A highly efficient heterogeneous palladium-catalyzed cascade three-component reaction of acid chlorides, terminal alkynes and hydrazines leading to pyrazoles

Article abstract of DOI:10.1016/j.jorganchem.2015.12.037

In the presence of 0.5 mol% of 3-(2-aminoethylamino)propyl-functionalized MCM-41-immobilized palladium(II) complex [MCM-41-2N-Pd(OAc)₂] and 1.0 mol% of CuI, acid chlorides were coupled with terminal alkynes in Et₃N at 50 °C to give α,β-unsaturated ynones, which were converted in situ into pyrazoles by the cycloaddition of hydrazines at room temperature with acetonitrile as cosolvent. The cascade reactions generated a variety of pyrazole derivatives in moderate to good yields, and this heterogeneous palladium catalyst exhibited higher catalytic activity than PdCl₂(PPh₃)₂ and could be recovered and reused for at least 10 consecutive trials without any decreases in activity.

Full text of DOI:10.1016/j.jorganchem.2015.12.037

Accepted Manuscript
A highly efficient heterogeneous palladium-catalyzed cascade three-component
reaction of acid chlorides, terminal alkynes and hydrazines leading to pyrazoles
Qiurong Chen, Fang Yao, Lin Yin, Mingzhong Cai
PII:
S0022-328X(15)30251-5
10.1016/j.jorganchem.2015.12.037
JOM 19343
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 5 August 2015
Revised Date: 20 December 2015
Accepted Date: 27 December 2015
Please cite this article as: Q. Chen, F. Yao, L. Yin, M. Cai, A highly efficient heterogeneous palladium-
catalyzed cascade three-component reaction of acid chlorides, terminal alkynes and hydrazines leading
to pyrazoles, Journal of Organometallic Chemistry (2016), doi: 10.1016/j.jorganchem.2015.12.037.
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ACCEPTED MANUSCRIPT
Graphical Abstract
A highly efficient heterogeneous palladium-catalyzed cascade
three-component reaction of acid chlorides, terminal alkynes
and hydrazines leading to pyrazoles
Qiurong Chen, Fang Yao, Lin Yin, Mingzhong Cai*
An efficient and practical method for the synthesis of pyrazoles has been developed
by a heterogeneous palladium-catalyzed cascade coupling-cyclocondensation reaction
of acid chlorides with terminal alkynes and hydrazines.

ACCEPTED MANUSCRIPT
A highly efficient heterogeneous palladium-catalyzed
cascade three-component reaction of acid chlorides, terminal
alkynes and hydrazines leading to pyrazoles
Qiurong Chen,a Fang Yao,b Lin Yin,a Mingzhong Caia,*
aDepartment of Chemistry, Jiangxi Normal University, Nanchang 330022, P. R. China
bCollege of Chemical and Material Engineering, Quzhou University, Quzhou 324000,
P. R. China
ABSTRACT
In the presence of 0.5 mol% of 3-(2-aminoethylamino)propyl-functionalized MCM
-41-immobilized palladium(II) complex [MCM-41-2N-Pd(OAc)2] and 1.0 mol% of
CuI, acid chlorides were coupled with terminal alkynes in Et3N at 50 ºC to give
α,β-unsaturated ynones, which were converted in situ into pyrazoles by the cyclo-
addition of hydrazines at room temperature with acetonitrile as cosolvent. The
cascade reactions generated a variety of pyrazole derivatives in moderate to good
yields, and this heterogeneous palladium catalyst exhibited higher catalytic activity
than PdCl2(PPh3)2 and could be recovered and reused for at least 10 consecutive trials
without any decreases in activity.
Keywords: Immobilized palladium catalyst; Tandem reaction; Cycloaddition;
Pyrazole; Heterogeneous catalysis
1. Introduction
Pyrazoles and its derivatives are very important N-heterocyclic compounds since
pyrazole scaffold is present in a plethora of biological relevant molecules displaying a
variety of pharmaceutical properties [1-5] and also useful synthetic building blocks
and metal ligands in organic chemistry [6-12]. Therefore, considerable effort has been
1
*Corresponding author. E-mail address: caimzhong@163.com (M. Cai)

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made in the development of new pyrazole structures and new methods for their
constructions [13-15]. The traditional methods for the synthesis of pyrazoles include
the cyclization of 1,3-diketones with hydrazines [16,17], 1,3-dipolar cycloaddition of
diazoalkanes with alkynes [18] and the reaction of α,β-unsaturated ketones with
hydrazines [19]. Very recently, rhodium- or phosphine-catalyzed synthesis of pyrazole
derivatives has also been reported [20-22].
Tandem reactions have emerged as powerful tools to meet the demands of modern
organic synthesis due to the synthetic efficiency, molecular diversity, low production
costs, etc [23-25]. Recently, tandem reactions have been widely applied to construct
interesting heterocyclic compounds, a large family of the natural products with wide-
ranging utility for drug candidates and fine chemicals [26,27]. Of these heterocycles,
one-pot construction of pyrazole derivatives has been developed based on some
intermediates generated in situ including 1,3-diketones [28], diazo compounds [18]
and ynones [29-31]. For example, Jiang et al. described one-pot three-component
synthesis of pyrazoles through a tandem coupling-cyclocondensation sequence of acid
chlorides with terminal alkynes and hydrazines [30]. Unfortunately, some of the
reagents used in these tandem reactions are toxic, sensitive to air and moisture,
difficult to obtain and expensive. Therefore, one-pot synthesis of pyrazole derivatives
starting from simple, cheap, safe and easily available materials via tandem reactions
would be more facile and efficient.
α,β-Unsaturated ynones are usually prepared by the cross-coupling of acid
chlorides with terminal alkynes in the presence of PdCl2(PPh3)2 or Pd(OAc)2 under
2

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mild conditions with high yields [32-34]. However, industrial applications of
homogeneous palladium complexes remain a challenge because they are expensive,
cannot be recycled, and difficult to separate from the product mixture, which is a
particularly significant drawback for their application in the pharmaceutical industry.
In contrast, heterogeneous catalysts can be easily separated from the reaction mixture
by simple filtration and reused in successive reactions provided that the active sites
have not become deactivated. Heterogeneous catalysis also helps to minimize wastes
derived from reaction workup, contributing to the development of green chemical
processes [35]. Therefore, the development of a stable heterogeneous palladium
catalyst that allows for highly efficient synthesis of ynones from a wide range of
substrates (acid chlorides and terminal alkynes) is worthwhile.
The discovery of mesoporous material MCM-41 has given an enormous stimulus to
research in heterogeneous catalysis and provided a new possible candidate for a solid
support for immobilizing homogeneous catalysts [36-38]. The hexagonally-ordered
material MCM-41 has a regular pore diameter of ca.5 nm and a specific surface area >
700 m2 g-1 and rich silanol groups in the inner walls [39]. To date, some functiona-
lized MCM-41-immobilized palladium, rhodium, and molybdenum complexes have
been prepared and successfully used in organic reactions [40-47]. Recently, we
reported the preparation of 3-(2-aminoethylamino)propyl-functionalized MCM-41-
immobilized palladium(II) complex [MCM-41-2N-Pd(OAc)2] and found that it is
highly efficient heterogeneous palladium catalyst for the Suzuki-Miyaura reaction of
aryl bromides with arylboronic acids [48]. In continuing our efforts to develop
3

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greener synthetic pathways for organic transformations, herein we wish to report a
highly efficient and practical one-pot three-component procedure for the construction
of pyrazoles via a tandem coupling-cyclocondensation reaction of acid chlorides with
terminal alkynes and hydrazines in the presence of MCM-41-2N-Pd(OAc)2 complex
and CuI (Scheme 1).
2. Experimental
2.1. General remarks
All chemicals were reagent grade and used as purchased, unless otherwise noted.
The MCM-41-2N-Pd(OAc)2 complex was prepared according to our previous
procedure [48], the palladium content was determined to be 0.26 mmol g-1. All
reactions were performed in dried solvent under an inert atmosphere of argon. All
products were characterized by comparison of their spectra and physical data with
1
authentic samples. IR spectra were determined on a Perkin-Elmer 683 instrument. H
NMR spectra (400 MHz) were recorded on a Bruker Avance 400 MHz spectrometer
with TMS as an internal standard in CDCl3 as solvent. 13C NMR spectra (100 MHz)
were recorded on a Bruker Avance 400 MHz spectrometer in CDCl3 as solvent.
2.2. General procedure for the synthesis of pyrazole derivatives
To a 25 mL round-bottomed flask, MCM-41-2N-Pd(OAc)2 (19 mg, 0.005 mmol),
CuI (2 mg, 0.01 mmol), acid chloride (1.3 mmol), terminal alkyne (1.0 mmol) and
Et3N (3 mL) were added under argon. The mixture was stirred at 50 ºC for 2 h and
4

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cooled to room temperature. Then hydrazine (3.0 mmol) and MeCN (2 mL) were
added and the reaction mixture was stirred at room temperature for an additional 16 h.
The reaction mixture was diluted with dichloromethane (20 mL), and filtered. The
MCM-41-2N-Pd(OAc)2 complex was washed with ethanol (2 × 5 mL) and diethyl
ether (2 × 5 mL) and reused in the next run. The filtrate was washed with water (2 × 5
mL), dried over MgSO4 and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate
= 4:1 to 2:1) to provide the desired product.
2.2.1. 3,5-Diphenyl-1H-pyrazole, 4a [49]
1
White solid. IR (KBr): νmax/cm-1 3010, 2922, 1635, 1496, 1462, 975, 753, 688. H
NMR (400 MHz, CDCl3) δ (ppm): 7.74 (d, J = 7.2 Hz, 4H), 7.43 (t, J = 7.2 Hz, 4H),
13
7.36 (t, J = 7.2 Hz, 2H), 6.89 (br, 1H). C NMR (100 MHz, CDCl3) δ (ppm): 148.8,
131.3, 128.8, 128.2, 125.6, 100.1.
2.2.2. 5-Phenyl-3-(p-tolyl)-1H-pyrazole, 4b [49]
White solid. IR (KBr): νmax/cm-1 3185, 2921, 1639, 1508, 1458, 1140, 1068, 952.
1H NMR (400 MHz, CDCl3) δ (ppm): 7.74 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 7.6 Hz,
2H), 7.40 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.81 (s,
1H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 138.2, 131.6, 129.6, 129.0,
128.8, 128.3, 128.2, 126.4, 125.6, 125.5, 99.8, 21.3.
2.2.3. 3-(4-Chlorophenyl)-5-phenyl-1H-pyrazole, 4c [49]
White solid. IR (KBr): νmax/cm-1 3227, 2923, 1611, 1567, 1492, 1095, 1053, 967,
1
765. H NMR (400 MHz, CDCl3) δ (ppm): 7.73-7.67 (m, 4H), 7.48-7.38 (m, 5H),
5

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6.84 (s, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm): 137.9, 133.7, 130.4, 129.0, 128.6,
126.9, 125.6, 125.5, 120.9, 100.3.
2.2.4. 3-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole, 4d [49]
White solid. IR (KBr): νmax/cm-1 3135, 2917, 1619, 1509, 1460, 1255, 1036, 832,
1
766. H NMR (400 MHz, CDCl3) δ (ppm): 7.74 (d, J = 7.6 Hz, 2H), 7.65 (d, J = 8.4
Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H),
6.80 (br, 1H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 159.8, 131.5, 128.9,
128.3, 126.9, 125.6, 123.9, 114.3, 99.9, 55.4.
2.2.5. 3-(Furan-2-yl)-5-phenyl-1H-pyrazole, 4e [49]
1
White solid. IR (KBr): νmax/cm-1 3393, 2943, 1614, 1492, 1460, 1115, 1026. H
NMR (400 MHz, CDCl3) δ (ppm): 7.72 (d, J = 7.4 Hz, 2H), 7.45-7.34 (m, 4H), 6.77
(s, 1H), 6.66 (d, J = 3.3 Hz, 1H), 6.48 (dd, J = 3.3, 1.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ (ppm): 142.1, 128.9, 128.4, 125.6, 111.5, 106.4, 99.4.
2.2.6. 5-Phenyl-3-(thiophen-2-yl)-1H-pyrazole, 4f [49]
1
White solid. IR (KBr): νmax/cm-1 3094, 2948, 1645, 1458, 1054. H NMR (400
MHz, CDCl3) δ (ppm): 7.65 (d, J = 7.2 Hz, 2H), 7.35-7.22 (m, 5H), 7.01-6.99 (m, 1H),
6.67 (s, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm): 145.5, 135.1, 130.3, 128.9, 128.4,
127.6, 125.6, 124.8, 124.1, 100.3.
2.2.7. 5-(4-Methylphenyl)-3-Phenyl-1H-pyrazole, 4g [49]
1
White solid. IR (KBr): νmax/cm-1 2958, 1642, 1567, 1459, 1150, 1076, 858. H
NMR (400 MHz, CDCl3) δ (ppm): 7.73 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H),
7.39 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 6.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 6.80 (s, 1H),
6

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2.37 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 147.0, 138.2, 129.6, 128.8, 128.1,
125.6, 125.5, 99.9, 21.3.
2.2.8. 5-(4-Methoxyphenyl)-3-Phenyl-1H-pyrazole, 4h
White solid. IR (KBr): νmax/cm-1 3129, 2918, 1614, 1533, 1509, 1461, 1254, 1177,
1030, 762. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.73 (d, J = 7.2 Hz, 2H), 7.64 (d, J =
8.0 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H),
6.77 (s, 1H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 148.6, 145.5, 143.6,
141.9, 130.0, 129.1, 128.9, 128.8, 111.3, 105.9, 103.1, 51.1. Anal. Calcd for
C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.61; H, 5.38; N, 11.33.
2.2.9. 5-(4-Methoxyphenyl)-3-(4-methylphenyl)-1H-pyrazole, 4i
White solid. IR (KBr): νmax/cm-1 3119, 2919, 1618, 1510, 1462, 1253, 1182, 1039,
828, 774. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.66 (d, J = 8.4 Hz, 2H), 7.61 (d, J =
8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.74 (s, 1H), 3.85 (s,
3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 159.7, 138.2, 129.6, 128.6,
126.9, 125.5, 124.3, 114.3, 99.4, 55.4, 21.3. Anal. Calcd for C17H16N2O: C, 77.25; H,
6.10; N, 10.59. Found: C, 76.96; H, 5.83; N, 10.35.
2.2.10. 3-(4-Chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrazole, 4j
White solid. IR (KBr): νmax/cm-1 3218, 2923, 1613, 1504, 1443, 1254, 1179, 1025,
842, 795. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.63 (d, J = 8.4 Hz, 2H), 7.55 (d, J =
8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.69 (s, 1H), 3.82 (s,
13
3H). C NMR (100 MHz, CDCl3) δ (ppm): 159.6, 133.6, 130.4, 128.8, 128.7, 128.3,
127.8, 126.8, 123.1, 114.2, 99.3, 55.2. Anal. Calcd for C16H13N2OCl: C, 67.48; H,
7

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4.60; N, 9.83. Found: C, 67.21; H, 4.47; N, 9.68.
2.2.11. 3,5-Bis(4-methoxyphenyl)-1H-pyrazole, 4k
White solid. IR (KBr): νmax/cm-1 3234, 2963, 1618, 1505, 1471, 1258, 1169, 1096,
1
967, 789. H NMR (400 MHz, CDCl3) δ (ppm): 7.64 (d, J = 8.8 Hz, 4H), 6.95-6.92
(m, 4H), 6.69 (s, 1H), 3.84 (s, 6H). 13C NMR (100 MHz, CDCl3) δ (ppm): 160.7,
147.8, 127.5, 121.5, 114.6, 99.4, 55.4. Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75;
N, 9.99. Found: C, 72.57; H, 5.46; N, 9.78.
2.2.12. 5-(4-Bromophenyl)-3-(4-methoxyphenyl)-1H-pyrazole, 4l [28]
White solid. IR (KBr): νmax/cm-1 3216, 2965, 1614, 1501, 1474, 1257, 1173, 1087,
964, 786. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.81 (d, J = 8.0 Hz, 2H), 7.74 (d,
J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 3.81
(s, 3H). 13C NMR (100 MHz, DMSO-d6) δ (ppm): 159.2, 131.8, 127.1, 126.6, 120.8,
114.4, 99.1, 55.3.
2.2.13. 3-(4-Methoxyphenyl)-5-(4-nitrophenyl)-1H-pyrazole, 4m [28]
Yellow solid. IR (KBr): νmax/cm-1 3635, 1625, 1515, 1346, 1258, 1176, 1089, 965,
1
783. H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29 (d, J = 8.8 Hz, 2H), 8.11 (d, J =
8.8 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 3.80 (s,
3H). 13C NMR (100 MHz, DMSO-d6) δ (ppm): 159.6, 146.4, 126.8, 125.9, 124.2,
100.1, 55.2.
2.2.14. 5-Butyl-3-phenyl-1H-pyrazole, 4n [50]
Colorless oil. IR (film): νmax/cm-1 3193, 2957, 1608, 1573, 1464, 1273, 1153, 1074,
963, 764. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.73 (d, J = 7.6 Hz, 2H), 7.37 (t, J =
8

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7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 6.41 (br, 1H), 2.62 (t, J = 7.2 Hz, 2H), 1.67-1.59
(m, 2H), 1.41-1.32 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
(ppm): 132.8, 128.7, 128.4, 127.7, 126.3, 125.3, 101.3, 31.3, 26.1, 22.3, 13.8.
2.2.15. 5-Butyl-3-(4-methylphenyl)-1H-pyrazole, 4o
Colorless oil. IR (film): νmax/cm-1 3191, 2930, 1614, 1584, 1511, 1457, 909, 824,
1
733. H NMR (400 MHz, CDCl3) δ (ppm): 7.60 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.6
Hz, 2H), 6.33 (s, 1H), 2.63 (t, J = 7.6 Hz, 2H), 2.36 (s, 3H), 1.66-1.60 (m, 2H),
1.40-1.33 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm):
137.6, 129.7, 129.4, 129.0, 126.4, 125.5, 100.8, 31.4, 26.3, 22.4, 21.3, 13.8. Anal.
Calcd for C14H18N2: C, 78.47; H, 8.47; N, 13.07. Found: C, 78.21; H, 8.69; N, 12.84.
2.2.16. 5-Butyl-3-(4-chlorophenyl)-1H-pyrazole, 4p
Colorless oil. IR (film): νmax/cm-1 3256, 2929, 1602, 1581, 1565, 1510, 1446, 1092,
962, 833, 799. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.66 (d, J = 8.4 Hz, 2H), 7.34 (d,
J = 8.4 Hz, 2H), 6.33 (s, 1H), 2.63 (t, J = 7.6 Hz, 2H), 1.65-1.59 (m, 2H), 1.39-1.32
(m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 149.8, 147.2,
133.5, 131.5, 128.8, 126.9, 101.0, 31.2, 25.8, 22.3, 13.8. Anal. Calcd for C13H15N2Cl:
C, 66.51; H, 6.44; N, 11.93. Found: C, 66.32; H, 6.15; N, 11.67.
2.2.17. 5-Butyl-3-(4-methoxyphenyl)-1H-pyrazole, 4q
Colorless oil. IR (film): νmax/cm-1 2958, 1615, 1530, 1510, 1456, 1250, 1178, 1032,
909, 835, 733. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.97 (br, 1H), 7.64 (d, J = 8.4 Hz,
2H), 6.90 (d, J = 8.4 Hz, 2H), 6.29 (s, 1H), 3.82 (s, 3H), 2.63 (t, J = 7.6 Hz, 2H),
1.67-1.60 (m, 2H), 1.42-1.32 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
9

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CDCl3) δ (ppm): 159.4, 128.2, 126.9, 125.3, 114.1, 113.7, 100.6, 55.3, 31.4, 26.2,
22.4, 13.8. Anal. Calcd for C14H18N2O: C, 73.02; H, 7.88; N, 12.16. Found: C, 72.83;
H, 7.65; N, 11.89.
2.2.18. 5-Hexyl-3-phenyl-1H-pyrazole, 4r [30]
Colorless oil. IR (film): νmax/cm-1 3253, 2958, 1588, 1569, 1464, 1266, 1140, 1072,
961, 764. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.73 (d, J = 8.0 Hz, 2H), 7.40 (t, J =
7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 6.38 (s, 1H), 2.67 (t, J = 7.6 Hz, 2H), 1.72-1.64
(m, 2H), 1.43-1.26 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
(ppm): 132.6, 128.7, 127.8, 125.6, 118.6, 112.7, 101.1, 31.6, 29.2, 29.0, 26.5, 22.6,
14.1.
2.2.19. 1-(2-Hydroxyethyl)-3,5-diphenyl-1H-pyrazole, 4s [30]
White solid. IR (KBr): νmax/cm-1 3245, 2951, 1640, 1604, 1548, 1483, 1465, 1294,
1143, 1076, 765, 692. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.83 (d, J = 7.2 Hz, 2H),
7.51-7.27 (m, 8H), 6.63 (s, 1H), 4.25 (t, J = 3.6 Hz, 2H), 4.10 (br, 1H), 4.03 (t, J = 3.6
Hz, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm): 151.0, 145.7, 132.9, 130.2, 129.1,
128.8, 128.7, 128.0, 125.6, 103.3, 62.1, 50.9.
2.2.20. 1-(2-Hydroxyethyl)-3-(4-methylphenyl)-5-phenyl-1H-pyrazole, 4t
White solid. IR (KBr): νmax/cm-1 3418, 2959, 1615, 1563, 1488, 1462, 1293, 1143,
1
1073, 766, 704. H NMR (400 MHz, CDCl3) δ (ppm): 7.72 (d, J = 8.0 Hz, 2H),
7.46-7.38 (m, 5H), 7.22 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 4.24 (t, J = 4.4 Hz, 2H),
4.13 (br, 1H), 4.01 (t, J = 4.4 Hz, 2H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
(ppm): 151.1, 145.5, 137.7, 130.2, 129.5, 129.4, 129.0, 128.8, 126.4, 125.5, 103.1,
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62.2, 50.9, 21.3. Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found: C,
77.40; H, 6.32; N, 9.89.
2.2.21. 1-(2-Hydroxyethyl)-3-(4-chlorophenyl)-5-phenyl-1H-pyrazole, 4u
White solid. IR (KBr): νmax/cm-1 3292, 2957, 1641, 1562, 1485, 1438, 1289, 1144,
1
1081, 831, 761. H NMR (400 MHz, CDCl3) δ (ppm): 7.76 (d, J = 8.4 Hz, 2H),
7.49-7.35 (m, 7H), 6.60 (s, 1H), 4.25 (t, J = 4.6 Hz, 2H), 4.03 (t, J = 4.6 Hz, 2H), 3.92
(br, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm): 150.4, 145.9, 133.7, 130.4, 129.1,
129.0, 128.9, 128.7, 126.8, 125.6, 103.3, 62.1, 51.0. Anal. Calcd for C17H15N2OCl: C,
68.33; H, 5.06; N, 9.37. Found: C, 68.11; H, 4.79; N, 9.13.
2.2.22. 1-(2-Hydroxyethyl)-3-(4-methoxyphenyl)-5-phenyl-1H-pyrazole, 4v
White solid. IR (KBr): νmax/cm-1 3259, 2955, 1614, 1525, 1489, 1441, 1247, 1144,
1
1074, 835, 768. H NMR (400 MHz, CDCl3) δ (ppm): 7.75 (d, J = 8.8 Hz, 2H),
7.48-7.38 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 6.55 (s, 1H), 4.24 (t, J = 4.6 Hz, 2H),
4.15 (br, 1H), 4.02 (t, J = 4.0 Hz, 2H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
(ppm): 159.5, 150.8, 145.6, 130.3, 129.1, 128.8, 128.7, 126.8, 125.8, 114.1, 102.8,
62.2, 55.4, 50.8. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.51. Found: C,
73.18; H, 5.88; N, 9.34.
2.2.23. 1-(2-Hydroxyethyl)-3-(furan-2-yl)-5-phenyl-1H-pyrazole, 4w
White solid. IR (KBr): νmax/cm-1 3390, 2952, 1639, 1544, 1481, 1462, 1297, 1121,
1
1072, 1010, 763. H NMR (400 MHz, CDCl3) δ (ppm): 7.46-7.38 (m, 6H), 6.68 (d, J
= 2.8 Hz, 1H), 6.54 (s, 1H), 6.46 (q, J = 1.6 Hz, 1H), 4.23 (t, J = 4.8 Hz, 2H), 4.01 (t,
J = 4.8 Hz, 2H), 3.65 (br, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm): 159.6, 148.4,
11

ACCEPTED MANUSCRIPT
131.6, 128.8, 128.1, 126.9, 125.6, 123.9, 114.2, 99.5, 55.3. Anal. Calcd for
C15H14N2O2: C, 70.85; H, 5.55; N, 11.01. Found: C, 70.59; H, 5.63; N, 10.78.
2.2.24. 1-(2-Hydroxyethyl)-3-(thiophen-2-yl)-5-phenyl-1H-pyrazole, 4x
White solid. IR (KBr): νmax/cm-1 3383, 2934, 1641, 1564, 1488, 1431, 1290, 1147,
1076, 764, 698. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.49-7.37 (m, 5H), 7.34 (d, J =
3.2 Hz, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.06-7.04 (m, 1H), 6.52 (s, 1H), 4.22 (t, J = 4.6
Hz, 2H), 4.00 (t, J = 4.6 Hz, 2H), 3.80 (br, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm):
146.3, 145.7, 136.3, 130.0, 129.1, 128.9, 128.8, 127.5, 124.7, 123.8, 103.3, 62.0, 51.0.
Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C, 66.35; H, 5.41;
N, 10.12.
2.2.25. 1-(2-Hydroxyethyl)-3-(4-nitrophenyl)-5-phenyl-1H-pyrazole, 4y
Yellow solid. IR (KBr): νmax/cm-1 3132, 2931, 1642, 1565, 1511, 1338, 1260, 1122,
1
1070, 956, 863. H NMR (400 MHz, CDCl3) δ (ppm): 8.27 (d, J = 8.8 Hz, 2H), 7.98
(d, J = 8.8 Hz, 2H), 7.49-7.42 (m, 5H), 6.72 (s, 1H), 4.29 (t, J = 4.4 Hz, 2H), 4.09 (t, J
= 4.4 Hz, 2H), 3.47 (br, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm): 148.7, 147.2,
146.4, 139.3, 129.9, 129.0, 128.8, 126.0, 125.6, 124.2, 104.3, 61.9, 51.3. Anal. Calcd
for C17H15N3O3: C, 66.01; H, 4.89; N, 13.58. Found: C, 65.85; H, 4.67; N, 13.35.
2.2.26. 1,3,5-Triphenyl-1H-pyrazole, 4z [51]
1
Yellow solid. IR (KBr): νmax/cm-1 3054, 2925, 1597, 1549, 1493, 1367, 765. H NMR
(400 MHz, CDCl3) δ (ppm): 7.91 (dd, J = 7.2, 1.2 Hz, 2H), 7.43-7.26 (m, 13H), 6.81
(s, 1H). 13C NMR (100 MHz, CDCl3) δ (ppm): 151.8, 144.3, 140.2, 133.1, 130.5,
128.9, 128.8, 128.7, 128.5, 128.4, 128.1, 127.4, 125.9, 125.4, 105.1.
12

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2.2.27. 3-Cyclohexyl-5-phenyl-1H-pyrazole, 4a' [30]
1
White solid. IR (KBr): νmax/cm-1 3010, 2928, 2853, 1645, 1567, 1462, 1027. H
NMR (400 MHz, CDCl3) δ (ppm): 7.75-7.73 (m, 2H), 7.41-7.25 (m, 3H), 6.37 (s, 1H),
3.37-3.31 (m, 1H), 2.70-2.65 (m, 2H), 2.06-1.80 (m, 2H), 1.49-1.25 (m, 6H). 13C
NMR (100 MHz, CDCl3) δ (ppm): 152.7, 150.1, 132.9, 128.7, 127.9, 125.7, 99.5, 36.0,
32.9, 26.2, 26.0.
3. Results and discussion
3.1. Optimization of reaction conditions
Although the phosphine ligands stabilize palladium and influence its reactivity, the
simplest and cheapest palladium catalysts are of course the phosphine-free systems,
specifically when used in low loading. The MCM-41-2N-Pd(OAc)2 complex was very
conveniently prepared from commercially available and inexpensive 3-(2-aminoethyl-
amino)propyltrimethoxysilane via immobilization on MCM-41, followed by reacting
with palladium acetate according to our previous procedure [48]. In our initial
screening experiments, the tandem reaction of benzoyl chloride, phenylacetylene and
hydrazine hydrate was examined to optimize the reaction conditions and the results
are summarized in Table 1. At first, the solvent effect was examined in the absence of
a cosolvent, and a significant solvent effect was observed. For the solvents evaluated
such as THF, dioxane, Et3N, toluene and DME, Et3N was the best choice (entries 1-5).
The base effect was also investigated and both DBU and Bu3N gave poor results
(entries 6 and 7). The reaction was completely blocked as inorganic bases such as
13

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K2CO3 and Cs2CO3 were used, presumably due to the poor solubility of these salts in
organic solvents (entries 8 and 9). When Et3N was used as both base and solvent, the
tandem reaction proceeded smoothly to afford the desired product in 57% yield (entry
3). In order to further improve the yield, a range of cosolvents were screened for the
reaction of ynone with hydrazine, and acetonitrile was found to be best choice (entries
10-12). The reaction was very slow in the absence of CuI as cocatalyst and only trace
of the desired product was observed (entry 13). The results in Table 1 revealed that
benzoyl chloride (1.3 mmol) coupled with phenylacetylene (1.0 mmol) smoothly in
the presence of 0.5 mol% of MCM-41-2N-Pd(OAc)2, 1.0 mol% of CuI in Et3N at 50
ºC for 2 h. Then, hydrazine hydrate (3.0 mmol) and acetonitrile (2 mL) were added
and stirred at room temperature for an additional 16 h, which gave 3,5-diphenyl-1H-
pyrazole in 81% isolated yield (entry 12).
3.2. Heterogeneous palladium-catalyzed tandem coupling-cyclocondensation reaction
To examine the scope for this heterogeneous palladium-catalyzed cascade coupling
-cyclocondensation reaction, we have investigated the reactions using a variety of
aromatic acid chlorides, a wide range of terminal alkynes and hydrazines as the
substrates under the optimized reaction conditions and the results are outlined in Table
2. As can be seen from Table 2, the tandem reactions of a variety of aroyl chlorides
with phenylacetylene and hydrazine hydrate proceeded smoothly to afford the desired
products 4a-d in good yields under the standard reaction conditions (entries 1-4).
Both electron-withdrawing and electron-donating groups on the benzene ring were
14

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tolerated well. The tandem reactions of heteroaroyl chlorides such as furan-2-carbonyl
chloride and thiophene-2-carbonyl chloride with phenylacetylene and hydrazine
hydrate could give the corresponding pyrazoles 4e and 4f in 84% and 88% yields,
respectively (entries 5 and 6). Substituted phenylacetylenes such as 4-methylphenyl-
acetylene, 4-methoxyphenylacetylene, 4-bromophenylacetylene and 4-nitrophenyl-
acetylene also underwent the tandem coupling-cyclocondensation reaction effectively
with various aroyl chlorides and hydrazine hydrate to furnish the corresponding
products 4g-m in good yields (entries 7-13). Aliphatic alkynes were also suitable
substrates in addition to aryl alkynes. For instance, the reactions of 1-hexyne with a
variety of aroyl chlorides and hydrazine hydrate could provide the corresponding
pyrazoles 4n-q in moderate yields (entries 14-17). However, use of longer chain
1-octyne led to the desired 4r with only 25% yield (entry 18). Subsequently, various
hydrazines were investigated by the cyclocondensation with the coupling products of
phenylacetylene with various aroyl chlorides. When 2-hydroxyethylhydrazine was
used as the substrate, the corresponding pyrazoles 4s-y were obtained in 58-87%
yields (entries 19-25). The reactivity of phenylhydrazine was much lower than that of
hydrazine hydrate or 2-hydroxyethylhydrazine, and the desired product 4z was
isolated in only 29% yield even in the presence of Na2CO3 (entry 26). We attempted
to carry out the tandem reaction of an aliphatic acid chloride such as cyclohexane-
carbonyl chloride with phenylacetylene and hydrazine hydrate, unfortunately, the
reaction did not work under the optimized conditions and no desired product was
observed since the coupling reaction of cyclohexanecarbonyl chloride with phenyl-
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acetylene did not occur. However, it was found that, in the presence of 1 mol% PPh3
the tandem reaction could proceed to give the desired product 4a' in moderate yield
(entry 27). The results indicated that the coupling reaction of acid chlorides with
terminal alkynes is a key step in the tandem reaction.
It was noteworthy that our catalytic system exhibited higher catalytic activity than
homogeneous PdCl2(PPh3)2/CuI [30]. For example, the reaction of benzoyl chloride
with 4-methylphenylacetylene in the presence of 0.5 mol% of MCM-41-2N-Pd(OAc)2
and 1.0 mol% of CuI in Et3N at 50 ºC for 2 h, followed by the cyclocondensation with
hydrazine hydrate in MeCN at room temperature for 16 h gave 4g in 83% yield (Table
2, entry 7), while the same reaction in the presence of 1.0 mol% of PdCl2(PPh3)2 and
3.0 mol% of CuI in THF with Et3N as base at room temperature for 2 h, followed by
the cyclocondensation with hydrazine hydrate in MeCN at room temperature for 16 h
provided 4g in only 63% yield [30]. Similarly, the reaction of benzoyl chloride with
phenylacetylene and 2-hydroxyethylhydrazine in our catalytic system afforded 4s in
79% yield (entry 19), whilst the same reaction in homogeneous PdCl2(PPh3)2/CuI
system gave 4s in 68% yield [30].
3.3. Recycling of the catalyst
For a heterogeneous transition-metal catalyst, it is important to examine its ease of
separation, recoverability and reusability. We next investigated the recyclability of the
MCM-41-2N-Pd(OAc)2 by using the cascade reaction of furan-2-carbonyl chloride
with phenylacetylene and hydrazine hydrate. After carrying out the reaction, the
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catalyst was separated by simple filtration and washed with ethanol and diethyl ether.
After being air-dried, it can be reused directly without further purification. This used
catalyst was re-employed in ten successive cycles under identical conditions and the
results are summarized in Table 3. It was seen that for the fresh catalyst and 2-6 cycles
the coupling reaction was completed within 2 h, but for the other 7-10 cycles the
desired conversion was achieved within 2.5-3 h, and almost consistent activity was
observed for 10 consecutive cycles. The high stability and excellent reusability of the
catalyst should result from the chelating action of bidentate nitrogen ligand on
palladium and the mesoporous structure of the MCM-41 support. The result is
important from industrial and environmental points of view. The high catalytic
activity, excellent reusability and the easy accessibility of the MCM-41-2N-Pd(OAc)2
complex make it a highly attractive heterogeneous palladium catalyst for the parallel
solution phase synthesis of diverse libraries of compounds.
4. Conclusion
In summary, we have developed a novel, practical and economic method for the
synthesis of pyrazoles through a tandem coupling-cyclocondensation reaction of acid
chlorides with terminal alkynes and hydrazines by using an 3-(2-aminoethylamino)-
propyl-functionalized MCM-41-immobilized palladium(II) complex [MCM-41-2N-
Pd(OAc)2] as catalyst. The reactions generated a variety of pyrazole derivatives in
moderate to good yields and were applicable to various acid chlorides and alkynes.
This heterogeneous palladium catalyst could be easily prepared by a simple two-step
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procedure from commercially available and inexpensive reagents and reused for at
least 10 consecutive trials without significant loss of catalytic activity, thus making
this procedure environmentally more acceptable.
Acknowledgements
We thank the National Natural Science Foundation of China (No. 21462021) for
financial support.
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Table 1 Optimization of conditions for the synthesis of 3,5-diphenyl-1H-pyrazole.a
Entry
1
Base
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
Bu3N
K2CO3
Cs2CO3
Et3N
Et3N
Et3N
Et3N
Solvent
THF
Cosolvent
Yieldb (%)
–
24
16
57
26
trace
11
2
dioxane
Et3N
–
3
–
4
toluene
DME
THF
–
5
–
6
–
7
THF
–
16
0
8
THF
–
9
THF
–
0
10
11
12
13c
Et3N
EtOH
MeOH
MeCN
MeCN
66
73
81
trace
Et3N
Et3N
Et3N
a Reaction conditions: benzoyl chloride (1.3 mmol), phenylacetylene (1.0 mmol), MCM-41-2N-
Pd(OAc)2 (0.005 mmol), CuI (0.01 mmol) and base (2.0 mmol) in solvent (3 mL) at 50 ºC under
argon for 2 h. Then, hydrazine hydrate (3.0 mmol) and cosolvent (2 mL) were added at room
temperature for 16 h.
b Isolated yield.
c Without CuI.
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Table 2 One-pot synthesis of pyrazole derivatives via heterogeneous palladium-
catalyzed cascade reaction.a
Entry
R1
R2
R3
Product
Yieldb(%)
1
2
Ph
Ph
H
4a
4b
4c
4d
4e
4f
81
75
77
80
84
88
83
80
77
74
85
81
78
60
56
54
61
25
79
72
74
80
85
87
58
29
57
4-MeC6H4
4-ClC6H4
4-MeOC6H4
2-furyl
Ph
H
3
Ph
H
4
Ph
H
5
Ph
H
6
2-thienyl
Ph
Ph
H
7
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
4-O2NC6H4
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C6H13
Ph
H
4g
4h
4i
8
Ph
H
9
4-MeC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
27d
H
4j
H
4k
4l
H
H
4m
4n
4o
4p
4q
4r
4s
H
4-MeC6H4
4-ClC6H4
4-MeOC6H4
Ph
H
H
H
H
Ph
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH2CH2OH
Ph
4-MeC6H4
4-ClC6H4
4-MeOC6H4
2-furyl
Ph
4t
Ph
4u
4v
4w
4x
4y
4z
4a'
Ph
Ph
2-thienyl
4-O2NC6H4
Ph
Ph
Ph
Ph
cyclohexyl
Ph
H
a Reaction conditions: acid chloride 1 (1.3 mmol), alkyne 2 (1.0 mmol), MCM-41-2N-Pd(OAc)2
(0.005 mmol), CuI (0.01 mmol) in Et3N (3 mL) at 50 ºC under argon for 2 h. Then, hydrazine 3
(3.0 mmol) and MeCN (2 mL) were added at room temperature for 16 h. b Isolated yield.
c Saturated aqueous Na2CO3 (1 mL) was added at the second step. d PPh3 (0.01 mmol) was added.
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Table 3 Cascade reaction of furan-2-carbonyl chloride with phenylacetylene and
hydrazine hydrate catalyzed by the recycled catalyst.a
Cycle
Timeb (h)
Yieldc (%)
Cycle
Timeb (h)
Yieldc (%)
1
3
5
7
9
2
84
83
83
82
82
2
2
84
82
83
83
82
2
4
2
2
6
2
2.5
8
2.5
3
10
3
a Reaction conditions: furan-2-carbonyl chloride (1.3 mmol), phenylacetylene (1.0 mmol), MCM-
41-2N-Pd(OAc)2 (0.005 mmol), CuI (0.01 mmol) in Et3N (3 mL) at 50 ºC under argon for 2-3 h.
Then, hydrazine hydrate (3.0 mmol) and MeCN (2 mL) were added at room temperature for 16 h.
b For the coupling reaction (the first step).
c Isolated yield.
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Research Highlights
► The first heterogeneous palladium-catalyzed synthesis of pyrazoles is described.
► The MCM-41-2N-Pd(OAc)2 complex exhibits higher catalytic activity than
PdCl2(PPh3)2.
► This palladium catalyst can be reused for 10 times without any decrease in activity.
► Our catalytic system provides a practical route for the synthesis of pyrazoles.