals (pet. ether 60–80/benzene), (35%), mp
148–150°C; IR: 3398, 3249, 3174 NH2, NH, 2919, 2851 alkyl-H,
1747, 1707 CO, 1594, 1557 C═N and/or C═C, 751 cmÀ1; 1H-NMR
(dimethylsulphoxide-d6): δ 2.61 (s, 3H, CH3), 7.18–8.26 (m, 4H, Ar-
H), 10.17 (broad doublet, 1H, NHb exchangeable), 10.66 (broad
doublet, 1H, NHa exchangeable). Anal. Calcd. For C10H9N3O2: C,
59.11; H, 4.46; N, 20.68. Found: C, 59.25; H, 4.22; N, 20.55.
Reactions of 6a, b with phenylhydrazine. A mixture of 6a
or b 0.5 g (0.0018–0.0021 mol) and phenylhydrazine (0.22 g) in
ethanol (20 mL) was refluxed for 6 h. The reaction mixture was
concentrated and left to stand at room temperature. The solid
formed was crystallized from a suitable solvent to give.
[16] Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Arzneil –
Forschun / Drug Res 2000, 50, 55.
[17] Matesic, L.; Lock, J. M.; Bremner, J. B.; Pyne, S. G.;
Skropeta, D.; Ranson, M.; Vine, K. L. Bioorg Med Chem 2008, 16, 3118.
[18] Bhattacharya, S. K.; Glover, V.; Mc Intyre, I.; Oxenkrug, G.;
Sandler, M. Neurosci Lett 1982, 92, 218.
[19] Bhattacharya, S. K.; Mirta, S. K.; Acharya, S. B.
J Psychopharmacol 1991, 5, 202.
[20] Da Silva, J. F. M.; Garden, S. J.; Pinto, A. J Braz Chem
2001, 12, 273.
(Z)-1-acetyl-3-(2-phenylhydrazono)indolin-2-one (11).
This
compound was obtained as yellow crystals (benzene), (78–81%),
mp 118–121°C; IR: 3229 NH, 3017 aryl-H, 2938 alkyl-H,
1707 CO, 1596, 1554 C═N and/or C═C, 689, 754 cmÀ1; H-
1
NMR (dimethylsulphoxide-d6): δ 2.68 (s, 3H, CH3CO), 7.12–
8.19 (m, 9H, Ar-H, J = 7.2, 7.8 Hz), 12.6 (br.s, 1H, NH,
excheangeable); ms: m/z 280 (M+ + 1), 279 (M+), 278 (M+ À 1),
238, 237, 236, 209, 208, 180, 160, 117, 77 (Ph), 65. Anal.
Calcd. For C16H13N3O2: C, 68.81; H, 4.69; N, 15.05. found C,
68.97; H, 4.52; N, 14.82.
[21] El-Ahl, A. S.; Afeefy, H.; Metwally, M. A. J. Chem Res
(January), 1994, 201.
[22] Joshi, K. C.; Dandia, A.; Baweja, S.; Joshi, A. J Heterocyclic
Chem 1989, 26, 1097.
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Chem Abstr 1981, 95, 25036r.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet