Silica-bonded DABCO hydrogen sulfate ((SB-DABCO)HSO4): a new dual-interphase catalyst for the diversity-oriented pseudo-five-component synthesis of bis(pyrazolyl)methanes and novel 4-[bis(pyrazolyl)methane]phenylmethylene-bis(indole)s

Article abstract of DOI:10.1007/s13738-018-1424-x

Silica bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydrogen sulfate ((SB-DABCO)HSO₄) was prepared as a new interphase dual-catalyst and was successfully applied for the diversity-oriented synthesis of bis(pyrazolyl)methanes via a one-pot

Full text of DOI:10.1007/s13738-018-1424-x

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1424-x
ORIGINAL PAPER
Silica-bonded DABCO hydrogen sulfate ((SB-DABCO)HSO4): a new dual-
interphase catalyst for the diversity-oriented pseudo-five-component
synthesis of bis(pyrazolyl)methanes and novel 4-[bis(pyrazolyl)
methane]phenylmethylene-bis(indole)s
Mohsen Shekouhy1 · Reza Kordnezhadian1 · Ali Khalafi‑Nezhad1
Received: 19 December 2017 / Accepted: 31 May 2018
© Iranian Chemical Society 2018
Abstract
Silica bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydrogen sulfate ((SB-DABCO)HSO4) was prepared as a new
interphase dual-catalyst and was successfully applied for the diversity-oriented synthesis of bis(pyrazolyl)methanes via a
one-pot pseudo-five-component condensation reaction. This approach provides a versatile range of available substrates and
high diversity of desired products. Moreover, ((SB-DABCO)HSO4) was successfully applied for the synthesis of some novel
[bis(pyrazolyl)methane]-bis(indole)s as more complex molecules.
Keywords Interphase catalyst · Silica bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane Hydrogen sulfate ·
Bis(pyrazolyl)methane · Pseudo-five-component reaction · Pyrazolone · Indole
Introduction
pathway for the preparation of efficient heterogeneous cata-
lysts [5–12]. An interphase defines as a region in a material
in which the molecules of a stationary (organic–inorganic
hybrid catalyst) and mobile component (solvent and reac-
tants) reach each other. To overcome the steric effects of the
catalyst surface, active sites will be connected to the surface
of the heterogeneous support with a flexible organic group
that provides sufficient mobility of the reactive centers [13].
Between various kinds of nitrogen heterocycles, pyrazole
and its derivatives occupied a special position. They are the
main backbone of numerous biological active compounds
and have been used as drug targets in the pharmaceutical
industries [14–20]. In addition, their derivatives such as
4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol)s have a broad spectrum of approved biological activ-
ity, being used as anti-inflammatory [21], antipyretic [22],
gastric secretion stimulatory [23], anti-depressant [24], anti-
bacterial [25] and anti-filarial agents [26].
Nowadays, environmental care is one of the worldwide
increasing worries of human society and in the evolution
towards a sustainable development; catalysis is one of the
most important tools available to introducing more clear,
efficient and benign chemical processes. The use of cata-
lyzed systems instead of stoichiometric reagents will provide
ideal conditions for the application of more benign reaction
media, minimizing the waste and undesired by-products and
the reduction of energy consumption. To gain a practical and
benign catalytic system, the covalent anchoring of soluble
acid or base catalysts to a heterogeneous recyclable sup-
port in such a way as to preserve its catalytic activity is an
important challenge in green catalysis [1, 2] and their use-
fulness by means of sustainable chemistry has been studied
several times [3, 4]. The immobilization of catalytic systems
onto a large surface area solid carrier such as SiO2 using
organic species as connectors to create new organic–inor-
ganic hybrids (interphase) is a practical and frequently used
One useful strategy to gain a versatile library of biologi-
cally active compounds is the diversity-oriented synthesis
[27–29]. This approach provides a widespread spectrum of
synthesized compounds with diverse substitution profiles
using simple starting materials. In this context, multicompo-
nent reactions (MCRs) are of increasing importance due to
their high efficiency for delivering molecular diversity [30].
* Ali Khalafi-Nezhad
khalafi@chem.susc.ac.ir
1
Department of Chemistry, College of Sciences, Shiraz
University, Shiraz 71454, Iran
Vol.:(0123456789)
1 3

Journal of the Iranian Chemical Society
More recently, a new pseudo-five-component strategy for the
synthesis of bis(pyrazolyl)methanes via a one-pot condensa-
tion reaction of aryl aldehydes (1 equivalent), phenylhydra-
zine (2 equivalents) and ethyl acetoacetate (2 equivalents)
has been reported and immediately attracted some research
groups to introduce more efficient catalytic systems and
reaction conditions to improve its efficiency for the diversity-
oriented synthesis of titled compounds [31–37]. However,
most of the reported catalysts as well as reaction conditions
suffer from some drawbacks such as harsh reaction condi-
tions [35], no reusability of catalyst [32], tedious work up
[37], application of hazardous solvents and reagents [37],
very low diversity of available starting materials [31, 32, 35,
36] and need to the special instruments [33] etc.
Experimental
All applied solvents and reagents are commercially avail-
able and purchased from Merck, Sigma-Aldrich, Fluka or
Acros companies. A Büchi B-545 apparatus was applied
for the melting point determination. All known compounds
were identified by comparison of their melting points and 1H
NMR data with those in the authentic samples. The 1H NMR
(400 and 250 MHz) and 13C NMR (100 and 62.5 MHz) were
run on Bruker Avance DPX-400 and Bruker Avance DPX-
250 FT-NMR spectrometers. Chemical shifts are given as
δ values against tetramethylsilane as an internal standard
and J values are given in Hz. TG analysis was done using
a METTLER TOLEDO TG analysis instrument at an air
flow of 3 mL min−1 and temperature ramp of 2 °C min−1.
The temperature programmed desorption (TPD) of CO2
was done using a self-made TG instrument. Mass spectra
were recorded with the Agilent 7000 Series Triple Quad-MS
apparatus. The microanalysis was performed on a Perkin-
Elmer 240-B microanalyzer. The BET surface area measure-
ments were performed on a Micrometric ASAP 2020 (USA)
instrument.
Considering above facts about the various therapeutic
activities of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s and
unique advantages of interphase catalysts and in continua-
tion of our works on introducing more efficient and environ-
mentally benign catalytic systems and methods for the fine
chemical synthesis [38–53], we herein report silica-bonded
n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydrogen
sulfate ((SB-DABCO)HSO4) as a new, highly efficient and
reusable dual-interphase catalyst for the diversity-oriented
one-pot pseudo-five-component synthesis of bis(pyrazolyl)
methanes. (Scheme 1).
The preparation of silica‑bonded
n‑propyl‑4‑aza‑1‑azoniabicyclo[2.2.2]octane
chloride (SB‑DABCO)
DABCO (0.56 g, 5 mmol) was added to a 50 mL round-bot-
tom flask contained the suspension of 3-chloropropyl silica
(1 g) in dried acetone (30 mL) and obtained mixture was
O
H
R1
R2
R2
R1
(1)
O
O
O
O
Cat: 6 mol%
EtOH/Reflux
N
N
N
N
R2
O
O
R2
R3
(2)
OHHO
(4a-t)
R3
H
H
H2N N
N NH2
R3
R3
(3)
35-480 min
81-89%
HSO4
N
O
2 O
Si
O
i
Cat:
N
S
O
Scheme 1 The one-pot pseudo-five-component synthesis of bis(pyrazolyl)methanes in the presence of silica-bonded DABCO hydrogen sulfate
((SB-DABCO)HSO4)
1 3

Journal of the Iranian Chemical Society
vigorously stirred for 36 h at reflux conditions. The reaction
mixture was cooled to room temperature and obtained solids
were filtered and washed [acetone (10 mL, two times)]. The
resulting solid was dried under vacuum at 50 °C for 4 h to
give SB-DABCO as a white powder (1.158 g) [54].
washed with CH2Cl2 (20 mL), dried under vacuum at 50 °C
(12 h) and reused.
Selected spectral data
4,4′-(Phenylmethylene)
The preparation of silica‑bonded
bis(1-phenyl-3-propyl-1H-pyrazol-5-ol) (4g)
n‑propyl‑4‑aza‑1‑azoniabicyclo[2.2.2]octane
hydrogen sulfate ((SB‑DABCO)HSO4)
White solid, υmax: 3620, 3050, 2980, 1665, 1610,
1460 cm−1. 1H NMR (400 MHz, DMSO d6): δ 0.91 (t,
J=7.5 Hz, 6H), 1.58 (m, 4H), 2.36 (t, J=7.5 Hz, 4H), 5.67
(s, 1H), 7.19 (d, J= 8.0 Hz, 2H), 7.28 (t, J= 8.0 Hz, 1H),
7.34 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.3 Hz, 2H), 7.60 (t,
J = 8.3 Hz, 4H), 7.68 (d, J = 8.3 Hz, 4H), 10.60 (s, 1H),
10.81 (s, 1H), 13C NMR (100 MHz, DMSO d6): δ 13.1, 21.9,
33.1, 35.9, 118.9, 122.5, 126.3, 128.7, 129.0, 129.4, 137.7,
138.0, 153.6, 154.7. MS (m/z): 492 (M+).
At 0 °C, the solution of H2SO4 (3 mL, 98%) in CH2Cl2
(20 mL) was added dropwise to a 50 mL round-bottom
flask contained the suspension of silica-bonded n-propyl-
4-aza-1-azoniabicyclo[2.2.2]octane chloride (SB-DABCO)
(1 g) in dried CH2Cl2 (20 mL) and the addition continued for
30 min. During this time, the mixture was stirred vigorously
and it continued for 12 h. The reaction mixture was filtered
and washed with methanol (20 mL, three times). The result-
ing solid was dried under reduced pressure at 50 °C for 4 h
to give ((SB-DABCO)HSO4) as a white powder (1.107 g).
4,4′-(Phenylmethylene)
bis(3-propyl-1-p-tolyl-1H-pyrazol-5-ol) (4 h)
The general procedure for the preparation
of bis(pyrazolyl)methanes
White solid, υmax: 3610, 3070, 2950, 1675, 1605, 1460,
850 cm−1. 1H NMR (400 MHz, DMSO d6): δ 0.90 (t,
J = 7.8 Hz, 6H), 1.54 (m, 4H), 2.35–2.39 (m, 10 H), 5.45
(s, 1H), 7.28–7.31 (m, 3H), 7.38 (t, J = 8.5 Hz, 2H), 7.41
(d, J=8.3 Hz, 4H), 7.53 (d, J=8.3 Hz, 4H), 10.62 (s, 1H),
10.89 (s, 1H), 13C NMR (100 MHz, DMSO d6): δ 13.4, 21.1,
22.8, 32.4, 36.0, 119.7, 125.1, 125.4, 128.5, 129.1, 129.7,
134.3, 135.8, 154.0, 154.7.
The catalyst ((SB-DABCO)HSO4) (6 mol%, 0.07 g) was
added to a 25 mL round-bottom flask contained a solution
of hydrazine derivative (2 mmol) and β-keto ester (2 mmol)
in ethanol (10 mL) and resulting mixture was stirred at reflux
conditions for 10 min. After this time, aldehyde (1 mmol)
was added to the reaction mixture and stirring was continued
at reflux conditions and the completion of the reaction was
monitored by TLC. After completion, insoluble catalyst was
separated by a simple filtration, and the filtrate was stand at
room temperature for 12 h, during this time pure crystals of
desired products were formed. The separated catalyst was
washed with CH2Cl2 (20 mL), dried under vacuum at 50 °C
(12 h) and reused.
4,4′-(Phenylmethylene)
bis(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-ol) (4i)
White solid, υmax: 3610, 3070, 2960, 1675, 1610, 1470,
1150 cm−1. 1H NMR (400 MHz, DMSO d6): δ 0.91 (t,
J=7.5 Hz, 6H), 1.55 (m, 4H), 2.34 (t, J=7.5 Hz, 4H), 3.81
(s, 6H), 5.49 (s, 1H), 6.91 (d, J = 8.4 Hz, 4H), 7.23–7.27
(m, 3H), 7.36 (t, J=8.4 Hz, 2H), 7.61 (d, J=8.6 Hz, 4H),
10.52 (s, 1H), 10.95 (s, 1H), 13C NMR (100 MHz, DMSO
d6): δ 13.3, 22.8, 32.7, 36.5, 55.9, 112.7, 115.0, 119.3, 125.5,
128.7, 129.0, 129.9, 153.8, 154.3, 158.3.
The general procedure for the preparation
of 4‑[bis(pyrazolyl)methane]
phenylmethylene‑bis(indole)s
To a mixture of hydrazine derivative (2 mmol), β-keto ester
(2 mmol) and 4-(di(1H-indol-3-yl)methyl)benzaldehyde
(1 mmol) and ethanol (10 mL) in a three-neck round-bot-
tom flask, catalyst ((SB-DABCO)HSO4) (6 mol%, 0.07 g)
was added and the resulting mixture was stirred under the
nitrogen atmosphere at reflux temperature. After completion
of the reaction as indicated by TLC, insoluble catalyst was
separated with a simple filtration and the filtrate was stand
at room temperature for 12 h, during this time pure crystals
of desired product were formed. The separated catalyst was
4,4′-(Phenylmethylene)
bis(3-phenyl-1-p-tolyl-1H-pyrazol-5-ol) (4j)
White solid, υmax: 3640, 3050, 2970, 1670, 1600, 1460,
810 cm−1. 1H NMR (400 MHz, DMSO d6): δ 2.36 (s,
6H), 5.46 (s, 1H), 7.21–7.26 (m, 3H), 7.40–7.45 (m, 8H),
7.51–7.56 (m, 8H), 7.83 (d, J = 8.3, 4H), 10.93 (s, 1H),
11.31, (s, 1H), 13C NMR (100 MHz, DMSO d6): δ 21.4,
36.1, 117.5, 125.3, 125.7, 127.3, 128.1, 128.5, 129.3, 129.5,
129.9, 132.9, 133.9, 135.6, 138.3, 150.1, 152.5.
1 3

Journal of the Iranian Chemical Society
4,4′-((4-Chlorophenyl)methylene)
4,4′-(p-Tolylmethylene)
bis(1,3-diphenyl-1H-pyrazol-5-ol) (4k)
bis(3-phenyl-1-p-tolyl-1H-pyrazol-5-ol) (4o)
White solid, υmax: 3650, 3040, 2950, 1670, 1620, 1450,
840, 650 cm−1. 1H NMR (400 MHz, DMSO d6): δ (ppm)
5.48 (s, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 7.41–7.49 (m, 4H), 7.51–7.58 (m, 8H), 7.64 (d,
J = 8.3 Hz, 4H), 7.81 (d, J = 8.5 Hz, 4H), 10.59 (s, 1H),
10.90 (s, 1H), 13C NMR (100 MHz, DMSO d6): δ (ppm)
34.9, 117.8, 122.6, 126.1, 127.8, 128.1, 129.0, 129.3,
130.1, 131.2, 133.6, 136.0, 137.1, 150.9.
White solid, υmax: 3610, 3050, 2960, 1670, 1600, 1470 cm−1.
1H NMR (400 MHz, DMSO d6): δ (ppm) 2.35 (s, 6H), 2.39
(s, 3H), 5.41 (s, 1H), 7.11–7.14 (m, 4H), 7.41–7.43 (m, 6H),
7.49–7.56 (m, 8H), 7.81 (d, J=8.3 Hz, 4H), 10.61 (s, 1H),
10.94 (s, 1H), 13C NMR (100 MHz, DMSO d6): δ (ppm)
21.1, 21.4, 35.6, 117.9, 125.3, 127.6, 128.3, 128.5, 128.9,
129.1, 129.5, 133.0, 134.3, 135.2, 135.4, 135.9, 150.0,
152.6.
4,4′-((4-Nitrophenyl)methylene)
4,4′-((4-Bromophenyl)methylene)
bis(3-phenyl-1-p-tolyl-1H-pyrazol-5-ol) (4p)
bis(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-ol) (4l)
White solid, υmax: 3600, 3070, 2960, 1670, 1590, 1470,
750 cm−1. 1H NMR (400 MHz, DMSO d6): δ (ppm) 2.36 (s,
6H), 5.46 (s, 1H), 7.41–7.49 (m, 8H), 7.50–7.63 (m, 8H),
7.81 (d, J=8.1 Hz, 4H), 8.16 (d, J=8.1 Hz, 2H), 10.6 (s,
1H), 10.9 (s, 1H), 13C NMR (100 MHz, DMSO d6): δ (ppm)
21.4, 35.6, 117.9, 124.0, 125.5, 127.1, 128.3, 129.0, 129.5,
132.7, 133.0, 134.1, 136.1, 144.7, 144.9, 150.1, 152.9.
White solid, υmax: 3650, 3050, 2940, 1670, 1610, 1460,
1430, 1250, 630 cm−1. 1H NMR (400 MHz, DMSO d6):
δ (ppm) 0.91 (t, J = 7.6 Hz, 6H), 1.68 (m, 4H), 2.51
(t, J = 7.6 Hz, 4H), 3.87 (s, 6H), 5.54 (s, 1H), 6.97 (d,
J = 8.3 Hz, 4H), 7.16 (d, J = 8.5 Hz, 2H), 7.58 (d,
J = 8.3 Hz, 4H), 7.79 (d, J = 8.5 Hz, 2H), 10.91 (s, 1H),
11.61 (s, 1H), 13C NMR (100 MHz, DMSO d6): δ (ppm)
14.01, 23.01, 33.1, 36.6, 55.5, 112.7, 115.1, 119.3, 120.4,
129.9, 131.1, 131.4, 154.0, 154.6, 158.3.
4,4′-((3-Nitrophenyl)methylene)
bis(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-ol) (4q)
White solid, υmax: 3620, 3040, 2950, 1665, 1595, 1470 cm−1.
1H NMR (400 MHz, DMSO d6): δ (ppm) 0.90 (t, J= 7.8,
6H), 1.67 (m, 4H), 2.55 (t, J=7.8 Hz, 4H), 3.85 (s, 3H), 5.46
(s, 1H), 6.97 (d, J=8.3 Hz, 4H), 7.51–7.68 (m, 6H), 7.93 (t,
J=8.5 Hz, 1H), 8.12 (s, 1H), 10.61 (s, 1H), 10.93 (s, 1H),
13C NMR (100 MHz, DMSO d6): δ (ppm) 13.9, 23.0, 32.1,
35.6, 56.1, 112.6, 114.6, 119.2, 121.1, 125.3, 129.5, 129.7,
135.3, 139.1, 147.7, 153.6, 154.5, 158.3.
4,4′-(p-Tolylmethylene)
bis(3-propyl-1-p-tolyl-1H-pyrazol-5-ol) (4m)
White solid, υmax: 3660, 3030, 2920, 1670, 1610, 1460,
1430, 650 cm−1. 1H NMR (400 MHz, DMSO d6): δ (ppm)
0.90 (t, J = 7.6 Hz, 6H), 1.63 (m, 4H), 2.38 (t, J = 7.6 Hz,
4H), 2.33 (s, 6H), 2.37 (s, 3H), 5.49 (s, 1H), 7.11–7.16
(m, 4H), 7.38 (d, J = 8.5 Hz, 4H), 7.48 (d, J = 8.5 Hz,
4H), 10.93 (s, 1H), 11.31 (s, 1H), 13C NMR (100 MHz,
DMSO d6): δ (ppm) 13.9, 21.4, 21.5, 23.0, 32.7, 36.4,
119.3, 125.1, 128.9, 129.2, 129.7, 133.9, 135.0, 135.3,
135.8, 153.7, 154.9.
4,4′-((4-Isopropylphenyl)methylene)
bis(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-ol) (4r)
White solid, υmax: 3610, 3050, 2950, 1670, 1610,
1465 cm−1. 1H NMR (400 MHz, DMSO d6): δ (ppm) 0.91
(t, J=7.5 Hz, 6H), 1.23 (d, J=7.5 Hz, 6H), 1.68 (m, 4H),
2.46 (t, J=7.5 Hz, 4H), 2.89 (m, 1H), 3.76 (s, 6H), 5.46 (s,
1H), 6.98 (d, J=8.3 Hz, 4H), 7.14–7.18 (m, 4H), 7.48 (d,
J = 8.3 Hz, 4H), 10.64 (s, 1H), 10. 96 (s, 1H), 13C NMR
(100 MHz, DMSO d6): δ (ppm) 13.8, 23.0, 23.4, 32.3, 33.1,
36.0, 55.4, 112.5, 114.4, 119.4, 126.3, 128.8, 129.6, 135.0,
145.9, 153.1, 154.7, 158.4.
4,4′-(Furan-2-ylmethylene)
bis(3-propyl-1-p-tolyl-1H-pyrazol-5-ol) (4n)
White solid, υmax: 3650, 3050, 2970, 1670, 1610, 1465,
1420, 850 cm−1. 1H NMR (400 MHz, DMSO d6): δ (ppm)
0.89 (t, J = 7.5 Hz, 6H), 1.61 (m, 4H), 2.29 (s, 6H), 2.41
(t, J = 7.5 Hz, 4H), 5.51 (s, 1H), 6.12 (d, J= 8.7 Hz, 1H),
6.38 (t, J=8.7 Hz, 1H), 7.39 (d, J=8.0 Hz, 4H), 7.51–7.53
(m, 5H), 10.81 (s, 1H), 11.02 (s, 1H), 13C NMR (100 MHz,
DMSO d6): δ (ppm) 13.4, 21.4, 22.8, 27.1, 31.6, 106.5,
109.1, 119.5, 125.1, 129.3, 134.5, 135.6, 142.7, 152.5,
154.6, 155.1.
4,4′-((4-Isopropylphenyl)methylene)
bis(1-(4-methoxyphenyl)-3-phenyl-1H-pyrazol-5-ol) (4s)
White solid, υmax: 3610, 3030, 2990, 1670, 1610, 1470,
655 cm−1. 1H NMR (400 MHz, DMSO d6): δ (ppm) 1.23
1 3

Journal of the Iranian Chemical Society
(d, J = 7.5 Hz, 6H), 2.89 (m, 1H), 3.81 (s, 6H), 5.47 (s,
1H), 6.93 (d, J = 8.6 Hz, 4H), 7.16–7.21 (m, 4H), 7.39 (t,
J=8.6 Hz, 2H), 7.50–7.58 (m, 8H), 7.81 (d, J=8.6 Hz, 4H),
10.91 (s, 1H), 11.12 (s, 1H), 13C NMR (100 MHz, DMSO
d6): δ (ppm) 23.4, 33.6, 35.1, 55.9, 112.5, 114.8, 117.9,
126.0, 127.9, 128.6, 129.1, 129.7, 133.0, 135.2, 145.6,
149.8, 152.5, 158.3.
4,4′-((4-(Di(1H-indol-3-yl)methyl)phenyl)methylene)
bis(3-methyl-1-p-tolyl-1H-pyrazol-5-ol) (6b)
Pink solid, m.p. >300 °C. 1H NMR (250 MHz, DMSO d6):
δ (ppm) 2.31 (s, 6H), 3.19 (s, 6H), 4.85 (s, 1H), 5.91 (s,
1H), 6.64 (s, 2H), 7.15–7.92 (m, 20H), 9.42 (br, 2H), 10.67
(s, 1H), 10.90 (s, 1H), 13C NMR (62.5 MHz, DMSO d6):
δ (ppm) 14.5, 22.1, 35.6, 53.5, 111.0, 112.7, 119.0, 119.3,
119.8, 122.0, 12.4, 125.0, 127.8, 128.9, 129.2, 129.9, 135.1,
135.6, 135.9, 136.3, 136.7, 147.0, 154.1.
4,4′-((3-Methoxyphenyl)methylene)
bis(1-(4-methoxyphenyl)-3-phenyl-1H-pyrazol-5-ol) (4t)
White solid, υmax: 3610, 3030, 2990, 1670, 1610, 1250,
870, 780, 690 cm−1. 1H NMR (400 MHz, DMSO d6): δ
(ppm) 3.76 (s, 6H), 3.79 (s, 3H), 5.47 (s, 1H), 6.79 6.81 (m,
2H), 6.98–7.06 (m, 5H), 7.19 (t, J = 8.5 Hz, 1H), 7.39 (t,
J=8.5 Hz, 2H), 7.51–7.63 (m, 8H), 7.81 (d, J=8.5 Hz, 4H),
10.63 (s, 1H), 10.91 (s, 1H), 13C NMR (100 MHz, DMSO
d6): δ (ppm) 35.6, 55.9, 60.1, 111.3, 112.5, 113.0, 114.9,
117.9, 121.3, 127.6, 128.4, 129.3, 129.5, 129.8, 133.0,
139.2, 149.9, 152.7, 158.3, 160.1.
4,4′-((4-(Di(1H-indol-3-yl)methyl)phenyl)methylene)
bis(1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-5-ol) (6c)
Pink solid, m.p. >300 °C. 1H NMR (250 MHz, DMSO d6):
δ (ppm) 2.33 (s, 6H), 3.41 (s, 6H), 4.81 (s, 1H), 5.90 (s,
1H), 6.66 (s, 2H), 6.91–7.84 (m, 20H), 9.50 (br, 2H), 10.51
(s, 1H), 10.87 (s, 1H), 13C NMR (62.5 MHz, DMSO d6):
δ (ppm) 14.1, 36.3, 55.5, 56.1, 111.0, 112.6, 112.9, 115.0,
118.5, 119.3, 119.8, 122.0, 123.1, 126.5, 129.0, 129.5,
130.1, 135.3, 136.4, 147.2, 153.8, 159.0.
4,4′-((4-(Di(1H-indol-3-yl)methyl)phenyl)methylene)
bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (6a)
Results and discussions
Pink solid, m.p. >300 °C. 1H NMR (250 MHz, DMSO d6):
δ (ppm) 2.31 (s, 6H), 4.88 (s, 1H), 5.83 (s, 1H), 6.68 (s, 2H),
7.13–7.98 (m, 22H), 9.31 (s, 2H), 10.67 (s, 1H), 10.90 (s,
1H), 13C NMR (62.5 MHz, DMSO d6): δ (ppm) 14.5, 36.7,
53.9, 111.0, 133.3, 118.8, 119.3, 119.8, 122.0, 122.5, 123.7,
126.9, 127.8, 128.8, 129.3, 129.9, 134.5, 135.1, 136.1,
136.9, 146.6, 154.5.
In the first step, SB-DABCO was prepared using a reported
procedure [54] and then was treated with H2SO4 to afford
silica-bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane
hydrogen sulfate ((SB-DABCO)HSO4) as a white powder
(Scheme 2).
The catalyst structure was studied with IR spectroscopy
(Fig. 1). There are seven characteristic peaks in the spec-
trum of ((SB-DABCO)HSO4). The acid O–H stretching at
3700–3200 cm−1 as a broad band, sp3 C–H stretching at
2990 cm−1, C–N+ stretching at 1620 cm−1, CH2 bending at
1460 cm−1, Si–C stretching at 1215 cm−1, Si–O stretching
O
O
O
OH
OH
2
N
2
2
(MeO)3Si
Cl
O
O
Si
O
i
N
N
Si
Cl
O
i
O
i
N
S
Cl
S
S
Toluene, Reflux, 48h
Acetone, Reflux
36h
O
OH
CH2Cl2 H2SO4
12h
HSO4
O
2
O
O
O
Si
N
i
N
S
Scheme 2 The preparation of silica-bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydrogen sulfate ((SB-DABCO)HSO4)
1 3

Journal of the Iranian Chemical Society
Fig. 1 The IR spectra of freshly
synthesized silica-bonded
n-propyl-4-aza-1-azoniabi-
cyclo[2.2.2]octane hydrogen
sulfate ((SB-DABCO)HSO4)
(blue line) and recovered ((SB-
DABCO)HSO4) after eighth
reuse (red line)
at 1110–1090 cm−1 as a broad bond and S–O stretching at
870 cm−1.
analysis results. Nitrogen and sulfur content of the silica-
bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydro-
gen sulfate ((SB-DABCO)HSO4) were 2.91% and 3.48%,
respectively, by conventional elemental analysis. The ther-
mal stability of ((SB-DABCO)HSO4) was also investigated
and obtained results are demonstrated in Fig. 2.
−
In another study, the loading level of HSO4 has been
determined (using an acid–base titrimetric method) to be
at around 1.10 mmol g−1, which is in good agreement with
thermal gravimetric analysis (TGA) as well as elemental
Fig. 2 The TG analysis of silica-bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydrogen sulfate ((SB-DABCO)HSO4)
1 3

Journal of the Iranian Chemical Society
The 9.2% weight lost at around 90 °C can be related to
desorption of water vapor and other volatile organic com-
pounds which have been adsorbed on the catalyst. Follow-
ing the thermogram, the decrease observed in the slope of
the diagram, starting at around 270 °C can be related to the
loss of the covalently bounded organic groups. Based on
the obtained results from the thermogram, the amount of
organic moiety was about 25% against solid support. Con-
sidering obtained data from TGA and elemental analysis
the empirical formula of this catalyst can be calculated as
SiO2·0.087(C9H18N2-HSO4)·0.44H2O.
The basicity of 3-chloropropyl silica (SiPrCl) and silica-
bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane hydro-
gen sulfate ((SB-DABCO)HSO4) was also compared by the
temperature programmed desorption (TPD) of CO2 using a
TGA method. The desorption temperature and amount of
CO2 desorbed are considered as indexes of base strength and
total number of base sites, respectively. Fig. 3 shows only
one major weight loss occurred over SiPrCl at the range of
220–260 °C, but there are two major weight losses in the
case of ((SB-DABCO)HSO4), the first occurred between
240 and 270 °C and the second occurred between 310 and
350 °C. This is obviously known that TPD could be used to
evaluate the relative strength of basic sites. Fig. 3 indicates
that the ((SB-DABCO)HSO4) can be considered as a basic
catalyst as well as an acid catalyst at the same time according
to desorption temperature and intensity of CO2 adsorbed.
The N2 adsorption–desorption isotherm and pore size
distribution of the ((SB-DABCO)HSO4) are presented in
Fig. 4. As it is clear from Fig. 4, the ((SB-DABCO)HSO4)
shows a lower BET surface area and average pore size
(272.10 m2 g−1 and 3.5 nm, respectively) compared with
silica gel (550 m2 g−1 and 6 nm, respectively). These results
confirmed the immobilization of (DABCO)HSO4 on the
surface of silica gel. The narrow pore size distribution of
(SB-DABCO)HSO4 confirms the uniform immobilization
of (DABCO)HSO4 on the surface of silica gel.
Fig. 4 The nitrogen adsorption–desorption isotherms (a) and the pore
size distribution (b) of (SB-DABCO)HSO4
In the next step, one-pot pseudo-five-component con-
densation reaction of phenylhydrazines (2 equivalents),
β-ketoesters (2 equivalents) and aldehydes (1 equivalent) for
the preparation of bis(pyrazolyl)methanes was investigated
in the presence of ((SB-DABCO)HSO4) as a new interphase
dual-catalyst. To find the best reaction conditions, the one-
pot condensation of benzaldehyde (1a) (1 mmol, 0.10 g),
ethyl acetoacetate (2a) (2 mmol, 0.26 g) and phenylhydra-
zine (3a) (2 mmol, 0.21 g) in the presence of ((SB-DABCO)
HSO4) was selected as a model reaction (Scheme 3).
The reaction was examined in the presence of different
molar ratios of ((SB-DABCO)HSO4) in various solvents at
different temperatures and obtained results are summarized
in Table 1.
As it is indicated in Table 1, the best results (maximum
yield and shortest reaction time) were obtained in the pres-
ence of 6 mol% of the catalyst in ethanol as a solvent at
reflux temperature. Under these conditions, the correspond-
ing product (4a) was obtained in 86% yield within 40 min
(Table 1, entry 4). The model reaction was also examined
in the presence of ((SB-DABCO)HSO4) at various tem-
peratures and in several solvents including CHCl3, CH3CN,
EtOAc, H2O, CH2Cl2, THF, DMF, DMSO and PEG 200
(Table 1, entries 11–19). As it is clear from Table 1, ethanol
was the best solvent for this reaction. Besides, the model
Fig. 3 The CO2-TPD plots of SiPrCl (blue) and (SB-DABCO)HSO4
(red)
1 3

Journal of the Iranian Chemical Society
NH2
CHO
HN
O
O
N
N
N
N
+
+
O
OHHO
(1a, 1 mmol)
(2a, 2 mmol)
(3a, 2 mmol)
(4a)
Scheme 3 The one-pot condensation of benzaldehyde (1a) (1 mmol, 0.10 g), ethyl acetoacetate (2a) (2 mmol, 0.26 g) and phenylhydrazine (3a)
(2 mmol, 0.21) in the presence of ((SB-DABCO)HSO4)
Table 1 The one-pot condensation of benzaldehyde (1a) (1 mmol,
0.10 g), ethyl acetoacetate (2a) (2 mmol, 0.26 g) and phenylhydrazine
(3a) (2 mmol, 0.21) in the presence of ((SB-DABCO)HSO4) under
different conditions
As it is shown in Table 2, various β-ketoesters, phenyl-
hydrazines and aryl aldehydes were successfully condensed
and desired products were obtained in short times and with
good yields. Moreover, acid-sensitive aldehydes such as fur-
fural and thiophene-2-carbaldehyde have been successfully
applied without the formation of any by-products (Table 2,
entries 4 and 14).
Entry Solvent
(5 mL)
Catalyst Temp. (°C) Time (min) Yield (%)a
(mol%)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3Cl
CH3CN
EtOAc
H2O
3
4
5
6
7
8
–
6
6
6
6
6
6
6
6
6
6
6
6
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t
120
120
70
40
40
41
45
86
86
85
86
Trace
–
39
79
40
55
35
25
28
Trace
46
52
Indole derivatives are important class of biologically
active compounds and have been frequently studied due
to their unique and extensive biological activities [57].
Bis(indolyl)methanes are one of the most important group of
indole derivatives which are found and isolated from some
natural sources [58]. These compounds have shown some
different pharmaceutical activities such as anticancer [59],
antihyperglycemic, antiviral and antimicrobial properties
[60] and are known as a promoter of estrogen metabolism
[61]. The resultant pharmacological interest in compounds,
which belong to the pyrazole, indole, bis(pyrazolyl)meth-
ane and bis(indolyl)methane families, has led us to apply
our presented method for the synthesis of some novel
4-[bis(pyrazolyl)methane]phenylmethylene-bis(indole)s.
For this, 4-(di(1H-indole-3-yl)methyl)benzaldehyde (7) was
prepared via the condensation of indole with terephthalal-
dehyde using a reported procedure [62] and was condensed
with ethyl acetoacetate (2a) and hydrazines (3) under the
optimized conditions and nitrogen atmosphere (Scheme 4)
and desired products were successfully obtained in good
yields after short times.
40
120
120
120
40
120
120
120
120
120
120
120
120
120
9
40
60
10
11
12
13
14
15
16
17
18
19
Reflux
Reflux
Reflux
80
Reflux
Reflux
80
CH2Cl2
THF
DMF
DMSO
PEG 200
80
80
70
aIsolated pure products
Although the detailed mechanism of this reaction is
still not completely clear, the formation of bis(pyrazolyl)
methanes via a one-pot pseudo-five-component conden-
sation reaction between aldehydes (1), β-ketoesters (2)
and hydrazines (3) could be explained by the reaction
sequences in Scheme 5. In the first step, a condensation
of hydrazines (3) with β-ketoesters (2) is proposed to
give the intermediate (5). After this, the tandem Knoeve-
nagel–Michael reaction of intermediate (5) with aldehydes
(1) leads to the formation of desired products (4). Based
on this mechanism, ((SB-DABCO)HSO4) is an effective
bifunctional catalyst (acid as well as base). Based on our
suggestion, ((SB-DABCO)HSO4) serves two catalytic
reaction was examined without the catalyst and only trace
amounts of desired product were obtained even after a long
time (Table 1, entry 7). This observation establishes the cru-
cial catalytic role of ((SB-DABCO)HSO4) as a new inter-
phase catalyst for the expedition of the one-pot pseudo-five-
component synthesis of bis(pyrazolyl)methanes.
With optimized conditions in hand and to probe the
efficiency and the scope of our method, a broad range of
structurally diverse aldehydes (1) were condensed with
β-ketoesters (2) and hydrazines (3) to furnish the corre-
sponding bis(pyrazolyl)methanes in high yields and in rela-
tively short reaction times (Scheme 1) and obtained results
are summarized in Table 2.
1 3

Journal of the Iranian Chemical Society
Table 2 The one-pot multicomponent synthesis of bis(pyrazolyl)methanes in the presence of ((SB-DABCO)HSO4) as a new interphase catalyst
Entry
R1
R2
R3
Product
Time (min)
Yield (%)a
M.P. (°C)
1
2
3
4
5
6
7
8
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2CH2
CH3CH2CH2
CH3CH2CH2
Ph
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
40
40
100
120
50
70
45
86
88
83
87
85
87
86
87
89
83
85
85
83
86
82
87
85
87
81
82
170–172 (171–172) [55]
211–213 (207–209) [55]
183–184 (185–188) [56]
193–195 (190–192) [56]
171–173 (172–175) [56]
202–204 (200–202) [56]
189–191
205–207
211–213
252–254
274–276
261–263
245–247
233–235
249–251
>300
>300
255–257
265–267
4-Cl-Ph
4-OEt-Ph
2-Thionyl
3-Br-Ph
4-Me-Ph
Ph
Ph
Ph
Ph
4-Cl-Ph
4-Br-Ph
4-Me-Ph
2-Furyl
4-Me-Ph
4-NO2-Ph
3-NO2-Ph
4-CH(CH3)2Ph
4-CH(CH3)2Ph
3-OMe-Ph
4-Me
4-OMe
4-Me
H
4-OMe
4-Me
4-Me
4-Me
4-Me
4-OMe
4-OMe
4-OMe
4-OMe
40
40
9
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
360
480
50
110
100
480
360
35
Ph
CH3CH2CH2
CH3CH2CH2
CH3CH2CH2
Ph
4m
4n
4o
4p
4q
4r
4s
4t
Ph
CH3CH2CH2
CH3CH2CH2
Ph
100
480
480
Ph
284–287
aIsolated yield
CHO
+
N
H
CHO
(1 eq)
(2 eq)
Ref. [24]
NH
HN
NH
HN
H2N
NH
O
O
((SB-DABCO)HSO4)
R
+
O
+
N
N
N
N
EtOH
Reflux
OHHO
(6a-c)
CHO
(5, 1 mmol)
R
R
(2a, 2 mmol)
(3, 2 mmol)
R
H (6a) CH3 (6b) OCH3 (6c)
Time (min)
Yield(%)
80
83
60
89
50
89
Scheme 4 The synthesis of some novel 4-[bis(pyrazolyl)methane]phenylmethylene-bis(indole)s in the presence of ((SB-DABCO)HSO4)
1 3

Journal of the Iranian Chemical Society
Step 1:
N
N
R1
NH
N
R1
NH
R2
N
H
N
O
H
N
N
O
O
H
N
R2
H
O
N
H
(2)
R1
R2
O
O
N
- H2O
- EtOH
O
R1
O
(3)
(5)
R2
H
O
O
O
H
S
O
O
O
O
S
O
O
O
Step 2:
O
S
O
N
R1
O
H
N
N
N
H
R2
R3
R2
N
O
R2
R2
N
H
R3
O
(1)
H
O
H
N
N
O
O
N
N
R1
- H2O
N
N
H
R1
R1
H
(5)
N
O
N
O
O
S
O
S
O
O
O
O
R2
R2
R2
R2
R3
R3
N
N
N
N
N
N
N
N
R1
R1
OHHO
R1
R1
OH
O
(4)
Scheme 5 The proposed mechanism for the synthesis of bis(pyrazolyl)methanes in the presence of ((SB-DABCO)HSO4)
functions: first, to electrophilically activate the aldehydes
and carbonyl group of β-ketoesters through the interaction
and finally it has been found that all pyrazolones are con-
verted to the corresponding bis(pyrazolyl)methane (4a).
To examine the possibility of recycling the catalyst, the
model reaction was run in the presence of recovered cata-
lyst and obtained results are summarized in Fig. 5. Upon
completion of reaction, insoluble catalyst was separated by
simple filtration, washed with CH2Cl2 and dried at 50 °C
under reduced pressure for 12 h. The filtrate was stand at
room temperature for 12 h and during this time pure crys-
tals of desired product were formed. The recovered cata-
lyst was reused ten times in the condensation reaction of
benzaldehyde (1a, 1 mmol, 0.10 g), ethyl acetoacetate (2a,
2 mmol, 0.28 g) and phenylhydrazine (3a, 2 mmol, 0.21 g)
and smooth loss of catalytic activity was observed from the
eighth time of reuse (Fig. 4). Moreover, the IR spectrum of
recovered catalyst after the eighth time of reuse was com-
pared with the IR spectrum of freshly synthesized catalyst
−
between positively charged hydrogen of HSO4 and the
carbonyl oxygen, and second, to enhance the nucleophi-
licity of the hydrazines and intermediate (5) through the
interaction between Cα-H with nitrogen of DABCO-like
part of the catalyst.
To corroborate the suggested mechanism, a benchmark
reaction in two steps was carried out. In this regard, ethyl
acetoacetate (2a, 2 mmol, 0.26 g) was treated with phenyl-
hydrazine (3a, 2 mmol, 0.21 g) under optimized conditions
and the completion of the reaction was followed by TLC. It
is found that ethyl acetoacetate was converted to correspond-
ing pyrazolone (3-methyl-1-phenyl-1H-pyrazol-5(4H)-one)
under applied conditions. In the next step, benzaldehyde
(1a, 1 mmol, 0.10 g) was added to the reaction mixture and
resulted mixture was stirred under the optimized conditions
1 3

Journal of the Iranian Chemical Society
Fig. 5 The catalytic activity of
((SB-DABCO)HSO
4) in ten
cycles for the one-pot reaction
of benzaldehyde (1a, 1 mmol,
0.10 g), ethyl acetoacetate (2a,
2 mmol, 0.28 g) and phenylhy-
drazine (3a, 2 mmol, 0.21 g)
6. B. Karimi, M. Ghoreishi-Nezhad, Clark JH. Org. Lett. 7, 625–
628 (2005)
(Fig. 1). As it is clear from Fig. 1, there are no differences
between the two IR spectra, so it is expressible that the cat-
alyst structure is stable under the applied conditions even
after the eighth time of reuse.
7. B. Karimi, M. Khalkhali, J. Mol. Catal. A Chem. 232, 113–117
(2005)
8. B. Karimi, A. Zamani, J.H. Clark, Organometallics 24, 4695–
4698 (2005)
9. B. Karimi, L. Ma’Mani, Org. Lett. 6, 4813–4815 (2004)
10. R. Gupta, S. Paul, R. Gupta, J. Mol. Catal. A Chem. 266, 1–2
(2007)
Conclusions
11. K. Niknam, A. Piran, Z. Karimi, J. Iran. Chem. Soc. 13, 859–
871 (2016)
In summary, an efficient protocol for the one-pot synthesis
of bis(pyrazolyl)methane derivatives via a multicomponent
reaction of β-ketoesters (2 equivalents), phenylhydrazines
(2 equivalents) and aryl aldehydes (1 equivalent) has been
described using silica-bonded n-propyl-4-aza-1-azoniabi-
cyclo[2.2.2]octane hydrogen sulfate ((SB-DABCO)HSO4)
as a recoverable and heterogeneous interphase catalyst.
Mild reaction conditions, versatile range of available sub-
strates and high diversity of products, operational simplicity,
enhanced rates and high isolated yields of pure products
are significant advantages of the protocol described here.
This easy removal and reusability of the catalyst makes this
method a better choice for chemical industries. Moreover,
some novel 4-[bis(pyrazolyl)methane]phenylmethylene-
bis(indole)s as more complex molecules were synthesized
successfully.
12. K. Niknam, N. Borazjani, Monatsh. Chem. 147, 1129–1135
(2016)
13. R. Noyori, M. Aoki, K. Sato, (2003) Chem. Commun.,
pp. 1977–1986
14. E. McDonald, K. Jones, P.A. Brough, M.J. Drysdale, P. Work-
man, Curr. Top. Med. Chem. 6, 1193–1203 (2006)
15. J. Elguero, in Comprehensive Heterocyclic Chemistry, ed. by
A.R. Katritzky, C.W. Rees, E.F.V. Scriven (Oxford, Pergamon,
1996)
16. J. Elguero, P. Goya, N. Jagerovic, A.M.S. Silva, Targets Hetero-
cycl. Syst. 6, 52–98 (2002)
17. J. Elguero, P. Goya, N. Jagerovic, A.M.S. Silva, in Targets in
Heterocyclic Systems, ed. by O.A. Attanasi, D. Spinelli (Italian
Society of Chemistry, Roma, 2002)
18. Y.R. Huang, J.A. Katzenellenbogen, Org. Lett. 2, 2833–2836
(2000)
19. K.Y. Lee, J.M. Kim, J.N. Kim, Tetrahedron Lett. 44, 6737–6740
(2003)
20. H. Nakagawa, R. Ohyama, A. Kimata, T. Suzuki, N. Miyata,
Bioorg. Med. Chem. Lett. 16, 5939–5942 (2006)
21. S. Sugiura, S. Ohno, O. Ohtani, K. Izumi, T. Kitamikado, H. Asai,
K. Kato, J. Med. Chem. 20, 80–85 (1977)
Acknowledgements We gratefully appreciate the Shiraz University
Research Councils for the financial support of this work.
22. L.C. Behr, R. Fusco, C.H. Jarboe, in The Chemistry of Heterocy-
clic Compounds, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles
and Condensed Rings, ed. by A. Weissberger (Interscience, New
York, 1967)
References
23. C.E. Rosiere, M.I. Grossman, Science 113, 651–659 (1951)
24. D.M. Bailey, P.E. Hansen, A.G. Hlavac, E.R. Baizman, J. Pearl,
A.F. Defelice, M.E. Feigenson, J. Med. Chem. 28, 256–260 (1985)
25. R.N. Mahajan, F.H. Havaldar, P.S. Fernandes, J. Indian Chem.
Soc. 68, 245–246 (1991)
1. R. Schlögl, Angew. Chem. Int. Ed. 54, 3465–3520 (2015)
2. J.R.H. Ross, Heterogeneous catalysis (Fundamentals and Applica-
tions, Elsevier, Amsterdam, 2012)
26. P.M.S. Chauhan, S. Singh, R.K. Chatterjee, Indian J Chem Sect
B 32, 858–863 (1993)
3. C.M. Friend, B. Xu, Acc. Chem. Res. 50, 517–521 (2017)
4. M. Boronat, P. Concepción, Catal. Today 285, 166–178 (2017)
5. M. Sheykhan, L. Mamani, A. Ebrahimi, A. Heydari, J. Mol. Catal.
A: Chem. 335, 253–261 (2011)
27. C.J. O’Connor, H.S.G. Beckmanna, D.R. Spring, Chem. Soc. Rev.
41, 4444–4456 (2012)
1 3

Journal of the Iranian Chemical Society
28. H.S.G. Beckmann, F. Nie, C.E. Hagerman, H. Johansson, Y.S.
Tan, D. Wilcke, D.R. Spring, Nat. Chem. 5, 861–867 (2013)
29. J.J. Ciardiello, W.R.J.D. Galloway, C.J. O’Connor, H.F. Sore, J.E.
Stokes, Y. Wu, D.R. Spring, Tetrahedron 72, 3567–3578 (2016)
30. E. Ruijter, R. Scheffelaar, R.V.A. Orru, Angew. Chem. Int. Ed. 50,
6234–6246 (2011)
46. A. Hasaninejad, A. Zare, M. Shekouhy, Tetrahedron 67, 390–400
(2011)
47. H.R. Safaei, M. Shekouhy, A. Shirinfeshan, S. Rahmanpur, Mol.
Divers. 16, 669–683 (2012)
48. A. Khalafi-Nezhad, S. Mohammadi, RSC Adv. 3, 4362–4371
(2013)
31. Sh. Tayebi, K. Niknam, Iran. J. Catal. 2, 69–74 (2012)
32. E. Soleimani, S. Ghorbani, M. Taran, A. Sarvary, C. R. Chim. 15,
955–961 (2012)
49. A. Khalafi-Nezhad, S. Mohammadi, Synthesis 44, 1725–1735
(2012)
50. A. Hasaninejad, M. Shekouhy, M.R. Mohammadizadeh, A. Zare,
RSC Adv. 2, 6174–6177 (2012)
33. A. Hasaninejed, M.R. Kazerooni, A. Zare, ACS Sustain. Chem.
Eng. 1, 679–684 (2013)
51. H.R. Safaei, M. Shekouhy, V. Shafiee, M. Davoodi, J. Mol. Liq.
180, 139–144 (2013)
34. J. Safaei-Ghomi, B. Khojastehbakht-Koopaei, H. Shahbazi-Alavi,
RSC Adv. 4, 46106–46113 (2014)
52. H.R. Safaei, M. Davoodi, M. Shekouhy, Synth. Commun. 43,
2178–2190 (2013)
35. F. Shirini, M. Seddighi, M. Mazloumi, M. Makhsous, M. Abedini,
J. Mol. Liq. 208, 291–297 (2015)
53. H.R. Safaei, M. Shekouhy, S. Khademi, V. Rahmanian, M. Safae,
J. Ind. Eng. Chem. 20, 3019–3024 (2014)
36. N.G. Khaligh, S.B.A. Hamid, S.J. Titinchi, Chin. Chem. Lett. 27,
104–108 (2016)
54. A. Hasaninejad, M. Shekouhy, N. Golzar, A. Zare, M.M. Dorood-
mand, Appl. Catal. A Gen. 402, 11–22 (2011)
55. W. Wang, S.X. Wang, X.Y. Qin, J.T. Li, Synth. Commun. 3,
1263–1269 (2005)
37. R. Jahanshahi, B. Akhlaghinia, Chem. Pap. 71, 1351–1364 (2017)
38. M. Shekouhy, A. Khalafi-Nezhad, Green Chem. 17, 4815–4829
(2015)
39. H.R. Safaei, M. Safaei, M. Shekouhy, RSC Adv. 5, 6797–6806
(2015)
56. A. Hasaninejad, A. Zare, M. Shekouhy, N. Golzar, Org. Prep.
Proced. Int. 43, 131–137 (2011)
40. M. Shekouhy, A. Moaddeli, A. Khalafi-Nezhad, Res. Chem.
Intermed. 42, 3805–3827 (2016)
57. R.J. Sundberg, The Chemistry of Indole (Academic Press, New
York, 1996)
41. A. Khalafi-Nezhad, M. Shekouhy, H. Sharghi, J. Aboonajmi, A.
Zare, RSC Adv. 6, 67281–67289 (2016)
58. R. Bell, S. Carmeli, N. Sar, A. Vibrindole, J. Nat. Prod. 57, 1587–
1590 (1994)
42. M. Shekouhy, A. Moaddeli, A. Khalafi-Nezhad, J. Ind. Eng.
Chem. 50, 41–49 (2017)
59. C. Hong, G.L. Firestone, L.F. Bjeldance, Biochem. Pharmacol.
63, 1085–1097 (2002)
43. H.R. Safaei, M. Shekouhy, S. Rahmanpur, A. Shirinfeshan, Green
Chem. 14, 1696–1704 (2012)
60. L. Povszsz, G.P. Katakin, S. Foleat, B. Malkovics, Acta Phys.
Acad. Sci. Hung. 29, 299–312 (1996)
44. A. Hasaninejad, M. Shekouhy, A. Zare, Catal. Sci. Technol. 2,
201–214 (2012)
61. M.A. Zeligs, J. Med. Food 1, 67–82 (1998)
62. A. Hasaninejad, A. Zare, H. Sharghi, K. Niknam, M. Shekouhy,
ARKIVOC xiv:39–50 (2007)
45. A. Hasaninejad, A. Zare, M. Shekouhy, J. Ameri-Rad, Green
Chem. 13, 958–964 (2011)
1 3