A simple procedure for the synthesis of novel 3-(benzofur-2-yl)pyrazole-based heterocycles

Article abstract of DOI:10.1007/s11696-017-0209-5

3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde was used, as a precursor for the synthesis of a series of novel heterocycles by facile reactions with 3-oxo-3-phenylpropanenitrile, 2-cyanoethanethioamide, and various hydrazides such as cyanoacetohydrazide, acetohydrazide, and carbohydrazide derivatives. The structures of the products were confirmed by various spectroscopic methods along with the X-ray crystal structures. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11696-017-0209-5

Chem. Pap.
DOI 10.1007/s11696-017-0209-5
ORIGINAL PAPER
A simple procedure for the synthesis of novel
3-(benzofur-2-yl)pyrazole-based heterocycles
Mohammed A. Baashen1 Bakr F. Abdel-Wahab1,2 Gamal A. El-Hiti3
•
•
Received: 10 March 2017 / Accepted: 20 May 2017
Ó Institute of Chemistry, Slovak Academy of Sciences 2017
Abstract 3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazole-4-
carbaldehyde was used, as a precursor for the synthesis of a
series of novel heterocycles by facile reactions with 3-oxo-
3-phenylpropanenitrile, 2-cyanoethanethioamide, and var-
ious hydrazides such as cyanoacetohydrazide, acetohy-
drazide, and carbohydrazide derivatives. The structures of
the products were confirmed by various spectroscopic
methods along with the X-ray crystal structures.
Introduction
Compounds containing benzofuran moieties are important
constituent of many fused heterocycles in which many
derivatives have been isolated from natural sources and
show various biological activities (Abdel-Wahab et al.
2009; Asif 2016; Dawood et al. 2006; Hiranita et al. 2010;
Hiremathad et al. 2015; Khanam 2015; Naik et al. 2015;
Rickli et al. 2015; Saha et al. 2011). Various synthetic
approaches are known to afford substituted benzofurans
(Abdel-Aziem 2015; Abd El-Wahab et al. 2011; Abu-
Hashem et al. 2014; Kadieva and Oganesyan 1997; Kumar
and Sharma 2016; Liu et al. 2016; Weissberger and Taylor
1974; Wu et al. 2016; Yeung 2012; Zhou et al. 2010). The
most common traditional methods involve the reaction of
salicylaldehyde and chloroacetic acid (Burgstahler and
Worden 1966), Perkin rearrangement of coumarin (Perkin
1871), and cyclization of 2-alkyne phenols (Fu¨rstner and
Davies 2005). The most recent examples of high yielding
synthesis of 2-alkyl/benzyl benzofurans involve the
cyclization of 2-styryl phenols at room temperature in
acetonitrile for 1–3 h in the presence of stoichiometric
amounts of (diacetoxyiodo) benzene (Singh and Wirth
2012), cyclization of 1-allyl-2-allyloxybenzenes at 90 °C
in toluene for 3 h in the presence of a ruthenium catalyst
(van Otterlo et al. 2005), cross-coupling of 2-iodophenols
and substituted acetylene in the presence of palladium
nanoparticles in a mixture of methanol and acetonitrile at
60 °C (Mandali and Chand 2015), and cyclization of 2-(1-
hydroxyprop-2-ynyl)phenols in the presence of palladium
acetate and cesium carbonate as catalysts in acetonitrile
(Rajesh et al. 2015). In addition, 2-arylbenzofurans can be
obtained in high yields from the reaction of arylboronic
acids or potassium aryl trifluoroborates (two mole equiv-
alents) and aliphatic nitriles in aqueous tetrahydrofuran in
Graphical Abstract
NC
N
NC
N
S
N
O
N
O
NH2
N
N
H
O
N
N
N
O
O
O
N
Keywords 2-Substituted benzofuran Á Pyrazole-4-
carbaldehyde Á Carbohydrazide Á Heterocycles Á Synthesis
& Bakr F. Abdel-Wahab
balshobia@su.edu.sa
& Gamal A. El-Hiti
gelhiti@ksu.edu.sa
1
Department of Chemistry, College of Science and
Humanities, Shaqra University, Duwadimi, Saudi Arabia
2
Applied Organic Chemistry Department, National Research
Centre, Dokki, Giza, Egypt
3
Cornea Research Chair, Department of Optometry, College
of Applied Medical Sciences, King Saud University, P.O.
Box 10219, Riyadh 11433, Saudi Arabia
123

Chem. Pap.
the presence of palladium acetate as a catalyst and excess
trifluoroacetic acid (Wang et al. 2013a, b). Moreover, the
reaction of phenols with diols or bromoalkynes at high
temperatures in the presence of a catalyst gave high yields
of 2-substituted benzo[b]furans (Lee et al. 2012; Wang
et al. 2011).
IR spectrum of 6 shows a characteristic absorption band
1
(2213 cm21) due to the nitrile group. In addition, its H
NMR spectrum shows an exchangeable singlet corre-
sponding to the NH2 protons (10.22 ppm). The structure of
6 was established further by the X-ray crystallography
(Fig. 1).
Recently, we have reported the synthesis of a variety of
heterocycles (Abdel-Wahab et al. 2016; Abdel-Megeed et al.
2012a, b; Baashen et al. 2016; Bekheit et al. 2016) as a part of
our program in preparation of bioactive heterocycles. The
current work deals with the synthesis of novel benzofur-2-
ylpyrazoles in which 3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazole-4-carbaldehyde was used as the starting material.
Formation of 6 could involve a retro-aldol reaction that
takes place first for 3 to produce intermediates 7 and 8.
Intermediate 8 yields the anion of 2 as a leaving group
along with intermediate 9. Reaction of 9 with the thioamide
anion, in the sense of an aldol reaction, affords 6 via
intermediate 10 (Scheme 2).
Reaction of 1 with 2-cyanoacetohydrazide (11; two
mole equivalents) in dry, boiling methanol containing
acetic acid gave benzofuran 12 in 83% yield (Scheme 3).
Compound 12 was previously synthesized under similar
reaction condition but in acetic acid (Abdel-Aziem 2015).
However, the physical and spectroscopic data for com-
pound 12 are not exactly the same as the reported ones. For
Results and discussion
The reaction of equimolar quantities of 1 (Kumar et al.
2007; El-Zahar et al. 2009) with a molar equivalent of 2 in
dry ethanol under reflux condition for 3 h, in the presence
of piperidine as a base, gave the corresponding benzofuran
3 in 76% yield (Scheme 1). In an attempt to synthesize
pyridine-3,5-dicarbonitrile derivative 5 through Michael
addition of 2-cyanoethanethioamide (4) to 3, the unex-
pected product 6 was obtained instead in 72% yield
(Scheme 1). In addition, product 6 was obtained in 84%
yield from direct reaction between 1 and 4.
1
example, the H NMR spectrum of 12 shows a character-
istic singlet (4.21 ppm) due to the methylene protons
compared to 3.98 ppm for the reported one. In addition, the
electron impact mass spectrum of 12 shows an intense
molecular ion peak at m/z 369 compared to m/z 368
(M - 1) for the reported one Condensation of 12 with 1 in
boiling methanol in the presence of piperidine gave sub-
stituted benzofuran 13 in 80% yield (Scheme 3). The
Scheme 1 Synthetic routes to
new thioamide derivative 6
NC
O
CN
O
O
2
N
N
O
N
O
N
MeOH/piperidine
3
1
(76%)
S
CN
H2N
4
MeOH/piperidine
X
N
NC
HS
NC
S
CN
NH2
N
N
O
N
O
N
6 (72%)
5
123

Chem. Pap.
1
region. The H NMR spectra of 15 show singlet signals
(2.10–2.36 ppm) due to the methyl protons .
Reaction of 1 with acetohydrazide 16 gave the corre-
1
sponding hydrazone 17 in 86% yield (Scheme 5). The H
NMR spectrum of 17 shows a characteristic singlet
(8.74 ppm) and an exchangeable singlet (11.43 ppm) due
to the CH=N and NH protons, respectively.
Finally, the reaction of 1 with carbohydrazide 18 gave
the corresponding hydrazone 19 in 85% yield (Scheme 6).
1
The H NMR spectrum of 19 shows a singlet (8.87 ppm)
and an exchangeable singlet (10.22 ppm) due to the CH=N
proton and NH proton, respectively. In addition, the X-ray
crystallography (Fig. 2) confirmed the structure of 19.
Fig. 1 X-ray structure of compound 6
Experimental
General
The melting points were taken on Electrothermal IA 9000
series digital melting point apparatus. The IR spectra (KBr)
were recorded on a Shimadzu CVT-04 spectrophotometer.
electron impact mass spectrum of 13 shows an intense
molecular ion peak at m/z 639 .
1
The H NMR spectra were measured in DMSO-d6 on a
In a similar manner, reaction of 1 with cyanoacetohy-
drazides 14a–c in boiling methanol containing piperidine
afforded acrylohydrazides 15a–c in 84–87% yields
(Scheme 4). The IR spectra of 15 show the presence of the
carbonitrile groups that appear within the 2217–2220 cm-1
JEOL E.C.A-500 MHz spectrometer in which tetram-
ethylsilane was used as internal standard. The mass spectra
were determined using a Varian MAT CH-5 spectrometer
(70 eV). Compounds 1 (Kumar et al. 2007), 14a (Mohareb
Scheme 2 Proposed
mechanism for the formation of
compound 6
Ph
CN
Ph
CN
Ph
O
H O
B
O
CN
B
BH
N
- 2-
N
N
O
N
N
O
N
O
N
Ph
Ph
Ph
3
7
8
NC
NC
H
N
S
S
-
+B
NH2
B
NC
Ph
NH2
NH2
S
- BH
N
N
O
O
O
N
N
Ph
Ph
9
6
10
BH = piperidine
123

Chem. Pap.
O
CN
H
N
N
O
N
H2N
CN
H
N
O
N
O
1
11
MeOH, AcOH
N
CN
N
N
N
MeOH
O
O
N
N
NH
N
O
1
12 (83%)
O
13
(80%)
Scheme 3 Synthetic access to new 2-cyanoacrylohydrazide 10
Scheme 4 Synthesis of novel
acrylohydrazides 12a–c
Me
N
Ar
NH
O
O
O
NC
N
Me
CN
N
H
Ar
14
EtOH / piperidine
N
O
N
N
O
N
1
15a: Ar = 2-furyl (84%)
15b: Ar = 2-benzofuryl (86%)
15c: Ar = 2-pyridyl (87%)
O
O
O
O
N
N
H
O
NH2
N
H
16
EtOH/AcOH
N
O
N
N
O
N
1
17 (86%)
Scheme 5 Synthetic route to novel acetohydrazide 15
et al. 2009), 14b (Rida et al. 2005), 14c (Zhang et al. 2012),
16 (Mullican et al. 1993), 18 (Abdel-Wahab et al. 2008)
were synthesized based on the reported procedures. The
Crystallographic data for compounds 6 and 19 were
deposited at the Cambridge Crystallographic Data Center
as CCDC1531680 and CCDC1531681, respectively.
123

Chem. Pap.
O
NH
NH2
N
O
N
N
O
O
N
N
N
H
18
O
N
N
O
N
O
N
EtOH/AcOH
1
19 (85%)
Scheme 6 Synthetic access to novel carbohydrazide 16
Fig. 2 X-ray structure of
compound 16
Synthesis of 3-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-4-
Synthesis of 3-(3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-
carbaldehyde (1)
4-yl)-2-benzoylacrylonitrile (3)
Phosphorus oxychloride (20 mL) was added dropwise to a
A mixture of 1 (1.44 g, 5.00 mmol) and 2 (0.72 g,
5.00 mmol), piperidine (0.3 mL, 3.04 mmol), and dry
EtOH (30 mL) was refluxed for 3 h. The solid obtained
was filtrated, dried, and crystallized from EtOH to give
pure 3 (1.58 g, 3.80 mmol; 76%). Mp 255–256 °C. IR
(KBr) mmax/cm-1 1650 (C=O), 2227 (CN). 1H NMR: d
7.41–7.98 (m, 15H, Ar–H), 8.60 (s, 1H, CH), 9.31 (s, 1H,
CH-pyrazole). 13C NMR: d 106.6, 109.3, 111.2, 114.9,
116.8, 119.9, 121.9, 123.8, 125.8, 127.6, 128.6, 129.1,
129.9, 130.0, 132.9, 134.6, 136.0, 138.3, 145.8, 146.6,
148.0, 154.4, 190.2. MS (EI) m/z (%): 415 (M?, 32), 57
stirred dimethyl formamide (150 mL) at 0–5 °C. (1-Benzo-
furan-2-yl)ethylidene-2-phenyl
hydrazine
(23.53 g,
0.0940 mol) was added to the mixture in a portion-wise
manner. The mixture was stirred overnight at room tempera-
ture, poured onto ice-cold water and neutralized with
ammonium hydroxide solution (5%). The solid produced was
filtered, dried, and crystallized from acetic acid to give 1
(24.39 g, 0.0846 mmol; 90%), Mp 160–162 °C (lit.
116–118 °C; Kumar et al. 2007; lit. 160–162 °C; El-Zahar
et al. 2009).
123

Chem. Pap.
3-(3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)-N’-((3-
(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-2-
cyanoacrylohydrazide (13)
(100). Anal. Calcd. for C27H17N3O2 (415.44): C, 78.06; H,
4.12; N, 10.11%. Found: C, 78.23; H, 4.40; N, 10.35%.
Synthesis of 3-(3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-
A
mixture of 12 (0.37 g, 1.00 mmol), 1 (0.29 g,
4-yl)-2-cyanoprop-2-enethioamide (6)
1.00 mmol), piperidine (0.3 mL, 3.04 mmol), and dry
EtOH (30 mL) was refluxed for 1 h. The solid product
formed on cooling was collected by filtration and dried to
give pure 13 (0.51 g, 0.80 mmol; 80%). Mp 237–238 °C.
IR (KBr) mmax/cm-1 1598 (C=O), 2223 (CN), 3280 (NH).
1H NMR: d 7.41–8.10 (m, 20H, Ar–H), 8.45 (s, 1H, CH),
8.56 (s, 1H, CH), 8.95 (s, 1H, CH-pyrazole), 9.34 (s, 1H,
CH-pyrazole), 11.13 (s, exch., 1H, NH). 13C NMR: 158.0,
155.2, 154.9, 150.2, 147.4, 145.7, 143.0, 141.4, 140.4,
139.9, 136.3, 130.3, 130.23, 130.19, 129.0, 128.8, 128.0,
126.9, 126.2, 125.7, 125.5, 123.9, 123.3, 119.5, 118.8,
111.7, 108.3, 106.7, 106.6. MS (EI) m/z (%): 640 (M? ? 1,
42), 639 (M?, 100). Anal. Calcd. for C39H25N7O3 (639.66):
C, 73.23; H, 3.94; N, 15.33%. Found: C, 73.47; H, 4.09; N,
15.52%.
Method A A mixture of 3 (0.83 g, 2.00 mmol), 4 (0.2 g,
2.00 mmol), piperidine (0.3 mL, 3.04 mmol), and dry
EtOH (30 mL) was refluxed for 5 h. The solid obtained
was filtrated, dried, and crystallized from DMF to give pure
6 (0.53 g, 1.44 mmol; 72%). Mp 205–206 °C. IR (KBr)
1
m
max/cm-1 1342 (C=S), 2213 (CN), 3286–3343 (NH2). H
NMR: d 7.34–8.00 (m, 10H, Ar–H), 8.48 (s, 1H, CH), 9.43
(s, 1H, CH-pyrazole), 10.22 (s, exch., 2H, NH2). 13C NMR:
d 106.9, 111.6, 114.8, 116.8, 119.4, 119.7, 121.9, 123.7,
125.7, 127.9, 127.9, 128.3, 129.5, 129.8, 129.9, 137.8,
138.5, 144.9, 147.7, 154.5, 191.4. MS (EI) m/z (%): 371
(M? ? 1, 43), 370 (M?, 56), 57 (100). Anal. Calcd. for
C21H14N4OS (370.43): C, 68.09; H, 3.81; N, 15.12%.
Found: C, 68.32; H, 3.98; N, 15.53%. Selected crystallo-
graphic data: orange plates, C21H14N4OS, FW = 370.42,
Synthesis of 15 A mixture of 1 (0.29 g, 1.00 mmol), 14
(1.00 mmol), piperidine (0.3 mL, 3.04 mmol), and dry
EtOH (30 mL) was refluxed for 2 h. The solid formed on
cooling was filtrated and dried to give pure 15.
˚
T = 296(2) k, k = 0.71073 A, triclinic, space group P1,
˚
a = 5.8807(8) A, b = 9.2390(11) A, c = 16.4270(2) A,
˚
˚
a = 89.882(10)°, b = 82.806(10)°, c = 77.795(11)°,
V = 865.2(2) A , Z = 2, qcalc. = 1.421 Mg/m-3, crystal
3
˚
size = 0.45 9 0.29 9 0.03 mm,
m = 0.021 mm-1
,
3-(3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)-2-
cyano-N’-(1-(furan-2-yl)ethylidene)acrylohydrazide (15a)
reflections collected = 3550,
independent
reflec-
tions = 5319, R = 0.075, wR = 0.196, R(int) = 0.033.
CDC1531680.
Yield 84% (0.39 g, 0.84 mmol); Mp 235–237 °C. IR (KBr)
m
max/cm-1 1608 (C=O), 2220 (CN), 3240 (NH). 1H NMR: d
Method B A mixture of 1 (0.57 g, 2.00 mmol), 4 (0.2 g,
2.00 mmol), piperidine (0.3 mL, 3.04 mmol), and dry
EtOH (30 mL) was refluxed for 3 h. The solid obtained
was filtrated, dried, and crystallized from EtOH to give
pure 6 (0.61 g, 1.64 mmol; 84%). The spectroscopic and
analytical data were similar to those obtained for 6 using
method A.
2.36 (s, 3H, CH3), 6.89–7.97 (m, 13H, Ar–H), 8.53 (s, 1H,
CH), 9.35 (s, 1H, CH-pyrazole), 10.55 (s, exch., 1H, NH).13C
NMR: d 11.7, 103.9, 106.2, 109.1, 110.8, 115.8, 111.6, 112.9,
119.3, 121.3, 123.3,124.6, 125.1, 126.2, 127.2, 127.8, 129.4,
137.9, 139.7, 141.6, 143.2, 144.9, 147.4 153.9, 190.2. MS (EI)
m/z (%): 462 (M? ? 1, 100), 461 (M?, 35). Anal. Calcd. for
C27H19N5O3 (461.47): C, 70.27; H, 4.15; N, 15.18%. Found:
C, 70.38; H, 4.31; N, 15.37%.
N’-((3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-
yl)methylene)-2-cyanoacetohydrazide (12)
3-(3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)-N’-(1-
(benzofuran-2-yl)ethylidene)-2-cyanoacrylohydrazide
(15b)
A
mixture of 1 (1.44 g, 5.00 mmol), 11 (0.50 g,
5.00 mmol), glacial AcOH (0.5 mL, 8.74 mmol), and dry
MeOH (20 mL) was refluxed for 1 h. The formed solid was
collected by filtration and dried to give pure 12 (1.53 g,
4.14 mmol; 83%). Mp 215–217 °C (lit 228–230 °C;
Abdel-Aziem 2015). IR (KBr) mmax/cm-1 1686 (C=O),
Yield 86% (0.41 g, 0.86 mmol); Mp 240-242 °C. IR (KBr)
m
max/cm-1 1605 (Cld=O), 2218 (CN), 3228 (NH). 1H
NMR: d 2.35 (s, 3H, CH3), 7.28–8.00 (m, 15H, Ar–H), 8.67
(s, 1H, CH), 9.30 (s, 1H, CH-pyrazole), 11.05 (s, exch., 1H,
NH). 13C NMR: d 11.9, 103.8, 106.3, 110.8, 114.3, 119.3,
121.3, 122.9, 123.1, 123.1, 125.1, 127.2, 127.3, 127.8,
129.0, 129.4, 137.9, 144.2, 147.2, 147.4, 152.8, 159.9,
190.4. MS (EI) m/z (%): 512 (M? ? 1, 100). Anal. Calcd.
for C31H21N5O3 (511.53): C, 72.79; H, 4.14; N, 13.69%.
Found: C, 72.99; H, 4.37; N, 13.96%.
1
1612 (C=N), 2215 (CN), 3282 (NH). H NMR: d 4.21 (s,
2H, CH2), 7.39–8.10 (m, 10H, Ar–H), 8.61 (s, 1H, CH),
9.33 (s, 1H, CH-pyrazole), 11.78 (s, exch., 1H, NH). MS
(EI) m/z (%): 370 (M? ? 1, 100), 369 (M?, 85). Anal.
Calcd. for C21H15N5O2 (369.38): C, 68.28; H, 4.09; N,
18.96%. Found: C, 68.39; H, 4.18; N, 19.21%.
123

Chem. Pap.
3-(3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)-2-
cyano-N’-(1-(pyridin-2-yl)ethylidene)acrylohydrazide
(15c)
processes involved required only commercially available
starting materials.
Acknowledgements The project was supported by King Saud
University, Deanship of Scientific Research, Research Chairs.
Yield 87% (0.39 g, 0.87 mmol); Mp 262–263 °C. IR (KBr)
m
1
max/cm-1 1608 (C=O), 2227 (CN), 3228 (NH). H NMR:
d 2.10 (s, 3H, CH3), 7.31-8.35 (m, 14H, Ar–H), 8.73 (s, 1H,
CH), 9.29 (s, 1H, CH-pyrazole), 11.13 (s, exch., 1H, NH).
MS (EI) m/z (%): 472 (M?, 45), 191 (100). Anal. Calcd. for
C28H20N6O2 (472.50): C, 71.17; H, 4.27; N, 17.79%.
Found: C, 71.29; H, 4.42; N, 17.96%.
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(s, 1H, CH), 9.13 (s, 1H, CH-pyrazole), 11.43 (s, exch., 1H,
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C30H22N4O3 (486.52): C, 74.06; H, 4.56; N, 11.52%.
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Yield 85% (0.50 g, 0.85 mmol); Mp 270–271 °C. 1H NMR:
7.12–7.91 (m, 20H, Ar–H), 8.87 (s, 1H, CH), 9.13 (s, 1H, CH-
pyrazole), 9.35(s, 1H, CH-pyrazole), 10.22(s, exch., 1H, NH).
MS (EI) m/z (%): 588 (M?, 100). Anal. Calcd. for
C36H24N6O3 (588.61): C, 73.46; H, 4.11; N, 14.28%. Found:
C, 73.62; H, 4.37; N, 14.64%. Selected crystallographic data:
orange plates, C39H31N7O4, FW = 661.71, T = 293(2) K,
˚
˚
k = 0.71073 A, triclinic, space group P1, a = 9.8227(5) A,
˚
˚
b = 11.4055(6) A, c = 29.4496(14) A, a = 91.753(4)°,
3
˚
b = 97.043(4)°, c = 93.894(4)°, V = 3264.3(3) A , Z = 4,
qcalc. = 1.346 Mg/m-3
,
crystal size = 0.38 9 0.24 9
0.12 mm, m = 0.090 mm-1, reflections collected = 28397,
independent reflections = 15581, R = 0.058, wR = 0.149,
R(int) = 0.030. CCDC1531681.
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Conclusion
Several novel heterocycles having
a 3-(benzofur-2-
yl)pyrazole moiety were synthesized in high yields using
simple and convenient procedures. Moreover, the synthetic
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