Synthesis of new PMB-substituted indoles containing 1,3,4-oxadiazole and 1,2,4-triazole units

Article abstract of DOI:10.1002/jhet.864

A series of new indolyl-1,3,4-oxadiazole derivatives 3-7 and 10, indolyl-1,2,4-triazole derivatives 14 and 15 was prepared, using 1-(4-methoxybenzyl)-1H-indole-3-carbohydrazide (2) as a key intermediate. Some of the new compounds were evaluated for their antineoplastic activity.

Full text of DOI:10.1002/jhet.864

July 2012
Synthesis of New PMB-Substituted Indoles Containing
799
1,3,4-Oxadiazole and 1,2,4-Triazole Units
c
d
Abdel-Rahman Farghaly,a,b Norbert Haider, and Duck-Hyung Lee
*
aDepartment of Chemistry, Faculty of Science, Jazan University, Jazan 2097, KSA
bDepartment of Chemistry, Faculty of Science, Assiut University, Assiut 71516, Egypt
cDepartment of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna,
Althanstraße 14A-1090 Vienna, Austria
dDepartment of Chemistry, Sogang University, Total Synthesis of Natural Product and Medicinal
Chemistry Laboratory, 1 Shinsoo-dong, Mapo-Gu, Seoul 121-742, Korea
*
E-mail: elrahman2001@hotmail.com
Received October 22, 2010
DOI 10.1002/jhet.864
View this article online at wileyonlinelibrary.com.
A series of new indolyl-1,3,4-oxadiazole derivatives 3–7 and 10, indolyl-1,2,4-triazole derivatives 14 and
15 was prepared, using 1-(4-methoxybenzyl)-1H-indole-3-carbohydrazide (2) as a key intermediate. Some
of the new compounds were evaluated for their antineoplastic activity.
J. Heterocyclic Chem., 49, 799 (2012).
INTRODUCTION
heterocycles. This is also due to their favorable metabolic
profile and their ability to engage in hydrogen bonding. In
particular, marketed antihypertensive agents such as
tiodazosin [13] and nesapidil [14] as well as antibiotics
such as furamizole [15] contain the oxadiazole nu-
cleus. 1,3,4-Oxadiazole-containing compounds are also
useful as HIV integrase inhibitors and as angiogenesis
inhibitors [15,16]. Furthermore, they exhibit antibacte-
rial, anticonvulsant, and anticancer activities, and they
are used to fight infections involving AIDS [17–19].
They are also applied in agriculture as herbicides,
fungicides, or insecticides [20,21]. As a closely related
class of compounds, 1,2,4-triazole derivatives are
known to exhibit anti-inflammatory [22,23], antiviral
[24], analgesic [25], antimicrobial [26–28], anticonvul-
sant [29], and antidepressant activity [30]. Combina-
tion of the oxadiazole or triazole motifs with the
indole nucleus may enhance these activities. In view
of these previous findings and in continuation of our
interest in the synthesis of new biologically active
azoles and in the development of new synthetic meth-
ods [31–36], we, here, report on the synthesis and
evaluation of their antitumor activity of some new in-
dole derivatives containing 1,3,4-oxadiazole or 1,2,4-
triazole substituents at C-3.
The indole structure represents a highly relevant hetero-
cyclic system, since numerous indole-containing natural
and synthetic products such as reserpine, vincristine, indol-
micine, mitomycine, pindolol, dolasetron mesylate, indo-
methacin, or sumatriptan are being used for the treatment
of various illnesses. More specifically, several reports de-
scribe that indole-2-carbohydrazides and related com-
pounds exhibit antihistaminic [1], antidepressant [2],
MAO inhibitory [3,4], and antimicrobial activity [5]. In
addition, it was reported that various three-substituted
indoles had been used as starting materials for the synthesis
of a number of alkaloids, agrochemicals, pharmaceuticals,
and perfumes [6]. Moreover, it has been demonstrated that
introduction of heterocyclic moieties such as isothiazoles
at position 3 of the indole nucleus can enhance these biolog-
ical activities [7]. On the other hand, 1,3,4-oxadiazoles are a
class of heterocycles, which have attracted considerable in-
terest in medicinal chemistry, as they are associated with a
wide range of biological effects, including antimicrobial,
antifungal, anti-inflammatory, and antihypertensive activity
[8–12]. The widespread use of the 1,3,4-oxadiazole system
as a scaffold in medicinal chemistry establishes this moiety
and its derivatives as an important bioactive class of
© 2012 HeteroCorporation

800
A.-R. Farghaly, N. Haider, and D.-H. Lee
Vol 49
RESULTS AND DISCUSSION
obtained in 80% yield. However, when the reaction was car-
ried out in boiling dioxane, the N-substituted analogue 4 was
obtained in 69% yield (Scheme 2). The formation of oxadiazo-
lethione derivative 3 was clearly evidenced by appearance of a
characteristic absorption band at 1170 cmꢀ1 (C═S) and disap-
pearance of the absorption bands belonging to the NHNH2
group. The IR spectrum of compound 4 showed a characteris-
tic absorption band at 1758 cmꢀ1 (C═O) which revealed that
the C═O is adjacent to oxygen in the five-membered ring. The
observed debenzylation during the formation of compound 5
was evidenced by disappearance of the characteristic signals
at d 3.69, 5.42 and 6.87/7.23 ppm (OCH3, CH2 and phenyl
protons, respectively). Further confirmation for the structure
of compound 5 was obtained by HRMS which showed the
[M+K]+ ion at m/z 240.0162.
The easily accessible methyl 1-(4-methoxybenzyl)-1
H-indole-3-carboxylate (1), which has not been reported
hitherto, was chosen as the starting material. The 4-
methoxybenzyl residue should ensure balanced lipophili-
city/hydrophilicity properties of the target compounds
and, on the other hand, can be easily removed from the
indole scaffold, if desired. The compound was prepared
by reaction of methyl 1H-indole-3-carboxylate with 4-
methoxybenzyl chloride in dry dimethylformamide in the
presence of potassium carbonate under nitrogen atmo-
sphere. Hydrazinolysis of the ester with hydrazine hydrate
in a high-boiling solvent (ethylene glycol) afforded the
corresponding hydrazide (2) in good yield (Scheme 1),
whereas when the reaction was conducted neat or in etha-
nol, it did not give satisfactory results. The structures of
compounds 1 and 2 were confirmed by their spectral data
On the other hand, condensation of carbohydrazide 2 with
trimethyl orthoformate gave the corresponding 2-[1-(4-
methoxybenzyl)-1H-indol-3-yl]-1,3,4-oxadiazole (6), whereas
its reaction with trimethyl orthoacetate afforded a mixture of
2-[1-(4-methoxybenzyl)-1H-indol-3-yl]-5-methyl-1,3,4-
oxadiazole (7) and methyl N-{[1-(4-methoxybenzyl)-1H-
indol-3-yl]carbonyl}ethanehydrazonoate (8) in 62 and 25%
yield, respectively (Scheme 3). The IR spectrum of compound
6 is characterized by the disappearance of the absorption bands
at 3350–3250 cmꢀ1 (NH and NH2 of the starting material 2).
The 1H NMR spectrum of compound 7 shows a new singlet
(IR, H NMR, 13C NMR, and HRMS) together with ele-
1
mental analyses. The IR spectrum of compound 1 reveals
1
the absence of an indole NH function. Its H NMR spec-
trum expectedly shows three new, characteristic signals
near d 3.82, 5.15, and 6.77/7.02 ppm, assignable to
OCH3, CH2 and the para-substituted benzene unit, respec-
tively. The 13C NMR spectrum shows signals at d 50.35
and 54.75 ppm for two methoxy carbons and at 59.30
ppm for the CH2 unit. The HRMS spectrum shows the
[M]+ peak at m/z 295.1225 in agreement with the molecu-
lar formula. In the case of compound 2, the IR spectrum is
1
at d 1.98 ppm due to the CH3 group, whereas the H NMR
spectrum of compound 8 shows characteristic signals at d
1.23, 3.40, and 10.11 ppm, corresponding to CH3, OCH3,
and NH, respectively.
characterized by two new bands at 3350–3250 cmꢀ1
,
1
which are due to NH and NH2 groups. Its H NMR spec-
trum revealed two new characteristic signals at d 4.41
and 9.18 ppm, assignable to NH2 and NH, respectively.
Further confirmation was achieved by the 13C NMR spec-
trum, which shows signals at d 48.99 and 55.09 ppm due to
OCH3 and CH2, respectively.
However, reaction of carbohydrazide 2 with acid chlorides
such as benzoyl chloride, phenylacetyl chloride and 2,4,
6-trimethylbenzoyl chloride in refluxing dry dioxane did not
lead to cyclized products but afforded the corresponding
substituted carbohydrazide derivatives 9a–c. The latter
compounds then could be cyclized into the oxadiazole
derivatives 10a–c by heating with phosphorus oxychloride
at 100ꢁC for 1–2 h (Scheme 4). As expected, the IR spectra
of the cyclized products 10a–c did not show the character-
istic bands of the precursors 9a–c at 3200 and 1680 cmꢀ1
(NH and C═O).
Treatment of the acid hydrazide 2 with carbon disulfide in
boiling pyridine led to the formation of the corresponding
oxadiazolethione 3 in 86% yield. Whereas reaction of 2 with
1,10-carbonyldiimidazole (CDI) in tetrahydrofuran (THF) at
70ꢁC did not afford the expected 5-[1-(4-methoxybenzyl)-
1H-indol-3-yl]-1,3,4-oxadiazol-2(3H)-one (4), an unexpected
debenzylation occurred and the oxadiazolone 5 [37] was
Scheme 2
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis of New PMB-Substituted Indoles Containing
1,3,4-Oxadiazole and 1,2,4-Triazole Units
801
Scheme 3
Scheme 5
Moreover, reaction of compound 2 with isothiocyanates
in refluxing ethanol afforded the substituted thiosemicarba-
zide derivatives 11–13, which were transformed into the
corresponding 1,2,4-triazole-3-thione derivatives 14a–c
by intramolecular cyclization in boiling ethanolic potas-
sium hydroxide solution. The formation of the thiosemicar-
bazides 11–13 was confirmed by their IR spectra, showing
characteristic absorption bands at 3400 and 3300 cmꢀ1
(three NH groups) and 1170 cmꢀ1 (C═S) in addition to
1H NMR and 13C NMR spectra and elemental analyses
(cf. Experimental). The disappearance of the most promi-
nent NH bands is in agreement with the formation of the
cyclized products 14a–c (Scheme 5).
Finally, hydrazinolysis of oxadiazolethione derivative 3
with hydrazine hydrate in boiling ethanol led to the forma-
tion of the N-amino-substituted 1,2,4-triazole 15 by a ring
opening and ring closure sequence. The structure of com-
pound 15 was confirmed by IR which showed new, charac-
teristic absorption bands at 3400, 3280, and 3180 cmꢀ1
(NH2 and NH). Furthermore, the 1H NMR spectrum exhibits
a new signal at d 5.84 ppm assignable to NH2 (Scheme 6).
dose-response curves gave valid values for four cell lines
(in the case of NCI H-460, EC50 was above the highest test
concentration). Further evaluation of all new compounds in
other biological assays is intended.
CONCLUSIONS
In conclusion, we have made available a series of hith-
erto unknown 1-PMB-substituted indole derivatives con-
taining 1,3,4-oxadiazole and 1,2,4-triazole units with
potential biological activity. All of these new compounds
1
were fully characterized by IR, H NMR, 13C NMR, and
HRMS in addition to elemental analysis.
EXPERIMENTAL
All reactions were carried out under an atmosphere of nitrogen
in flame-dried or oven-dried glassware with magnetic stirring.
Air-sensitive reagents and solutions were transferred via syringe
or cannula and were introduced to the apparatus through rubber
septa. THF, diethyl ether and toluene were distilled from so-
dium-benzophenone ketyl. Dichloromethane was distilled from
phosphorus pentoxide. Triethylamine and other nitrogen-containing
bases were distilled from calcium hydride under nitrogen atmo-
sphere before use. Methanol was distilled from sodium. Reac-
tions were monitored by thin layer chromatography with 0.25
mm E. Merck precoated silica gel plates (60 F254). Visualization
was accomplished with either UV light or by immersion in
solutions of p-anisaldehyde or phosphomolybdic acid, followed
PHARMACLOGICAL EVALUATION
The new compounds were tested in vitro for antitumor
activity, using the Alamar Blue assay [38] on a panel of
five human tumor cell lines. It turned out that only the ester
1 showed significant cell-growth inhibitory activity
(>50%) at a fixed concentration of 3.16 μg/mL (Table 1).
Subsequent determination of EC50 concentrations from
Scheme 4
Scheme 6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

802
A.-R. Farghaly, N. Haider, and D.-H. Lee
Vol 49
Table 1
pressure, the residue formed was triturated with water, and the
product obtained was filtered off, air-dried, and recrystallized
In-vitro antitumor activity (percentage cell-growth inhibition at fixed
concentration and EC50 values) for compound 1.
from ethanol to afford 2 as buff crystals.
Yield: 2.45 g (83%); mp 178–180ꢁC; IR (KBr): 3350–3250
1
(bs, NHNH2), 1650 (C¼O), 1610 cmꢀ1 (C¼N); H NMR (500
Cell line
Description
Percentage
MHz, dimethyl sulfoxide d6): d = 3.71 (s, 3H, OCH3), 4.41 (s, 2H,
NH2), 5.36 (s, 2H, benzyl CH2), 6.89 (d, 2H, ArH, J = 8.70 Hz),
7.18 (m, 2H, H-5,6), 7.22 (d, 2H, ArH, J = 8.70 Hz, shows positive
NOE on irradiation at 5.36 ppm), 7.54 (d, 1H, H-7, J = 7.20 Hz,
shows positive NOE on irradiation at 5.36 ppm), 8.07 (s, 1H, H-2,
shows positive NOE on irradiation at 5.36 ppm), 8.14 (d, 1H, H-4,
J = 7.20 Hz,), 9.18 (s, 1H, NH), 13C NMR (75 MHz, dimethyl
sulfoxide d6): d = 48.99 (OMe), 55.09 (CH2), 108.59, 109.90,
110.69, 114.04, 120.65, 121.20, 122.03, 126.68, 128.82, 129.23,
130.44, 135.52, 135.89, 158.76, 164.81 (CO); Anal. Calcd. for
C17H17N3O2 (295.34): C, 69.14; H, 5.80; N, 14.23. Found: C,
69.10; H, 5.87; N, 14.39.
inhibition at
EC50
3.16 (mg/mL) (mg/mL)
Code
KB/HELA Cervical carcinoma
SK OV-3 Ovarial carcinoma
87
59
56
75
68
0.559
0.724
0.490
ꢀ
SF-268
NCI H-460 Non-small-cell lung cancer
RKOp27 Colon adenocarcinoma
CNS cancer
0.373
by heating on a hot plate for ∼15 sec. Purification of reaction
products was carried out by flash chromatography using EM
Reagents silica gel 60 (230–400 mesh). Melting points were de-
termined using a Thomas Hoover capillary melting point appa-
ratus and are uncorrected. 1H NMR and 13C NMR spectra
were obtained using a Varian Gemini-300 (300 MHz for 1H
5-[1-(4-Methoxybenzyl)-1H-indol-3-yl]-1,3,4-oxadiazole-2
(3H)-thione (3). A mixture of carbohydrazide 2 (295 mg, 1
mmol) and carbon disulfide (2 mL, 26 mmol) in dry pyridine
(10 mL) was heated at 50ꢁC for 6 h. After cooling, the excess
of carbon disulfide and the solvent was removed under
reduced pressure. The residue obtained was treated with water
and the precipitate formed was filtered off and recrystallized
from ethanol to give 3 as white crystals.
1
and 75 MHz for 13C), or a Varian Inova-500 (500 MHz for H
and 125 MHz for 13C) spectrometer. Chemical shifts are
reported relative to chloroform (d 7.26) for 1H NMR and chloro-
form (d 77.2) for 13C NMR. Data are reported as: br = broad, s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet; coupling
constants in Hz. Ambiguous assignments were resolved on the basis
of standard one-dimensional proton decoupling experiments. Elemen-
tal analyses were performed by the Organic Chemistry Research Cen-
ter at Sogang University, using a Carlo Erba EA 1180 elemental
analyzer. High-resolution mass spectra were recorded on a 4.7 Tesla
IonSpec ESI-FTMS or a Micromass LCT ESI-TOF mass spectrome-
ter. The progress of the reactions was monitored by high performance
liquid chromatography (HPLC).
Yield: 289 mg (86%); mp 160–162ꢁC; IR (KBr): 3100 (NH),
1
1620 (C¼N), 1170 cmꢀ1 (C¼S); H NMR (500 MHz, dimethyl
sulfoxide d6): d = 3.69 (s, 3H, OCH3), 5.44 (s, 2H, benzyl
CH2), 6.87 (d, 2H, ArH, J = 8.70 Hz), 7.28 (m, 4H, H-5,6 and
ArH), 7.64 (d, 1H, H-7, J = 7.20 Hz), 7.90 (d, 1H, H-4,
J = 7.80 Hz), 8.39 (s, 1H, H-2), 8.71 (s, 1H, NH). Anal. Calcd.
for C18H15N3O2S (337.40): C, 64.08; H, 4.48; N, 12.45; S,
9.50. Found: 64.14; H, 4.59; N, 12.60; S, 9.66.
Methyl 1-(4-methoxybenzyl)-1H-indole-3-carboxylate (1).
To a stirred solution of methyl 1H-indole-3-carboxylate (1.75 g,
10 mmol) and potassium carbonate (4.14 g, 30 mmol) in dry
dimethylformamide (10 mL), 4-methoxybenzyl chloride (1.72 g, 11
mmol) was added. The reaction mixture was heated at 140ꢁC for
8 h. The progress of the reaction was monitored by HPLC. The
solvent was removed under reduced pressure, and the residue was
triturated with water, then the product was extracted with
dichloromethane (3 × 50 mL). The combined extracts were washed
with water (3 × 50 mL) and dried over Na2SO4. The solvent was
removed under reduced pressure, and the buff semisolid product
obtained was purified using n-hexane to afford 1 as buff solid.
5-[1-(4-Methoxybenzyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2(3H)-
one (4). A suspension of carbohydrazide 2 (295 mg, 1 mmol) and
CDI (178 mg, 1.1 mmol) in dioxane (10 mL) was heated at 110ꢁC
for 8 h. The solvent was removed under reduced pressure. The
solid product obtained was washed with water, filtered off, and
recrystallized from ethanol to afford 4 as white crystals.
Yield: 222 mg (69%); mp 345–347ꢁC; IR (KBr): 3280 (NH),
1
1758 (C¼O), 1615 cmꢀ1 (C¼N); H NMR (500 MHz, dimethyl
sulfoxide d6): d = 3.69 (s, 3H, OCH3), 5.42 (s, 2H, benzyl CH2),
6.87 (d, 2H, ArH, J = 8.70 Hz), 7.23 (m, 4H, H-5,6 and ArH), 7.80
(d, 1H, H-7, J = 7.80 Hz), 7.91 (d, 1H, H-4, J = 8.10 Hz), 8.19 (s,
1H, H-2), 12.24 (s, 1H, NH); 13C NMR (75 MHz, dimethyl sulfoxide
d6): d = 49.07, 55.06, 94.53, 111.41, 114.03, 120.38, 121.38, 122.95,
124.12, 128.93, 129.07, 130.48, 136.13, 152.18, 154.24, 158.80.
Anal. Calcd. for C18H15N3O3 (321.34): C, 67.28; H, 4.71; N,
13.08. Found: C, 67.22; H, 4.66; N, 13.02.
Yield: 2.80 g (95%); mp 40–42ꢁC; IR (KBr): 2950 (CH aliph.),
1
1710 (C¼O), 1620 cmꢀ1 (C¼N); H NMR (500 MHz, deuterio-
chloroform): d = 3.69 (s, 3H, COOCH3), 3.82 (s, 3H, OCH3),
5.15 (s, 2H, benzyl CH2), 6.77 (d, 2H, ArH, J = 8.70 Hz), 7.02
(d, 2H, ArH, J = 8.70 Hz), 7.21 (m, 2H, H-5,6), 7.74 (s, 1H, H-7),
7.92 (s, 1H, H-2), 8.13 (m, 1H, H-4); 13C NMR (125 MHz,
deuteriochloroform): d = 50.35 (OMe), 54.75 (OMe), 59.30
(CH2), 106.60 (C), 110.03 (C), 113.81 (C), 121.41 (C), 122.35 (C),
126.40 (C), 127.48 (C), 128.25 (C), 131.52 (C), 132.14 (C), 133.17
(C), 134.00 (C), 136.20 (C), 158.96 (C), 164.82 (CO); HRMS
(ESI): m/z calcd for C18H17NO3 [M]+: 295.1208, found: 295.1225.
Anal. Calcd. for C18H17NO3 (295.34): C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.13; H, 5.68; N, 4.62.
5-(1H-Indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (5). A suspension of
carbohydrazide 2 (295 mg, 1 mmol) and CDI (178 mg, 1.1 mmol) in
THF (10 mL) was heated at 70ꢁC for 8 h. Then, the solvent was
removed under reduced pressure. The solid residue was triturated
with water, filtered off, and recrystallized from ethanol to yield 5 as
white crystals.
Yield: 160 mg (80%); mp 203–205ꢁC (lit. [38] mp 204–205ꢁC);
1H NMR (500 MHz, dimethyl sulfoxide d6): d = 6.74 (s, 1H,
NH), 7.19 (m, 2H, H-5,6), 7.80 (d, 1H, H-7, J = 8.40 Hz),
8.10 (d, 1H, H-4, J = 7.80 Hz), 8.27 (s, 1H, H-2), 9.29 (s,
1H, NH); IR (KBr): 3230 (NH), 1755 (C¼O), 1615 cmꢀ1
(C¼N); HRMS (ESI): m/z calcd. for C10H7N3O2K [M+K]+:
240.0175. Found: 240.0162.
1-(4-Methoxybenzyl)-1H-indole-3-carbohydrazide (2).
A
mixture of 1 (2.95 g, 10 mmol) and hydrazine hydrate (5 mL,
100 mmol) in ethylene glycol (10 mL) was heated under reflux
for 4 h. After cooling, the solvent was removed under reduced
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis of New PMB-Substituted Indoles Containing
1,3,4-Oxadiazole and 1,2,4-Triazole Units
803
General procedure for the preparation of 2-[1-(4-methoxybenzyl)-
N0-(2,4,6-Trimethylbenzoyl)-1-(4-methoxybenzyl)-1H-indole-
3-carbohydrazide (9c). This compound was obtained as white
crystals. Yield: 170 mg (39%) (EtOH); mp 256–258ꢁC; IR
(KBr): 3200 (NH), 3030 (CH arom.), 1680 cmꢀ1 (C¼O); 1H
NMR (500 MHz, dimethyl sulfoxide d6): d = 2.24 (s, 3H,
CH3); 2.34 (s, 6H, CH3), 3.72 (s, 3H, OCH3), 5.41 (s, 2H,
benzyl CH2), 6.88 (m, 2H, mesityl H), 6.91 (d, 2H, ArH,
J = 8.70 Hz,), 7.19 (m, 2H, H-5,6), 7.26 (d, 2H, ArH,
J = 8.70 Hz), 7.60 (d, 1H, H-7, J = 7.80 Hz), 8.16 (d, 1H,
H-4, J = 7.80 Hz), 8.22 (s, 1H, H-2), 9.95 (s, 1H, NH),
9.90 (s, 1H, NH). Anal. Calcd. for C27H27N3O3 (455.56): C,
73.45; H, 6.16; N, 9.52. Found: C, 73.32; H, 6.04; N, 9.43.
General procedure for the preparation of 2-[1-(4-
methoxybenzyl)-1H-indol-3-yl]-5-substituted-1,3,4-oxadiazoles
(10a–c). A suspension of 9a–c (1 mmol) in phosphoryl chloride (5
mL, 33 mmol) was heated at 100ꢁC for 1–2 h. The excess of
phosphoryl chloride was eliminated under reduced pressure, and
the residue was triturated with ethyl acetate, filtered off, and
1H-indol-3-yl]-1,3,4-oxadiazole derivatives (6–8). A suspension of
carbohydrazide 2 (295 mg, 1 mmol) and trimethyl orthoformate or
trimethyl orthoacetate (5 mL), respectively, was heated under reflux
for 12 h. Then, the reagent was removed under reduced pressure.
The residue was triturated with ethanol, filtered off, and recrystallized
from ethanol.
2-[1-(4-Methoxybenzyl)-1H-indol-3-yl]-1,3,4-oxadiazole (6). This
compound was obtained as white crystals. Yield 112 mg (37%);
mp 144–146ꢁC; IR (KBr): 3070 (CH arom.), 1620 cmꢀ1 (C¼N);
1H NMR (300 MHz, dimethyl sulfoxide d6): d = 3.71 (s, 3H,
OCH3), 5.37 (s, 2H, benzyl CH2), 6.89 (d unresolved, 2H, ArH),
7.16 (m, 4H, H-5,6 and ArH), 7.54 (m, 1H, H-7), 8.11 (d
unresolved, 1H, H-4), 8.13 (s, 1H, oxadiazole H), 8.41 (s, 1H, H-2).
Anal. Calcd. for C18H15N3O2 (305.34): C, 70.81; H, 4.95; N, 13.76.
Found: C, 70.73; H, 4.84; N, 13.60.
2-[1-(4-Methoxybenzyl)-1H-indol-3-yl]-5-methyl-1,3,4-oxadiazole
(7). This compound was obtained as white crystals. Yield: 197 mg
(62%); mp 228–230ꢁC; IR (KBr): 3050 (CH arom.), 1620 cmꢀ1
recrystallized from the appropriate solvent.
1
2-[1-(4-Methoxybenzyl)-1H-indol-3-yl]-5-phenyl-1,3,4-oxadiazole
(C¼N); H NMR (500 MHz, dimethyl sulfoxide d6): d =1.98 (s,
(10a). This compound was obtained as buff crystals. Yield: 374 mg
3H, CH3), 3.71 (s, 3H, OCH3), 5.38 (s, 2H, benzyl CH2), 6.82 (m,
2H, ArH), 7.22 (m, 4H, H-5,6 and ArH), 7.84 (d, 1H, H-7,
J = 6.60 Hz,), 8.11 (s, 1H, H-4), 8.37 (s, 1H, H-2). Anal. Calcd. for
C19H17N3O2 (319.37): C, 71.46; H, 5.37; N, 13.16. Found: C,
71.35; H, 5.23; N, 13.05.
(91%); mp 126–128ꢁC (EtOH); IR (KBr): 3050 (CH arom.), 1620
1
cmꢀ1 (C¼N); H NMR (500 MHz, deuteriochloroform): d = 3.79
(s, 3H, OCH3), 5.34 (s, 2H, benzyl CH2), 6.88 (d, 2H, ArH, J = 8.70
Hz), 7.16 (d, 2H, ArH, J = 8.70 Hz), 7.42 (m, 8H, H-5,6,7 and
ArH), 8.14 (m, 1H, H-2), 8.35 (s, 1H, H-4). Anal. Calcd. for
C24H19N3O2 (381.44): C, 75.57; H, 5.02; N, 11.02. Found: C, 75.41;
H, 5.12; N, 11.13.
Methyl N-{[1-(4-methoxybenzyl)-1H-indol-3-yl]carbonyl}
ethanehydrazonoate (8). This compound was obtained from the
filtrate of the reaction as white crystals. Yield: 88 mg (25%); mp
136–138ꢁC; IR (KBr): 3200 (NH), 2950 (CH aliph.), 1650 (C¼O),
2-[1-(4-Methoxybenzyl)-1H-indol-3-yl]-5-benzyl-1,3,4-oxadiazole
(10b). This compound was obtained as white crystals. Yield: 250
mg (63%) (EtOAc); mp 112–114ꢁC; IR (KBr): 3030 (CH
arom.), 1620 cmꢀ1 (C¼N); 1H NMR (500 MHz,
deuteriochloroform): d = 3.77 (s, 3H, OCH3), 4.26 (s, 2H,
benzyl CH2), 5.27 (s, 2H, benzyl CH2), 6.83 (d, 2H, ArH,
J = 8.70 Hz), 7.10 (d, 2H, ArH, J = 8.70 Hz), 7.30 (m, 8H,
H-5,6,7 and ArH), 7.74 (s, 1H, H-2), 8.21 (s, 1H, H-4). Anal.
Calcd. for C25H21N3O2 (395.47): C, 75.93; H, 5.35; N, 10.63.
Found: C, 75.78; H, 5.22; N, 10.57.
1
1620 cmꢀ1 (C¼N); H NMR (500 MHz, dimethyl sulfoxide d6):
d = 1.23 (s, 3H, CH3); 3.40 (s, 3H, OCH3), 3.76 (s, 3H, OCH3),
5.39 (s, 2H, benzyl-CH2), 6.92 (m, 2H, ArH), 7.35 (m, 4H, H-5,6
and ArH), 7.87 (d, 1H, H-7, J = 6.70 Hz), 8.18 (s, 1H, H-4), 8.34
(s, 1H, H-2), 10.11 (s, 1H, NH). Anal. Calcd. for C20H21N3O3 (351.41):
C, 68.36; H, 6.02; N, 11.96. Found: C, 68.27; H, 5.89; N, 11.86.
General procedure for the preparation of N-substituted-1-(4-
methoxybenzyl)-1H-indole-3-carbohydrazides (9a–c). A mixture
of carbohydrazide 2 (295 mg, 1 mmol) and the appropriate acid
chloride (1 mmol) in dry dioxane (10 mL) was heated under reflux
for 6–8 h. The reagent was removed under reduced pressure, and
the residue was recrystallized from the proper solvent.
2-[1-(4-Methoxybenzyl)-1H-indol-3-yl]-5-mesityl-1,3,4-
oxadiazole (10c). This compound was obtained as buff crystals.
Yield: 269 mg (64%) (EtOH); mp 188–190ꢁC; IR (KBr): 3050
(CH arom.), 1615 cmꢀ1 (C¼N); 1H NMR (500 MHz, dimethyl
sulfoxide d6): d = 2.27 (s, 3H, CH3), 2.50 (s, 6H, CH3), 3.70
(s, 3H, OCH3), 5.45 (s, 2H, benzyl CH2), 6.86 (d, 2H, ArH,
J = 8.70 Hz), 7.09 (d, 2H, ArH, J = 8.70 Hz), 7.29 (m, 5H, H-5,6,7
and mesityl H), 8.13 (m, 1H, H-2), 8.45 (s, 1H, H-4). Anal. Calcd.
for C27H25N3O2 (423.52): C, 76.57; H, 5.95; N, 9.92. Found: C,
76.39; H, 5.82; N, 9.80.
N0-Benzoyl-1-(4-methoxybenzyl)-1H-indole-3-carbohydrazide
(9a). This compound was obtained as white crystals. Yield: 282 mg
(71%); mp 180–182ꢁC (EtOH); IR (KBr): 3200 (NH), 3050 (CH
arom.), 1650 cmꢀ1 (C¼O); 1H NMR (500 MHz, dimethyl sulfoxide
d6): d = 3.72 (s, 3H, OCH3), 5.42 (s, 2H, benzyl CH2), 6.92 (d, 2H,
benzoyl H, J = 8.40 Hz,), 7.25 (m, 4H, H-5,6 and benzoyl H), 7.52
(m, 4H, H-7 and ArH), 7.92 (m, 2H, ArH), 8.14 (d, 1H, H-4,
J = 7.50 Hz), 8.22 (s, 1H, H-2), 9.99 (s, 1H, NH), 10.36 (s, 1H,
NH). Anal. Calcd. for C24H21N3O3 (399.45): C, 72.16; H, 5.30; N,
10.52. Found: C, 72.07; H, 5.21; N, 10.30.
N1-[1-(4-Methoxybenzyl)-1H-indol-3-ylcarbonyl]-N4-
benzylthiosemicarbazide (11). A suspension of 2 (295 mg, 1
mmol) and benzyl isothiocyanate (149 mg, 1 mmol) in ethanol
(10 mL) was heated under reflux for 7 h. The solvent was
concentrated and the solid product thus formed was filtered off
and recrystallized from ethanol to afford 11 as white crystals.
N0-(2-Phenylacetyl)-1-(4-methoxybenzyl)-1H-indole-3-
carbohydrazide (9b). This compound was obtained as white
crystals. Yield: 340 mg (82%) (EtOH/EtOAc, 1:2); mp 186–188ꢁC;
IR (KBr): 3200 (bs, NH), 3030 (CH arom.), 1660 cmꢀ1
(C¼O); 1H NMR (500 MHz, deuteriochloroform): d = 3.65
(s, 2H, COCH2); 3.71 (s, 3H, OCH3), 4.99 (s, 2H, benzyl CH2),
6.73 (d, 2H, ArH, J = 8.40 Hz), 6.97 (d, 2H, Ar, J = 8.40 Hz),
7.28 (m, 9H, H-4,5,6,7 and ArH), 7.77 (s, 1H, H-2), 8.14 (s,
1H, NH), 9.33 (s, 1H, NH). Anal. Calcd. for C25H23N3O3
(413.48): C, 72.62; H, 5.61; N, 10.16. Found: C, 72.51; H,
5.49; N, 10.04.
Yield: 366 mg (85%); mp 218–220ꢁC; IR (KBr): 3400, 3300 (NH),
1
2950 (CH aliph.), 1660 (C¼O), 1170 cmꢀ1 (C¼S); H NMR (500
MHz, dimethyl sulfoxide d6): d = 3.70 (s, 3H, OCH3), 4.73 (d, 2H,
CH2NH, J = 7.00 Hz), 5.37 (s, 2H, benzyl CH2), 6.88 (d, 2H, ArH,
J = 8.70 Hz), 7.22 (m, 9H, H-5,6 and ArH), 7.57 (d, 1H, H-7, J = 7.20
Hz), 8.14 (m 2H, H-2,4), 8.59 (s, 1H, NH), 9.35 (s, 1H, NH), 9.87 (s,
1H, NH); 13C NMR (125 MHz, dimethyl sulfoxide d6): d = 46.74,
49.74, 55.17, 107.71, 110.86, 114.12, 121.16, 122.39, 126.62, 126.97,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

804
A.-R. Farghaly, N. Haider, and D.-H. Lee
Vol 49
127.19, 128.06, 129.00, 129.08, 131.95, 134.70, 135.97, 139.59, 158.85,
163.10, 184.20. Anal. Calcd. for C25H24N4O2S (444.55): C, 67.54; H,
5.44; N, 12.60; S, 7.21. Found: C, 67.61; H, 5.39; N, 12.67; S, 7.28.
N1-[1-(4-Methoxybenzyl)-1H-indol-3-ylcarbonyl]-N4-
cyclohexylthiosemicarbazide (12). A solution of 2 (295 mg, 1
mmol) and cyclohexyl isothiocyanate (141 mg, 1 mmol) in ethanol
(10 mL) was heated under reflux for 7 h. The solvent was removed
under reduced pressure, the residue was triturated with ethyl
acetate, and the precipitate formed was collected and recrystallized
from ethanol to afford 12 as white crystals.
Yield: 408 mg (93%); mp 152–154ꢁC; IR (KBr): 3400, 3300
(NH), 2930 (CH aliph.), 1660 (C¼O), 1180 cmꢀ1 (C¼S); 1H
NMR (500 MHz, dimethyl sulfoxide d6): d = 1.26 (m, 5H, cyclo-
hexane H), 1.67 (m, 6H, cyclohexane H), 3.71 (s, 3H, OCH3),
5.39 (s, 2H, benzyl CH2), 6.89 (d, 2H, ArH, J = 8.70 Hz), 7.18
(m, 2H, H-5,6), 7.24 (d, 2H, ArH, J = 8.70 Hz), 7.59 (m 2H,
H-4,7), 8.16 (m, 2H, NH and H-2), 9.16 (s, 1H, NH), 9.74 (s, 1H,
NH); 13C NMR (75 MHz, dimethyl sulfoxide d6): d = 18.59, 24.94,
34.91, 54.14, 55.89, 59.60, 110.82, 112.40, 114.06, 118.70, 120.40,
121.09, 122.40, 126.93, 128.99, 130.00, 135.92, 158.84, 164.60,
183.70. Anal. Calcd. for C24H28N4O2S (436.57): C, 66.03; H, 6.46;
N, 12.83; S, 7.34. Found: C, 65.98; H, 6.41; N, 12.90; S, 7.30.
N1-[1-(4-Methoxybenzyl)-1H-indol-3-ylcarbonyl]-N4-4-
methoxyphenylthiosemicarbazide (13). A mixture of 2 (295 mg,
1 mmol) and 4-methoxyphenyl isothiocyanate (165 mg, 1 mmol)
in ethanol (10 mL) was heated under reflux for 7 h. The solvent
was removed under reduced pressure, and the solid product thus
formed was filtered off and recrystallized from ethanol to afford
13 as white crystals.
obtained as white crystals. Yield: 363 mg (87%); mp 208–210ꢁC; IR
(KBr): 3400–3100 (NH), 2900 and 2850 (CH aliph.), 1620 (C¼N),
1180 cmꢀ1 (C¼S); 1H NMR (500 MHz, deuteriochloroform):
d = 1.20 (m, 5H, cyclohexane H), 1.76 (m, 6H, cyclohexane H),
3.78 (s, 3H, OCH3), 5.31 (s, 2H, benzyl CH2), 6.85 (d, 2H, ArH,
J = 8.40 Hz), 7.14 (d, 2H, ArH, J = 8.40 Hz), 7.27 (m, 2H, H-5,6),
7.41 (d, 1H, H-7, J = 7.50 Hz), 7.62 (d, 1H, H-4, J = 7.50 Hz), 7.88
(s, 1H, H-2). Anal. Calcd. for C24H26N4OS (418.55): C, 68.87; H,
6.26; N, 13.39; S, 7.66. Found: C, 68.79; H, 6.21; N, 13.29; S, 7.59.
4-(4-Methoxyphenyl)-5-[1-(4-methoxybenzyl)-1H-indol-3-yl]-
2,4-dihydro-1,2,4-triazole-3-thione (14c). This compound was
obtained as fluffy crystals. Yield: 254 mg (58%); mp 272–74ꢁC; IR
(KBr): 3400–3100 (NH), 2900 (CH aliph.), 1620 (C¼N),
1
1180 cmꢀ1 (C¼S); H NMR (500 MHz, dimethyl sulfoxide d6):
d = 3.73 (s, 3H, OCH3); 3.84 (s, 3H, OCH3), 5.16 (s, 2H, benzyl
CH2), 6.82 (d, 2H, ArH, J = 8.10 Hz), 6.99 (d, 2H, ArH, J = 8.10
Hz,), 7.04 (m, 2H, H-5,6), 7.24 (m, 4H, ArH), 7.55 (d, 1H, H-7,
J = 7.50 Hz), 7.68 (d, 1H, H-4, J = 7.50 Hz), 7.91 (s, 1H, H-2), 8.10
(s, 1H, NH). Anal. Calcd. for C25H22N4O2S (442.54): C, 67.85; H,
5.01; N, 12.66; S, 7.25. Found: C, 67.74; H, 5.12; N, 12.49; S, 7.12.
4-Amino-5-[1-(4-methoxybenzyl)-1H-indol-3-yl]-2,4-dihydro-
1,2,4-triazole-3-thione (15). A suspension of 3 (337 mg, 1 mmol)
and hydrazine hydrate (99%, 2 mL, 44 mmol) in ethanol (10 mL)
was refluxed for 6 h. After cooling, the solvent was removed
under reduced pressure, the residue was triturated with water, and
the precipitate was collected and recrystallized from ethanol to
afford 15 as white crystals.
Yield: 273 mg (78%); mp 182–184ꢁC; IR (KBr): 3400, 3280,
3180 (NH2 and NH), 2900 (CH aliph.), 1620 (C¼N),
1
1180 cmꢀ1 (C¼S); H NMR (500 MHz, dimethyl sulfoxide d6):
Yield: 400 mg (87%); mp 190–192ꢁC; IR (KBr): 3300–3100
(NH), 2950 (CH aliph.), 1660 (C¼O), 1180 cmꢀ1 (C¼S); 1H
NMR (500 MHz,, dimethyl sulfoxide d6): d = 3.73 and 3.70
(2s, 6H, OCH3); 5.13 (s, 2H, benzyl CH2), 6.77 (m, 4H, ArH),
7.04 (d, 2H, ArH, J = 8.10 Hz), 7.25 (m, 6H, H-4,5,6,7 and
ArH), 7.84 (s, 1H, H-2), 8.15 (s, 1H, NH), 8.64 (s, 1H, NH),
9.50 (s, 1H, NH); 13C NMR (75 MHz, dimethyl sulfoxide d6):
d = 29.88, 50.43, 55.43, 55.53, 107.51, 110.89, 114.51, 121.00,
122.51, 123.32, 125.87, 126.96, 127.73, 128.80, 130.03,
132.76, 136.84, 158.28, 159.59, 164.00, 175.80. Anal. Calcd.
for C25H24N4O3S (460.56): C, 65.20; H, 5.25; N, 12.17; S,
6.96. Found: C, 65.11; H, 5.09; N, 12.03; S, 6.88.
d = 3.68 (s, 3H, OCH3), 5.43 (s, 2H, benzyl CH2), 5.84 (sb, 2H,
NH2), 7.20 (m, 4H, H-5,6 and ArH), 7.59 (d, 1H, H-7, J = 7.80
Hz), 8.12 (d, 1H, H-4, J = 7.80 Hz), 8.56 (s, 1H, H-2), 8.86
(d, 2H, ArH, J = 8.10 Hz,), 9.35 (s, 1H, NH); MS m/z (%) 351
(M+, 42), 318 (100). Anal. Calcd. for C18H17N5OS (351.43): C,
61.52; H, 4.88; N, 19.93; S, 9.12. Found: C, 61.45; H, 4.73; N,
19.86; S, 9.04.
Acknowledgments. The authors are grateful to the Korea Science
and Engineering Foundation (KOSEF) for financial support of this
research and to Æterna Zentaris GmbH (Frankfurt/Main, Germany)
for performing the in-vitro screening for antitumor activity.
General procedure for the preparation of 4-substituted-5-[1-(4-
methoxy-benzyl)-1H-indol-3-yl]-2,4-dihydro-1,2,4-triazole-
3-thiones (14a–c). To a suspension of 11–13 (1 mmol) in
ethanol (10 mL), 4N aqueous potassium hydroxide (3 mL)
was added. The reaction mixture was gently refluxed for 3 h,
then it was concentrated, cooled, and filtered, and the filtrate
was adjusted to pH 5–6 with dilute acetic acid. The white
solid formed was filtered off and recrystallized from the
appropriate solvent.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis of New PMB-Substituted Indoles Containing
1,3,4-Oxadiazole and 1,2,4-Triazole Units
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