International Journal of Organic Chemistry, 2011, 1, 97-104
doi:10.4236/ijoc.2011.13015 Published Online September 2011 (http://www.SciRP.org/journal/ijoc)
Reactivity of 3-Cyanoacetylindole Derivatives: Synthesis
of 3-Hydrazonopyrazolyl and 3-Thiadiazolyl
Indole Derivatives
Hamdi M. Hassaneen*, Huwaida M. E. Hassaneen, Zakaria Ahmed Gomaa
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Received May 27, 2011; revised June 27, 2011; accepted July 5, 2011
Abstract
The coupling reaction of 3-cyanoacetyl-2-methylindole 1a with the aromatic diazonium salts gave the corre-
sponding arylhydrazones 2a-e. Compounds 2 were used for synthesis of 4-aminopyrazole-5-carbonitrile 4a-e
and 5-amino-4-arylazo-3-pyrazoles 5a-e derivatives. Also, treatment of 3-cyanoacetyl-2-phenylindole 1b
with phenyl isothiocyanate gave the corresponding thioacetanilide 7. The later compound 7 was utilized as
the key intermediate for the synthesis of some new thiadiazole derivatives 9a-r. The structures of all new
compounds were elucidated on the basis of elemental analysis and spectral data.
Keywords: 3-Methyl Indole, 3-Phenyl Indole, Phenyl Isothiocyanate, Cyanoacetic Acid
1. Introduction
The indole moiety is found in various pharmacologically
and biologically active compounds [1,2]. Many indole
alkaloids are recognized as one of the rapidly growing
groups of marine invertebrate metabolites for their broad
spectrum of biological properties [3-6]. For example,
five novel indole alkaloids [7,8], tunicate aplidium me-
ridianum A-E, have been isolated from tunical splidium
meridianum. They show cytotoxicity toward murine tu-
mor cell lines and have potent inhibition against several
protein kinases [9,10]. Along with these, the substitution
at the 3-position of the indole ring can take place by
connecting an additional heterocyclic ring, such as imi-
dazole (topsentins [11,12], nortopsentins [13]), dihy-
droimidazole (disc odermindole [14]), oxazole (mar-
tefragin [15], amazole [16]), oxadiazine (alboinon [17]),
maleimide (didemidines [18]), and piperazine (dragma-
cidone [19]). Therefore, 3-substituted indoles still repre-
sent a significant synthetic challenge.
2. Results and Discussion
As a part of our program aimed at developing a synthesis
for pyrazole [20] and thiadiazole derivatives [21-23], we
report here an efficient synthesis for aminopyrazoles,
which are used as precursors for biologically active fused
pyrazoles. Thus, reacting 2-methylindole with cyanoace-
tic acid in acetic anhydride, utilizing a literature proce-
dure [24], led to formation of 3-cyanoacetyl-2-methyl-
indole 1a. The latter compound 1 reacted with aromatic
diazonium salts to yield the corresponding arylhydra-
zones 2a-e in excellent yields (Scheme 1). The E-struc-
ture for hydrazones 2A was preferred over possible hy-
drogen-bonded Z-structure 2B based on analog of the
recently-reported structure of 3-substituted-2-aryl-hy-
drazono-3-oxoalkanenitriles, whose E-structure has con-
firmed by X-ray crystal structure determination [25] and
supported by theoretical calculation [26].
Compound 2 reacted readily with chloroacetonitrile in
presence of triethylamine to give products of molecular
Scheme 1. MCR of α-cyanoketenes S, S-acetals, amine and
guanidine carbonate.

H. M. HASSANEEN ET AL.
98
formula corresponding to structure 4 or its isomeric str-
ucture 3 in excellent yield. Structure 4 was readily estab-
lished based on 1H NMR data which revealed the ab-
sence of a signal for the methylene group and appearance
of two deuterium oxide exchangeable protons at δ 6.40
ppm for amino group. it is believed that 4a-e has resulted
from in stiu cyclization of the initially formed 3a-e
(Scheme 2). Also, treatment of 2a-e with hydrazine hy-
drate in refluxing ethanol gave 5-amino-4-arylazo-3- -
(indole-3`-yl)pyrazoles 5a-e in excellent yield (Scheme
2). The structures of the products 5a-e were established
on the basis of elemental analysis and spectral data (see
exeperimental).
It is known that a great variety of reactants bearing the
N=C=S fragment undergo cyclization on reaction of hy-
drazonoyl halide compounds to afford thiadiazole de-
rivatives [21-23], which have been shown to exhibit anti-
protozoal [27] and fungicidal properties [28]. Thus, the
base-catalyzed reaction of the 3-cyanoacetyl-2-phenyl-
indole 1b with phenyl isothiocyanate in dry DMF at
room temperature yielded the non-isolable potassium salt
which by treatment with dilute hydrochloric acid gave
the corresponding thioacetanilide 7 (Scheme 3). The
structure of 7 was confirmed based on analytical and sp-
ectral data (see experimental section). For example 7 had
characteristic absorption peaks in its IR spectrum at 3343,
2202, 1675 cm–1 due to NH, CN, CO groups respectively.
In addition, the mass spectrum revealed a peak at m/z =
395 corresponding to the molecular ion.
Treatment of thioacetanilide 7 with hydrazonoyl hal-
ides 8a-e in refluxing ethanol and in presence of triethy-
lamine, afforded, in each case, only the
1,3,4-thiadiazoles 9a-e (Scheme 4). Elemental analyses
and spectral data of the reaction products were in com-
plete agreement with the proposed structures. For exam-
ple 9b had characteristic absorption peaks in its IR spec-
trum at 3327, 2195 cm–1 due to NH, CN groups respec-
tively. In addition, the mass spectrum revealed a peak at
m/z = 522 corresponding to its molecular ion (see ex-
perimental section).
To study the effect of carbonyl group of hydrazonoyl
halide in the cyclization reaction, the thioacetanilide 7
was treated with hydrazonoyl halides 8f-r in refluxing
ethanol and in presence of triethylamine, afforded, in
each case, only one isomer 1,3,4-thiadiazole derivatives
9f-r (Scheme 5), which indicate that, there is no effect of
the presence of carbonyl group in the cyclization reaction.
Elemental analyses and spectral data of the reaction
products were in complete agreement with the proposed
structures. For example, 9k had characteristic absorption
peaks in its IR spectrum at 3304, 2195, 1693 cm–1 due to
NH, CN, CO groups respectively. In addition, the mass
spectrum revealed a peak at m/z = 476 corresponding to
Scheme 2. Synthesis of amino-pyrazole derivatives 4 and 5.
Scheme 3. Synthesis of thioacetanilide 7.
Scheme 4. 1,3,4-thiadiazoles 9.
the molecular ion. Its 1H NMR showed two singlet sig-
nals at δ = 2.35 and 2.61 ppm due to two methyl groups,
in addition to one singlet signal due to proton at δ 11.9
ppm represents NH group. Also, the ¹³C NMR spectrum
displayed characteristic signals at δ = 190.40, 184.27,
114.7, 25.91, 20.79 ppm due to 2CO, CN, 2CH3 carbons
respectively, in addition to all the other carbons at the
expected chemical shifts (Scheme 5).

H. M. HASSANEEN ET AL. 99
Scheme 5. Synthesis of 1,3,4-thiadiazoles 9.
3. Experimental Section
3.1. General
All melting points were determined on an electrothermal
GallenKamp melting point apparatus and are uncorrected.
The IR spectra were recorded as KBr Pellets on a Jasco
FTIR-460 plus Fourier transform infrared spectropho-
tometer.1H and 13C NMR spectra were recorded at (300
MHz) and (75 MHz) respectively on Varian EM-300
MHz spectrometer. Chemical shifts (δ) are given from
TMS (ppm) as internal standard for ¹H NMR and ¹³C
NMR. Mass spectra were recorded on AEI MS 30 mass
spectrometer operating at 70 eV. The elemental analyses
were performed at the Microanalytical Center of Cairo
University.
3.2. General Method for Preparation of
(E)-N’-aryl-2-(2-methyl-1H-indol-3-yl)
-2-oxo-acetohydrazonoyl cyanide 2a-e
A cold solution of aryldiazonium salt (10 mmol) was
prepared by adding a solution of sodium nitrite (10 mmol
in water) to a cold solution of the aromatic amine hy-
drochloride (10 mmol) with stirring. The resulting solu-
tion of the diazonium salt was added to a cold solution of
compound 1a (10 mmol) in pyridine (100 mL). The reac-
tion mixture was stirred at room temperature for 30 min.
the solid product so formed was collected, washed with
water, and crystallized from suitable solvent to afford
2a-e.
(E)-N'-(4-Chlorophenyl)-2-(2-methyl-1H-indol-3-yl)-
2-oxoacetohydrazonoyl cyanide 2a:
Orange crystals; m.p: 244˚C (acetonitrile); yield (85%);
IR (KBr): υ = 3299 (NH), 2204 (CN) cm–1; 1H NMR
(DMSO-d6): δ = 2.50 (s, 3H, indole-CH3), 7.01-7.72 (m,
8H, ArH), 11.91 (s, 1H, NH), 12.02 (s, 1H, NH). MS:
m/z (%) = 336 [M+], 307, 210, 158, 130. Anal. for
C18H13ClN4O: calcd. C, 64.19; H, 3.89; Cl, 10.53; N,
16.64. found C, 63.88; H, 3.56; Cl, 10.20; N, 16.31.
(E)-2-(2-Methyl-1H-indol-3-yl)-2-oxo-N'-p-tolylaceto-
hydrazonoyl cyanide 2b:
Yellow crystals; m.p: 207˚C (methanol); yield ( 87%);
IR(KBr): υ = 3348 (NH), 2216 (CN) cm–1; 1H NMR
(DMSO-d6): δ = 2.21 (s, 3H, CH3), 2.50 (s, 3H, in-
dole-CH3), 7.04 - 7.75 (m, 8H, Ar H), 11.85 (s, 1H, NH),
11.98 (s, 1H, NH).¹³C NMR (DMSO-d6): δ = 23.92,
29.81, 120.05, 120.12, 123.0, 194.94, 125.01, 130.01,
130.42, 131.01, 136.97, 139.15, 143.0, 144.32, 149.22,
153.32, 192.56. MS: m/z (%) = 316 [M+], 287, 210, 158,
130, 91. Anal. for C19H16N4O: Calcd. C, 72.13; H, 5.1; N,
17.71. found C, 71.81; H, 4.7; N, 17.39.
(E)-2-(2-Methyl-1H-indol-3-yl)-2-oxo-N'-phenyl-Acet-
ohydrazonoyl cyanide 2c:
Yellow crystals ; m.p: 235˚C (ethanol); yield (83%);
IR (KBr): υ = 3366 (NH), 2200 (CN) cm–1; 1
H NMR
(DMSO-d6): δ = 2.50 (s, 3H, indole-CH3), 7.03 - 7.71 (m,
9H, ArH), 11.94 (s, 1H, NH),11.98 (s, 1H, NH).MS: m/z
(%) = 302 [M+], 273, 210, 158, 130, 77. Anal. for
C18H14N4O: calcd. C, 71.51; H, 4.67; N, 18.53. found C,
71.12; H, 4.41; N, 18.28.
(E)-N'-(4-Methoxyphenyl)-2-(2-methyl-1H-indol-3-yl)-
2-oxoacetohydrazonoyl cyanide 2d:
Yellow crystals; m.p: 194˚C (ethanol); yield (77%); IR
(KBr): υ = 3265 (NH), 2201 (CN) cm–1; ¹H NMR
(DMSO-d6): δ = 2.50 (s, 3H, indole-CH3), 3.69 (s, 3H,
OCH3), 6.82 - 7.69 (m, 8H, Ar H), 11.89 (s, 1H, NH),
11.98 (s, 1H, NH). MS: m/z (%) = 332 [M+], 158, 130.
Anal. for C19H16N4O2: calcd. C, 68.66; H, 4.85; N, 16.86.
found C, 68.29; H, 4.46; N, 16.38.
(E)-2-(2-Methyl-1H-indol-3-yl)-N'-(4-nitrophenyl)-2-
oxoacetohydrazonoyl cyanide 2e:
Orange crystals; m.p: 274˚C (acetonitrile); yield (88%);
IR (KBr): υ = 3266 (NH), 2218 (CN) cm-1; 1H NMR
(DMSO-d6): δ = 2.52 (s, 3H, indole-CH3), 7.02 - 8.16 (m,
8H, ArH), 12.06 (s, 1H, NH), 12.39 (s, 1H, NH).MS: m/z
(%) = 347 [M+], 318, 158, 130. Anal. for C18H13N5O3:
calcd. C, 62.24; H, 3.77; N, 20.16. found C, 61.90; H,
3.46; N, 19.89.
3.3. General Method for Preparation of
4-amino-1-aryl-3-(2-methyl-1H-indole-3-car
bonyl)-1H-pyrazole-5-carbonitrile
Derivatives 4a-e
To a solution of 2 (5 mmol) in triethylamine (10 mmol),
chloroacetonitrile (16 mmol) was added. The reaction
mixture was refluxed for 2 h, and then poured onto cold
dilute HCl. The solid product formed was filtered off and
crystallized from suitable solvent to afford 4a-e.
4-Amino-1-(4-chlorophenyl)-3-(2-methyl-1H-indole-3-

H. M. HASSANEEN ET AL.
100
carbonyl)-1H-pyrazole-5-carbonitrile 4a:
Yellow crystals; m.p: 252˚C (acetic acid); yield (88%);
IR (KBr ): υ = 3471 & 3353 (NH2), 3313 (NH), 2212
(CN) cm–1; 1H NMR (DMSO-d6): δ = 2.50 (s, 3H, in-
dole-CH3), 6.40 (s, 2H, NH2), 7.04 - 7.81 (m, 8H, ArH),
12.02 (s, 1H, NH). MS: m/z (%) = 375 [M+], 360, 158,
130. Anal. for C20H14ClN5O: calcd. C, 63.92; H, 3.75; Cl,
9.43; N, 18.64. found C, 63.51; H, 3.50; Cl, 9.03;
N,18.22.
4-Amino-3-(2-meth yl-1H-indole-3-carbonyl)-1-p-tolyl-
1H-pyrazole-5-carbonitrile 4b:
Brown crystals; m.p: 188˚C (methanol); yield (91%);
IR (KBr): υ = 3473 & 3356 (NH2), 3312 (NH), 2212 (CN)
cm–1; 1H NMR (DMSO-d6): δ = 2.21 (s, 3H, CH3), 2.50
(s, 3H, indole-CH3), 6.41 (s, 2H, NH2), 7.05 - 7.79 (m,
8H, ArH), 11.98 (s, 1H, NH). MS: m/z (%) = 355 [M+],
340, 225, 158, 130, 91. Anal. for C21H17N5O: calcd. C,
70.97; H, 4.82; N, 19.71. found C, 70.55; H, 4.61; N,
19.33.
4-Amino-3-(2-methyl-1H-indole- 3-carbonyl)-1-phenyl-
1H-pyrazole-5-carbonitrile 4c:
Brown crystals; m.p: 204˚C (ethanol); yield (87%); IR
(KBr): υ = 3470 & 3358 (NH2), 3311 (NH), 2213 (CN)
cm–1; 1H NMR (DMSO-d6): δ = 2.50 (s, 3H, indole-CH3),
6.42 (s, 2H, NH2), 7.03 - 7.81 (m, 9H, ArH) , 12.0 (s, 1H,
NH). MS: m/z (%) = 341 [M+], 326, 158, 130, 77. Anal.
for C20H15N5O: calcd. C, 70.37; H, 4.43; N, 20.52. found
C, 69.98; H, 4.11; N, 20.13.
4-Amino-1-(4-methoxyphenyl)-3-(2-methyl-1H-indole-
3-carbonyl)-1H-pyrazole-5-carbonitrile 4d:
Brown crystals; m.p: 214˚C (acetonitrile); yield (89%);
IR (KBr): υ = 3471 & 3358 (NH2), 3313 (NH), 2213 (CN)
cm–1; 1H NMR (DMSO-d6): δ = 2.50 (s, 3H, indole-CH3),
3.82 (s, 3H, OCH3), 6.40 (s, 2H, NH2), 7.10 - 7.83 (m,
8H, Ar H), 11.95 (s, 1H, NH). MS: m/z (%) = 371 [M+],
356, 158, 130, 77. Anal. for C21H17N5O2: calcd. C, 67.91;
H, 4.61; N, 18.86. found C, 67.50; H, 4.33; N, 18.43.
4-Amino-3-(2-methyl-1H- indole-3-carbonyl)-1-(4-
nitrophenyl)-1H-pyrazole-5-carbonitrile 4e:
Brown crystals; m.p: 289˚C (acetonitrile); yield (88%);
IR (KBr): υ = 3472 & 3355 (NH2), 3311 (NH), 2217 (CN)
cm–1; 1H NMR (DMSO-d6): δ = 2.50 (s, 3H, indole-CH3),
6.54 (s, 2H, NH2), 7.08 - 8.46 (m, 8H, ArH), 12.06 (s, 1H,
NH). MS: m/z (%) = 386 [M+], 371, 158, 130, 77. Anal.
for C20H14N6O3: calcd. C, 62.17; H, 3.65; N, 21.75.
found C, 61.80; H, 3.41; N, 21.33.
3.4. General Method for Preparation of
(Z)-4-(2-Aryl-hydrazono)-5-(2-methyl-1H-in
dol-3-yl)-4H-pyrazol-3-amine derivatives
5a-e
To an appropriate compounds 2 (10 mmol) hydrazine
hydrate (10 mmol) was added in ethanol (20 mL). The
reaction mixture was refluxed for 6 h, the solvent was
evaporated and the crude product was collected then
crystallized from benzene to afford the corresponding
compounds 5a-e.
(Z)-4-(2-(4-Chlorophenyl)hydrazono)-5-(2-methyl-
1H-indol-3-yl)-4H-p yrazol-3-amine 5a:
Orange crystals; m.p: 232˚C; yield (87%); IR (KBr): υ
= 3473 & 3454 (NH2), 3356 (NH) cm–1; 1H NMR
(DMSO-d6): δ = 2.49 (s, 3H, indole-CH3), 6.19 (s, 2H,
NH2), 7.02 - 7.64 (m, 8H, ArH), 11.48 (s, 1H, NH),
12.30 (s, 1H, NH). MS: m/z (%) = 350 [M+], 335, 224.
Anal.for C18H15ClN6: calcd. C, 61.63; H, 4.31; Cl, 10.11;
N, 23.96. found C, 61.29; H, 4.10; Cl, 9.75; N, 23.48.
(Z)-5-(2-Methyl-1H-indol-3-yl)-4-(2-p-tolylhydra-zono
)-4H-pyrazol-3-amine 5b:
Yellow crystals; m.p: 235˚C; yield (89%); IR (KBr): υ
= 3468 & 3450 (NH2), 3355 (NH) cm–1; 1H NMR
(DMSO-d6): δ = 2.29 (s, 3H, CH3), 2.49 (s, 3H, in-
dole-CH3), 6.15 (s, 2H, NH2), 7.01 - 7.53 (m, 8H, ArH),
11.45 (s, 1H, NH) ,12.28 (s, 1H, NH).MS: m/z (%) = 330
[M+], 315, 224, 91. Anal. for C19H18N6: Calcd. C, 69.07;
H, 5.49; N, 25.44. found C, 68.72; H, 5.30; N, 25.01.
(Z)-5-(2-Methyl-1H-indol-3-yl)-4-(2-phenylhydrazono)
-4H-pyrazo l-3-amine 5c:
Yellow crystals; m.p: 202˚C; yield (85%); IR (KBr): υ
= 3468 & 3450 (NH2), 3353 (NH) cm–1; 1H NMR
(DMSO-d6) : δ = 2.50 (s, 3H, indole-CH3), 6.21 (s, 2H,
NH2), 7.0 - 7.62 (m, 9H, ArH), 11.43 (s, 1H, NH), 12.28
(s, 1H, NH). M: m/z (%) = 316 [M+], 301, 224, 77. Anal.
for C18H16N6: calcd. C, 68.34; H, 5.10; N, 26.56. found C,
67.98; H, 4.82; N, 26.13.
(Z)-4-(2-(4-Methoxyphenyl)hydraono)-5-(2-methyl-
1H-indol-3-yl)-4H-pyrazo l-3-amine 5d:
Yellow crystals; m.p: 180˚C; yield (80%);IR (KBr): υ
= 3389 & 3187 (NH2) cm–1; 1H NMR (DMSO-d6): δ =
2.49 (s, 3H, indole-CH3), 3.76 (s, 3H, OCH3), 6.18 (s, 2H,
NH2), 6.93 - 7.60 (m, 8H, ArH), 11.41 (s, 1H, NH),
12.11 (s, 1H, NH). MS: m/z (%) = 346 [M+], 331, 224,
123. Anal. for C19H18N6O: calcd. C, 65.88; H, 5.24; N,
24.26. found: C, 65.45; H, 5.01; N, 23.86.
(Z)-5-(2-Methyl-1H-indol-3-yl)-4-(2-(4-nitrophenyl)
hydrazono)-4H-pyrazo l-3-amine 5e:
Red crystals; m.p: 285˚C; yield (81%); IR (KBr): υ =
3467 & 3399 (NH2), 3349 (NH) cm–1; 1H NMR
(DMSO-d6): δ = 2.50 (s, 3H, indole-CH3), 6.50 (s, 2H,
NH2), 7.0 - 8.26 (m, 8H, ArH), 11.30 (s, 1H, NH), 12.18
(s, 1H, NH). MS: m /z (%) = 361 [M+], 346, 224. Anal.
for C18H15N7O2: calcd. C, 59.83; H, 4.18; N, 27.13.
found C, 59.44; H, 4.01; N, 26.87.

H. M. HASSANEEN ET AL. 101
3.5. General Method for Preparation of
(Z)-3mercapto-2-(2-phenyl-1H-indole-3-car
bonyl)-3-(phenylamino)
Acrylonitrile 7.
To a stirred solution of potassium hydroxide (0.56 g, 10
mmol) in dimethylformamide (50 mL), 3-cyan-oace-
tyl-2-phenylindole 1b (2.6 g, 10 mmol) was added. After
stirring for 30 min, phenyl isothiocyanate (1.4 g, 10
mmol) was added, and stirring was continued for further
6 h. The mixture was then poured over crushed ice con-
taining hydrochloric acid. The solid product was filtered
off, washed with water, dried and finally recrystallized
from acetonitrile to afford 7.
(Z)-3-Mercapto-2-(2-phenyl-1H-indole-3-carbonyl)-3-
(phenylamino)acrylonitrile 7:
Yellow crystals; m.p. 186˚C; yield (78%). IR (KBr): υ
= 3343 (NH), 2202 (CN), 1676 (CO) cm–1. MS: m/z (%)
= 395 [M+]. Anal. for C24H17N3OS: calcd. C, 72.89; H,
4.33; N, 10.63; S, 8.11.found C, 72.45; H, 4.10; N, 10.47;
S, 7.87.
3.6. General Procedure for the Preparation of
2-(3,5-Diaryl-1,3,4-thiadiazol-2-ylidene)-3-(2
-phenyl-1H-indole-3-yl)-3-oxo-propionitriles
9a-r .
To a solution of the thioacetanilide 7 (0.79 g, 2 mmol) in
absolute ethanol (20 mL), hydrazonoyl halides 8 (2
mmol) was added. To the resulting mixture triethylamine
(0.3 mL) was added, and the reaction mixture was re-
fluxed for 3 h and then cooled. The solid product was
filtered off, washed with ethanol and crystallized from
suitable solvent to afford the corresponding thiadiazole
derivatives 9a-r.
(Z)-2-(3,5-diphenyl-1,3,4-thiadiazol-2(3H)-ylidene)-3-
oxo-3-(2-phenyl-1H-indol-3-yl)propane-nitrile 9a:
Yellow crystals; m.p. 305˚C (dioxane); yield (79%).
IR (KBr): υ = 3277 (NH), 2199 (CN) cm–1. MS: m/z (%)
= 496 [M+]. Anal. for C31H20N4OS: calcd. C, 74.98; H,
4.06; N, 11.28; S, 6.46.found C, 74.49; H, 3.89; N, 10.92;
S, 6.17.
(Z)-3-Oxo-3-(2-phenyl-1H-indol-3-yl)-2-(3-phenyl-5-s
tyryl-1,3,4-thiadiazol-2(3H)-ylidene)prop-anenitrile 9b:
Yellow crystals; m.p. 299˚C (acetonitrile); yield (73%).
IR (KBr): υ = 3327 (NH), 2195 (CN) cm–1. 1H NMR
(CDCl3): δ = 7.18 - 7.9 (m, 21H, ArH), 8.8 (s, 1H, NH).
MS: m/z (%) = 522 [M+]. Anal. for C33H22N4OS: calcd.
C, 75.84; H, 4.24; N, 10.72; S, 6.14.found C, 75.40; H,
4.01; N, 10.43; S, 5.86.
(Z)-2-(3-(4-Nitrophenyl)-5-(thiophen-2-yl)-1,3,4-thiad
ia-zol-2(3H)-ylidene)-3-oxo-3-(2-phenyl-1H-indol-3-yl)
propanenitrile 9c:
Yellow crystals; m.p. 361˚C (dioxane); yield (80%).
IR (KBr): υ = 3340 (NH), 2203 (CN) cm–1. MS: m/z (%)
= 547 [M+]. Anal. for C29H17N5O3S2: calcd. C, 63.61; H,
3.13; N, 12.79 S, 11.71.found C, 63.19; H, 3.01; N,
12.45; S, 11.35.
(Z)-2-(5-(Furan-2-yl)-3-(4-nitrophenyl)-1,3,4-thiadiaz
ol-2(3H)-ylidene)-3-oxo-3-(2-phenyl-1H-indol-3-yl)
propanenitrile 9d:
Yellow crystals; m.p. 328˚C (acetonitrile); yield (78%).
IR (KBr): υ = 3345 (NH), 2203 (CN) cm–1. MS: m/z (%)
= 531 [M+].Anal. for C29H17N5O4S: calcd. C, 65.53; H,
3.22; N, 13.18; S, 6.03. found: C, 65.11; H, 3.0; N, 12.84;
S, 5.73.
(Z)-2-(3-(4-Nitrophenyl)-5-phenyl-1,3,4-thiadiazol-2(3
H)-ylidene)-3-oxo-3-(2-phenyl-1H-indol-3-yl)propane-
nitrile 9e:
Yellow crystals; m.p.310˚C (dioxane); yield (81%). IR
(KBr): υ = 3336 (NH), 2200 (CN) cm–1. MS: m/z (%) =
541 [M+]. Anal. for C31H19N5O3S: calcd. C, 68.75; H,
3.54; N, 12.93; S, 5.92. found: C, 68.24; H, 3.31; N,
12.61; S, 5.70.
(Z)-2-(5-Acetyl-3-phenyl-1,3,4-thiadizol-2(3H)-ylidene)
-3-oxo-3-(2-phenyl-1H-indol-3-yl)propanenitrile 9f:
Yellow crystals; m.p. 311˚C (acetonitrile); yield (76%).
IR (KBr): υ = 3300 (NH), 2194 (CN), 1693 (CO) cm–1.1H
NMR (CDCl3): δ = 2.67 (s, 3H, indole-CH3), 7.19 - 8.21
(m, 14H, Ar H), 8.56 (s, 1H, NH). MS: m/z (%) = 462
[M+]. Anal. for C27H18N4O2S: calcd. C, 70.11; H, 3.92; N,
12.11; S, 6.93. found C, 69.51; H, 3.73; N, 11.81; S,
6.70.
(Z)-Methyl-5-(1-cyano-2-oxo-2-(2-phenyl-1H-indol-3-
yl) ethylidene)-4-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-
carboxylate 9g:
Yellow crystals; m.p.247˚C (acetonitrile); yield (73%).
IR (KBr): υ = 3322 (NH), 2200 (CN), 1752 (CO), 1725
(CO) cm–1. 1H NMR (CDCl3): δ = 4.05 (s, 3H, es-
ter-CH3), 7.19 - 7.90 (m, 14H, Ar H), 8.57 (s, 1H, NH).
MS: m/z (%) = 478 [M+]. Anal. for C27H18N4O3S: calcd.
C, 67.77; H, 3.79; N, 11.71; S, 6.70.found C, 67.40; H,
3.58; N, 11.43; S, 6.49.
(Z)-Ethyl-5-(1-cyano-2-oxo-2-(2-phenyl-1H-indol-3-yl)
ethylidene)-4-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-car-
boxylate 9h:
Yellow crystals; m.p.272˚C (acetonitrile); yield (74%).
IR (KBr): υ = 3309 (NH), 2202 (CN), 1743 (CO), 1712
(CO) cm–1. 1H NMR (DMSO-d6): δ = 1.36 (t, 3H, es-
ter-CH3), 4.46 (q, 2H, ester-CH2), 7.09 - 7.63 (m, 14H,
Ar H), 11.94 (s, 1H, NH). MS: m/z (%) = 492 [M+].
Anal. for C28H20N4O3S: calcd. C, 68.28; H, 4.09; N,
11.37; S, 6.51.found C, 67.91; H, 3.92; N, 11.02; S, 6.25.
(Z)-2-(5-Benzoyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylid
ene)-3-oxo-3-(2-phenyl-1H-indol-3-yl)-propanenitrile 9i:
Yellow crystals; m.p. 282˚C (dioxane); yield (78%).

H. M. HASSANEEN ET AL.
102
IR (KBr): υ = 3316 (NH), 2202 (CN), 1650 (CO) cm–1.
MS: m/z (%) = 524 [M+]. Anal. for C32H20N4O2S: calcd.
C, 73.27; H, 3.84; N, 10.68; S, 6.11. found C, 72.92; H,
3.61; N, 10.29; S, 5.89.
(Z)-3-Oxo-3-(2-phenyl-1H-indol-3-yl)-2-(3-phenyl-5-
(thiophene-2-carbonyl)-1,3,4-thiadiazol-2(3H)-ylidene)
propanenitrile 9j:
Yellow crystals; m.p. 303˚C (acetonitrile); yield (72%).
IR (KBr): υ = 3264 (NH), 2199 (CN), 1632 (CO) cm–1.
MS: m/z (%) = 530 [M+]. Anal. for C30H18N4O2S2: calcd.
C, 67.91; H, 3.42; N, 10.56, S, 12.09. found C, 67.48; H,
3.21; N, 10.28; S, 11.81.
(Z)-2-(5-Acetyl-3-p-tolyl-1,3,4-thiadiazol-2(3H)-
ylidene)-3-oxo-3-(2-phenyl-1H-indol-3-yl)propanenitrile
9k:
Yellow crystals; m.p. 327˚C (dioxane); yield (78%).
IR (KBr): υ = 3304 (NH), 2195 (CN), 1693 (CO) cm–1.
1H NMR (DMSO-d6): δ = 2.35 (s, 3H, CH3), 2.61 (s, 3H,
CH3), 7.12-7.63 (m, 13H, ArH), 11.9 (s, 1H, NH).¹³C
NMR (DMSO-d6): δ = 20.79, 25.91, 66.26, 79.28,
111.45, 114.70, 119.68, 120.51, 122.32, 126.58, 127.17,
128.31, 128.51, 129.38, 131.80, 135.55, 139.90, 140.25,
155.68, 164.65, 184.27, 190.40. MS: m/z (%) = 476 [M+].
Anal. for C28H20N4O2S: calcd. C, 70.57; H, 4.23; N,
11.76; S, 6.73.found C, 70.09; H, 4.02; N, 11.47; S, 6.49.
(Z)-Methyl5-(1-cyano-2-oxo-2-(2-phenyl-1H-indol-3-yl)
ethylidene-4-p-tolyl-4,5-dihydro-1,3,4-thiadiazole-2-
carboxylate 9l:
Yellow crystals; m.p. 270˚C (dioxane); yield (82%).
IR (KBr): υ = 3342 (NH), 2199 (CN), 1752 (CO), 1726
(CO) cm–1. MS: m/z (%) = 492 [M+]. Anal. for
C28H20N4O3S: calcd. C, 68.28; H, 4.24; N, 11.37; S,
6.51.found C, 67.93; H, 4.01; N, 11.03; S, 6.28.
(Z)-Ethyl-5-(1-cyano-2-oxo-2-(2-phenyl-1H-indol-3-yl)
ethylidene-4-p-tolyl-4,5-dihydro-1,3,4-thiadiazole-2-
carboxylate 9m:
Yellow crystals; m.p. 280˚C (acetonitrile); yield (73%).
IR (KBr): υ = 3317 (NH), 2206 (CN), 1752 (CO), 1720
(CO) cm–1.1H NMR (DMSO-d6): δ = 1.35 (t, 3H, es-
ter-CH3), 2.34 (s, 3H, CH3), 4.45 (q, 2H, ester-CH2), 7.09
- 7.62 (m, 13H, Ar H), 11.93 (s, 1H, NH). MS: m/z (%) =
506 [M+]. Anal.for C29H22N4O3S: calcd. C, 68.76; H,
4.38; N, 11.06; S, 6.33.found C, 68.33; H, 4.15; N, 10.31;
S, 6.14.
(Z)-5-(1-Cyano-2-oxo-2-(2-phenyl-1H-indo l-3-yl)ethyl
idene)-N-phenyl-4-p-tolyl-4,5-dihydro-1,3,4-thiadiazole-
2-carboxamide 9n:
Yellow crystals; m.p. 298˚C (dioxane); yield (81%).
IR (KBr): υ =3276 (NH), 2207 (CN), 1667 (CO) cm–1.1H
NMR (DMSO-d6): δ = 2.36 (s, 3H, CH3), 7.24 - 7.82 (m,
18H, Ar H), 10.92 (s, 1H, NH), 11.87 (s, 1H, NH).13C
NMR (DMSO-d6): δ = 20.79, 66.24, 78.92, 111.53,
114.91, 119.72, 120.41, 120.65, 120.93, 122.23, 124.73,
126.99, 127.19, 128.19, 128.49, 128.60, 129.23, 131.82,
135.53, 137.28, 139.63, 140.24, 153.82, 155.96, 164.63,
184.18. MS: m/z (%) = 553 [M+]. Anal. for C33H23N5O2S:
calcd. C, 71.59; H, 4.19; N, 12.65; S, 5.79.found C,
71.12; H, 3.98; N, 12.30; S, 5.61.
(Z)-2-(5-Acetyl-3-(4-chlorophenyl)-1,3,4-thiadiazol-2(3H
)-ylidene)-3-oxo-3-(2-phenyl-1H-indol-3-yl)propanenitrile
9o:
Yellow crystals; m.p. 347˚C (dioxane); yield (81%).
IR (KBr): υ = 3312 (NH), 2194 (CN), 1692 (CO) cm–1.
MS: m/z (%) = 496 [M+]. Anal. for C27H17ClN4O2S:
calcd. C, 65.25; H, 3.45; Cl, 7.13; N, 11.27; S, 6.45.
found C, 64.76; H, 3.22; Cl, 6.85; N, 10.88; S, 6.21.
(Z)-Methyl-4-(4-chlorophenyl)-5-(1-cyano-2-(2-oxo-2-
(2-phenyl-1H-indol-3-yl)ethylidene)-4,5-dihydro-1,3,4-
thiadiazole-2-carboxylat 9p:
Yellow crystals; m.p.260˚C (dioxane); yield (80%). IR
(KBr): υ =3350 (NH), 2197(CN), 1757(CO) cm–1. 1
H
NMR (DMSO-d6): δ = 3.98 (s, 3H, ester-CH3), 7.11 -
7.68 (m, 13H, Ar H), 11.99 (s, 1H, NH).¹³C NMR
(DMSO-d6): δ = 53.84, 66.32, 79.15, 111.14, 111.70,
114.91, 119.82, 120.72, 122.49, 127.25, 128.43, 128.49,
128.67, 128.87, 129.09, 131.85, 135.14, 135.63, 136.82,
140.37, 149.24, 158.33, 164.59, 183.98. MS: m/z (%) =
512 [M+]. Anal.for C27H17ClN4O3S: calcd. C, 63.22; H,
3.34; Cl, 6.91; N, 10.92; S, 6.25.found: C, 62.81; H, 3.20;
Cl, 6.65; N, 10.59; S, 6.01.
(Z)-Ethyl4-(4-chlorophenyl)-5-(1-cyano-2-(2-oxo-2-(2-
phenyl-1H-indol-3-yl)ethylidene)-4,5-dihydro-1,3,4-
thiadiazole-2-carboxylate 9q:
Yellow crystals; m.p. 266˚C (acetonitrile); yield (79%).
IR (KBr): υ = 3302 (NH), 2202 (CN), 1758 (CO), 1720
(CO) cm–1. MS: m/z (%) = 526 [M+]. Anal. for
C28H19ClN4O3S: calcd. C, 63.81; H, 3.63; Cl, 6.73; N,
10.63; S, 6.08.found C, 63.39; H, 3.37; Cl, 6.45; N,
10.30; S, 5.81.
(Z)-4-(4-Chlorophenyl)-5-(1-cyano-2-(2-oxo-2-(2-
phenyl-1H-indol-3-yl)ethylidene)-N-phenyl-4,5-dihydro-
1,3,4-thiadiazole-2-carboxamide 9r:
Yellow crystals; m.p. 328˚C (dioxane); yield (83%).
IR (KBr): υ = 3289 (NH), 2205 (CN), 1664 (CO) cm–1.
MS: m/z (%) = 573 [M+]. Anal. for C32H20ClN5O2S:
calcd. C, 66.95; H, 3.51; Cl, 6.18; N, 12.20; S, 5.59.
found C, 66.47; H, 3.28; Cl, 5.92; N, 11.78; S, 5.24.
4. References
[1] W. J. Houlihan, W. A. Remers and R. K. Brown, Wiley,
New York, 1992.
[2] R. J. Sundberg, “The Chemistry of Indoles: Part I,” Aca-
demic Press, New York, 1996.
[3] A. Casapullo, G. Bifulco, I. Bruno and R. Riccio, “New
Bisindole Alkaloids of the Topsentin and Hamacanthin

H. M. HASSANEEN ET AL. 103
Classes from the Mediterranean Marine Sponge Rhaphi-
sia Lacazei,” Journal of Natural Products, Vol. 63, No. 4,
2000, pp. 447-451. doi:10.1021/np9903292
[4] B. Bao, Q. Sun, X. Yao, J. Hong, C. O. Lee, C. J. Sim, K.
S. Im and J. H. Jung, “Bisindole Alkaloids from a Marine
Sponge Spongosorites sp,” Journal of Natural Products,
Vol. 68, No. 5, 2005, pp. 711-715.
doi:10.1021/np049577a
[5] T. Kouko, K. Matsumura and T. Kawasaki, “Total Syn-
thesis of Marine Bisindole Alkaloids, (+)-Hamacanthins
A, B and (−)-Antipode of Cis-Dihydrohamacanthin B,”
Tetrahedron, Vol. 61, 2005, pp. 2309-2318.
[6] K. Kaniwa, M. A. Arai, X. Li and M. Ishibashi, “Synthe-
sis, Determination of Stereochemistry, and Evaluation of
New Bisindole Alkaloids from the Myxomycete Arcyria
ferruginea: An Approach for Wnt Signal Inhibitor,” Bio-
organic & Medicinal Chemistry Letters, Vol. 17, No. 5,
2007, pp. 4254-4257. doi:10.1016/j.bmcl.2007.05.033
[7] L. H. Franco, E. B. K. Joffe, L. Puricelli, M. Tatian, A. M.
Seldes and J. A. Palermo, “Indole Alkaloids from the
Tunicate Aplidium Meridianum,” Journal of Natural Pro-
ducts, Vol. 61, No. 9, 1998, pp. 1130-1132.
doi:10.1021/np970493u
[8] A. A. R. Mohamed and E.-S. Mahmound, “Synthesis and
Antitumor Activity of Indolylpyrimidines: Marine Natu-
ral Product Meridianin D Analogue,” Bioorganic & Me-
dicinal Chemistry Letters, Vol. 15, No. 3, 2007, pp. 1206-
1217. doi:10.1016/j.bmc.2006.11.023
[9] B. Jiang, C. G. Yang, W. N. Xiong and J. Wang, “Syn-
thesis and Cytotoxicity Evaluation of Novel Indo-
lylpyrimidines and Indolylpyrazines as Potential Antitu-
mor Agents,” Bioorganic & Medicinal Chemistry Letters,
Vol. 9, No. 5, 2001, pp. 1149-1154.
doi:10.1016/S0968-0896(00)00337-0
[10] M. Gompel, M. Leost, E. B. K. Joffe, L. Puricelli, L. H.
Franco, J. Palermo and L. Meijer, “Meridianins, a New
Family of Protein Kinase Inhibitors Isolated from the As-
cidian Aplidium meridianum,” Bioorganic & Medicinal
Chemistry Letters, Vol. 14, No. 7, 2004, pp. 1703-1707.
doi:10.1016/j.bmcl.2004.01.050
[11] I. Kawasaki, M. Yamashita and S. Ohta, “Successive
Diarylation at the Carbon Positions of 1H-Imidazole and
Its Application to the Total Synthesis of Nortopsentin D,”
Journal of the Chemical Society, Chemical Communica-
tions, No. 18, 1994, pp. 2085-2086.
doi:10.1039/c39940002085
[12] I. Kawasaki, M. Yamashita and S. Ohta, “Total Synthesis
of Nortopsentins A-D, Marine Alkaloids,” Chemical and
Pharmaceutical Bulletin, Vol. 44, No. 10, 1996, pp. 1831-
1839.
[13] I. Kawasaki, H. Katsuma, Y. Nakayama, M. Yamashita
and S. Ohta, “Total Synthesis of Topsentin, Antiviral and
Antitumor Bis(indolyl)imidazole,” Heterocycles, Vol. 48,
1998, pp. 1887-1901.
[14] H. H. Sun and J. Sakemi, “A Brominated (Aminoimida-
zolinyl)indole from the Sponge Discodermia Polydiscus,”
The Journal of Organic Chemistry, Vol. 56, No. 13, 1991,
pp. 4307-4308. doi:10.1021/jo00013a045
[15] H. C. Vervoort, S. E. Richards-Gross, W. Fenical, A. Y.
Lee and J. Clardy, “Didemnimides A-D: Novel, Preda-
tor-Deterrent Alkaloids from the Caribbean Mangrove
Ascidian Didemnum conchyliatum,” The Journal of Or-
ganic Chemistry, Vol. 62, No. 5, 1997, pp. 1486-1490.
doi:10.1021/jo961789s
[16] S. Takahashi, T. Matsunaga, C. Hasegawa, H. Saito, D.
Fujita, F. Kiuchi and Y. Tsuda, “Martefragin A, a Novel
Indole Alkaloid Isolated from Red Alga, Inhibits Lipid
Peroxidation,” Chemical & Pharmaceutical Bulletin, Vol.
46, No. 10, 1996, pp. 1527-1529.
[17] I. N’Diaye, G. Guella, G. Chiasera, Y. Mancini and F.
Pietra, “Almazole A and Almazole B, Unusual Marine
Alkaloids of an Unidentified Red Seaweed of the Family
Delesseriaceae from the Coasts of Senegal,” Tetrahedron
Letters, Vol. 35, No. 27, 1994, pp. 4827-4830.
doi:10.1016/S0040-4039(00)76979-6
[18] T. Bergmann, D. Schories and B. Steffan, “Alboinon, an
Oxadiazinone Alkaloid from the Ascidian Dendrodoa
grossularia,” Tetrahedron, Vol. 53, 1997, pp. 2055-2060.
[19] S. Kohmoto, Y. Kashman, O. J. McConnell, K. L. Rine-
hart Jr., A. Wright and F. Koehn, “Dragmacidin, a New
Cytotoxic Bis(Indole) Alkaloid from a Deep Water Ma-
rine Sponge, Dragmacidon sp,” The Journal of Organic
Chemistry, Vol. 53, No. 13, 1988, pp. 3116-3118.
doi:10.1021/jo00248a040
[20] H. M. E. Hassaneen, H. M. Hassaneen and M. H. Elnagdi,
“Enamines in Heterocyclic Synthesis: A Route to 4-Subs-
tituted Pyrazoles and Condensed Pyrazoles,” Z. Natur-
forch., Vol. 59b, 2004, p. 1132.
[21] N. M. Elwan, H. M. E. Hassaneen and H. M. Hasssaneen,
“Synthesis and Reactions of Indane-1,3-Dione-2-Thiocar-
boxanilides with Hydrazonoyl Halides and Active Chlo-
romethylene Compounds,” Heteroatom Chemistry, Vol.
13, No. 7, 2002, pp. 585-591. doi:10.1002/hc.10132
[22] M. A. A. Radwan, E. A. Ragab, N. M. Sabry and S. M.
El-Shenawy, “Synthesis and Biological Evaluation of New
3-Substituted Indole Derivatives as Potential Anti-In-
flammatory and Analgesic Agents,” Bioorganic & Me-
dicinal Chemistry, Vol. 15, No. 11, 2007, pp. 3832-3841.
doi:10.1016/j.bmc.2007.03.024
[23] H. M. E. Hassaneen and R. M. Pagni, “Synthesis of New
3-Substituted Indole Derivatives,” Verlag der Zeitschrift
Naturforschung, Vol. 65b, 2010, pp. 1491-1497.
[24] J. Slatt, I. Romero and J. Bergman, “Cyanoacetylation of
Indoles, Pyrroles and Aromatic Amines with the Combi-
nation Cyanoacetic Acid and Acetic Anhydride,” Synthe-
sis, 2004, pp. 2760-2765.
[25] O. M. E. El-Dusouqui, M. M. Abdelkhalik, N. A. Al-
Awadi, H. Dib, B. J. George and M. H. Elnagdi, “Chem-
istry of 2-Arylhydrazonals: Utility of Substituted 2-Ary-
lhydrazono-3-oxoalkanals as Precursors for 3-oxoalka-
nonitriles, 3-Aminoisoxazole and 1,2,3- and 1,2,4-Tria-
zoles,” Journal of Chemical Research, Vol. 2006, No. 5,
2006, pp. 295-302.
[26] I. M. Kenawi and M. H. Elnagdi, “DFT and FT-IR

H. M. HASSANEEN ET AL.
104
Analyses of Hydrogen Bonding in 3-Substistuted-3-oxo-
arylhydrazonopropanenitriles,” Spectrochimica Acta Part
A: Molecular and Biomolecular Spectroscopy, Vol. 65,
No. 3-4, 2006, pp. 805-810.
doi:10.1016/j.saa.2006.01.017
[27] S. K. Mallick and A. R. Martin, “Synthesis and Antim-
icrobial Evaluation of Some 5-(5-Nitrofurylidene)rho-
danines, 5-(5-Nitrofurylidene)thiazolidine-2,4-diones, and
Their Vinylogs,” Journal of Medicinal Chemistry, Vol.
14, No. 6, 1971, pp. 528-532. doi:10.1021/jm00288a017
[28] S. R. Singh, Journal of the Indian Chemical Society, Vol.
52, 1975, pp. 734-735.