Synthesis of pyrazoles through copper-catalyzed three-component coupling of aldehydes, alkynes, and p-toluenesulfonylhydrazide

Article abstract of DOI:10.3987/COM-12-12646

A convenient one-pot synthesis of 3,5-disubstitued 1H-pyrazoles through copper-catalyzed three-component coupling of aldehydes, alkynes, and p-toluenesulfonylhydrazide has been developed. This method provides a flexible and rapid route to 3,5-disubstituted 1H-pyrazoles.

Full text of DOI:10.3987/COM-12-12646

HETEROCYCLES, Vol. 87, No. 3, 2013
657
HETEROCYCLES, Vol. 87, No. 3, 2013, pp. 657 - 663. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 10th December, 2012, Accepted, 16th January, 2013, Published online, 18th January, 2013
DOI: 10.3987/COM-12-12646
SYNTHESIS OF PYRAZOLES THROUGH COPPER-CATALYZED
THREE-COMPONENT COUPLING OF ALDEHYDES, ALKYNES, AND
p-TOLUENESULFONYLHYDRAZIDE
*
Feng Wu,1 Lu Hao,2 and Zhuang-ping Zhan1,2
1 School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, Fujian,
2
P. R. China. Department of Chemistry, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. China. e-mail:
zpzhan@xmu.edu.cn
Abstract – A convenient one-pot synthesis of 3,5-disubstitued 1H-pyrazoles
through copper-catalyzed three-component coupling of aldehydes, alkynes, and
p-toluenesulfonylhydrazide has been developed. This method provides a flexible
and rapid route to 3,5-disubstituted 1H-pyrazoles.
Substituted pyrazoles are important synthetic targets in the pharmaceutical industry because the pyrazole
motif makes up the core structure of numerous biologically active compounds. Therefore, various
approaches have been developed for their synthesis.1,2 Two important methods are usually adopted: one is
the reaction of reacting hydrazines with 1,3-dicarbonyl compounds, and the other is 1,3-dipolar
cycloaddition of diazoalkanes or nitrilimines with olefins or alkynes.1a,1c However, the former often
results in a mixture of regioisomers, while the latter has found only limited applications in pyrazole
synthesis because 1,3-dipoles are often difficult to prepare and are potentially explosive. As a result, new
approaches allowing for efficient assembly of different pyrazole skeletons with diverse substitution
patterns are in high demand.
In recent years, three-component coupling reactions of an aldehyde, an alkyne and an amine, commonly
called A3-coupling, have received considerable attention due to their convenience in the organic
synthesis.3,4 Recently, Liu et al. described an efficient gold(III)-catalyzed multi-component reaction of
heteroaryl aldehydes, amines and alkynes.4a This pioneer method allows for the facile synthesis of
substituted aminoindolizines with high atom economy. Subsequently, in 2010, Gevorgyan and co-workers
demonstrated a copper-catalyzed three-component coupling towards imidazoheterocycles.4b Fujii and
Ohno also reported a gold-catalyzed three-component annulation for the dihydropyrazoles in 2012.4c

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However, further development of three-component coupling reaction towards heterocycles is still an
extremely attractive, yet challenging task. We herein wish to report an efficient three-component coupling
reaction for the synthesis of pyrazoles from aldehydes, alkynes, and p-toluenesulfonylhydrazide.
Table 1. Screening of catalysts and solventsa
H
O
N
reaction conditions
N
TsNHNH2
+
+
Ph
Ph
Ph
H
Ph
1a
2
3a
4a
Entry
1
Catalyst (mol%)
FeCl3
Solvent
Time (h)
Yield (%)b
MeCN
toluene
PhCl
12
12
24
24
24
3
0
2
ZnCl2
0
38
3
AgOTf
4
AgBF4
PhCl
33
5
AgOAc
PhCl
trace
60
6
Cu(OTf)2(20)
Cu(OTf)2(10)
CuCl
PhCl
PhCl
7
15
24
24
2
45
8
PhCl
trace
41
9
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
InCl3
PhCl
10
11
12
13
14
15
MeNO2
toluene
PhCl
complex
40
6
24
24
24
13
0
In(OTf)3
Zn(OTf)2
PhCl
0
PhCl
complex
47
Cu(OTf)2(10), CuCl(10)
PhCl
a Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), 3a (1.5 mmol) and catalyst (20 mol%) in solvent
(3 mL) at reflux for an appropriate time (Tf=triflyl).
b Isolated yields based on 1a.
Our research began with the solvent and catalyst screening (Table 1). We attempted a range of metallic
catalysts including Cu(I), Cu(II), Zn(II), In(III), Fe(III), and Ag(I). Notably, a low yield was obtained in
the presence of both CuCl and Cu(OTf)2 (Table 1, entry 15). In the work of Gevorgyan and co-workers,

HETEROCYCLES, Vol. 87, No. 3, 2013
659
the combination of CuCl and Cu(OTf)2 worked very well.4b After careful screening, the optimal condition
was determined as show in Table 1, entry 6, which using 20 mol% Cu(OTf)2 as the catalyst in
chlorobenzene at reflux, leading to the 4a in 60% yield.
Table 2. Synthesis of 3,5-disustituted 1H-pyrazolesa
H
N
H
N
Cu(OTf)2 (20 mol%)
R1 CHO
N
R2
R2
+
+
H2N
Ts
PhCl, reflux
R1
in air
1
2
3
4
H
N
H
H
N
N
Ph
N
Ph
Ph
N
N
H
N
N
Ph
Ph
Br
MeO
Me
4a - 3 h, 60%
R1 = Ph
4b - 2 h, 61%
R1 = p-MePh
R2 = Ph
4c - 2 h, 62%
R1 = p-MeOPh
R2 = Ph
4d - 3h, 55%
R1 = p-BrPh
R2 = Ph
R2 = Ph
H
N
H
N
H
N
Ph
N
H
N
Ph
N
Ph
N
N
Ph
O
NC
F
Cl
4e - 1.5 h, 55%
R1 = p-ClPh
R2 = Ph
4f - 1.5 h, 57%
R1 = p-FPh
R2 = Ph
4g - 2 h, 32%
R1 = p-NCPh
4h - 3.5 h, 30%
R1 = 2-furanyl
R2 = Ph
R2 = Ph
H
H
N
H
N
n-Bu
N
H
N
n-Bu
Ph
N
N
N
n-Bu
N
Ph
O2N
Me
Cl
4i - 1.1h, 38%
R1 = p-NO2Ph
4j - 6 h, 51%b
R1 = Ph
R2 = n-Bu
4k - 5 h, 56%b
R1 = p-MePh
R2 = n-Bu
4l - 7 h, 42%b
R1 = p-ClPh
R2 = n-Bu
R2 = Ph
H
n-Bu
N
H
Ph
N
N
H
N
N
N
n-pent
Ph
MeOOC
4m - 7.5 h, 35%b
R1 = p-MeOOCPh
R2 = n-Bu
4n - 8.5 h, 45%b
4o - 24 h, 0%
R1 = n-pent
R2 = Ph
R1 = Ph
R2 = cyclopropyl
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), 3 (1.5 mmol) and Cu(OTf)2 (20 mol%) in
PhCl (3 mL) at reflux for an appropriate time. Isolated yields based on 1.
b The reactions were performed in 25 mL sealed tube.

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We next sought to evaluate the substrate scope of this three-component coupling reaction (Table 2). It
was pleased to find that the reactions of aromatic aldehydes proceeded well, offering an easy access to
3,5-disubstituted 1H-pyrazoles with various substituents. In addition, a wide range of functional groups
including F, Cl, Br, MeO, CN, NO2 and COOMe could be well tolerated, leading to the products in
moderate to good yields. In the examples of aromatic terminal alkynes (R2 = aryl), both electron-donating
and electron-withdrawing substituted aromatic aldehydes proceeded well (Table 2, 4b-4i). On the other
hand, relatively lower yields were obtained in the reactions of the aliphatic terminal alkyne (Table 2,
4j-4n), possibly due to their decreasing acidity. It should be mentioned that the reaction of
furanyl-substituted aldehyde also generated the pyrazole in 30% yield (Table 2, 4h). We also investigate
the reaction of aliphatic aldehyde, however, it was found that no corresponding pyrazole was produced
(Table 2, 4o).
As a working hypothesis, we proposed the following plausible mechanism (Scheme 1). First, a
Cu(II)-catalyzed three-component coupling of aldehyde, p-toluenesulfonylhydrazide, and alkyne occurred
to afford 5 via a Mannich-Grignard reaction.3,5 Coordination of the triple bond in alkyne 5 to the copper
catalyst enhanced the electrophilicity of the alkyne, and the subsequent nucleophilic attack of the nitrogen
would produce the cation 6. Cation 6 would undergo deprotonation to afford 7 which was followed by
demetalation leading to 8. Finally, pyrazoles 4 was afforded by the elimination of p-tolylsulfinic acid.
O
R1
H
1
Ts
Ts
NH
H
H
N
Cu2+
HN
R1
5-endo-dig
HN
R2
N
+
Ts
NH2
R1
2
Cu+
R2
2+Cu
6
R2
3
5
-H+
Ts
Ts
H
N
N
H+
- TsH
N
HN
R1
N
R2
Cu+
HN
R1
R2
R2
R1
Cu2+
4
8
7
Scheme 1. Proposed mechanism
EXPERIMENTAL
Unless otherwise noted, all reagents were obtained commercially and used without further purification.
All reaction mixtures were stirred with a magnetic bar in flame-dried glassware. Thin layer

HETEROCYCLES, Vol. 87, No. 3, 2013
661
chromatography (TLC) was performed on Huanghai pre-coated glass-backed TLC plates and visualized
by UV lamp (254 nm). Column chromatography on silica gel (300-400 mesh) was carried out using
o
Technical Grade 60-90 C v/v petroleum ether (distillated prior to use) and Analytical Grade EtOAc
(without further purification). Concentration under reduced pressure was performed by rotary evaporation.
Purified compounds were further addressed under high vacuum (3-5 mmHg). Yields referred to
1
chromatographically purified compounds. H and 13C spectra were recorded on a Bruker AV-400
spectrometer. Chemical shifts were reported in ppm. 1H-NMR spectra were referenced to TMS in CDCl3
(0 ppm) or DMSO-d6 (2.50 ppm), and 13C-NMR spectra were referenced to CDCl3 (77.0 ppm) or
DMSO-d6 (39.5 ppm). All 13C-NMR spectra were measured with complete proton decoupling. Peak
multiplicities were designated by the following abbreviations: s, singlet; d, doublet; t, triplet; m, multiplet;
brs, broad singlet and J, coupling constant in Hz. Melting points were measured on a Bűchi Melting Point
B-540 Apparatus using open glass capillaries and are uncorrected. IR spectra were recorded on a Nicolet
AVATER FTIR360 spectrometer as thin film. Absorptions were given in wavenumbers (cm-1). MS
measurements were performed on Bruker Reflex III mass spectrometer. Data were obtained via
Ultra-high Resolution Hybrid Qh-Fourier Transform Mass Spectrometer (En Apex ultra 7.0 FT-MS)
operated by Department of Chemistry, Xiamen University.
General procedure for preparation of 3,5-disubstitued 1H-pyrazoles 4.
To a flame-dried 5-mL flask or 25-mL sealed tube equipped with a magnetic bar, aldehyde 1 (0.5 mmol,
1.0 equiv.), p-toluenesulfonylhydrazide 2 (0.6 mmol, 1.2 equiv.), alkyne 3 (1.5 mmol, 3.0 equiv.), Cu
(OTf)2 ( 20 mmol%, 0.1 mmol), and chlorobenzene (3 mL) were added successively. The mixture was
stirred at room temperature until the 2 was dissolved, then heated to reflux for an appropriate time, and
monitored periodically by TLC. Upon completion, the product was purified by column chromatography
on silica gel to afford 4.
Spectroscopic data for the new compounds 4k and 4m.
5-Butyl-3-p-tolyl-1H-pyrazole (4k): Prepared according to the general procedure and the reaction was
performed for 5 h. The product (4k) was purified by column chromatography on silica gel to afford a
1
yellow oil in 56% yield. H-NMR (400 MHz, CDCl3) δ 0.90 (t, 3H, J = 7.6 Hz), 1.30-1.37 (m, 2H),
1.59-1.63 (m, 2H), 2.36 (s, 3H), 2.59 (t, 2H, J = 7.6 Hz), 6.32 (s, 1H), 7.16 (d, 2H, J = 8.0 Hz), 7.62 (d,
2H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3): δ 13.7, 21.2, 22.3, 26.1, 31.3, 100.6, 125.6, 129.2, 137.4;
IR (film): 3420, 3092, 1598, 1517 cm-1; HRMS(ESI): calc. for C14H18N2 [M+H]+: m/z (%) = 215.1548;
found: 215.1541.

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Methyl 4-(5-butyl-1H-pyrazol-3-yl)benzoate (4m): Prepared according to the general procedure and the
reaction was performed for 7.5h. The product (4m) was purified by column chromatography on silica gel
o
1
to afford a white solid in 35% yield (mp 87-89 C). H-NMR (400 MHz, CDCl3): δ 0.87 (t, 3H, J = 7.6
Hz), 1.28-1.33 (m, 2H), 1.55-1.63 (m, 2H), 2.59 (t, 2H, J = 7.6 Hz), 3.91 (s, 3H), 6.39 (s, 1H), 7.78 (d, 2H,
J = 8.4 Hz), 8.00 (d, 2H, J = 8.4 Hz); 13C-NMR (100MHz, CDCl3): δ 13.7, 22.2, 25.8, 31.2, 52.0, 101.5,
125.4, 129.0, 130.0, 137.3, 147.4, 149.5, 166.9; IR (film): 3322, 3002, 1772, 1604, 1095 cm-1;
HRMS(ESI): calc. for C15H18N2O2 [M+H]+: m/z (%) = 259.1447; found: 259.1442.
See Supporting Information for the spectroscopic data and corresponding references for the known
compounds.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China (Nos. 21072159 and 21272190), the 973
Projects (No.2011CB935901), and the Xiamen Science & Technology Bureau (No.3502Z20103006) for
financial support of this project.
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