Synthesis of 3,5-disubstituted-1H-pyrazoles from acid chlorides, alkynes, and hydrazine in the presence of silica-supported-zinc bromide

Article abstract of DOI:10.3184/174751915X14382642961716

An efficient one-pot palladium- And copper-free procedure has been developed for a convenient synthesis of 3,5-disubstituted-1H-pyrazoles from various acid chlorides, terminal alkynes and hydrazine by a coupling reaction and cyclocondensation sequence. Acid chlorides react with terminal alkynes in the presence of silica-supported-zinc bromide to give α,β-unsaturated ynones, and in situ conversion into pyrazoles by the hydrazine cyclocondensation.

Full text of DOI:10.3184/174751915X14382642961716

484 RESEARCH PAPER
VOL. 39 AUGUST, 484–486
JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis of 3,5-disubstituted-1H-pyrazoles from acid chlorides, alkynes, and
hydrazine in the presence of silica-supported-zinc bromide
Ali Keivanloo*, Mohammad Bakherad and Shahrzad Samangooei
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
An efficient one-pot palladium- and copper-free procedure has been developed for a convenient synthesis of 3,5-disubstituted-1H-pyrazoles
from various acid chlorides, terminal alkynes and hydrazine by a coupling reaction and cyclocondensation sequence. Acid chlorides
react with terminal alkynes in the presence of silica-supported-zinc bromide to give α,β-unsaturated ynones, and in situ conversion into
pyrazoles by the hydrazine cyclocondensation.
Keywords: palladium and copper free conditions, terminal alkynes, pyrazoles, silica supported zinc bromide
The development of new methodologies aimed at improving
synthetic efficiency is an important goal in organic synthesis.
Multicomponent reactions (MCRs), which involve several
bond-forming reactions in a one-pot manipulation, represent
an attractive strategy in the facile assembly of molecular
architecture.1,2 Such reactions are able to create combinatorial
libraries of complex and diverse structures efficiently by virtue
of their convergent nature.
Pyrazole and its derivatives, which is a large class of
N-containing heterocycles, possess important biological
and pharmaceutical activities such as anti-inflammatory,
anti-coagulant, anti-bacterial, and anti-tumor agents, CDK
inhibitors, and cyclooxygenase-2 (Cox-2) inhibitors.3–9 The
pyrazole motif also makes up the core structure of some well-
known drugs (e.g. Viagra, Acomplia and Celebrex),10 and are
also useful synthetic building blocks and metal ligands in
organic chemistry.11,12
The most commonly used method for the preparation of
pyrazoles involves the cyclocondensation of an appropriate
hydrazine (mainly arylhydrazines), which acts as a double
nucleophile, with a three-carbon unit featuring two electrophilic
carbons in a 1,3-relationship such as 1,3-dicarbonyl, α,β-
unsaturated carbonyl compounds,13–15 β-enaminones or related
compounds.16–18
coupling-cyclocondensation of acid chlorides 1, terminal
alkynes 2, and hydrazine in the presence of SiO2-ZnBr2 under
aerobic conditions (Scheme 1).
Many methods exist for the synthesis of ynones by the
coupling of acid chlorides and terminal alkynes.22-24 We have
recently reported the synthesis of ynones by cross-coupling
reaction of acid chlorides with terminal alkynes in the presence
of silica-supported-zinc bromide (SiO2-ZnBr2) under solvent-
free and aerobic conditions.25 We decided to use the same
procedure followed by hydrazine cyclocondensation for the
synthesis of 3,5-disubstituted-1H-pyrazoles 3 (Scheme 1).
When the reaction of phenyl acetylene with 4-chlorobenzoyl
chloride was carried out using SiO2-ZnBr2 catalyst under
solvent-free conditions at room temperature followed by
hydrazine cyclocondensation in various solvents at 50 °C,
3-(4-chlorophenyl)-5-phenyl-1H-pyrazole 3d was obtained
in different yields. The results obtained are shown in Table 1.
Optimisation of the conditions was reached when 10 mol% of
SiO2-ZnBr2 was used as the catalyst under solvent-free conditions
at room temperature followed by hydrazine cyclocondensation
in CH3CN at 50 °C (Table 1, entry 6).
In order to explore the scope and generality of this protocol,
we examined various benzoyl chlorides and different terminal
alkynes using the optimised procedure (Table 2). The results
obtained show that this reaction is equally facile with both
electron-donating and electron-withdrawing substituents
present on the benzoyl chloride, resulting in good-to-high yields
of the corresponding pyrazoles. Aliphatic terminal alkynes
also reacted smoothly, affording the desired products in good
yields. The structures of the compounds were established by
spectroscopic data and elemental analysis.
Results and discussion
One-pot synthesis of pyrazoles has been developed that are based
on intermediates generated in situ including 1,3-diketones,19
diazo compounds,20 and ynones.21 Unfortunately, some of the
reagents used in these cases are expensive, toxic, sensitive to
air, difficult to obtain and dangerous. Thereby, the construction
of pyrazoles with simple, cheap, safe and easily available
organic molecules as the components in one-pot would be
advantageous.
The key step of the reaction is cross-coupling reaction of
terminal alkynes with benzoyl chlorides to afford the ynone
intermediate A. Subsequent cyclocondensation with hydrazine
completed the reaction pathway (Scheme 2).
We now report an efficient one-pot palladium- and copper-
free procedure for the construction of pyrazoles using a tandem
Ar
1) SiO2 -ZnBr2
rt 3h
,
DIPEA
O
,
N
R
C
CH
R
+
N
H
2) NH2NH2 , CH3CN
50 °C 3h
Ar
Cl
,
3
1
2
Scheme 1 Synthesis of 3,5-disubstituted-1H-pyrazoles from various acid chorlides, terminal alkyes, and hydrazine in the presence
of SiO2-ZnBr2 in aerobic conditions.
* Correspondent. E-mail: akeivanloo@yahoo.com; keivanloo@shahroodut.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2015 485
Table
1
Coupling reaction of p-chlorobenzoyl chloride with
Table 2 Synthesis of 3,5-disubstituted-1H-pyrazoles in the presence of
phenylacetylene followed by hydrazine cyclocondensation in the
SiO2-ZnBr2a
presence of SiO2-ZnBr2 in different bases and solventsa
Ar
1) SiO2 -ZnBr2
rt 3h
, DIPEA
O
Catalyst loading / Cyclocondensation
,
Entry Base
Yield/%
N
mol%
5
solvent
CH3CN
DMF
R
C
CH
R
+
N
H
2) NH2NH2 , CH3CN
50 °C 3h
Ar
Cl
1
2
3
4
5
6
7
8
9
10
11
12
13
DIPEAb
80
66
67
55
42
96
71
58
96
74
18
70
35
,
DIPEA
DIPEA
Et3N
5
Entry Ar
R
Product
Yield/%b
93
85
90
96
92
73
85
83
Ref
21
26
26
26
21
27
28
28
5
THF
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C4H9
3a
3b
3c
3d
3e
3f
3g
3h
3i
5
CH3CN
DMF
CH3CN
DMF
4-CH3C6H4
4-BrC6H4
4-ClC6H4
4-CH3OC6H4
C6H5
Thiophen-2-yl C6H5
Cyclohexyl
2-NO2C6H4
Et3N
10
10
10
10
20
20
10
10
10
DIPEA
DIPEA
Et3N
DIPEA
Et3N
DIPEA
DIPEA
K2CO3
DMF
CH3CN
CH3CN
H2O
DMSO
DMSO
C6H5
C6H5
92
28
10 C6H5
n-C6H13
n-C6H13
n-C4H9
n-C3H7
3k
3l
3m
3n
90
87
82
70
28
11 2-ClC6H4
12 2-ClC6H4
13 C6H5
new
new
new
a Reaction conditions and reagents: p-chlorobenzoyl chloride (1.2 mmol), phenylacetylene
(1.0 mmol), base (1.2 mmol), solvent (1 mL), catalyst.
b Diisopropylethylamine.
a Reaction conditions: benzoyl chloride (1.2 mmol), termina alkyne (1.0 mmol), base (1.2
mmol), SiO2-ZnBr2 (10 mol%), stir room temperature (3h), followed by hydrazine addition
in CH3CN (3 mmol), 50 °C (3h).
b Isolated yield.
Ar
O
O
ZnBr2 -SiO2
NH2NH2
CH3CN
R
C
CH
+
Cl
N
Ar
Ar
DIPEA
R
N
H
R
2
3
1
A
Scheme 2 Ynone intermediate in the synthesis of 3,5-disubstituted-1H-pyrazoles.
Conclusion
(monitored by TLC), hydrazine (3 mmol) in CH3CN (2 mL) was
added, and the mixture was heated at 50 ºC with stirring for another
3 h. After completion of the reaction (monitored by TLC), the solvent
was evaporated and the residue left was extracted with CH3CN.
Concentrating the solution gave the crude product, which was
subjected to column chromatography using CHCl3–CH3OH (98:2) as
eluent to obtain an analytically pure product.
We have developed an efficient, convenient, one-pot palladium-
and copper-free method for the synthesis of 3,5-disubstituted-
1H-pyrazoles using a coupling reaction/cyclocondensation of
acid chlorides, terminal alkynes, and hydrazine in the presence
of SiO2-ZnBr2 in aerobic conditions.
3-(2-Chlorophenyl)-5-hexyl-1H-pyrazole (3l): Yellow oil; yield
87%; H NMR (400 MHz, DMSO-d6): δ 0.85 (t, J = 7.0 Hz, CH3),
Experimental
1
All the reagents used were of general reagent grade. IR spectra were
obtained as potassium bromide pellets or solvent in the range of 400-
4000 cm-1 on a Shimadzu Model 460 spectrometer. H NMR spectra
were recorded on a Brucker BRX 400 Avance spectrometer. Elemental
analyses were performed on a VarioEL CHNS microanalyser.
1.23–1.34 (m, 6H, 3CH2), 1.59–1.65 (m, 2H, 2CH2), 2.68 (t, 2H, J =
7.5 Hz, CH2), (6.49, s, 1H, CH pyrazole); 7.18–7.50 (m, 3H, ArH),
7.68–7.75 (m, 1H, ArH), 11.12 (b, 1H, NH); IR (KBr): 3320 (NH),
2980, 2820, 1610, 1460, 1368, 1163 cm-1. Anal. calcd for C15H19ClN2: C,
68.56; H, 7.29; N, 10.66; found: C, 68.59; H, 7.27; N, 10.64%.
5-Butyl-3-(2-chlorophenyl)-1H-pyrazole (3m): Yellow oil; yield
82%; 1H NMR (400 MHz, DMSO-d6): δ 0.87 (t, 3H, J = 7.1 Hz, CH3),
1.23–1.34 (m, 2H), 1.48–1.60 (m, 2H), 2.67 (t, 2H, J = 7.3 Hz), 6.50 (s,
1H, CH pyrazole), 7.23–7.50 (m, 3H, ArH), 7.62–7.70 (m, 1H, ArH),
12.52 (b, 1H, NH) ; IR (KBr): 3310 (NH), 2950, 1600, 1560, 1260,
1085 cm-1. Anal. calcd for C13H15ClN2: C, 66.52; H, 6.44; N, 11.93;
found: C, 66.50; H, 6.45; N, 11.96%.
3-(Phenyl)-5-propyl-1H-pyrazole (3n): Yellow oil; yield 70%; 1H NMR
(400 MHz, DMSO-d6): δ 0.90 (t, 3H, J = 7.2 Hz, CH3), 11.52–1.62 (m, 2H),
2.70 (t, 2H, J = 7.2 Hz), 6.48 (s, 1H, CH pyrazole), 7.25–7.42 (m, 3H, ArH),
7.67–7.72 (m, 2H, ArH), 12.65 (b, 1H, NH) ; IR (KBr): 3300 (NH), 2900,
1590, 1550, 1257, 1090 cm-1. Anal. calcd for C12H14N2: C, 77.38; H, 7.58; N,
15.04; found: C, 77.42; H, 7.60; N, 14.98%.
1
Synthesis of silica-supported-zinc bromide
Silica gel (Wakogel C-100, 3.65 g) was added to a solution of ZnBr2
(6 mmol, 1.35 g) in EtOH (20 mL), and the mixture was heated at
reflux for 1 h. The solvent was removed on a rotary evaporator, and
the product was dried under vacuum at 150 °C for 10 h. Inductively
coupled plasma atomic absorption spectrometry (ICP) indicated that
1.2 mmol of ZnBr2 was supported on 1 g of SiO2-ZnBr2.
Synthesis of 3,5-disubstituted-1H-pyrazoles (3a–n); general procedure
A test tube was charged with the acyl chloride (1.2 mmol), a terminal
alkyne (1.0 mmol), SiO2–ZnBr2 (0.1 g, 0.12 mmol), and DIPEA
(1.2 mmol), and the mixture was stirred at room temperature for 3 h
under anhydrous conditions. On completion of the coupling reaction

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Received 6 May 2015; accepted 24 July 2015
Paper 1503350 doi: 10.3184/174751915X14382642961716
Published online: 7 August 2015
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