One-pot three-component synthesis of pyrazoles through a tandem coupling-cyclocondensation sequence

Article abstract of DOI:10.1016/j.tetlet.2008.03.153

An efficient and general one-pot procedure for the synthesis of pyrazoles from acid chlorides, terminal alkynes and hydrazines was described via a coupling and cyclocondensation sequence. Acid chlorides coupled with terminal alkynes to give α,β-unsaturated ynones, and in situ converted into pyrazoles by the cycloaddition of hydrazines. The desired pyrazoles were obtained with 15-85% isolated yields.

Full text of DOI:10.1016/j.tetlet.2008.03.153

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3805–3809
One-pot three-component synthesis of pyrazoles through
a tandem coupling-cyclocondensation sequence
Hai-Ling Liu, Huan-Feng Jiang *, Min Zhang, Wen-Juan Yao, Qiu-Hua Zhu, Zhou Tang
The College of Chemistry, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China
Received 21 January 2008; revised 26 March 2008; accepted 28 March 2008
Available online 8 April 2008
Abstract
An efficient and general one-pot procedure for the synthesis of pyrazoles from acid chlorides, terminal alkynes and hydrazines was
described via a coupling and cyclocondensation sequence. Acid chlorides coupled with terminal alkynes to give a,b-unsaturated ynones,
and in situ converted into pyrazoles by the cycloaddition of hydrazines. The desired pyrazoles were obtained with 15–85% isolated yields.
Ó 2008 Published by Elsevier Ltd.
Tandem reactions refer to two reactions operating in
succession in the same reaction vessel.1 Nowadays, tandem
reactions have emerged as powerful tools to meet the
demands of modern organic chemistry due to the synthetic
efficiency, molecular diversity, low production costs, etc.2
Perhaps the most synthetically useful version of tandem
processes is to construct interesting cyclic compounds, a
large family of the natural products with significant biolog-
ical activities, synthetic intermediates with wide-ranging
utility for drug candidates and fine chemicals.3 In this con-
text, we have recently developed tandem sequences for the
synthesis of polysubstituted tetrahydropyrimidines or 2,5-
dihydro-1,3-oxazin-6-ones.4 Encouraged by these results,
we are interested in investigating similar tandem reactions
to broaden N-containing heterocycles.
Pyrazoles and its derivatives, which are a large class of N-
containing heterocycles, possess important biological and
pharmaceutical activities,5 and are also useful synthetic
building blocks and metal ligands in organic chemistry.6,7
Therefore, a number of synthetic methods have been devel-
oped for theconstruction of this skeleton, including the cycli-
zation of 1,3-diketones with hydrazine,8 1,3-dipolar
cycloaddition of diazoalkanes with alkynes,9 the reaction
of hydrazines with a,b-unsaturated ketones10 and several
other methods.11 Recently, great interest is focused on one-
pot construction of heteroaromatic compounds, such as oxa-
diazoles,12 pyrimidines,13 N-sulfonyl pyrroles, indoles and
carbazoles,14 furan,15 ethyl3-hydroxyquinoxaline-2-carbox-
ylates,16 pyrano- and furanoquinolines,17 and pyrazoles. Of
these heterocycles, one-pot synthesis of pyrazoles has been
developed based on these intermediates generated in situ
including 1,3-diketones,8a diazo compounds9 and ynones.18
Unfortunately, some of the reagents used in these cases are
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 more facile and efficient.
Many methods exist for the synthesis of ynones from the
coupling of acid chlorides and terminal alkynes.19 Herein,
we report an efficient and general one-pot three-component
procedure for the construction of pyrazoles via a tandem
coupling-cyclocondensation sequence. Ynones were syn-
thesized directly from acid chlorides and terminal alkynes,
and were then converted in situ into pyrazoles by the cyclo-
addition of hydrazines.
Our first attempt at this one-pot transformation
employed 2-furancarbonyl chloride (1a) as a substrate cou-
pled with phenylacetylene (2a) and hydrazine hydrate (3a)
(Table 1). Using CuI as a catalyst, the desired product 3-
furan-5-phenyl-1H-pyrazole (4aaa) was obtained in only
25% isolated yield. The use of PdCl2(PPh3)2/CuI19c could
*
Corresponding author. Tel.: +86 20 22236518; fax: +86 20 87112906.
E-mail address: jianghf@scut.edu.cn (H.-F. Jiang).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.03.153

3806
H.-L. Liu et al. / Tetrahedron Letters 49 (2008) 3805–3809
Table 1
Optimization of conditions for the synthesis of pyrazole 4aa
O
1. PdCl2(PPh3)2/ CuI
Et3N, THF, rt
Ph
+
Ph
O
Cl
2. cosolvent rt
NH2NH2 H2O
N
NH
O
1a
2a
3a
4aaa
Entry
Catalyst
CuIc
PdCl2(PPh3)2/CuI
PdCl2(PPh3)2/CuI
PdCl2(PPh3)2/CuI
PdCl2(PPh3)2/CuI
PdCl2(PPh3)2/CuI
NH2NH2 (mmol)
Cosolvent
Yield b (%)
1
2
3
4
5
6
a
2
2
3
3
3
3
—
—
—
MeOH
EtOH
CH3CN
25
52
58
67
60
73
Reaction conditions: 1a (1.5 mmol), 2a (1.0 mmol), PdCl2(PPh3)2 (0.01 mmol), CuI (0.03 mmol) and Et3N (2.0 mmol) in THF (5 mL) at room
temperature for 2 h. Then 3a and consolvent (2 mL) were added at room temperature for 16 h.
b
Isolated yields.
c
The reaction was carried out with CuI (0.05 mmol) as a catalyst for 12 h.
Table 2
One-pot synthesis of pyrazoles 4a
1. PdCl2(PPh3)2/ CuI
Et3N THF
R2
O
R1
R2
+
R1
Cl
2. R3NHNH2
N
N
3
4
2
R3
1
1
2
3
Product
Yield b (%)
73
1a
2a
3a
O
4aaa
4baa
N
NH
1b
1b
2a
2b
3a
3a
76
15
N NH
N NH
nHexyl
4bba
1b
1b
2c
2d
3a
3a
63
41
N
NH
4bca
4bda
N
NH
1b
1b
2a
2a
3b
3c
33c
N N
4bab
Ph
68
N
N
4bac
OH

H.-L. Liu et al. / Tetrahedron Letters 49 (2008) 3805–3809
3807
Table 2 (continued)
1
2
3
Product
Yield b (%)
68
1c
1d
1e
2a
3a
4caa
N
NH
N
O2N
2a
2a
2a
3a
3a
3a
52
85
51
4daa
NH
S
4eaa
N NH
1f
4faa
N
NH
a
Reaction conditions: 1 (1.5 mmol), 2 (1.0 mmol), PdCl2(PPh3)2 (0.01 mmol), CuI (0.03 mmol) and Et3N (2.0 mmol) in THF (5 mL) at room tem-
perature for 2 h. Then, 3 (3.0 mmol) and CH3CN (2 mL) were added at room temperature for 16 h.
b
Isolated yields.
c
1 mL saturated aqueous Na2CO3 was added at the second step.
greatly increase the yield of 4aaa (Table 1, entry 2). The
amount of hydrazine hydrate (3a) affected the reaction to
some extent. It was found that 3 equiv of 0.5 M hydrazine
hydrate resulted in 4aaa in 58% yield (Table 1, entry 3). In
order to improve the conversion, a range of cosolvents
were screened for the reaction of ynone with hydrazine,
and acetonitrile was found to offer the highest yield (Table
1, entries 4–6).
1. PdCl2(PPh3)2/CuI
Et3N, THF, 2 h
O
Ph
Cl +
Ph
N
N
2. CH3CN, reflux
Na2CO3
2a
1b
6ba
yield: 42%
NH
NH2
5
HCl
The results in Table 1 revealed that 2-furancarbonyl
chloride (1a) (1.5 mmol) smoothly reacted with phenylacet-
ylene (2a) (1.0 mmol) in the presence of 1 mol % of Pd
(PPh3)2Cl2, 3 mol % of CuI and 2 mmol of triethylamine
for 2 h in THF. Then, 3 mmol of 0.5 M hydrazine hydrate
(3a) and acetonitrile (2 mL) were added and stirred for an
additional 16 h, which gave pyrazole (4aaa) in 73% isolated
yield (Table 1, entry 6).
Under the given optimized reaction conditions, we first
conducted this one-pot tandem reaction of different termi-
nal alkynes 2 with benzoyl chloride (1b) and hydrazine 3.20
As can be seen from Table 2, the corresponding pyrazoles
4baa to 4bac were obtained in 15–76% isolated yields. The
use of aliphatic terminal alkyne (2b) led to 4bba with only
15% yield. The reactivity of phenylhydrazine (3b) was
much lower than that of hydrazine hydrate, and the addi-
tion of Na2CO3 could improve the yield of 4bab. Subse-
quently, various acid chlorides 1 were investigated by
coupling with 2a and 3a. The desired products 4caa to
4faa were obtained in 51–85% isolated yields.
Scheme 1.
the one-pot three-component synthesis of pyrimidine
(Scheme 1). It was found that pyrimidine 6ba was obtained
in 42% isolated yield.21
In conclusion, we have developed a convenient one-pot
synthesis of pyrazoles via a three-component coupling-
cyclocondensation sequence catalyzed by Pd(PPh3)2Cl2/
CuI. The protocol offers several advantages such as the
use of commercially available materials, easy isolation, sim-
ple workup procedures and compatibility to various sub-
strates making it an appealing alternative to construct
heteroaromatic ring.
Acknowledgements
The authors thank the National Natural Science Foun-
dation of China (Nos. 20772034, 20625205, 20572027 and
20332030) and the Guangdong Natural Science Founda-
tion (No. 07118070) for financial support of this work.
The coupling of acid chloride and terminal alkyne could
give ynone which may undergo dehydration reaction with
hydrazine and subsequent 1,4-addition process to afford
the desired pyrazole.
Encouraged by the successful one-pot procedure to the
synthesis of the pyrazoles, we attempted this method to
References and notes
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20. A typical procedure for the preparation of compound 4. To a 25 mL
round-bottomed flask, PdCl2(PPh3)2 (0.01 mmol), CuI (0.03 mmol),
Et3N (2.0 mmol) acid chloride 1 (1.5 mmol) and terminal alkyne 2
(1.0 mmol) were added in THF (5 mL) at room temperature for 2 h
under N2. Then hydrazine 3 (3.0 mmol) and CH3CN (2 mL) were
added and reacted for an additional 16 h. Then the reaction mixture
was diluted with water (10 mL) and extracted with dichloromethane
(2 Â 20 mL). The combined organic layers were dried with sodium
sulfate, concentrated to dryness and isolated by preparative TLC or
column chromatography to obtain pure products 4. 3-Furan-2-yl-5-
phenyl-1H-pyrazole (4aaa): 1H NMR (CDCl3, 400 MHz) d: 6.48 (q,
J = 1.6 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.78 (s, 1H), 7.35–7.46 (m,
4H), 7.70–7.72 (m, 2H); IR (KBr) m: 3392 br s, 2946, 2837, 1609, 1552,
1460, 1115, 1026 cmÀ1; MS (70 eV) m/z (%): 210 (MÅ+, 100), 181, 152,
127, 105, 79, 77. 3,5-Diphenyl-1H-pyrazole (4baa): 1H NMR (CDCl3,
400 MHz) d: 6.86 (s, 1H), 7.33–7.45 (m, 6H), 7.74 (d, J = 7.2 Hz, 4H);
IR (KBr) m: 3096, 2921, 1639, 1565, 1457, 1084 cmÀ1; MS (70 eV) m/z
(%): 220 (MÅ+ , 100), 191, 165, 110, 77, 51, 32. 5-Hexyl-3-phenyl-1H-
pyrazole (4bba): 1H NMR (CDCl3, 400 MHz) d: 0.87 (t, J = 6.8 Hz,
3H), 1.27–1.37 (m, 6H), 1.63–1.68 (m, 2H), 2.65 (t, J = 7.6 Hz, 2H),
5.40–6.20 (br s, 1H), 6.36 (s, 1H), 7.29–7.40 (m, 3H); 7.70–7.72 (m,
2H); 13C NMR (CDCl3, 400 MHz) d: 150.0, 147.9, 132.7, 128.6, 127.7,
125.7, 100.9, 31.5, 29.2, 28.9, 26.4, 22.5, 14.0; IR (KBr) m: 3249, 2928,
2855, 1642, 1569, 1458, 1264 cmÀ1; MS (70 eV) m/z (%): 228 (MÅ+),
213, 199, 171, 158 (100), 145, 128, 104, 91; Anal. Calcd for C15H20N2:
C, 78.90; H, 8.83; N, 12.27. Found: C, 79.15; H, 8.60; N, 12.32. 3-
Phenyl-5-p-tolyl-1H -pyrazole (4bca): 1H NMR (CDCl3, 400 MHz) d:
2.39 (s, 3H), 6.82 (s, 1H), 7.23–7.45 (m, 5H), 7.61 (d, J = 8 Hz, 2H);
7.74 (d, J = 4 Hz, 2H); 13C NMR (CDCl3, 400 MHz) d: 147.0, 138.3,
129.6, 128.9, 128.2, 125.5, 99.9, 21.3; IR (KBr) m: 2957, 2923, 1647,
1459, 1097 cmÀ1; MS (70 eV) m/z (%): 234 (MÅ+, 100), 219, 205, 189,
178, 165, 152, 130, 117, 104, 89, 77,63, 51. 5-Naphthalen-2-yl-3-
phenyl-1H-pyrazole (4bda): 1H NMR (CDCl3, 400 MHz) d: 6.86 (s,
1H), 7.31–7.52 (m, 6H), 7.57 (d, J = 6.4 Hz, 1H), 7.76–7.89 (m, 4H),
8.28 (d, J = 8 Hz, 1H); 13C NMR (CDCl3, 400 MHz) d: 149.3, 146.6,
133.8, 131.8, 131.3, 129.0, 128.8, 128.4, 128.1, 127.1, 126.7, 125.7,
125.5, 125.3, 103.9; IR (KBr) m: 3190 br s, 3056, 2961, 1645, 1565,
1460, 1269, 1171 cmÀ1; MS (70 eV) m/z (%): 270 (MÅ+ , 100), 241, 215,
191, 167, 152, 135, 119, 104, 95, 77, 63, 51; Anal. Calcd for C19H14N2:
C, 84.42; H, 5.22; N, 10.36. Found: C, 84.38; H, 5.50; N, 10.53. 1,3,5-
Triphenyl-1H-pyrazole (4bab): 1H NMR (CDCl3, 400 MHz) d: 6.81 (s,
1H), 7.27–7.42 (m, 13H), 7.90 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 2H); IR
(KBr) m: 3057, 2924, 1598, 1549, 1494, 1364 cmÀ1; MS (70 eV) m/z
(%): 296 (MÅ+ , 100), 268, 217, 192, 180, 165, 147, 134, 116, 77, 64, 51,
32. 2-(3,5-Diphenyl-1H-pyrazol-1-yl)ethanol(4bac): 1H NMR (CDCl3,
400 MHz) d: 4.03 (t, J = 4.0 Hz, 2H), 4.26 (t, J = 4.0 Hz, 2H), 6.63 (s,
1H), 7.25–7.50 (m, 8H), 7.83 (d, J1 = 8.0 Hz, 2H); 13C NMR (CDCl3)
d: 151.0, 145.6, 132.9, 130.2, 129.0, 128.8, 128.7, 127.9, 125.6, 103.3,
62.2, 50.9; IR (KBr) m: 3063, 2926, 1640, 1549, 1461, 1071 cmÀ1; MS
(70 eV) m/z (%): 264 (MÅ+ ), 233 (100), 220, 206, 191, 179, 165, 130,
117, 104, 91, 77, 57; Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10;
N, 10.60. Found: C, 77.32; H, 6.14; N, 10.55. 5-Phenyl-3-p-tolyl-1H-
pyrazole (4caa): 1H NMR (CDCl3, 400 MHz) d: 2.38 (s, 3H), 6.81 (s,
1H), 7.22–7.44 (m, 4H), 7.59–7.74 (m, 5H); IR (KBr) m: 3184 br s,
2922, 1651, 1540, 1506, 1400, 1295 cmÀ1; MS (70 eV) m/z (%): 234
(MÅ+, 100), 219, 205, 189, 178, 165, 152, 130, 117, 104, 89, 77, 63, 51,
32. 3-(4-Nitro-phenyl)-5-phenyl-1H-pyrazole (4daa): 1H NMR (CDCl3,
400 MHz) d: 7.36–7.40 (t, J = 8.0 Hz, 4H), 7.81 (s, 2H), 8.11 (d,
J = 4.0 Hz, 2H); 8.29 (d, J = 8.0 Hz, 2H), 13.7 (s, 1H); 13C NMR
(CDCl3) d: 146.9, 129.5, 128.9, 126.3, 125.6, 124.7, 101.6; IR (KBr) m:
3190, 2920, 1644, 1515, 1457, 1330, 1299 cmÀ1; MS (70 eV) m/z (%):
265 (MÅ+ , 100), 249, 235, 219, 207, 191, 178, 165, 152, 139, 116, 104,
89, 77, 63, 51, 30. 5-Phenyl-3-thiophen-2-yl-1H-pyrazole (4eaa): 1H
NMR (CDCl3, 400 MHz) d: 6.68 (s, 1H), 6.99–7.01 (m, 1H), 7.21–7.34
(m, 5H), 7.64 (d, J = 7.2 Hz, 2H); 13C NMR (CDCl3) d: 145.4, 135.0,
130.3, 128.9, 128.4, 127.5, 125.6, 124.8, 124.1, 100.2; IR (KBr) m: 3096,
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¨

H.-L. Liu et al. / Tetrahedron Letters 49 (2008) 3805–3809
2950, 2842, 1646, 1457, 1052 cmÀ1; MS (70 eV) m/z (%): 226 (MÅ+
3809
,
mmol), Et3N (2.0 mmol), benzoyl chloride (1.5 mmol) and phenyl-
acetylene (1.0 mmol) were added in THF (5 mL) at room temper-
ature for 2 h under N2. Then 5 (2.0 mmol), CH3CN (2 mL) and
Na2CO3 (2.5 mmol) were added and refluxed for 24 h. Then the
reaction mixture was diluted with water (10 mL) and extracted with
dichloromethane (2 Â 20 m). The combined organic layers were
dried with sodium sulfate, concentrated to dryness and isolated by
preparative TLC to obtain pure products 6ba. 2-Methyl-4,6-diphen-
ylpyrimidine (6ba): 1H NMR (CDCl3, 400 MHz) d: 2.86 (s, 3H),
7.50–7.52 (m, 6H), 7.88 (s, 1H), 8.10–8.13 (m, 4H); IR (KBr) m:
3061, 2955, 2924, 2853, 1574, 1532, 1459, 1368 cmÀ1; MS (70 eV)
m/z (%): 246 (MÅ+, 100), 236, 205, 195, 167, 152, 123, 102, 98, 76,
63, 51, 42.
100), 197, 171, 165, 113, 77, 40; Anal. Calcd for C13H10N2S:C, 69.00;
H, 4.45; N, 12.38. Found: C, 69.22; H, 4.28; N, 12.57. 3-Cyclohexyl-5-
phenyl-1H-pyrazole (4faa): 1H NMR (CDCl3, 400 MHz) d: 1.24–1.48
(m, 6H), 1.81–2.05 (m, 2H), 2.65–2.69 (m, 2H), 3.30–3.36 (m, 1H),
6.36 (s, 1H), 7.25–7.40 (m, 3H), 7.72–7.74 (m, 2H); 13C NMR (CDCl3)
d: 152.7, 150.0, 132.8, 128.7, 127.8, 125.6, 99.4, 35.9, 32.9, 26.1, 26.0;
IR (KBr) m: 3007, 2927, 2854, 1647, 1568, 1459, 1029 cmÀ1; MS
(70 eV) m/z (%): 226 (MÅ+, 100), 211, 197, 185, 171, 158, 145, 128, 115,
104, 91, 77, 67, 55; Anal. Calcd for C15H18N2: C, 79.61; H, 8.02; N,
12.38. Found: C, 79.55; H, 8.28; N, 12.59.
21. A typical procedure for the preparation of compound 6ba. To a
25 mL round-bottomed flask, PdCl2(PPh3)2 (0.01 mmol), CuI (0.03