An Efficient and Facile Synthesis of Functionalized Indole-3-yl Pyrazole Derivatives Starting from 3-Cyanoacetylindole

Article abstract of DOI:10.1002/jhet.2654

The versatile hitherto reported 3-(1H-indol-3-yl)-1H-pyrazol-5-amine (4) was synthesized by the reaction of 3-cyanoacetylindole (3) with hydrazine hydrate in refluxing ethanol and used as a key intermediate for the synthesis of novel pyrazolo[1,5-a]pyrimidines via its reactions with appropriate 1,3-biselectrophilic reagents or through three-component condensations with triethyl orthoformate and compounds possessing an activated methylene group. Besides, the applicability and synthetic potency of (4) to attain polyfunctionally substituted imidazo[1,2-b]pyrazole, pyrazolo[1,5-a][1,3]diazepine and pyrazolo[1,5-c][1,3,5]thiadiazine derivatives of an expected pharmaceutical interest have been investigated. The mechanistic aspects for the formation of the newly synthesized compounds are discussed.

Full text of DOI:10.1002/jhet.2654

Month 2016
An Efficient and Facile Synthesis of Functionalized Indole-3-yl Pyrazole
Derivatives Starting from 3-Cyanoacetylindole
Ahmed El-Mekabaty,* Ahmed Mesbah, and Ahmed A. Fadda
Chemistry Department, Faculty of Science, Mansoura University, El-Gomhoria Street, ET-35516 Mansoura, Egypt
*
E-mail: a_el_m11@yahoo.com, elmekabaty@mans.edu.eg
Additional Supporting Information may be found in the online version of this article.
Received December 10, 2015
DOI 10.1002/jhet.2654
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
The versatile hitherto reported 3-(1H-indol-3-yl)-1H-pyrazol-5-amine (4) was synthesized by the reaction of
3
-cyanoacetylindole (3) with hydrazine hydrate in refluxing ethanol and used as a key intermediate for the
synthesis of novel pyrazolo[1,5-a]pyrimidines via its reactions with appropriate 1,3-biselectrophilic reagents
or through three-component condensations with triethyl orthoformate and compounds possessing an acti-
vated methylene group. Besides, the applicability and synthetic potency of (4) to attain polyfunctionally
substituted imidazo[1,2-b]pyrazole, pyrazolo[1,5-a][1,3]diazepine and pyrazolo[1,5-c][1,3,5]thiadiazine de-
rivatives of an expected pharmaceutical interest have been investigated. The mechanistic aspects for the for-
mation of the newly synthesized compounds are discussed.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
consequence of our recent work aimed at synthesis of new
heterocyclic systems with remarkable biological importance
[12–15], it was planned to present an efficient regioselec-
tive synthesis of some novel biologically active heterocy-
cles such as pyrazolo[1,5-a]pyrimidines, imidazo[1,2-b]
pyrazoles, pyrazolo[1,5-a][1,3]diazepine and pyrazolo
[1,5-c][1,3,5]thiadiazine bearing indole ring system,
which have not been reported hitherto. The results of
screening of their biological activity will be reported in
due course.
Indole nucleus was considered as an important heterocyclic
compound in nature and used in commercial drug develop-
ment [1–4]. The essential amino acid, tryptophan, and metab-
olites thereof, for example tryptamine and serotonin, all
contain the indole skeleton and participate in vital biological
processes [5]. On the other hand, 3-substituted indole has
exhibited various pharmacological activities as anticancer,
antitumor [6], analgesic, and antipyretic activities [7,8]. It is
also a versatile synthon that can act as a common intermediate
for the synthesis of a wide variety of natural products [9,10].
We have recently reviewed the methods of preparation and
the chemical reactivity of 3-cyanoacetylindole as building
block for the synthesis of polyfunctionalized 3-substituted
indole derivatives with pharmacological interest [11]. As a
RESULTS AND DISCUSSION
Chemistry.
The key precursor, 3-cyanoacetylindole
(3) was prepared in excellent yield by short heating of
©
2016 Wiley Periodicals, Inc.

A. El-Mekabaty, A. Mesbah, and A. A. Fadda
Vol 000
indole in acetic anhydride at 85°C with cyanoacetic acid as
cyanoacetylating agent [16]. Treatment of (3) with excess
of 85% hydrazine hydrate in refluxing ethanol afforded
the corresponding aminopyrazole derivative (4) [17]
3-(phenyldiazenyl)pentane-2,4-dione [25] under the same ex-
perimental conditions produced in each case a single product,
as examined by TLC. The reaction products can be formulated
as pyrazolo[1,5-a]pyrimidine derivatives (6) and (7), respec-
tively, evidence for assigned structures being provided by ele-
mental analysis and spectroscopic data (see Experimental). It
is worth to mention that the regioselectivity for the formation
of compounds (6) and (7) is in line with the reported results of
the reaction of aminopyrazoles with 1,3-dielectrophilic centers
(Scheme 1).
3
(5)-Aminopyrazoles are versatile reagents and have been
extensively used as building blocks in the synthesis of sev-
eral polysubstituted pyrazolo[1,5-a]pyrimidines of potential
biological activity [18–20] via cyclocondensation with some
reagents having 1,3-dielectrophilic centers [21–24]. In this
context, we initially investigated the reactivity of compound
[25] (Scheme 2).
On the other hand, we have also studied the regioselec-
tivity of the reaction of the aminopyrazole (4) with 3-
cyanoacetylindole (3) as a possible synthetic route to attain
pyrazolo [1,5-a]pyrimidine. Thus, the reaction of
aminopyrazole (4) with 3-cyanoacetylindole (3) in refluxing
pyridine afforded only one regioisomeric product that was
identified as 2,5-di(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-
(4) towards different reactive azo compounds having 1,3-
dielectrophilic centers to attain pyrazolo[1,5-a]pyrimidines
linked directly to indole moiety of potential pharmaceutical
interest. Thus, the reaction of (4) with 2-(phenyldiazenyl)
malononitrile [25] in ethanol containing a catalytic amount
of pyridine under reflux yielded 2-(1H-indol-3-yl)-6-
(phenyldiazenyl)pyrazolo[1,5-a] pyrimidine-5,7-diamine (5)
7-amine (8). Although one may argue that the reaction of
in good yield. The plausible mechanism for the formation of
compound (5) could be attributed to the nucleophilic addition
of the exocyclic amino group of (4) on nitrile function of
(4) with 3-cyanoacetylindole (3) may lead to the other
regioisomer, the regioselectivity of such reactions is well
established [25,26]. The formation of compound (8) is
believed to proceed via initial attacks of the exocyclic amino
group of (4) on the keto group of 3-cyanoacetylindole (3),
followed by elimination of water, and subsequent cyclization
by the nucleophilic addition of the endocyclic imino
group to the nitrile function. The spectral data of the iso-
lated product were in complete agreement with the struc-
ture of (8) (see Experimental).
Shifting to Scheme 3, the foregoing results prompted us to
investigate the applicability and synthetic potency of the
condensation of aminopyrazole (4) with triethyl orthoformate
and compounds possessing an activated methylene group to
develop a facile and convenient route via one-pot synthesis
to pyrazolo[1,5-a]pyrimidine derivatives. We first examined
three-component condensations of aminopyrazole (4) with
triethyl orthoformate and ethyl cyanoacetate. So, heating an
equimolar mixture of (4) and ethyl cyanoacetate in boiling
triethyl orthoformate afforded the pyrazolo[1,5-a]pyrimidine
derivative (9). The formation of compound (9) was believed
to take place through the formation of the ethoxymethylidene
derivative at the activated methylene group of ethyl
cyanoacetate. The subsequent reaction with the exocyclic
amino group in aminopyrazole (4) is accompanied by loss
of an ethanol molecule, followed by cyclization through the
nucleophilic addition of the endocyclic imino group to the
nitrile function. The structure of the latter product (9) was
supported on the basis of elemental analysis and spectral data
2-(phenyldiazenyl)malononitrile to yield the acyclic interme-
diate which underwent in situ intramolecular cyclization via
the nucleophilic addition of the ring nitrogen atom to the other
nitrile function to afford the target molecule. The structure of
compound (5) was established on the basis of elemental anal-
ysis and spectral data. The IR spectrum exhibited absorption
-1
bands at 3422–3280, 3222, and 1563cm corresponding to
1
two NH , NH, and N¼N functions, respectively. The H-
2
NMR spectrum (DMSO-d ) revealed two broad singlet sig-
6
nals at δ 11.54 and 8.80 ppm assignable to indole-NH and
NH protons, respectively, sharp singlet signal at δ 6.95 ppm
2
because of pyrazole-CH, in addition to a multiplet signals at
δ 8.68–7.11ppm region owing to aromatic protons. The mass
+
spectrum revealed molecular ion peak at m/z=368 (M , 17.1)
with relative abundance corresponding to the molecular
formula C H N (Scheme 2).
20 16 8
In a similar manner, cyclocondensation of compound (4)
with either ethyl 2-cyano-2-(phenyldiazenyl)acetate or
Scheme 1. Synthesis of 3-(1H-indol-3-yl)-1H-pyrazol-5-amine (4).
(see Experimental). The scope of the present method was
further explored to include cyclic dicarbonyl compounds
possessing an activated methylene group. Thus the reaction
of aminopyrazole (4) with 5,5-dimethylcyclohexane-
1
,3-dione (dimedone) and triethyl orthoformate afforded
a single product that was identified as 2-(1H-indol-3-
yl)-8,8-dimethyl-8,9-dihydropyrazolo[1,5-a]quinazolin-6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Some Functionalized Indole-3-yl Pyrazole Derivatives
Scheme 2. Synthesis of pyrazolo[1,5-a]pyrimidine derivatives (5–8).
Scheme 3. Condensation of (4) with triethyl orthoformate and compounds possessing an activated methylene group.
(
7H)-one (10), based on elemental analysis and spectral
the corresponding imidazo[1,2-b]pyrazole derivative (15),
through elimination of two ethanol molecules (Scheme 4).
On the other hand, the behavior of aminopyrazole (4)
towards succinyl dichloride was also investigated as a
possible synthetic route to attain pyrazolo[1,5-a][1,3]
diazepine derivative. Thus, the corresponding pyrazolo
[1,5-a][1,3]diazepine (16) could be synthesized from the
reaction of (4) with succinyl dichloride in refluxing diox-
ane. The reaction of compound (4) with an equimolar
amount of phenyl isothiocyanate in ethanol catalyzed by
piperidine gave the non-isolable adduct (17), which sub-
sequently reacted with formaldehyde to give only one
regioisomeric product (as examined by TLC) that was
identified as pyrazolo[1,5-c][1,3,5]thiadiazine (18) rather
than pyrazolo[1,5-a][1,3,5]triazine (19). The pyrazolo
[1,5-c][1,3,5]thiadiazine (18) was considered most likely
based on its spectroscopic data. The IR spectrum showed
no absorption band characteristic to C¼S group and the
data. Surprisingly, treatment of (4) with 1,3-dimethylb
arbituric acid in refluxing triethyl orthoformate afforded the
corresponding linear condensation product (11). All attempts
at cyclization of this acyclic product to obtain pyrazolo[1,5-
a]pyrimidine derivative (12) were unsuccessful.
Finally, in view of the growing biological importance of
imidazo[1,2-b]pyrazole derivatives [27,28], it was of inter-
est to turn our attention to study the regioselectivity of the
cyclization reactions of the aminopyrazole (4) with
chloroacetyl chloride and phenacyl bromide with the aim
of preparing functionalized imidazo[1,2-b]pyrazoles. So,
the reaction of (4) with each of chloroacetyl chloride in
dioxane or phenacyl bromide in glacial acetic acid under
reflux yielded the corresponding imidazo[1,2-b]pyrazole
derivatives (13) and (14), respectively. Although the
endocyclic imino group in (4) is the most nucleophilic
center [29–31], it is the most sterically hindered site [32].
The formation of the target compounds (13) and (14) was
illustrated through elimination of two HCl molecules in case
of compound (13) and elimination of HBr molecule followed
by cyclization through elimination of a water molecule in
case of compound (14). Moreover, cyclocondensation of (4)
with diethyl oxalate in glacial acetic acid at reflux afforded
ꢀ
1
presence of absorption bands at 3224 and 3185 cm
1
because of two NH functions. The H-NMR spectrum
(DMSO-d ) displayed a sharp singlet signal at δ
6
5.55 ppm assignable to methylene protons of thiadiazine
ring, two broad singlet signals at δ 10.14 and 11.42 ppm
owing to two NH protons, besides the other expected
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. El-Mekabaty, A. Mesbah, and A. A. Fadda
Vol 000
signals. The mass spectrum showed a molecular ion
peak at m/z = 346 (M + 1), which agrees with a molec-
followed by TLC (Silica gel, aluminum sheets 60F254,
Merck). 3-Cyanoacetylindole (3) and 3-(1H-indol-3-yl)-1H-
pyrazol-5-amine (4) were prepared according to literatures
procedures [16,17].
General procedure for the synthesis of pyrazolo[1,5-a]
pyrimidine derivatives (5–7). A mixture of aminopyrazole
(4) (1.98g, 0.01mol) and the appropriate 1,3-dielectrophilic
reagents namely; 2-(phenyldiazenyl)malononitrile, ethyl 2-
cyano-2-(phenyldiazenyl)acetate, or 3-(phenyldiazenyl)pent
ane-2,4-dione (0.01mol) in ethanol (20mL) containing a
catalytic amount of pyridine (0.5mL) was refluxed for 14–
+
ular formula C H N S. The formation of (18) rather
1
9 15 5
than (19) may be attributed to the higher nucleophilicity
of a thiol group in compared with secondary amino
group.
In conclusion, the results of the present study indicate
that 3-(1H-indol-3-yl)-1H-pyrazol-5-amine (4), synthe-
sized by the reaction of 3-cyanoacetylindole (3) with
hydrazine hydrate in refluxing ethanol, is useful precursor
for the facile and convenient synthesis of polyfunctionally
substituted heterocycles (e.g. pyrazolo[1,5-a]pyrimidines,
imidazo[1,2-b]pyrazoles, pyrazolo[1,5-a][1,3]diazepine and
pyrazolo[1,5-c][1,3,5]thiadiazine) bearing indole moiety.
The compounds prepared are expected to be of pharmaco-
logical interest.
18h. The reaction mixture was left to cool and poured into
ice-cold water. The precipitated solid was filtered off, dried,
and recrystallized from ethanol.
2-(1H-Indol-3-yl)-6-(phenyldiazenyl)pyrazolo[1,5-a]pyrimidine-
5
2
,7-diamine (5).
Compound (5) was prepared from
-(phenyldiazenyl)malononitrile (1.70g, 0.01 mol) by
heating for 14h under reflux. Brown crystals; yield 79%;
ꢀ
1
mp 188–190°C. IR (KBr) νmax/cm : 3422–3280 (2NH ),
2
1
EXPERIMENTAL
3222 (NH), 1634 (C¼N), 1601 (C¼C), 1563 (N¼N). H-
NMR (DMSO-d ) δ : 11.54 (s, 1H, indole-NH), 8.80 (br,
6
ppm
General.
All melting points were determined on an
2H, NH ), 8.68–7.11 (m, 12H, Ar―H, NH ), 6.95 (s, 1H,
2
2
+
electrothermal Gallenkamp apparatus (Germany). The IR
spectra were measured on a Mattson 5000 FTIR
Spectrometer (USA) in potassium bromide discs. The H-
pyrazole-CH). MS: (m/z, %): 368 (M , 17.1), 339 (12.4),
262 (26.8), 170 (9.5), 93 (31.4), 77 (100.0), 65 (30.7), 51
(27.9). Anal. Calcd. for C H N (368.39): C, 65.21; H,
1
20 16 8
NMR spectra were recorded in DMSO-d on a Bruker WP
4.38; N, 30.42%. Found: C, 65.23; H, 4.40; N, 30.43%.
7-Amino-2-(1H-indol-3-yl)-6-(phenyl-diazenyl)pyrazolo[1,5-a]
pyrimidin-5(4H)-one (6). Compound (6) was prepared from
ethyl 2-cyano-2-(phenyldiazenyl)acetate (2.17g, 0.01mol)
by heating for 16h under reflux. Reddish brown crystals;
6
spectrometer (USA) (300MHz) and the chemical shifts δ
downfield from TMS as an internal standard. The mass
spectra were recorded on Finnegan MAT 212 instrument
(USA), and the ionizing voltage was 70eV, at the Faculty
ꢀ
1
of Science, Cairo University. Elemental analyses were
carried out by the Micro-analytical unit of Faculty of
Science, Cairo University, Giza, Egypt. All reactions were
yield 71%; mp 222–224°C. IR (KBr) νmax/cm : 3389–
3310 (NH
), 3293, 3184 (2NH), 1645 (C¼O, amidic),
1623 (C¼N), 1598 (C¼C), 1542 (N¼N). H-NMR
2
1
Scheme 4. Synthesis of imidazo[1,2-b]pyrazoles (13–15), pyrazolo[1,5-a][1,3]diazepine (16) and pyrazolo[1,5-c][1,3,5]thiadiazine (18).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Some Functionalized Indole-3-yl Pyrazole Derivatives
indole-NH), 8.58 (s, 1H, indole-H ), 8.46 (br, 2H, NH ),
(
DMSO-d ) δppm: 13.21 (s, 1H, NH), 11.52 (s, 1H, indole-
6
2
2
NH), 8.02–7.13 (m, 12H, Ar―H, NH ), 6.70 (s, 1H,
pyrazole-CH). MS: (m/z, %): 369 (M , 9.2), 353 (14.5),
8.10–7.13 (m, 4H, Ar―H), 7.72 (s, 1H, pyrimidine-CH),
2
+
6.92 (s, 1H, pyrazole-CH), 4.30 (q, J=7.2, 2H, CH ), 1.32
2
+
3
7
38 (22.7), 329 (9.9), 262 (30.2), 196 (29.1), 93 (100.0),
7 (67.0), 66 (54.5), 51 (43.2). Anal. Calcd. for
(t, J=7.2, 3H, CH ). MS: (m/z, %): 322 (M +1, 17.4), 321
3
+
(M , 26.7), 301 (13.2), 275 (19.6), 249 (16.4), 211 (10.6),
C H N O (369.38): C, 65.03; H, 4.09; N, 26.54%.
136 (17.6), 114 (13.4), 80 (38.5), 64 (100.0), 52 (21.5).
2
0 15 7
Found: C, 65.05; H, 4.10; N, 26.57%.
Anal. Calcd. for C H N O (321.33): C, 63.54; H, 4.71;
1
7 15 5 2
2
-(1H-Indol-3-yl)-5,7-dimethyl-6-(phenyldiazenyl)pyrazolo
1,5-a]pyrimidine (7). Compound (7) was prepared from
-(phenyldiazenyl)pentane-2,4-dione (2.04 g, 0.01 mol)
by heating for 18 h under reflux. Red crystals; yield
N, 21.79%. Found: C, 63.57; H, 4.72; N, 21.81%.
[
3
2-(1H-Indol-3-yl)-8,8-dimethyl-8,9-dihydropyrazolo[1,5-a]
quinazolin-6(7H)-one (10). Compound (10) was prepared
from 5,5-dimethylcyclohexane-1,3-dione (1.4g) by heating
for 3h. Brown crystals; yield 51%; mp 250–252°C. IR
ꢀ
1
6
1
7%; mp 261–263°C. IR (KBr) νmax/cm : 3222 (NH),
1
ꢀ1
616 (C¼N), 1600 (C¼C), 1554 (N¼N). H-NMR
(KBr) νmax/cm : 3283 (NH), 2980, 2963 (C–H aliph.),
1
(
DMSO-d ) δ : 11.62 (s, 1H, indole-NH), 8.89 (s,
1680 (C¼O), 1636 (C¼N), 1592 (C¼C). H-NMR
6
ppm
1
3
2
H, indole-H ), 8.58–7.16 (m, 10H, Ar―H), 3.12 (s,
H, CH ), 2.79 (s, 3H, CH ). MS: (m/z, %): 366 (M ,
2.5), 262 (8.2), 233 (11.2), 204 (32.4), 92 (17.4), 79
74.4), 52 (100.0). Anal. Calcd. for C H N (366.42):
C, 72.11; H, 4.95; N, 22.94%. Found: C, 72.14; H,
.97; N, 22.96%.
(DMSO-d ) δ : 11.84 (s, 1H, indole-NH), 8.43–7.21 (m,
2
6
ppm
+
3
3
6H, Ar―H), 7.84 (s, 1H, pyrimidine-CH), 2.69 (s, 2H,
CH ), 2.49 (s, 2H, CH ), 1.19 (s, 6H, 2CH ). MS: (m/z, %):
2
2
3
+
+
(
331 (M +1, 17.1), 330 (M , 64.5), 298 (26.1), 274 (8.8),
142 (13.7), 117 (10.3), 89 (10.7), 80 (17.9), 64 (100.0), 51
(39.3). Anal. Calcd. for C H N O (330.38): C, 72.71; H,
2
2
18
6
4
2
0 18 4
Synthesis of 2,5-di(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7-
5.49; N, 16.96%. Found: C, 72.73; H, 5.49; N, 16.98%.
5-{[(3-(1H-Indol-3-yl)-1H-pyrazol-5-yl)-amino]-methylene}-1,3-
dimethyl-pyrimidine-2,4,6 (1H,3H,5H)-trione (11). Compound
(11) was prepared from 1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (1.56 g) by heating for 3h. Brown
amine (8). An equimolar amount of (4) (1.98g, 0.01mol)
and 3-cyanoacetylindole (3) (1.84g, 0.01mol) in pyridine
15mL) was refluxed for 13h. The reaction mixture was
(
left to cool, poured into ice-cold water, and acidified by
drops of dilute HCl. The precipitated solid was filtered off,
dried, and recrystallized from ethanol. Brown crystals; yield
ꢀ
1
crystals; yield 82%; mp 294–296°C. IR (KBr) νmax/cm :
3282, 3214, 3166 (3NH), 2971, 2963 (C―H aliph.), 1684,
ꢀ
1
1
5
(
8%; mp 233–235°C. IR (KBr) νmax/cm : 3379–3315
1665 (3C¼O), 1611 (C¼N), 1591 (C¼C). H-NMR
1
NH ), 3254, 3235 (2NH), 1644 (C¼N), 1621 (C¼C). H-
(DMSO-d ) δ : 12.67 (s, 1H, NH), 11.49 (s, 1H, indole-
2
6
ppm
NMR (DMSO-d ) δ : 11.55 (s, 2H, two indole-NH), 9.25
NH), 10.74 (d, 1H, NH), 8.62 (d, 1H, CH=), 7.88–7.13 (m,
6
ppm
(
9
br, 2H, NH ), 8.64 (s, 2H, two indole-H ), 8.18–7.11 (m,
5H, Ar―H), 6.67 (s, 1H, pyrazole-CH), 3.12 (s, 6H, 2CH ).
2
2
3
+
+
H, Ar―H, pyrimidine-CH), 6.95 (s, 1H, pyrazole-CH).
MS: (m/z, %): 365 (M +1, 24.1), 364 (M , 19.4), 346
(16.7), 226 (11.7), 212 (8.0), 198 (96.6), 169 (35.9), 156
(41.3), 144 (25.0), 117 (29.0), 99 (18.1), 89 (26.8), 71 (9.7),
64 (100.0), 51 (20.9). Anal. Calcd. for C H N O
18 16 6 3
(364.36): C, 59.34; H, 4.43; N, 23.07%. Found: C, 59.36;
H, 4.44; N, 23.09%.
+
MS: (m/z, %): 364 (M , 16.5), 310 (31.7), 298 (22.9), 262
(
(
(
59.8), 144 (100.0), 131 (14.1), 116 (43.1), 89 (41.9), 80
39.7), 64 (42.7), 51 (19.1). Anal. Calcd. for C H N
364.40): C, 72.51; H, 4.43; N, 23.06%. Found: C, 72.53;
22
16
6
H, 4.45; N, 23.07%.
General procedure for the reaction of aminopyrazole (4) with
General procedure for the synthesis of imidazo[1,2-b]
triethyl orthoformate and active methylene compounds.
mixture of aminopyrazole derivative (4) (1.98g, 0.01 mol),
and active methylene compounds namely, ethyl cyanoacetate,
A
pyrazole derivatives (13–15). An equimolar amounts of
aminopyrazole derivative (4) (1.98g, 0.01mol) and
chloroacetyl chloride (0.01 mol) in 1,4-dioxane (15 mL),
phenacyl bromide or diethyl oxalate (0.01 mol) in glacial
acetic acid (15 mL) was refluxed for 14h. The reaction
mixture was left to cool at room temperature. The
precipitated solid was filtered off, washed with ethanol,
dried, and recrystallized from ethanol.
5,5-dimethylcyclohexane-1,3-dione or 1,3-dimethylpyri midi
ne-2,4,6(1H,3H,5H)-trione (0.01 mol), and triethyl ortho
formate (2.22g, 0.015mol) was heated under reflux for 2–
3
h. The reaction mixture was left to cool at room
temperature. The precipitated solid was washed with
petroleum ether, filtered off, dried, and recrystallized from a
mixture of DMF–EtOH (2:1).
6-(1H-Indol-3-yl)-1H-imidazo[1,2-b]pyrazol-2(3H)-one (13).
Compound (13) was prepared from chloroacetyl chloride
(1.12g). Yellow crystals; yield 78%; mp 256–258°C. IR
Ethyl 7-amino-2-(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidine-6-
carboxylate (9). Compound (9) was prepared from ethyl
cyanoacetate (1.13g) by heating for 2h. Brown crystals;
ꢀ
1
(KBr) νmax/cm : 3328, 3259 (2NH), 1671 (CO), 1623
1
(C¼N), 1595 (C¼C). H-NMR (DMSO-d ) δppm: 11.48 (s,
6
ꢀ
1
yield 73%; mp 269–271°C. IR (KBr) νmax/cm : 3380–
1H, indole-NH), 10.83 (br, 1H, NH), 7.78 (s, 1H, indole-H ),
2
3
303 (NH ), 3245 (NH), 1723 (C¼O, ester), 1621 (C¼N),
7.47–7.16 (m, 4H, Ar―H), 6.82 (s, 1H, pyrazole-CH), 4.27
2
1
+
1
595 (C¼C). H-NMR (DMSO-d ) δ : 11.55 (s, 1H,
(s, 2H, CH ). MS: (m/z, %): 238 (M , 8.5), 225 (31.1), 213
6
ppm
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. El-Mekabaty, A. Mesbah, and A. A. Fadda
Vol 000
(
6
4
10.6), 198 (11.3), 185 (9.9), 141 (13.2), 115 (1.12), 80 (100.0),
Reddish brown crystals; yield 55%; mp 289–291°C. IR
ꢀ
1
4 (90.5). Anal. Calcd. for C H N O (238.24): C, 65.54; H,
(KBr) ν /cm : 3224, 3185 (2NH), 1640 (C¼N), 1597
max
13
10
4
1
.23; N, 23.52%. Found: C, 65.56; H, 4.25; N, 23.54%.
(C¼C). H-NMR (DMSO-d ) δ : 11.42 (s, 1H, indole-
6
ppm
3
-(3-Phenyl-1H-imidazo[1,2-b]pyrazol-6-yl)-1H-indole (14).
NH), 10.14 (s, 1H, NH), 8.58–7.10 (m, 10H, Ar―H), 6.42
Compound (14) was prepared from phenacyl bromide
(
(
(
3
1
(
s, 1H, pyrazole-CH), 5.55 (s, 2H, CH ). MS: (m/z, %):
2
1.99g). Yellow crystals; yield 70%; mp 278–280°C. IR
+
+
46 (M +1, 13.2), 345 (M , 1.3), 271 (21.29), 198 (39.9),
69 (16.1), 156 (15.5), 115 (9.9), 80 (26.8), 64 (100.0), 55
ꢀ
1
KBr) ν /cm : 3385, 3252 (2NH), 1640 (C¼N), 1590
max
1
(
1
C¼C). H-NMR (DMSO-d ) δ : 11.48 (s, 1H, NH),
6
ppm
10.3). Anal. Calcd. for C H N S (345.42): C, 66.07; H,
19 15 5
1.23 (s, 1H, indole-NH), 8.53–7.09 (m, 12H, Ar―H).
4
.38; N, 20.28%. Found: C, 66.08; H, 4.39; N, 20.30%.
+
+
MS: (m/z, %): 299 (M +1, 10.3), 298 (M , 9.4), 288
(11.5), 185 (16.6), 144 (7.4), 116 (1.9), 105 (18.0), 80
(
7
1
100.0), 64 (74.2). Anal. Calcd. for C H N (298.34): C,
6.49; H, 4.73; N, 18.78%. Found: C, 76.51; H, 4.75; N,
8.80%.
1
9 14 4
REFERENCES AND NOTES
[
1] Sundberg, R. J. In Best Synthetic Methods, Indoles; Academic
Press: New York, 1996, p 7.
6-(1H-Indol-3-yl)-1H-imidazo[1,2-b]pyrazole-2,3-dione (15).
Compound (15) was prepared from diethyl oxalate (1.46 g).
Yellow crystals; yield 62%; mp 253–255°C. IR (KBr) νmax/
[2] Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Verber, D. F.; Anderson,
P. S.; Chang, R. S.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J Med Chem 1988, 31, 2235.
[3] Joule, J. A. In Indole and its Derivatives. In Science of Synthe-
sis: Houben-Weyl Methods of Molecular Transformations; Thomas, E. J.
Ed.; George Thieme Verlag: Stuttgart, Germany Category 2, 2000, p 10.
[4] Katritzky, R.; Ress, C. W.; Scriven, E. F. Comprehensive Het-
erocyclic Chem., A Review of the Literature 1982–1995; Elsevier Science
Limited Oxford: New York, 1996, p 2.
ꢀ
1
cm : 3258, 3159 (2NH), 1682, 1661 (2CO), 1632 (C¼N),
1
1
598 (C¼C). H-NMR (DMSO-d ) δ : 12.74 (br, 1H,
6
ppm
NH), 11.51 (s, 1H, indole-NH), 7.61 (s, 1H, indole-H ),
2
7
.42–7.06 (m, 4H, Ar―H), 7.04 (s, 1H, pyrazole-CH). MS:
+
+
+
(
m/z, %): 254 (M +2, 20.18), 253 (M +1, 8.3), 252 (M ,
1.2), 240 (21.8), 226 (43.8), 198 (100.0), 169 (38.3), 140
21.8), 115 (23.7), 85 (15.0), 57 (17.4). Anal. Calcd. for
C H N O (252.23): C, 61.90; H, 3.20; N, 22.21%.
1
(
[5] Rose, W. C. Physiol Rev 1938, 18, 109.
[6] Zhu, S.; Ji, S.; Su, X.; Sun, C.; Liu, Y. Tetrahedron Lett 2008,
13 8 4 2
4
9
9, 1777.
Found: C, 61.92; H, 3.22; N, 22.23%.
Synthesis of 2-(1H-indol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-
[
[
7] Kathrotiya, H. G.; Patel, M. P. J Chem Sci 2013, 125, 993.
8] Zhu, S.; Ji, S.; Zhao, K.; Liu, Y. Tetrahedron Lett 2008, 49, 2578.
a][1,3]diazepine-5,8-dione (16).
To
a
solution of
[9] Xiong, W. N.; Yang, C. G.; Jiang, B. Bioorg Med Chem 2001,
, 1773.
10] Thirumurugan, P.; Nandakumar, A.; Muralidharan, D.; Perumal,
aminopyrazole derivative (4) (1.98g, 0.01mol) in 1,4-
dioxane (15 mL), succinyl dichloride (1.54 g, 0.01mol)
was added dropwise with stirring at room temperature.
The reaction mixture was then heated under reflux for
[
P. T. J Comb Chem 2010, 12, 161.
[11] Fadda, A. A.; El-Mekabaty, A.; Mouse, I. A.; Elattar, K. M.
Synth Commun 2014, 44, 1579.
[12] Habib, O. M. O.; Hassan, H. M.; El-Mekabaty, A. Med Chem
6
h, left to cool. The solid product that obtained was
Res 2013, 22, 507.
[
13] El-Mekabaty, A.; Etman, H. A.; Mosbah, A. J Heterocyclic
collected by filtration, washed with ethanol, dried well,
and recrystallized from ethanol.
Chem 2015 accepted paper. DOI:10.1002/jhet.2218.
[14] El-Mekabaty, A. Chem Heterocycl Compd 2015, 50, 1698.
Brown crystals; yield 57%; mp 286–288°C. IR (KBr)
[15] Soliman, H. A.; Mubarak, A. Y.; El-Mekabaty, A.; Awad,
ꢀ
1
νmax/cm : 3221, 3180 (2NH), 1697, 1644 (2CO), 1612
H. M.; Elmorsy, S. S. Monatsh Chem 2015 accepted paper.
DOI:10.1007/s00706-015-1536-2.
1
(
1
C¼N), 1596 (C¼C). H-NMR (DMSO-d ) δppm: 13.18 (s,
6
[16] Abdel-Motaleb, R. M.; Makhloof, A. A.; Ibrahim, H. M.;
H, NH), 11.49 (s, 1H, indole-NH), 7.81–7.09 (m, 5H,
Elnagdi, M. H. J Heterocyclic Chem 2007, 44, 109.
[17] Siena Biotech, S. P.A., Wyeth Pharmaceuticals, Patent:
WO2008/87529 A1, 2008.
Ar―H), 6.51 (s, 1H, pyrazole-CH), 2.82 (s, 4H, 2CH ).
2
+
+
MS: (m/z, %): 281 (M + 1, 17.5), 280 (M , 38.2), 140
8.0), 80 (53.3), 64 (100.0), 55 (15.7). Anal. Calcd. for
C H N O (280.28): C, 64.28; H, 4.32; N, 19.99%. Found:
[18] Portilla, J.; Quiroga, J.; Nogueras, M.; Cobo, J. Tetrahedron
(
2012, 68, 988.
[19] Aggarwal, R.; Sumran, G.; Garg, N.; Aggarwal, A. Eur J Med
15 12 4 2
Chem 2011, 46, 3038.
C, 64.30; H, 4.34; N, 20.02%.
Synthesis of 7-(1H-indol-3-yl)-N-phenyl-4H-pyrazolo[1,5-c]
[
20] Petrov, A. A.; Kasatochkin, A. N.; Emelina, E. E.; Nelyubina,
Y. V.; Antipin, M. Y. Russ J Org Chem 2009, 45, 1390.
21] Brigance, R. P.; Meng, W.; Fura, A.; Harrity, T.; Wang, A.; Zahler,
R.; Kirby, M. S.; Hamann, L. G. Bioorg Med Chem Lett 2010, 20, 4395.
22] Daniels, R. N.; Kim, K.; Lebois, E. P.; Muchalski, H.; Hughes,
[
[
(
1,3,5]thiadiazin-2-amine (18).
A mixture of compound
4) (1.98g, 0.01mol) and an equimolar amount of phenyl
isothiocyanate (1.35g, 0.01mol) and formaldehyde (0.30g,
.01mol) in ethanol (10mL) containing a catalytic amount
[
M.; Lindsley, C. W. Tetrahedron Lett 2008, 49, 305.
0
[23] Gommermann, N.; Buehlmayer, P.; Von Matt, A.;
Breitenstein, W.; Masuya, K.; Pirard, B.; Furet, P.; Cowan-Jacob, S. W.;
Weckbecker, G. Bioorg Med Chem Lett 2010, 20, 3628.
of piperidine was stirred under reflux for 12h, then allowed
to cool at room temperature and diluted with ice-cold water
[24] Quiroga, J.; Portilla, J.; Abonía, R.; Insuasty, B.; Nogueras,
(30mL). The solid product was filtered off, dried well, and
M.; Cobo, J. Tetrahedron Lett 2008, 49, 6254.
recrystallized from ethanol.
[25] Karcı, F.; Demirçalı, A. Dyes Pigments 2007, 74, 288.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Some Functionalized Indole-3-yl Pyrazole Derivatives
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7009k, 278(148).
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[
8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet