An efficient one-pot synthesis of 3,5-disubstituted 1H-pyrazoles

Article abstract of DOI:10.1055/s-0031-1290772

An efficient, general, one-pot, three-component procedure for the preparation of 3,5-disubstituted 1H-pyrazoles via condensation of substituted aromatic aldehydes, tosylhydrazine and terminal alkynes in toluene is reported. The reaction tolerates a variety of functional groups and sterically hindered substrates to afford the desired pyrazoles in yields of 67-91%.

Full text of DOI:10.1055/s-0031-1290772

PAPER
▌1577
paper
An Efficient One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazoles
Lei-Lei Wu,a Yi-Cen Ge,a Ting He,b Lei Zhang,a Xing-Li Fu,c Hai-Yan Fu,a Hua Chen,*a Rui-Xiang Lia
a
Key Lab of Green Chemistry and Technology, Ministry of Education, The Institute of Homogeneous Catalysis, College of Chemistry,
Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. of China
Fax +86(28)85412904; E-mail: scuhchen@scu.edu.cn
b
c
Institute of Chemical Materials, China Academy of Engineering Physics (CAEP), Chengdu, Sichuan 610065, P. R. of China
Guangxi Vocational and Technical Institute of Industry, Nanning, Guangxi 530001, P. R. of China
Received: 01.12.2011; Accepted after revision: 29.02.2012
generating aryldiazomethanes in situ from stable tosylhy-
drazone derivatives.10 They utilized this approach in a
convenient one-pot preparation of pyrazoles, with excel-
lent regioselectivity, via the 1,3-dipolar cycloaddition of
Abstract: An efficient, general, one-pot, three-component proce-
dure for the preparation of 3,5-disubstituted 1H-pyrazoles via con-
densation of substituted aromatic aldehydes, tosylhydrazine and
terminal alkynes in toluene is reported. The reaction tolerates a va-
riety of functional groups and sterically hindered substrates to af- various aldehydes and alkynes. This method has also
ford the desired pyrazoles in yields of 67–91%.
proved to be a highly effective and safe alternative to han-
dling aryldiazomethanes,11 and has been employed in the
Key words: pyrazoles, heterocycles, condensation, cycloaddition,
aldehydes
sulfur ylide mediated synthesis of epoxides from carbonyl
compounds, aziridination of imines, cyclopropanation of
alkenes, homologation of aldehydes and Wittig reac-
tions.12 Furthermore, Shi et al. have described the synthe-
sis of indazole compounds using a similar procedure.13
Although this system has proved to be very useful, only a
few substrates have been studied, and the typically low
yields and long reaction times are drawbacks. In order to
improve this method, we undertook an investigation of the
reaction conditions. Herein, we report a general and high-
ly effective, one-pot, three-component procedure for the
preparation of 3,5-disubstituted 1H-pyrazoles by conden-
sation of various aldehydes, tosylhydrazine and terminal
alkynes.
Pyrazoles and their derivatives represent a large class of
nitrogen-containing five-membered heterocycles, many
of which possess biological and pharmaceutical activity.1
Numerous examples of these compounds are used as syn-
thetic building blocks and ligands in organic chemistry.2
As a result, researchers have paid increasing attention to-
ward the synthesis of pyrazoles.
A number of methods have been developed for the prepa-
ration of pyrazoles and their derivatives.3 Among these,
the most practical method involves the reaction of hydra-
zines with 1,3-difunctional ketones or their derivatives,4
this being due to the ready availability of 1,3-diketones.4e
However, this particular condensation reaction also leads
to the formation of undesired isomers as major products.5
In order to obtain 3,5-disubstituted pyrazoles, various
chalcones were employed as the starting materials in reac-
tions with hydrazine hydrate in the presence of sulfur,6
and the expected products were obtained in high yields.
However, due to their structural limitations, chalcones
cannot be used widely in this process. Another common
route to synthesize pyrazoles is via 1,3-dipolar cycloaddi-
tions of diazo compounds or nitrile imines onto triple
bonds.7 Diazo compounds are remarkably versatile build-
ing blocks in organic synthesis,8 but they are known to be
toxic and potentially explosive. Cycloadditions of nitrile
imines and alkyne derivatives usually afford mixtures of
4- and 5-substituted pyrazoles.9
This reaction is actually a two-step reaction: initial con-
densation of tosylhydrazine with the aldehyde affords a
tosylhydrazone which on treatment with an alkyne yields
the pyrazole product. As tosylhydrazones can be readily
prepared by reaction of tosylhydrazine with the appropri-
ate aldehyde or ketone,14 initial examinations were carried
out with benzylidene tosylhydrazone (2a) and phenylacet-
ylene (3a) as model substrates in order to optimize the re-
action conditions. The results are summarized in Table 1.
We screened a variety of solvents including dimethyl sulf-
oxide, N,N-dimethylformamide, 1,4-dioxane, n-butanol
and toluene (Table 1, entries 1–5). Toluene was found to
offer the highest yield (Table 1, entry 5) of product. Next,
we examined the influence of base on the synthesis of pyr-
azoles. Of those studied (Table 1, entries 5–11), inexpen-
sive sodium ethoxide (NaOEt) was found to be the most
appropriate affording a 70% isolated yield of 3,5-diphe-
nyl-1H-pyrazole (4aa) (Table 1, entry 11). Further studies
indicated that the optimum ratio of substrates (2a:3a:base)
was 1:3:2.5 (Table 1, entry 12). Finally, the reaction tem-
perature and time were investigated as the probability of
side reactions can increase with long reaction times at
high temperature (Table 1, entries 12–17). The highest
yield of pyrazole 4aa (85%) was obtained after reaction
for 12 hours at a temperature of 90 °C (Table 1, entry 16),
The construction of 3,5-disubstituted pyrazoles using
cheap, safe and readily available organic reagents in one-
pot would represent a more simple and efficient method.
In 2003, Aggarwal et al. reported a new procedure for
SYNTHESIS 2012, 44, 1577–1583
Advanced online publication: 19.04.2012
DOI: 10.1055/s-0031-1290772; Art ID: SS-2012-H1123-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1578
L.-L. Wu et al.
PAPER
Table 1 Optimization of the Reaction Conditions for the Synthesis 3,5-Diphenyl-1H-pyrazole (4aa)a
N
NH
base, solvent
temp, time
NHTs
+
Ph
Ph
N
Ph
Ph
2a
3a
4aa
Yield (%)c
Entry
Solvent
Base
Temp (°C)
Time (h)
1
2
DMSO
DMF
KOH
KOH
KOH
KOH
KOH
110
110
110
110
110
110
110
110
110
110
110
110
90
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
9
4
32
54
15
67
22
42
37
65
31
70
75
83
81
65
85
81
3
1,4-dioxane
n-BuOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
4
5
6
KOt-Bu
K3PO4
K2CO3
Cs2CO3
NaOMe
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
7
8
9
10
11
12b
13b
14b
15b
16b
17b
70
50
90
90
a Reaction conditions: benzylidene tosylhydrazone 2a (0.5 mmol, 1 equiv), phenylacetylene (3a) (2 equiv), base (3 equiv), solvent (5 mL).
b Reaction conditions: benzylidene tosylhydrazone 2a (0.5 mmol, 1 equiv), phenylacetylene (3a) (3 equiv), NaOEt (2.5 equiv), toluene (5 mL).
c Yield of isolated product determined from an average of two runs.
and the reaction showed excellent regioselectivity for the tions. In comparison with the previously described
3,5-disubstituted pyrazoles.
method,10 this system showed much higher activity (Table
2, entries 1, 10 and 13). In particular, a significantly in-
creased 91% yield of pyrazole 4ma (Table 2, entry 13)
was obtained compared to the earlier reported yield of
51%.10
Next, we investigated the scope of this one-pot, three-
component protocol. A range of aromatic aldehydes 1 was
reacted with phenylacetylene (3a) and tosylhydrazine (5)
under the optimized reaction conditions. As shown in
Table 2, the corresponding 3,5-disubstituted pyrazoles Encouraged by the biological and pharmaceutical activi-
4aa–qa were obtained in yields of up to 91%.
ties demonstrated by 3,5-disubstituted pyrazoles15 and the
generality of this reaction system, the cycloadditions of
various aromatic aldehydes 1 and terminal alkynes 3 were
studied. Gratifyingly, the expected pyrazoles were ob-
tained in yields ranging from 67–89% (Table 3, entries 1–
9) using this one-pot strategy. To the best of our knowl-
edge, this is the first time that these particular terminal al-
kynes have been applied to synthesize pyrazoles.
Terminal alkynes possessing bulky naphthyl groups react-
ed with ortho-substituted (Table 3, entries 6 and 7) and di-
substituted aromatic aldehydes (Table 3, entries 8 and 9)
to give the desired products in high yields. These results
showed that steric hindrance did not affect the cycloaddi-
tion reaction.
From the results in Table 2, several important points
should be noted. Aldehydes containing electron-donating
groups had no adverse effects on the activity of the reac-
tion (Table 2, entries 11–15). In addition, high yields of
products were obtained when aldehydes containing elec-
tron-withdrawing groups were used (Table 2, entries 8–
10). The expected pyrazoles were also obtained in accept-
able yields when using ortho-substituted (Table 2, entries
4, 7 and 15) and disubstituted aromatic aldehydes (Table
2, entries 16 and 17), indicating that steric hindrance was
not detrimental to the reactivity. Products 4ba–ga (Table
2, entries 2–7) contain halide substituents which may un-
dergo further transformation via Suzuki or Heck reac-
Synthesis 2012, 44, 1577–1583
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazoles
1579
Infrared spectra were recorded on a Perkin-Elmer Spectrum One
FT-IR spectrometer using an ATR sample accessory unless other-
Table 2 One-Pot Synthesis of 3,5-Disubstituted Pyrazoles via the
Reaction of Aldehydes 1, Tosylhydrazine (5) and Phenylacetylene
(3a)a
1
wise specified. H (400 MHz) and 13C (100 MHz) NMR spectra
were recorded on a Bruker Avance 400 MHz spectrometer. Chemi-
cal shifts (δH) are quoted in parts per million (ppm) and referenced
to TMS. The following abbreviations were used to describe splitting
patterns: s = singlet, d = doublet, t = triplet, q = quartet (or variations
thereof). Coupling constants (J) are given in Hz. High-resolution
mass spectra were recorded on a Waters Q-TOF Premier instrument
using the ESI method. Mass spectra were obtained using a Thermo
Finnigan Polaris-Q GC–MS instrument (Shimazu, Kyoto, Japan).
The spectral data of known compounds: 4aa,10 4ba,16 4ca,17 4da,18
4ea,18 4fa,16 4ha,18 4ja,10 4ka,16 4la,6 4ma,10 4na,15b 4oa,19 4pa,17
4qa,20 4ac21 and 4ad22 were consistent with those reported in the lit-
erature.
i) TsNHNH2 5, toluene
O
NH
N
iii)
PhC CH
3a
50 °C, 1.5 h
R1
R1
H
Ph
ii) NaOEt, r.t., 15 min
90 °C, 12 h
1
4
Aldehyde R1
Yield (%)b
Entry
Product
77 (61)c
73
1
2
1a
1b
1c
1d
1e
1f
Ph
4aa
4ba
4ca
4da
4ea
4fa
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-FC6H4
3-FC6H4
4-NCC6H4
4-MeC6H4
3-MeC6H4
3
74
N′-Benzylidene-4-methylbenzenesulfonohydrazide (2a)
Benzaldehyde (1a) (1.22 mL, 12 mmol) was slowly added dropwise
to a soln of tosylhydrazine (5) (2.49 g, 13.4 mmol) in MeOH (10
mL) at 40 °C. The resulting mixture was stirred for 2 h. Following
completion of the reaction, the mixture was cooled in an ice–H2O
bath which led to precipitation of the product as a white solid. The
solid was isolated by filtration and purified by recrystallization from
MeOH.
4
86
5
74
6
75
7
1g
1h
1i
4ga
4ha
4ia
82
8
77
3,5-Disubstituted Pyrazoles 4aa–qc; General Procedure
Aldehyde 1 (0.5 mmol) and tosylhydrazine (5) (93 mg, 0.5 mmol)
were added to a Schlenk tube equipped with a stir bar. Toluene (3
mL) was added and the mixture was stirred at r.t. for 5 min and then
at 50 °C for 1.5 h. After cooling to r.t., NaOEt (85 mg, 2.5 mmol)
was added and the resulting mixture stirred for a further 15 min at
r.t. A soln of the terminal alkyne 3 (3 mmol) and toluene (2 mL) was
added, and the Schlenk tube sealed and heated in an oil bath at 90
°C with vigorous stirring for 12 h. Following completion of the
reaction, H2O (5 mL) was added and the aq layer extracted with
EtOAc (3 × 5 mL). The combined organic layer was dried over
MgSO4, filtered and the solvent evaporated under reduced pressure.
The crude residue was purified by column chromatography on silica
gel (20% EtOAc in PE).
9
82
81 (67)c
84
10
11
12
13
14
15
16
17
1j
4ja
1k
1l
4ka
4la
84
91 (51)c
85
1m
1n
1o
1p
1q
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2,4-Cl2C6H3
3,4-Cl2C6H3
4ma
4na
4oa
4pa
4qa
81
81
3,5-Diphenyl-1H-pyrazole (4aa)10
Yield: 85.0 mg (77%); white solid; mp 168–174 °C.
81
IR (KBr): 3097, 3003, 2858, 1946, 1742, 1461, 1272, 1075, 971,
871, 753, 688 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.0 Hz, 4 H), 7.38 (t,
J = 8.0 Hz, 4 H), 7.30 (t, J = 8.0 Hz, 2 H), 6.80 (s, 1 H).
a Reaction conditions: aldehyde 1 (0.5 mmol, 1 equiv), tosylhydrazine
(5) (1 equiv), phenylacetylene (3a) (3 equiv), NaOEt (2.5 equiv), tol-
uene (5 mL), 90 °C, 12 h.
b Yield of isolated product determined from an average of two runs.
c Literature yield.10
13C NMR (100 MHz, DMSO-d6): δ = 149.65, 134.74, 128.78,
127.74, 125.07, 99.58.
MS (EI, 70 eV): m/z (%) = 220 (100) [M]+.
In summary, we have reported a simple and efficient pro-
cedure for the regioselective preparation of 3,5-disubsti-
tuted 1H-pyrazoles via a one-pot, three-component
reaction of an aromatic aldehyde, tosylhydrazine and a
terminal alkyne. The protocol was applied to a wide range
of substrates and demonstrated excellent tolerance to a va-
riety of substituents, including both electron-donating and
electron-withdrawing examples. In addition, sterically
hindered substrates underwent the cycloaddition reaction
efficiently.
3-(4-Chlorophenyl)-5-phenyl-1H-pyrazole (4ba)16
Yield: 93.0 mg (73%); white solid; mp 215–216 °C.
IR (KBr): 3143, 3064, 3010, 2869, 1878, 1490, 1457, 970, 825, 759
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.69 (t, J = 8.0 Hz, 4 H), 7.44 (t,
J = 8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 3 H), 6.83 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 151.24, 150.76, 144.02,
133.05, 131.13, 129.24, 128.64, 127.26, 125.59, 124.40, 100.35.
MS (EI, 70 eV): m/z (%) = 254 (100) [M]+.
3-(3-Chlorophenyl)-5-phenyl-1H-pyrazole (4ca)17
Solvents were dried by standard methods when necessary. Petro-
leum ether (PE) refers to the fraction boiling in the 60–90 °C range.
Commercially obtained reagents were used without further purifica-
tion. Reactions were monitored by TLC with HSGF 254 (10–40
μm) silica gel coated plates. Flash column chromatography was car-
ried out using 300–400 mesh silica gel under positive pressure.
Melting points were obtained using a Khöfler hot-stage apparatus.
Yield: 94.5 mg (74%); white solid; mp 158–162 °C.
IR (KBr): 3142, 3104, 3064, 2875, 1598, 1570, 1461, 979, 872, 757,
681 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.68 (t, J = 8.0 Hz,
3 H), 7.46 (t, J = 8.0 Hz, 2 H), 7.44–7.31 (m, 3 H), 6.86 (s, 1 H).
© Georg Thieme Verlag Stuttgart · New York
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Table 3 One-Pot Synthesis of 3,5-Disubstituted Pyrazoles via the Reaction of Substituted Aldehydes 1, Tosylhydrazine (5) and Terminal
Alkynes 3a
i) TsNHNH2 5, toluene
50 °C, 1.5 h
N
NH
O
2
iii)
R C CH
3
R1
R1
H
R2
ii) NaOEt, r.t., 15 min
90 °C, 12 h
1
4
Yield (%)b
71
Entry Aldehyde
Alkyne
Product
1
1a
3b
4ab
N
NH
CHO
N
N
N
N
NH
NH
NH
NH
2
3
4
5
6
1a
1a
1a
1a
1d
3c
3d
3e
3f
4ac
4ad
4ae
4af
4dc
80
76
89
67
81
CHO
CHO
CHO
CHO
OH
HO
F
F
Cl
Br
Cl
Br
N
N
NH
3c
CHO
NH
N
7
8
9
1g
1p
1q
3c
3c
3c
4gc
4pc
4qc
88
86
85
CHO
Cl
Cl
NH
NH
Cl
Cl
CHO
Cl
Cl
N
Cl
CHO
Cl
a Reaction conditions: aldehyde 1 (0.5 mmol, 1 equiv), tosylhydrazine (5) (1 equiv), terminal alkyne 3 (3 equiv), NaOEt (2.5 equiv), toluene (5
mL), 90 °C, 12 h.
b Yield of isolated product determined from an average of two runs.
13C NMR (100 MHz, DMSO-d6): δ = 140.77, 134.11, 131.18,
129.36, 128.45, 127.91, 127.10, 125.58, 125.14, 124.11, 112.49,
100.70, 99.97.
13C NMR (100 MHz, DMSO-d6): δ = 146.23, 145.41, 131.87,
131.07, 130.42, 130.25, 129.14, 128.84, 127.86, 127.32, 126.42,
125.15, 103.16.
MS (EI, 70 eV): m/z (%) = 254 (100) [M]+.
MS (EI, 70 eV): m/z (%) = 254 (100) [M]+.
3-(2-Chlorophenyl)-5-phenyl-1H-pyrazole (4da)18
Yield: 109.5 mg (86%); white solid; mp 112–115 °C.
3-(4-Bromophenyl)-5-phenyl-1H-pyrazole (4ea)18
Yield: 110.7 mg (74%); white solid; mp 211–216 °C.
IR (KBr): 3207, 3032, 2926, 1926, 1567, 1460, 1186, 971, 807, 751,
687 cm–1.
IR (KBr): 3220, 3101, 3062, 2870, 1878, 1486, 1454, 1070, 967,
798, 761, 681 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 2 H), 7.69 (dd,
J = 4.0, 2.0 Hz, 1 H), 7.50–7.43 (m, 3 H), 7.38–7.33 (m, 3 H), 6.98
(s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.66 (dd, J = 12.0, 8.0 Hz, 4 H),
7.55 (d, J = 8.0 Hz, 2 H), 7.45 (t, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0
Hz, 1 H), 6.83 (s, 1 H).
Synthesis 2012, 44, 1577–1583
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One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazoles
1581
13C NMR (100 MHz, DMSO-d6): δ = 147.76, 143.87, 133.21,
132.19, 129.35, 128.43, 127.55, 125.58, 123.43, 121.20, 100.37.
MS (EI, 70 eV): m/z (%) = 298 (100) [M]+.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.0 Hz, 2 H), 7.72 (d,
J = 8.0 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.61 (s, 1 H), 7.475 (t,
J = 6.0 Hz, 2 H), 6.92 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 147.97, 142.30, 133.35,
133.02, 131.11, 128.84, 127.23, 125.10, 124.06, 119.25, 109.27,
102.03.
3-(3-Bromophenyl)-5-phenyl-1H-pyrazole (4fa)16
Yield: 112.4 mg (75%); white solid; mp 171–172 °C.
1H NMR (400 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.70 (t, J = 8.0 Hz,
3 H), 7.49–7.44 (m, 3 H), 7.40–7.31 (m, 1 H), 7.29–7.26 (m, 1 H),
6.88 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 150.22, 144.09, 142.03,
136.47, 131.40, 130.57, 129.47, 128.68, 128.00, 125.58, 124.49,
122.68, 100.60.
MS (EI, 70 eV): m/z (%) = 245 (100) [M]+.
5-Phenyl-3-p-tolyl-1H-pyrazole (4ka)16
Yield: 98.4 mg (84%); white solid; mp 112–117 °C.
IR (KBr): 3214, 3133, 3012, 2912, 2861, 1913, 1508, 1457, 1361,
1323, 1165, 1048, 946, 815, 757 cm–1.
IR (KBr): 3220, 3102, 3066, 2874, 1740, 1565, 1456, 1178, 1066,
976, 785, 760, 682 cm–1.
MS (EI, 70 eV): m/z (%) = 298 (100) [M]+.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.0 Hz, 2 H), 7.61 (d,
J = 8.0 Hz, 2 H), 7.42 (t, J = 8.0 Hz, 2 H), 7.355 (t, J = 2.0 Hz, 1 H),
7.23 (d, J = 8.0 Hz, 2 H), 6.84 (s, 1 H), 2.38 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 147.57, 143.86, 140.36,
136.64, 131.44, 130.09, 129.83, 129.25, 127.69, 127.19, 125.54,
99.73, 21.44.
3-(2-Bromophenyl)-5-phenyl-1H-pyrazole (4ga)
Yield: 123.0 mg (82%); light-yellow solid; mp 106–108 °C.
MS (EI, 70 eV): m/z (%) = 234 (100) [M]+.
IR (KBr): 3206, 3031, 2927, 1948, 1565, 1458, 1189, 1075, 968,
807, 750, 684 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.0 Hz, 2 H), 7.69 (dd,
J = 8.0, 2.0 Hz, 1 H), 7.62 (dd, J = 8.0, 2.0 Hz, 1 H), 7.45 (t, J = 8.0
Hz, 2 H), 7.41–7.36 (m, 2 H), 7.23 (dd, J = 8.0, 2.0 Hz, 1 H), 6.94
(s, 1 H).
5-Phenyl-3-m-tolyl-1H-pyrazole (4la)6
Yield: 98.4 mg (84%); yellow solid; mp 120–124 °C.
IR (KBr): 3220, 3032, 2918, 1956, 1609, 1566, 1459, 1163, 1072,
961, 788, 762, 690 cm–1.
13C NMR (100 MHz, DMSO-d6): δ = 145.97, 143.54, 133.40,
132.46, 131.04, 129.74, 128.85, 127.98, 127.79, 126.02, 125.14,
121.33, 103.07.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz, 2 H), 7.65 (d,
J = 8.0 Hz, 1 H), 7.44–7.31 (m, 4 H), 7.355 (t, J = 2.0 Hz, 1 H), 7.28
(d, J = 8.0 Hz, 1 H), 6.81 (s, 1 H), 2.42 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 298 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H12BrN2: 299.0184; found:
13C NMR (100 MHz, DMSO-d6): δ = 162.02, 151.85, 143.88,
138.51, 134.05, 132.52, 130.43, 129.20, 127.92, 126.17, 125.55,
122.75, 100.05, 21.58.
299.0190.
MS (EI, 70 eV): m/z (%) = 234 (100) [M]+.
3-(4-Fluorophenyl)-5-phenyl-1H-pyrazole (4ha)18
Yield: 91.8 mg (77%); white solid; mp 163–166 °C.
3-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole (4ma)10
Yield: 114.0 mg (91%); yellow solid; mp 102–106 °C.
IR (KBr): 3145, 3066, 3011, 2868, 1871, 1531, 1494, 1460, 1223,
974, 828, 756, 683 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.18 (br s, 1 H), 7.65–7.61 (m, 4
H), 7.36–7.29 (m, 3 H), 7.01 (t, J = 8.0 Hz, 2 H), 6.72 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.23 (d, J = 243 Hz),
150.23, 147.47, 129.32, 128.40, 127.61, 127.53, 126.43, 125.56,
116.14 (d, J = 20 Hz), 100.07.
IR (KBr): 3221, 3014, 2924, 2857, 1611, 1517, 1461, 1257, 1161,
1037, 953, 830, 764, 666 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 8.0 Hz, 1 H), 7.75–
7.71 (m, 3 H), 7.67–7.65 (m, 2 H), 7.515 (t, J = 6.0 Hz, 2 H), 7.45–
7.42 (m, 1 H), 6.78 (s, 1 H), 3.86 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 160.75, 147.01, 143.31,
136.18, 129.57, 128.72, 128.33, 127.21, 126.43, 126.25, 125.04,
114.22, 98.83, 55.23.
MS (EI, 70 eV): m/z (%) = 238 (100) [M]+.
MS (EI, 70 eV): m/z (%) = 250 (100) [M]+.
3-(3-Fluorophenyl)-5-phenyl-1H-pyrazole (4ia)
Yield: 97.7 mg (82%); white solid; mp 171–173 °C.
3-(3-Methoxyphenyl)-5-phenyl-1H-pyrazole (4na)15b
Yield: 106.5 mg (85%); white solid; mp 134–138 °C.
IR (KBr): 3147, 3066, 3023, 2871, 1939, 1615, 1592, 1473, 1170,
858, 758, 682 cm–1.
IR (KBr): 3151, 3112, 2995, 2864, 1615, 1576, 1494, 1461, 1295,
1238, 1168, 1055, 987, 887, 756 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.0 Hz, 2 H), 7.375 (t,
J = 14.0 Hz, 2 H), 7.33–7.23 (m, 5 H), 6.82 (s, 1 H), 3.84 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 160.13, 151.72, 143.79,
134.15, 130.53, 129.32, 128.56. 127.97, 125.57, 117.98, 114.15,
113.61, 110.96, 100.34, 55.59.
1H NMR (400 MHz, CDCl3): δ = 8.73 (br s, 1 H), 7.67 (d, J = 8.0
Hz, 2 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.45–7.31 (m, 5 H), 7.01 (td,
J = 8.0, 1.0 Hz, 1 H), 6.82 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.08 (d, J = 241 Hz),
150.39, 143.97, 135.46, 131.21, 129.41, 128.65, 127.47, 125.58,
121.61, 114.65 (d, J = 20 Hz), 112.11 (d, J = 22 Hz), 100.67.
MS (EI, 70 eV): m/z (%) = 238 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H12FN2: 239.0985; found:
MS (EI, 70 eV): m/z (%) = 250 (100) [M]+.
239.0992.
3-(2-Methoxyphenyl)-5-phenyl-1H-pyrazole (4oa)19
Yield: 101.5 mg (81%); light-yellow solid; mp 84 °C.
4-(5-Phenyl-1H-3-pyrazolyl)benzonitrile (4ja)10
Yield: 99.5 mg (81%); light-yellow solid; mp 250–252 °C.
IR (KBr): 3263, 3011, 2976, 2842, 1603, 1486, 1455, 1255, 1165,
969, 813, 748, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz, 2 H), 7.68 (dd,
J = 8.0, 1.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 2 H), 7.29–7.24 (m, 2 H),
7.03–6.97 (m, 2 H), 6.88 (s, 1 H), 3.94 (s, 3 H).
IR (KBr): 3262, 3130, 3064, 2866, 2226, 1610, 1495, 1458, 1106,
970, 839, 758, 682 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1577–1583

1582
L.-L. Wu et al.
PAPER
13C NMR (100 MHz, DMSO-d6): δ = 159.95, 155.83, 147.21,
129.22, 128.67, 127.62, 127.39, 125.03, 120.61, 115.92, 111.85,
101.81, 99.49, 55.43.
13C NMR (100 MHz, DMSO-d6): δ = 133.14, 132.48, 128.84,
127.93, 127.66, 125.11, 123.64, 123.43, 100.00, 56.03, 18.54.
MS (EI, 70 eV): m/z (%) = 216 (100) [M]+.
MS (EI, 70 eV): m/z (%) = 250 (100) [M]+.
5-(3-Fluorophenyl)-3-phenyl-1H-pyrazole (4ae)
Yield: 106 mg (89%); white solid; mp 190–192 °C.
3-(2,4-Dichlorophenyl)-5-phenyl-1H-pyrazole (4pa)17
Yield: 117.4 mg (81%); white solid; mp 169–172 °C.
IR (KBr): 3147, 3066, 3023, 2871, 1939, 1615, 1473, 1170, 1069,
858, 759, 682 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 2 H), 7.49 (d,
J = 8.0 Hz, 1 H), 7.375 (dd, J = 12.0, 4.0 Hz, 3 H), 7.33–7.30 (m, 2
H), 6.98 (dd, J = 8.0, 6.0 Hz, 1 H), 6.79 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.58 (d, J = 241 Hz),
150.35, 147.32, 131.79, 130.79, 128.86, 127.18, 125.08, 124.15,
121.12, 114.30 (d, J = 24 Hz), 111.62 (d, J = 23 Hz), 100.18.
IR (KBr): 3211, 3045, 1592, 1552, 1474, 1368, 1103, 1041, 971,
806, 759, 682 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.0 Hz, 2 H), 7.67 (d,
J = 8.0 Hz, 1 H), 7.51 (s, 1 H), 7.465 (t, J = 6.0 Hz, 2 H), 7.40–7.37
(m, 1 H), 7.325 (dd, J = 8.0, 4.0 Hz, 1 H), 6.98 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 148.41, 143.28, 133.16,
132.33, 132.01, 131.86, 130.08, 129.52, 129.14, 128.76, 128.21,
127.97, 125.67, 103.62.
MS (EI, 70 eV): m/z (%) = 238 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H12FN2: 239.0985; found:
MS (EI, 70 eV): m/z (%) = 288 (100) [M]+.
239.0989.
3-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrazole (4qa)20
Yield: 117.3 mg (81%); white solid; mp 210–214 °C.
5-(Cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole (4af)
Yield: 75.3 mg (67%); light-yellow solid; mp 168–171 °C.
IR (KBr): 3238, 3041, 1572, 1476, 1439, 1176, 1062, 975, 882, 799,
764, 683 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.905 (d, J = 2.0 Hz, 1 H), 7.67–
7.64 (m, 3 H), 7.50–7.45 (m, 3 H), 7.44 (d, J = 8.0 Hz, 1 H), 6.84 (s,
1 H).
13C NMR (100 MHz, DMSO-d6): δ = 149.23, 148.85, 131.60,
130.97, 129.71, 128.92, 128.19, 126.62, 125.09, 123.96, 122.52,
100.43.
IR (KBr): 3132, 3094, 3065, 2931, 2858, 1651, 1460, 1270, 1173,
964, 759, 689 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.68–7.66 (m, 2 H), 7.33 (t, J = 8.0
Hz, 2 H), 7.25 (dd, J = 10.0, 4.0 Hz, 1 H), 6.48 (s, 1 H), 6.21–6.19
(m, 1 H), 2.36–2.33 (m, 2 H), 2.13–2.17 (m, 2 H), 1.75–1.69 (m, 2
H), 1.64–1.58 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 146.42, 129.27, 129.11,
127.87, 125.55, 125.44, 124.24, 124.21, 98.70, 26.06, 25.23, 22.51,
22.20.
MS (EI, 70 eV): m/z (%) = 288 (100) [M]+.
5-(Naphthalen-1-yl)-3-phenyl-1H-pyrazole (4ab)
Yield: 96.0 mg (71%); white solid; mp 152–154 °C.
MS (EI, 70 eV): m/z (%) = 224 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H17N2: 225.1392; found:
IR (KBr): 3228, 3047, 1560, 1457, 1173, 1072, 963, 790, 763, 687
cm–1.
225.1397.
1H NMR (400 MHz, CDCl3): δ = 8.29–8.26 (m, 1 H), 7.92 (t, J = 6.0
Hz, 2 H), 7.845 (d, J = 4.0 Hz, 2 H), 7.635 (d, J = 4.0 Hz, 1 H), 7.44–
7.54 (m, 5 H), 7.38 (d, J = 8.0 Hz, 1 H), 6.89 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 146.55, 142.25, 138.82,
133.49, 130.57, 128.81, 128.32, 127.79, 127.63, 126.87, 126.59,
125.99, 125.46, 125.23, 125.11, 117.76, 103.24.
3-(2-Chlorophenyl)-5-(naphthalen-2-yl)-1H-pyrazole (4dc)
Yield: 123.5 mg (81%); white solid; mp 173–175 °C.
IR (KBr): 3224, 3056, 2926, 1630, 1462, 1182, 980, 800, 747, 649
cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.96–7.89 (m, 3 H),
7.86–7.84 (m, 1 H), 7.71 (dd, J = 8.0, 1.0 Hz, 1 H), 7.495 (dd, J =
8.0, 4.0 Hz, 3 H), 7.37–7.31 (m, 2 H), 7.11 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 270 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H15N2: 271.1235; found:
271.1242.
13C NMR (100 MHz, DMSO-d6): δ = 150.09, 141.37, 133.32,
133.07, 132.86, 131.40, 130.92, 130.31, 128.89, 128.71, 128.50,
128.14, 128.10, 127.87, 126.89, 126.46, 124.12, 106.16, 104.06.
MS (EI, 70 eV): m/z (%) = 304 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H14ClN2: 305.0846; found:
5-(Naphthalen-2-yl)-3-phenyl-1H-pyrazole (4ac)21
Yield: 108.3 mg (80%); white solid; mp 200–202 °C.
IR (KBr): 3227, 3057, 2945, 2920, 1564, 1461, 1072, 960, 799, 764,
691 cm–1.
305.0812.
1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1 H), 7.93–7.85 (m, 4 H),
7.77 (d, J = 8.0 Hz, 2 H), 7.53–7.45 (m, 4 H), 7.38 (t, J = 8.0 Hz, 1
H), 7.00 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 138.41, 134.51, 130.00,
129.49, 129.13, 128.59, 128.21, 127.17, 126.32, 125.55, 124.90,
123.81, 122.34, 102.78, 99.50, 98.24.
3-(2-Bromophenyl)-5-(naphthalen-2-yl)-1H-pyrazole (4gc)
Yield: 153.7 mg (88%); white solid; mp 161–165 °C.
IR (KBr): 3220, 3053, 1629, 1460, 1183, 1049, 979, 799, 746, 711
cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.26 (s, 1 H), 7.935 (t, J = 14.0 Hz,
3 H), 7.87–7.85 (m, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0
Hz, 1 H), 7.53–7.50 (m, 2 H), 7.385 (t, J = 6.0 Hz, 1 H), 7.23 (d, J =
8.0 Hz, 1 H), 7.08 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 149.99, 143.08, 133.93,
133.69, 133.39, 133.00, 131.56, 130.96, 128.70, 128.50, 128.32,
128.14, 127.05, 126.89, 126.59, 126.45, 124.05, 123.89, 105.97,
103.95.
MS (EI, 70 eV): m/z (%) = 270 (100) [M]+.
2-Methyl-1-(3-phenyl-1H-5-pyrazolyl)propan-2-ol (4ad)22
Yield: 82.3 mg (76%); white solid; mp 157–158 °C.
IR (KBr): 3217, 3138, 2979, 2932, 1554, 1458, 1397, 1267, 1156,
953, 818, 772, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 2 H), 7.40 (t,
J = 8.0 Hz, 2 H), 7.325 (t, J = 6.0 Hz, 1 H), 6.41 (s, 1 H), 3.71 (s, 1
H), 2.05 (s, 2 H), 1.64 (s, 6 H).
MS (EI, 70 eV): m/z (%) = 348 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H14BrN2: 349.0340; found:
349.0344.
Synthesis 2012, 44, 1577–1583
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazoles
1583
3-(3,4-Dichlorophenyl)-5-(naphthalen-2-yl)-1H-pyrazole (4qc)
Berretta, S.; Crescentini, L. D.; Favi, G.; Filippone, P.;
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Fuentes, A. Chem. Rev. 2011, 111, 6984.
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8, 286. (c) Armstrong, A.; Jones, L. H.; Knight, J. D.;
Kelsey, R. D. Org. Lett. 2005, 7, 713. (d) Wang, Z. X.; Qin,
H. L. Green Chem. 2004, 6, 90. (e) Kost, A. N.; Grandberg,
I. I. Advances in Heterocyclic Chemistry Progress in
Pyrazole Chemistry, In Vol. 6; Katritzky, A. R.; Boulton, A.
J., Eds.; Academic Press: London, 1966, 347.
(5) (a) Katritzky, A. R.; Wang, M. Y.; Zhang, S. M.; Vonkov,
A.; Steel, P. J. J. Org. Chem. 2001, 66, 6787. (b) Luo, Y.;
Potvin, P. G. J. Org. Chem. 1994, 59, 1761. (c) Murray, W.;
Wachter, M.; Barton, D.; Forerokelly, Y. Synthesis 1991, 18.
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Vol. 2; Padwa, A., Ed.; John Wiley & Sons: New York,
1984, 83.
Yield: 146.0 mg (85%); white solid; mp 210–212 °C.
IR (KBr): 3244, 3049, 2928, 1580, 1441, 1369, 1173, 973, 877, 783,
681 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.95 (t, J = 14.0 Hz,
4 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.49–7.54
(m, 3 H), 6.97 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 148.42, 143.87, 134.87,
133.53, 133.03, 132.16, 132.13, 131.52, 130.35, 129.09, 128.42,
128.19, 127.17, 126.91, 126.87, 125.61, 124.47, 124.04, 101.28.
MS (EI, 70 eV): m/z (%) = 338 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H13Cl2N2: 339.0456;
found: 339.0455.
3-(2,4-Dichlorophenyl)-5-(naphthalen-2-yl)-1H-pyrazole (4pc)
Yield: 144.5 mg (86%); white solid; mp 172–177 °C.
IR (KBr): 3210, 3056, 1596, 1552, 1370, 1104, 961, 803, 737, 662
cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.23 (s, 1 H), 7.91–7.85 (m, 4 H),
7.65 (d, J = 8.0 Hz, 1 H), 7.53–7.48 (m, 3 H), 7.29 (dd, J = 8.0, 1.0
Hz, 1 H), 7.11 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 147.79, 134.40, 133.66,
133.60, 133.21, 133.03, 132.42, 132.02, 130.23, 130.19, 128.47,
128.15, 128.08, 127.12, 124.19, 124.04, 105.56, 104.15, 82.87.
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D.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. Green Chem.
2009, 11, 156.
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Bernardi, L.; Franchini, M. C. Eur. J. Org. Chem. 2010,
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438. (c) Abunada, N. M.; Hassaneen, H. M.; Kandile, N. G.;
Miqdad, O. A. Molecules 2008, 1501. (d) Bonini, B. F.;
Franchini, M. C.; Gentili, D.; Locatelli, E.; Ricci, A. Synlett
2009, 2328.
MS (EI, 70 eV): m/z (%) = 338 (100) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H13Cl2N2: 339.0456;
found: 339.0454.
Acknowledgment
(10) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. J. Org.
Chem. 2003, 68, 5381.
(11) Creary, X. Org. Synth. 1986, 64, 207.
We are grateful to the Analytical and Testing Center of Sichuan
University for providing support with the characterization of com-
pounds.
(12) (a) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.;
Palmer, M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem.
Int. Ed. 2001, 40, 1430. (b) Aggarwal, V. K.; Alonso, E.;
Fang, G. Y.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew.
Chem. Int. Ed. 2001, 40, 1433. (c) Aggarwal, V. K.; Fulton,
J. R.; Sheldon, C. G.; de Vicente, J. J. Am. Chem. Soc. 2003,
125, 6034. (d) Aggarwal, V. K.; de Vicente, J.; Bonnert, R.
V. Org. Lett. 2001, 3, 2785. (e) Velikorodov, A. V.;
Kovalev, V. B.; Krivosheev, O. O. Russ. J. Org. Chem.
2009, 45, 1208. (f) Aggarwal, V. K.; de Vicente, J.; Pelotier,
B.; Holmes, I. P.; Bonnert, R. V. Tetrahedron Lett. 2000, 41,
10327.
(13) Li, P.; Zhao, J.; Wu, C.; Larock, R. C.; Shi, F. Org. Lett.
2011, 13, 3340.
(14) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C.
Nat. Chem. 2009, 1, 494.
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2010, 131, 584. (b) Shaw, A. Y.; Liau, H.; Lu, P.; Yang, C.;
Lee, C.; Chen, J.; Xu, Z.; Flynn, G. Bioorg. Med. Chem.
2010, 18, 3270.
(16) Huang, X. Q.; Dou, J. M.; Li, D. C.; Wang, D. Q. J. Chil.
Chem. Soc. 2009, 54, 20.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinIfatgnonmSorti
i
npfurotIangSiuptor
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1577–1583