Selective synthesis of functionalized pyrazoles from 5-amino-1H-pyrazole-4-carbaldehydes with sodium nitrite: 5-Amino-4-nitrosopyrazoles and pyrazole-4-carbaldehydes

Article abstract of DOI:10.1016/j.tet.2019.06.048

A novel and efficient redox reaction was developed to react 5-amino-1H-pyrazole-4-carbaldehyde with sodium nitrite (NaNO₂) in an acidic solution (HCl/MeOH) to generate 5-amino-4-nitrosopyrazole, pyrazole-4-carbaldehyde, or diazenylpyrazole selectively. The results showed that 5-amino-4-nitrosopyrazoles were formed as the major product in the diluted acidic solution (≤2 N HCl in MeOH solution) through redox, formylation, and nitrosation reactions of NaNO₂. Intriguingly, pyrazole-4-carbaldehyde was the main product under 6 N HCl in MeOH solution.

Full text of DOI:10.1016/j.tet.2019.06.048

Accepted Manuscript
Selective synthesis of functionalized pyrazoles from 5-amino-1H-pyrazole-4-
carbaldehydes with sodium nitrite: 5-Amino-4-nitrosopyrazoles and pyrazole-4-
carbaldehydes
Rong-Hong Hsiao, Ching-Chun Tseng, Jia-Jun Xie, Shuo-En Tsai, Naoto Uramaru,
Ching-Ya Lin, Ching-Yuh Chern, Fung Fuh Wong
PII:
S0040-4020(19)30720-3
https://doi.org/10.1016/j.tet.2019.06.048
TET 30440
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 May 2019
Revised Date: 26 June 2019
Accepted Date: 28 June 2019
Please cite this article as: Hsiao R-H, Tseng C-C, Xie J-J, Tsai S-E, Uramaru N, Lin C-Y, Chern C-Y,
Wong FF, Selective synthesis of functionalized pyrazoles from 5-amino-1H-pyrazole-4-carbaldehydes
with sodium nitrite: 5-Amino-4-nitrosopyrazoles and pyrazole-4-carbaldehydes, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.06.048.
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ACCEPTED MANUSCRIPT
Seletive
Synthesis
of
Functionalized
with
Pyrazoles
Sodium
from
Nitrite:
5-Amino-1H-pyrazole-4-carbaldehydes
5-Amino-4-nitrosopyrazoles and Pyrazole-4-carbaldehydes
Rong-Hong Hsiao, Ching-Chun Tseng, Jia-Jun Xie, Shuo-En Tsai, Naoto Uramaru,
Ching-Ya Lin, Ching-Yuh Chern,* and Fung Fuh Wong*
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Selective Synthesis of Functionalized Pyrazoles from
5-Amino-1H-pyrazole-4-carbaldehydes with Sodium Nitrite:
5-Amino-4-nitrosopyrazoles and Pyrazole-4-carbaldehydes
Rong-Hong Hsiao,a Ching-Chun Tseng,b,c Jia-Jun Xie,d Shuo-En Tsai,b Naoto
Uramaru,e Ching-Ya Lin,f Ching-Yuh Chern,*,g and Fung Fuh Wong*,a,b
aSchool of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung,
40402, Taiwan
bThe Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University,
No. 91, Hsueh-Shih Rd., Taichung, 40402, Taiwan
cThe contribution equal to first author.
dMaster Program for Pharmaceutical Manufacture, China Medical University, No. 91,
Hsueh-Shih Rd., Taichung 40402, Taiwan
eDepartment of Environmental Science, Nihon Pharmaceutical University, 10281,
Komuro, Ina-machi, Kitaadachi-gun, Saitama, Japan
fDepartment of Biological Science and Technology, China Medical University, No. 91,
Hsueh-Shih Rd., Taichung 40402, Taiwan
gDepartment of Applied Chemistry, National Chiayi University, Chiayi City, 60004,
Taiwan
Key words: 5-Amino-1H-pyrazole-4-carbaldehydes, 5-amino-4-nitrosopyrazole,
pyrazole, pyrazole-4-carbaldehyde, nitrosation, sodium nitrite
ABSTRACT: A novel and efficient redox reaction was developed to react
5-amino-1H-pyrazole-4-carbaldehyde with sodium nitrite (NaNO2) in an acidic
solution
(HCl/MeOH)
to
generate
5-amino-4-nitrosopyrazole,
pyrazole-4-carbaldehyde, or diazenylpyrazole selectively. The results showed that
5-amino-4-nitrosopyrazoles were formed as the major product in the diluted acidic
solution (≤ 2 N HCl in MeOH solution) through redox, formylation, and nitrosation
reactions of NaNO2. Intriguingly, pyrazole-4-carbaldehyde was the main product
under 6 N HCl in MeOH solution.
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INTRODUCTION
The pyrazole system is a class of heterocyclic molecules, containing in some
anti-inflammatory drugs and anabolic steroids, which attract the attention in medicinal
and pharmaceutical fields.1-9 Therefore, development of efficient synthetic methods
for pharmaceutically active pyrazole derivatives is important for drug discovery. For
example, substituted 5-amino-4-nitrosopyrazoles, bearing nitroso group at the
pyrazolic ring, were designed
for the synthesis of 5-substituted
imidazo[4,5-c]pyrazoles as central nervous system (CNS) depressants10 or
pyrazolo[3,4,-b]pyrazine as various medical agents.11-13 Moreover, compounds
carrying azomethine functional group (–C=N–), which is known as Schiff base, have
gained importance in the medicinal and pharmaceutical fields.14 Many
pharmacologically active drugs are in fact derived from the pyrazole through
formation of Schiff base.15-16 Moreover, pyrazole-4-carbaldehydes were considered to
be one of the versatile intermediates or precursors for the construction of the central
structure of pyrazoles via Schiff base.17
Nitrosation chemistry18 is an important method in organic synthesis, including
nitroso aldol reactions,19 [4 + 2],20 [3 + 3],21 and [2 + 2] cycloadditions,22 and ene
reactions.23 Many organic and biological chemists have made significant efforts to
combine both the synthetic and mechanistic aspects of nitrosation or transnitrosation
in constructing novel pharmacological molecules.24-25 Recently, sodium nitrite
(NaNO2) in an acidic solution was found to act as an effective oxidant26 to oxidize
hydrocarbons to the corresponding alcohol,27 or acyclic and cyclic secondary alcohols
to ketones and dicarboxylic acids.28 Herein, we report a novel and efficient method to
synthesize 5-amino-4-nitrosopyrazole, pyrazole-4-carbaldehyde, and diazenylpyrazole
from 5-amino-1H-pyrazole-4-carbaldehyde in diffenent concentrations of acidic
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solution. In this reaction, we also discovered a new deformylation reaction for
5-amino-1H-pyrazole-4-carbaldehyde, which led to the formation of
5-amino-4-nitrosopyrazole and diazenylpyrazole.
RESULTS AND DISCUSSION
NaNO2 in acidic medium, such as acetic acid, methanesulfonic acid, acetic
anhydride, or trifluoroacetic acid etc., has been reported as an effective oxidizing
agent to generate the active species, including nitrosonium ion (NO+) and nitronium
+
ion (NO2 ).26,29 The oxidation rates were dependent on the reaction temperature,
concentration of the acidic substrate, and the presence of metal ion catalysts.30 To
investigate the reactivity of such reactions, we prepared
a
series of
5-amino-1H-pyrazole-4-carbaldehydes 1a–l as the starting materials based on the
reported method.31 5-Amino-1H-pyrazole-4-carbaldehyde 1a was served as the model
reactant, which was reacted with NaNO2 in the presence of various equivalent
concentrations (0.5 N, 1.0 N, 2.0 N, 3.0 N, and 6.0 N) of HCl in a THF/MeOH
solution. The new procedure was involved in the treatment of
5-amino-1H-pyrazole-4-carbaldehyde 1a with ~3.0 equivalent of NaNO2 at room
temperature in THF/MeOH solution containing different equivalent concentrations of
HCl aqueous solution. According to the results shown in Table 1, the
5-amino-4-nitrosopyrazole 2a could be formed as the major product with a trace
amount of pyrazole-4-carbaldehyde 3a or diazenylpyrazole 4a under the ≤ 2N acidic
condition once the redox reaction time was prolonged to more than 11 h (Entries 1–3,
Table 1). When the HCl concentration was increased to 3 N and 6 N, the
dediazonation product pyrazole-4-carbaldehyde 3a was obtained as the major product
(Entries 4–5, Table 1). In a further control experiment under 6 N HCl/THF/MeOH,
the reduction reaction was performed with bubbling H2 or N2 under atmospheric
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pressure. We found that both H2 and N2 were unbeneficial for the redox reaction
(Entries 6 and 7, Table1). Particularly, when the reaction time was prolonged to more
than 16 h, the reactant 1a was recovered in 41% under H2 atmospheric pressure (Entry
7, Table1). On the other hand, when the same reaction was carried out in the 9 N
HCl/MeOH, the reaction produced carbaldehyde 3a and diazenylpyrazole 4a with
27% and 36% yield, respectively, without detectable nitrosation product 2a (Entry 8,
Table 1).
Table 1. Nitrosation of 5-amino-1,3-diphenyl-1H-pyrazole-4-carbaldehyde 1a with
sodium nitrite (NaNO2) in different concentrations of HCl(aq) and various organic
acids.
R.T.
Entry
Acid medium
pH pKa
2a (%) 3a (%) 4a (%)
(h)
a
1
2
3
4
5
6
7
8
9
0.5 N HCl(aq)
1.0 N HCl(aq)
<1
<1
<1
<1
<1
<1
<1
<1
–8
–8
–8
–8
–8
–8
48
56
81
86
43
-
20
4
24
11
5
9
a
2.0 N HCl(aq)
12
52
88
52
12
27
52
-
a
3.0 N HCl(aq)
-
a
a
6.0 N HCl(aq)
3
-
-
6.0 N HCl(aq) bubble N2
6.0 N HCl(aq) bubble H2
9.0 N HCl(aq)
3
9
5
a
–8 >16
29
-
a
–8
2
3
-
36
9
Methanesulfonic acid/THF
–1.3 –1.9
–0.93 –1.9
8
Methanesulfonic
acid/THF/MeOH
10
3
14
69
8
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a
a
a
a
a
a
a
a
a
11
Trifluoroacetic acid/THF
0.30 0.30
17
17
17
17
17
17
-
-
-
-
-
-
-
18
17
12 Trifluoroacetic acid/THF/MeOH 0.84 0.30
-
a
13
14
15
16
Formic acid/THF
Formic acid/THF/MeOH
Acetic acid/THF
0.63 3.75
1.2 3.75
0.63 4.76
1.2 4.76
-
-
-
-
-
a
a
a
a
-
a
-
a
Acetic acid/THF/MeOH
-
aNon-detectable
To further investigate the effect of acidity, we studied the reactions under
various organic acids, including acetic acid, formic acid, methanesulfonic acid, and
trifluoroacetic acid in protic or aprotic solvents at room temperature (Entries 9–16,
Table 1). Several experimental observations are worthy discussions . Firstly, we found
that the relative nitrosation reaction, formylation, and dimerization did not occur
under weak organic acids such as formic acid (pKa = 3.75) and acetic acid (pKa =
4.76) (Entries 13–16, Table 1). Secondly, under the stronger trifluoroacetic acid (pKa
= 0.30), a low isolated yield (<18%) of dimer products was observed, which showed
that the nitrosation reaction and formylation were slightly initiated and the
dimerization was enhanced (Entries 11–12, Table 1). Unexpected, most of the
starting material 1a was recovered. Thirdly, when the strong methanesulfonic acid
(pKa = –0.19) was used, the 5-amino-1H-pyrazole-4-carbaldehyde 1a was found to be
completely consumed and converted to the corresponding products
5-amino-4-nitrosopyrazole 2a, pyrazole-4-carbaldehyde 3a, and diazenylpyrazole 4a
(Entries 9–10, Table 1). Moreover, pyrazole-4-carbaldehyde 3a was formed as the
major product (52% and 69%). We also found that the protic solvent system
(THF/MeOH) seemed to facilitate the formation of pyrazole-4-carbaldehyde 3a in the
methanesulfonic acid system (69%).
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The structures of all the products were fully characterized by spectroscopic
methods as described below. The diazenylpyrazole 4a shows a singlet peak at δ 10.20
1
ppm for its 4-formyl functional group (–CH=O) H NMR and at a peak at δ 186.14
13
ppm in C NMR spectrum. It also presented two characteristic absorptions peaks at
3279 cm–1 for the stretching of the NH2 group and at 1627 cm–1 for the stretching of
the –CH=O group in IR spectrum. As a result, we believe that diazenylpyrazole 4a is
generated
from
the
reaction
of
starting
material
5-amino-1H-pyrazole-4-carbaldehydes 1a with 5-amino-4-nitrosopyrazole product 2a.
Moreover, the structure of compound 4a was further confirmed by X-ray
crystallographic analyses and the result of single-crystal X-ray diffraction study
(ORTEP) is presented in Figure 1.
Figure 1. The ORTEP diagram of diazenylpyrazole 4a (CCDC No. 1903694).
5-Amino-4-nitrosopyrazole derivatives 2 and central building precursors are
functionally important in biologically active materials,32 as well as in chelating and
extracting ligands for transition metal ions.33 Following the above experimental
results,
we
explored
of
the
reliable
synthetic
procedure
for
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5-amino-4-nitrosopyrazoles 2 in the 2 N HCl/MeOH solution. To demonstrate the
practical usefulness of the new methodology, 5-amino-1H-pyrazole-4-carbaldehydes
1a–j bearing various N-1 substituents, including o-, m-, p-Me-Ph, o-, m-, p-Cl-Ph,
p-Br-Ph, and p-OMe-Ph, were treated with NaNO2 at room temperature in 2 N
HCl/MeOH solution. The redox reaction also took place smoothly to generate the
corresponding 5-amino-4-nitrosopyrazoles 2a–i with 73–91% yields as the major
products and pyrazole-4-carbaldehyde 3a as minor products with <14% yields
(Entries 1–11, Table 2). Introduction of a methyl or chloro group at the ortho-position
of the pyrazolic moiety of compound 1b and 1e seemed to afford lower conversions
yields (2b, 78% yield and 2e, 74% yield). Other substitutions at the para-position
ofpyrazolic ring with electron-donating groups, such as methyl, chloro, bromo, and
methoxy electron-withdrawing groups appeared to favor this conversion system (2d,
87% yield; 2g, 83% yield; 2h, 91% yield; 2i, 88% yield). With the optimized reaction
conditions
in
hand,
the
5-amino-1H-pyrazole-4-carbaldehydes
with
electron-withdrawing groups including p-CN-Ph and p-NO2-Ph scope of the
substrates were then examined under the same conditions. Unfortunately, no targeted
products were obtained.
Subsequently, we further screened 5-amino-1H-pyrazole-4-carbaldehydes 1j–l
with p-Me-Ph, p-Cl-Ph, or p-OMe-Ph groups on the C-3 position of pyrazolic ring.
The results revealed that the corresponding 5-amino-4-nitrosopyrazoles 2j–l were the
major products with 71%, 73%, and 74% yields, respectively (Entries 12–14, Table 2).
The minor pyrazole-4-carbaldehydes 3a–l were obtained with < 14% yields
(calculated from 1H-NMR spectra). According to the spectra, compound 2d presented
two characteristic absorptions peaks at 3278 cm–1 for the stretching of the NH2 group
and at 1630 cm–1 for the stretching of the –N=O group in IR spectrum. On the other
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hands, the structure of compound 2d was further confirmed by X-ray crystallographic
analyses and the result of single-crystal X-ray diffraction study (ORTEP) is presented
in Figure 2.
Table
2.
The
study
results
of
Nitrosation
of
5-amino-1,3-diphenyl-1H-pyrazole-4-carbaldehydes 1a–m with sodium nitrite in 2N
HCl(aq)/THF/MeOH.
Sarting materials 1a–l
Entry
2a–l (%)a
3a–l (%)b
No
Ar1
Ar2
1
2
Ph
Ph
86
78
12
6
1a
2a
2b
3a
3b
o-Me-Ph
Ph
1b
3
m-Me-Ph
p-Me-Ph
o-Cl-Ph
m-Cl-Ph
p-Cl-Ph
p-Br-Ph
p-OMe-Ph
Ph
Ph
Ph
83
87
74
73
83
91
88
71
73
74
10
7
1c
1d
1e
1f
2c
2d
2e
2f
3c
3d
3e
3f
4
5
Ph
14
11
13
3
6
Ph
7
Ph
1g
1h
1i
2g
2h
2i
3g
3h
3i
8
Ph
9
Ph
9
10
11
12
p-Me-Ph
p-Cl-Ph
p-OMe-Ph
10
9
1j
2j
3j
Ph
1k
2k
2l
3k
3l
Ph
8
1l
a Isolated yield.
b Determined by1H-NMR.
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Figure
2.
The
ORTEP
diagram
of
5-Amino-4-nitroso-1-(4-methylphenyl)-3-phenylpyrazole 2d (CCDC No. 1903691).
Interestingly, we explored a series of 5-amino-1H-pyrazole-4-carbaldehydes
1a–k with NaNO2 (~6.0 equiv) at room temperature in 6N HCl(aq)/MeOH solution.
Reactants 1a–k were tolerated under above reaction conditions, giving the
deamination pyrazole-4-carbaldehyde products 3a–k as the major products with
74–91%
yields
(Table
3).
However,
the
expected
products,
5-amino-4-nitrosopyrazoles 2, were not obtained. On the other hand, trace amount of
diazenylpyrazoles 4 (< 9% yields) were observed and characterized as the minor
products.
Based on the results, both electron-donating (1a−d, and 1i) and halogen
substituents (1e−h) were well tolerated to give pyrazole-4-carbaldehyde products
3a–h with better yields (Table 3). A broad range of substituent groups with diverse
steric and electronic properties (o-, m-, and, p-Me, o-, m-, and, p-Cl, Br, and OMe)
was compatible with this versatile functionalized transformations. All of
pyrazole-4-carbaldehyde 3a–h were also fully characterized by spectroscopic methods.
For example, compound 3a possessed one two peaks at δ 8.52 ppm for pyrazole ring
1
and at δ 10.03 ppm for formyl group in H NMR and at δ 185.12 ppm for formyl
carbon H–C=O in 13C NMR spectrum. The IR absorptions of 3a showed singlet peaks
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at 1673 cm–1 for the stretching of the O=C–H group. The formylation of selectively
sole main products seemed to be related to the amount of NaNO2 used and the
concentration of aqueous HCl/MeOH solution employed.
In addition, 5-amino-1H-pyrazole-4-carbaldehydes 1j–l substrates containing
p-Me-Ph, p-Cl-Ph, or p-OMe-Ph groups on the C-3 position of pyrazolic moiety were
subjected to the above reaction conditions to produce the corresponding
pyrazole-4-carbaldehyde products 3j–l with 74%, 79%, and 81% yields, respectively
(Entries 10–11, Table 3). For all the cases above, the nitrosation reactions did not
occur and no 5-amino-1,3-diaryl-4-nitroso-1H-pyrazoles 2 were detected by 1H-NMR
spectra. A trace amount of diazenylpyrazoles 4 (< 6% yield) was also detected, which
could be produced from 5-amino-1H-pyrazole-4-carbaldehydes 1 after reaction with
pyrazole-4-carbaldehyde 2 equivalents. However, we did not carry out futher
investigations because of insufficient amount of compounds 4b–k, except for
compound 4a.
Table 3. Nitrosation of 5-amino-1,3-diphenyl-1H-pyrazole-4-carbaldehydes 1a–l with
sodium nitrite in 6 N HCl(aq)/THF/MeOH.
Sarting materials 1a–k
Entry
3a–l (%)a
4a–l (%)b
No
Ar1
Ar2
1
2
3
4
Ph
Ph
88
82
77
91
-
3
6
-
1a
3a
3b
3c
3d
4a
4b
4c
4d
o-Me-Ph
m-Me-Ph
p-Me-Ph
Ph
Ph
Ph
1b
1c
1d
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5
6
o-Cl-Ph
m-Cl-Ph
p-Cl-Ph
p-Br-Ph
p-OMe-Ph
Ph
Ph
Ph
84
82
81
83
86
74
79
81
3
2
4
3
-
1e
1f
3e
3f
4e
4f
7
Ph
1g
1h
1i
3g
3h
3i
4g
4h
4i
8
Ph
9
Ph
10
11
11
p-Me-Ph
p-Cl-Ph
p-OMe-Ph
5
-
1j
3j
4j
Ph
1k
3k
3l
4k
4l
Ph
-
1l
a Isolated yield.
b Determined by 1H-NMR.
Based on the current results and our previous reports,34 we provided a plausible
mechanism of the reaction shown in Scheme 1. In the diluted ≤ 2 N HCl/THF/MeOH
acid solution (Path A in Scheme 1), NaNO2 was rapidly oxidized and transferred to
NO+ as the oxidant.35 5-Amino-1H-pyrazole-4-carbaldehyde 1 initially reacted with
NO+ for electron transformation to produce intermediate 5 at room temperature under
atmospheric pressure.36 Simultaneously, NO+ was also converted to NO· by O2. Under
the following oxidation and electron transformation reactions, the oxidized
carboxylation took place and subsequtntly formed intermediate 6.37 Its exposure to
NaNO2 in the presence of acidic medium could initiate the decaroxylation and
nitrosation
reaction
to
generate
the
corresponding
major
product
5-amino-4-nitrosopyrazole 2 (Path A in Scheme 1). In the present stiudy, the
carboxylated intermediate 6a was synthesized via the reported method38 and treated
with
NaNO2
under
the
same
conditions.
The
corresponding
5-amino-4-nitrosopyrazole 2a was successfully obtained with 76% yield. This result
was consistence with the reported data38 and provided the supporting evidence for the
Path A of proposed mechanism. On the other hand, the redox reaction would become
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more tardiness under ≤ 1 N HCl/THF/MeOH condition (Path B in Scheme 1). Part of
5-amino-4-nitrosopyrazole 2 was believe to have sufficient reaction time to react with
the starting material 5-amino-1H-pyrazole-4-carbaldehyde 1 for coupling dimeric
reaction and to yield trace amount of diazenylpyrazole product 4.
When 5-amino-1H-pyrazole-4-carbaldehyde 1 was treated with NaNO2 under
high concentration of acidic medium (≥ 6N HCl/THF/MeOH),39,40
pyrazole-5-diazonium chloride 7 was generated as the intermediate, as reported inin a
previous study (Path C in Scheme 1).41 Notably, the hydro-dediazoniation occurred
with a higher protonic medium to provide the unexpected pyrazole-4-carbaldehyde
product 3. This observed phenomenon was consistent with the finding from Prof.
Moyano’s group.42 Intriguingly, pyrazole-4-carbaldehydes 3 were firstly reported as
the main product through the novel and efficient redox reaction in the present study.
In the further control experiment of path C, pyrazole-4-carbaldehyde 3a was exposed
to NaNO2 under acidic medium 1 N, 2 N, and 6 N HCl(aq) in THF/MeOH solution. No
nitrosation product 2a and diazenylpyrazole 4a were detected after 24 h. This
observation was taken as supportive data for path C as individual and independent
reaction pathway.
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Scheme 1. The plausible mechanism for new redox reaction of
5-amino-1H-pyrazole-4-carbaldehyde with sodium nitrite (NaNO2) under acidic
medium solution.
CONCLUSIONS
We have successfully developed the one-pot selective redox reaction by using
5-amino-1H-pyrazole-4-carbaldehyde with NaNO2 under acidic solution to furnish the
product of 5-amino-4-nitrosopyrazole, pyrazole-4-carbaldehyde, or trace
diazenylpyrazole selectively. Based on our experimental results, under mild acidic
solution (≤ 2 N HCl in MeOH solution), 5-amino-4-nitrosopyrazole is formed as the
major product through redox reaction, deformylation and, nitrosation. Furthermore,
5-amino-1H-pyrazole-4-carbaldehyde 1 is efficiently converted to diazonium salt by
NaNO2 with highacidic medium (≥ 6 N HCl/MeOH). Subsequently, the dediazonation
on reducing surfaces happened to afford pyrazole-4-carbaldehyde as the sole product.
EXPERIMENTAL SECTION
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General Procedure: All reagents were used as obtained commercially. All reactions
were carried out under argon or nitrogen atmosphere and monitored by TLC. Flash
column chromatography was carried out on silica gel (230–400 mesh). Analytical
thin-layer chromatography (TLC) was performed using precoated plates (silica gel 60
F-254) purchased from Merck Inc. Flash column chromatography purification was
carried out by gradient elution using n-hexane in ethyl acetate (EtOAc) unless
otherwise stated. Infrared (IR) spectra were measured with a Bomem Michelson
Series FT-IR spectrometer. The wavenumbers reported are referenced to the
polystyrene absorption at 1601 cm–1. Absorption intensities are recorded by the
following abbreviations: s, strong; m, medium; w, weak. All proton and carbon-13
NMR spectra were obtained by a Bruker (400 MHz or 500 MHz) and a Bruker (100
MHz or 125 MHz) instrument. Proton and carbon-13 NMR spectra were acquired
using deuterochloroform (CDCl3) solvent. Multiplicities are recorded by the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; J, coupling
constant (Hz). ESI-MS analyses were performed on an Applied Biosystems API 300
mass spectrometer. High-resolution mass spectra were obtained from a JEOL
JMS-HX110 mass spectrometer.
Standard procedure for synthesis of 5-amino-4-nitrosopyrazole 2a,
pyrazole-4-carbaldehyde 3a, and diazenylpyrazole 4a. The reliable procedure were
involved the treatment of 5-amino-1H-pyrazole-4-carbaldehyde 1a (1.0 equiv.) with
sodium nitrite (NaNO2, ~3.0 equiv.) in THF/MeOH (0.5 mL/8.0 mL) or THF (8.5 mL)
at room temperature. The reaction mixture was cooled in an ice-bath and added with
the different concentration of aqueous hydrochloride acid (0.5 N, 1.0 N, 2.0 N, 3.0 N,
and 6.0 N, 5.0 mL) or organic acids (1.5 mL) including acetic acid, formic acid,
methanesulfonic acid, and trifluoroacetic acidfor stirring 3h to 48h. The clearly
solution was transferred to the red suspension. On completion of the reaction (TLC),
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the mixture was concentrated under reduced pressure and extracted with CH2Cl2 (20
mL × 2), washed with 5% NaHCO3 (20 mL × 2), brine (20 mL × 2), and dry over
MgSO4. The organic layer was concentrated under reduced pressure. Consequently,
the residue was charged onto the column in a little CH2Cl2 and the solvent was
allowed to percolate down to the surface of silica gel. The column was then eluted
with EtOAc/n-Hexane (2:8) to isolated 5-amino-4-nitrosopyrazole 2a,
pyrazole-4-carbaldehyde 3a, and diazenylpyrazole 4a in 28–65%, 9–72%, and 4–25%
yields, respectively.
1
5-Amino-4-nitroso-1,3-diphenyl-pyrazole (2a): crimson solid; mp 208–211 °C; H
NMR (CDCl3, 400 MHz) δ 7.01 (br, 2H, NH2), 7.45–7.50 (m, 4H, ArH), 7.53–7.57
13
(m, 4H, ArH), 8.40–8.42 (m, 2H, ArH); C NMR (CDCl3, 100 MHz) δ 123.99 (2 ×
CH), 128.61 (2 × CH), 128.77 (2 × CH), 129.22, 129.91, 130.25 (2 × CH), 130.57,
135.08, 135.70, 150.88, 151.29; IR (KBr): 3351, 3267, 3057, 1641, 1499, 1449, 1250,
1158, cm-1; EIMS m/z: 264 (M+, 100), 265 (18), 246 (24), 144 (39), 128 (21), 117(24),
91(21), 77(73). HRMS calcd. for C15H12ON5: 264.1011; found: 264.1003.
1
Pyrazole-4-carbaldehyde (3a): Dark brown solid; mp 83–86 °C; H NMR (CDCl3,
400 MHz) δ 7.35–7.39 (m, 1H, ArH), 7.45–7.51 (m, 5H, ArH), 7.76–7.82 (m, 4H,
ArH), 8.52 (s, 1H, ArH), 10.03 (s, 1H, CHO); 13C NMR (CDCl3, 100 MHz) δ 119.68
(2 × CH), 122.45, 127.89, 128.70 (2 × CH), 128.90 (2 × CH), 129.23, 129.61 (2 ×
CH), 130.94, 131.28, 138.94, 154.70, 185.12; IR (KBr): 3124, 3064, 1678, 1527,
1203, 757 cm–1; MS (EI): 249.1(15), 248.1(100), 247.1(83), 219.1(19), 77.1(31),
51.0(12) ; HRMS: Calcd. for C16H12N2O: 248.0950. Found: 248.0958.
1
Diazenylpyrazole (4a): Orange solid; mp 192–197 °C; H NMR (CDCl3, 400 MHz)
δ 6.73 (br, 2H, NH2), 7.35 (m, 2H, ArH), 7.44–7.48 (d, 8H, ArH), 7.56–7.57 (m, 4H,
ArH), 7.63–7.65 (m, 2H, ArH), 7.85–7.90 (m, 4H, ArH), 10.20 (s, 1H, CHO); 13C
NMR (CDCl3, 100 MHz) δ 110.97, 124.01 (2 × CH), 125.64 (2 × CH), 126.01,
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128.02 (2 × CH), 128.26 (2 × CH), 128.45 (2 × CH), 128.54, 128.80, 129.15 (4 × CH),
129.28 (2 × CH), 130.10 (2 × CH), 130.86, 131.83, 136.63, 138.93, 139.33, 150.37,
153.70, 153.97, 186.14; IR (KBr): 3279, 3065, 1628, 1528, 1493, 1451, 1264, 1166,
967 cm–1; MS (EI): 510(30), 509(93), 508(46) , 480(13), 464(20), 406(24), 405(34),
403(19), 263(35), 262(100), 261(54), 260(24), 250(25), 249(20), 235(13), 144(21),
129(14), 128(23),119(45), 77(82); HRMS: Calcd. for C31H23N7O: 509.1964 Found:
509.1960.
Standard procedure for synthesis of 5-amino-4-nitrosopyrazole 2b–l. The reliable
procedure were involved the treatment of 5-amino-1H-pyrazole-4-carbaldehydes 1b–l
(1.0 equiv.) with sodium nitrite (NaNO2, ~3.0 equiv.) in MeOH (5.0 mL) at room
temperature. The reaction mixture was cooled in an ice-bath and added with 2.0 N
aqueous hydrochloride acid (5.0 mL) for stirring 3h. The clearly solution was
transferred to the red suspension. On completion of the reaction (TLC), the mixture
was concentrated under reduced pressure and extracted with CH2Cl2 (20 mL × 2),
washed with 5% NaHCO3 (20 mL × 2), brine (20 mL × 2), and dry over MgSO4. The
organic layer was concentrated under reduced pressure. Consequently, the residue was
charged onto the column in a little CH2Cl2 and the solvent was allowed to percolate
down to the surface of silica gel. The column was then eluted with EtOAc/n-Hexane
(3:7) to isolate 5-amino-4-nitrosopyrazoles 2b–l in 71–91% yields.
5-Amino-4-nitroso-1-(2-methylphenyl)-3-phenylpyrazole (2b): Orange solid; mp
1
237–240 °C; H NMR (CDCl3, 400 MHz) δ 2.22 (s, 3H, CH3), 6.67 (br, 2H, NH2),
7.34–7.36 (m, 2 H, ArH), 7.41–7.44 (m, 2H, ArH), 7.46–7.48 (m, 3H, ArH),
8.38–8.41 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 17.60, 127.33, 127.61,
128.58 (2 × CH), 128.72 (2 × CH), 129.82, 130.69, 130.76, 132.09, 133.41, 136.04,
136.49, 150.42, 150.93; IR (KBr): 3336, 2925, 2862, 1650, 1502, 1242, 1164, 963
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cm–1; EIMS: 278, 260 (14), 158 (25), 132 (25), 131 (58), 128 (21), 104 (19), 103 (13);
HRMS: Calcd. for C16H14N4O: 278.1168. Found: 278.1176.
5-Amino-4-nitroso-1-(3-methylphenyl)-3-phenylpyrazole (2c): Orange solid; mp
1
144–147 °C; H NMR (CDCl3, 400 MHz) δ 2.42 (s, 3 H, CH3), 7.03 (br, 2H, NH2),
7.26 (d, 1H, J =7.52 Hz, ArH), 7.30 (d, 1H, J =8.36 Hz, ArH), 7.36 (s, 1H, ArH), 7.42
(t, 1H, J =7.76 Hz, ArH), 7.46 (d, 2H, J =2.08 Hz, ArH), 7.48 (d, 1H, J =1.76 Hz,
ArH), 8.37–8.41 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 21.40, 120.76, 124.74
128.58 (3 × CH), 128.76 (2 × CH), 129.86, 129.91, 130.01, 130.59, 135.12, 135.55,
140.70, 150.86, 151.17; IR (KBr): 3275, 3198, 3061, 1633, 1495, 1451, 1269, 1161,
1105 cm–1; EIMS: 278 (100), 262 (19), 260 (30), 158 (31), 131 (39), 129 (14), 128
(20) HRMS: Calcd. for C16H14N4O: 278.1168. Found: 278.1175.
5-Amino-4-nitroso-1-(4-methylphenyl)-3-phenylpyrazole (2d): Dark green solid;
mp 142–145 °C; 1H NMR (CDCl3, 400 MHz) δ 2.42 (s, 3 H, CH3), 6.95 (br, 2H, NH2),
7.34 (d, 2H, J = 8.28 Hz, ArH), 7.40 (d, 2H, J = 8.44 Hz, ArH), 7.46–7.48 (m, 3H,
ArH) 8.38–8.41 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 21.23, 123.95, 128.58
(3 × CH), 128.74 (2 × CH), 129.83, 130.64, 130.77 (2 × CH), 133.00, 135.12, 139.57,
150.89, 151.08; IR (KBr): 3279, 3055, 1627, 1527, 1264, 1165, 967 cm–1; EIMS: 278
(100), 279 (16), 158 (30), 145(12), 131(12), 128(13), 91(22), 77(11) HRMS: Calcd.
for C16H14N4O: 278.1168. Found: 278.1166.
5-Amino-1-(2-chlorophenyl)-4-nitroso-3-phenylpyrazole (2e): Orange solid; mp
1
235–238 °C; H NMR (CDCl3, 400 MHz) δ 6.84 (br, 2H, NH2), 7.45–7.49 (m, 6H,
ArH), 7.52 (d, 1H, J = 2.39 Hz, ArH), 7.53 (d,1H, J = 2.34 Hz, ArH), 7.57–7.60 (m, 1
H, ArH), 7.59–7.61 (m, 1 H, ArH), 8.38–8.40 (m, 2 H, ArH); 13C NMR (CDCl3, 100
MHz) δ 128.61 (3 × CH), 128.81 (2 × CH), 129.80, 129.96, 130.49, 131.10, 131.86,
131.94, 132.74, 136.24, 150.25, 151.53; IR (KBr) 3333, 2861, 1656, 1532, 1499,
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1450, 1237, 1166 cm–1; EIMS: 298 (100), 282 (16), 178 (21), 153 (16), 143 (31), 128
(30), 111 (27), 103 (40), 77 (35); HRMS: Calcd. for C15H11ClN4O: 298.0621. Found:
298.0628.
5-Amino-1-(3-chlorophenyl)-4-nitroso-3-phenylpyrazole (2f): Dark brown solid;
mp 140–143 °C; 1H NMR (CDCl3, 400 MHz) δ 7.09 (br, 2H, NH2), 7.42.–7.44 (m, 1
H, ArH), 7.45 (t, 1 H, J = 1.66 Hz, ArH), 7.47–7.49 (m, 4H, ArH), 7.59 (t, 1 H, J =
1.80 Hz, ArH), 8.38–8.41 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 121.61,
124.25, 128.65 (3 × CH), 128.79 (2 × CH), 129.25, 130.08, 130.34, 131.15, 134.97,
136.08, 150.71, 151.63; IR (KBr): 3279, 3069, 2927, 1633, 1593, 1485, 1450, 1286,
1092 cm–1; EIMS : 298 (100), 282 (29), 280 (26), 178 (28), 153 (14), 129 (26), 128
(31), 125 (23), 111 (40),77 (62); HRMS: Calcd. for C15H11ClN4O: 298.0621. Found:
298.0625.
5-Amino-1-(4-chlorophenyl)-4-nitroso-3-phenylpyrazole (2g): Light yellow solid;
mp 151–154 °C; 1H NMR (CDCl3, 400 MHz) δ 7.04 (br, 2H, NH2), 7.46–7.54 (m, 7H,
13
ArH), 8.37–8.39 (m, 2H, ArH); C NMR (CDCl3, 100 MHz) δ 125.20, 128.65 (3 ×
CH), 128.75 (2 × CH), 130.05 (2 × CH), 130.41 (2 × CH), 134.24, 135.02,
135.05,150.74, 151.52; IR (KBr): 3347, 3263, 3195, 1632, 1499, 1450, 1260 cm–1;
EIMS: 298 (100), 282 (29), 280 (31), 178 (28), 153 (27), 151 (52), 28 (28), 125 (31),
111 (37), 103 (21), 77 (40); HRMS: Calcd. for C15H11ClN4O: 298.0621. Found:
298.0628.
5-Amino-1-(4-bromophenyl)-4-nitroso-3-phenylpyrazole (2h): Light orange solid;
mp 162–165 °C; 1H NMR (CDCl3, 400 MHz) δ 7.44–7.46 (m, 5H, ArH), 7.67 (d, 2H,
13
J = 8.64 Hz, ArH), 8.29–8.32 (m, 2H, ArH); C NMR (CDCl3, 100 MHz) δ 123.04,
125.41, 128.67 (3 × CH), 128.77 (2 × CH), 130.12 (2 × CH), 130.31 (2 × CH), 133.45,
134.75, 150.65, 151.58; IR (KBr): 3271, 3061, 2920, 2851, 1633, 1492, 1450, 1232,
1164 cm–1; EIMS: 342 (100), 328 (39), 326 (62), 324 (28), 197 (50), 195 (40), 171
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(37), 169 (39), 143 (83), 103 (65), 77 (60); HRMS: Calcd. for C15H11BrN4O:
342.0116. Found: 342.0121.
5-Amino-1-(4-methoxyphenyl)-4-nitroso-3-phenylpyrazole (2i): Dark brown solid;
mp 162–165 °C; 1H NMR (CDCl3, 400 MHz) δ 3.85 (s, 3H, CH3), 6.88 (br, 2H, NH2),
7.03–7.05 (d, 2H, J = 8.92 Hz, ArH), 7.41–7.48 (m, 5H, ArH), 8.37–8.40 (m, 2H,
13
ArH); C NMR (CDCl3, 100 MHz) δ 55.69, 115.37, 125.96 (2 × CH), 128.07 (2 ×
CH), 128.58 (2 × CH), 128.74, 129.82, 130.65, 135.32, 150.83, 150.97, 160.21; IR
(KBr): 3282, 2933, 2835, 1628, 1513, 1451, 1250, 1171, 967, 834 cm–1; EIMS: 294.2
(100), 294.2(100), 276.1(32), 159.1(25), 144.1(31), 77.1(66); HRMS: Calcd. for
C16H14N4O2: 294.1117. Found: 294.1123.
5-Amino-3-(4-methylphenyl)-4-nitroso-1-phenylpyrazole (2j): Orange solid; mp
1
212–215 °C; H NMR (CDCl3, 400 MHz) δ 2.41 (s, 3H, CH3), 7.04 (br, 2H, NH2),
7.28 (d, 2H, J = 8.00 Hz, ArH), 7.43–7.47 (m, 1H, ArH), 7.52–7.57 (m, 4H, ArH),
8.29 (d, 2H, J =8.12 Hz, ArH); 13C NMR (CDCl3, 100 MHz) δ 21.46, 123.96 (2 ×
CH), 127.71, 128.63 (2 × CH), 129.12, 129.33 (2 × CH), 130.20 (2 × CH), 135.09,
135.74, 140.06, 150.94, 151.31; IR (KBr): 3339, 2954, 2864, 1648, 1503, 1250, 1160,
1095, 960 cm–1; EIMS: 278 (100), 145 (14), 144 (58), 143 (22), 117 (10), 77 (40);
HRMS : Calcd. for C16H14N4O: 278.1168. Found: 278.1170.
5-Amino-3-(4-chlorophenyl)-4-nitroso-1-phenylpyrazole (2k): brown solid; mp
222–225 °C; 1H NMR (CDCl3, 400 MHz) δ 6.98 (br, 2H, NH2), 7.45 (d, 2H, J = 8.64
Hz, ArH), 7.48–7.52 (m, 2H, ArH), 7.54–7.57 (m, 3H, ArH), 8.39 (d, 2H, J = 8.60 Hz,
ArH); 13C NMR (CDCl3, 100 MHz) δ 123.98 (2 × CH), 128.87 (2 × CH), 129.12,
129.35, 129.95 (2 × CH), 130.30 (2 × CH), 135.05, 135.58, 136.09, 150.07, 150.72;
IR (KBr): 3354, 3274, 3204, 3124, 3069, 1641, 1503, 1250, 1158, 965 cm–1; EIMS:
298 (100), 284 (12), 282 (36), 280 (29), 255 (11), 163 (21), 144 (45), 137 (24), 117
(34), 91 (46), 77(76); HRMS: Calcd. for C15H11ClN4O: 289.0621 Found: 298.0616.
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5-Amino-3-(4-methoxyphenyl)-4-nitroso-1-phenylpyrazole (2l): Orange solid; mp
1
184–187°C; H NMR (CDCl3, 400 MHz) δ 3.86 (s, 3H, CH3), 7.00 (d, 2H, J = 8.90
Hz, ArH), 7.43–7.47 (m, 1 H, ArH), 7.52–7.57 (m, 4 H, ArH), 8.36 (d, 2 H, J = 8.90
Hz, ArH); 13C NMR (CDCl3, 100 MHz) δ 55.35, 114.07 (2 × CH), 123.17, 123.94 (2×
CH), 129.11, 130.22 (4 × CH), 135.11, 135.77, 150.97, 151.03, 161.16; IR (KBr):
3278, 3064, 2965, 2935, 2835, 1611, 1503, 1250, 1030, 688 cm–1; MS (EI): 295.1(18),
294.1(100), 278.1(25), 176.0(35), 148.1(43), 147.0(54), 133.0(40), 128.0(15),
122.0(20), 103.0(60), 77.0(34); HRMS (EI): Calcd. for C16H14N4O2: 294.1117. Found:
294.1114.
Standard procedure for synthesis of pyrazole-4-carbaldehyde 3a–l. The reliable
procedure were involved the treatment of 5-amino-1H-pyrazole-4-carbaldehydes 1a–l
(1.0 equiv.) with sodium nitrite (NaNO2, ~6.0 equiv.) in MeOH (5.0 mL) at room
temperature. The reaction mixture was cooled in an ice-bath and added with 6.0 N
aqueous hydrochloride acid (5.0 mL) for stirring 3h. The clearly solution was
transferred to the red suspension. On completion of the reaction (TLC), the mixture
was concentrated under reduced pressure and extracted with CH2Cl2 (20 mL × 2),
washed with 5% NaHCO3 (20 mL × 2), brine (20 mL × 2), and and dry over MgSO4.
The organic layer was concentrated under reduced pressure. Consequently, the residue
was charged onto the column in a little CH2Cl2 and the solvent was allowed to
percolate down to the surface of silica gel. The column was then eluted with
EtOAc/n-Hexane (2:8) to isolate 5-amino-4-nitrosopyrazoles 3a–l in 74–91% yields.
3-Phenyl-1-(o-tolyl)-1H-pyrazole-4-carbaldehyde (3b): light brown solid; mp
1
123–125 °C; H NMR (CDCl3, 400 MHz) δ 2.31 (s, 3 H, CH3), 7.32–7.40 (m, 4 H,
ArH), 7.44–7.48 (m, 3 H, ArH), 7.79–781 (m, 2 H, ArH), 8.20 (s, 1 H, ArH), 10.05 (s,
1H, CHO); 13C NMR (CDCl3, 100 MHz) δ 18.07, 121.55, 125.89, 126.84, 128.67 (2 ×
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CH), 128.94 (2 × CH), 129.13, 129.38, 131.34, 131.54, 133.55, 135.11, 138.76,
154.23, 185.20; IR (KBr): 3124, 3059, 2929, 2859, 1678, 1526, 1188, 762 cm–1; MS
(EI): 262.1(100), 261.1(48), 233.1(26), 130.0(12); HRMS: Calcd. for C17H14N2O:
262.1106. Found: 262.1101.
3-Phenyl-1-(m-tolyl)-1H-pyrazole-4-carbaldehyde (3c): Dark green solid; mp
94–98 °C; 1H NMR (CDCl3, 400 MHz) δ 2.41 (s, 3 H, CH3), 7.16 (d, 1H, J = 7.68 Hz,
ArH), 7.34 (t, 1 H, J = 7.84 Hz, ArH), 7.42–7.54 (m, 4 H, ArH), 7.61 (s, 1 H, ArH),
7.80–7.82 (m, 2 H, ArH), 8.49 (s, 1 H, ArH), 10.02 (s, 1H, CHO); 13C NMR (CDCl3,
100 MHz) δ 21.35, 116.64, 120.37, 122.30, 128.64 (3 × CH), 128.87 (2 × CH), 129.15,
129.33, 131.00, 131.29, 138.85, 139.77, 154.54, 185.03; IR (KBr): 3059, 2919, 2832,
1681, 1529, 1214, 1060, 783 cm–1; MS (EI): 261.2(100), 233.2(22), 91.1(21),
77.1(15); HRMS: Calcd. for C17H14N2O: 262.1106. Found: 262.1115.
3-Phenyl-1-(p-tolyl)-1H-pyrazole-4-carbaldehyde (3d): Brown solid; mp 141–145
°C; 1H NMR (CDCl3, 400 MHz) δ 2.37 (s, 3H, CH3), 7.25 (d, 2H, J = 8.36 Hz, ArH),
7.40–7.50 (m, 3H, ArH), 7.63 (d, 2H, J = 8.44 Hz, ArH), 7.80–7.82 (m, 2H, ArH)
8.45 (s, 1H, ArH), 10.01 (s, 1H, CHO); 13C NMR (CDCl3, 100 MHz) δ 20.90, 119.50
(2 × CH), 122.22, 128.62 (2 × CH), 128.85 (2 × CH), 129.10, 130.04 (2 × CH),
130.78, 131.33, 136.63, 137.85, 154.43, 185.01; IR (KBr): 3124, 2914, 2833, 1672,
1529, 1223, 818 cm–1; MS (EI): 262.2(100), 261.2(76), 233.2(13); HRMS: Calcd. for
C17H14N2O: 262.1106. Found: 262.1096.
1-(2-Chlorophenyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (3e): Yellow orange
1
solid; mp 83–85 °C; H NMR (CDCl3, 400 MHz) δ 7.34–7.37 (m, 2H, ArH),
7.42–7.48 (m, 3H, ArH), 7.50–7.52 (m, 1H, ArH), 7.63–7.66 (m, 1H, ArH), 7.81–7.83
(m, 2H, ArH), 8.45 (s, 1H, ArH), 10.04 (s, 1H, CHO); 13C NMR (CDCl3, 100 MHz) δ
121.74, 127.52, 127.73, 128.06, 128.52 (2 × CH), 128.82 (2 × CH), 129.12, 129.91,
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130.64, 130.95, 136.21, 136.84, 154.12, 184.73; IR (KBr): 3064, 2828, 1682, 1528,
1198, 1075, 757 cm–1; MS (EI): 284.2(31), 283.2(41), 282.2(100), 270.2(13),
111.0(16), 77.1(16); HRMS: Calcd. for C16H11ClN2O: 282.0560. Found: 282.0553.
1-(3-Chlorophenyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (3f): Light brown solid;
mp 101–105 °C; 1H NMR (CDCl3, 400 MHz) δ7.34–7.36 (m, 1 H, ArH), 7.42 (t, 1 H,
J = 8.08 Hz ArH), 7.46–7.52 (m, 3 H, ArH), 7.65 (dq, 1 H, J = 8.0, 1.0 Hz, ArH),
7.79–7.81 (m, 2 H, ArH), 7.87 (t, 1 H, J = 2.02 Hz ArH), 8.52 (s, 1 H, ArH), 10.04 (s,
1 H, CHO); 13C NMR (CDCl3, 100 MHz) δ 117.45, 120.18, 122.83, 127.97, 128.82 (2
× CH), 128.94 (2 × CH), 129.47, 130.71, 130.98, 131.05, 135.63, 139.92, 155.02,
185.05; IR (KBr): 3119, 3064, 2919, 2853, 1678, 1526, 1208, 775 cm–1; MS (EI):
284.2(31), 283.2(43), 282.2(100), 281.1(85), 253.2(15), 218.1(11), 111.0(17),
77.1(13); HRMS: Calcd. for C16H11ClN2O: 282.0560. Found: 282.0556.
1-(4-Chlorophenyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (3g): Light brown solid;
mp 138–142 °C; 1H NMR (CDCl3, 400 MHz) δ 7.44–7.49 (m, 5 H, ArH), 7.72 (d, 2 H,
J = 8.88 Hz ArH), 7.79 (dd, 2 H, J = 3.09 Hz, ArH), 8.49 (s, 1H, ArH), 10.02 (s, 1H,
CHO); 13C NMR (CDCl3, 100 MHz) δ120.78 (2 × CH), 122.69, 128.76 (2 × CH),
128.88 (2 × CH), 129.38, 129.74 (2 × CH), 130.81, 131.07, 133.55, 137.47, 154.87,
185.00; IR (KBr): 3129, 3054, 2833, 1675, 1529, 1213, 822 cm–1; MS (EI): 284.2(31),
283.2(42), 282.2(100), 281.1(79), 253.1(14), 111.0(17), 77.1(13); HRMS: Calcd. for
C16H11ClN2O: 282.0560. Found: 282.0555.
1-(4-Bromophenyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (3h): Brown solid; mp
146–149 °C; 1H NMR (CDCl3, 400 MHz) δ 7.46–7.51 (m, 3H, ArH), 7.60 (d, 2H, J =
8.97 Hz, ArH), 7.66 (d, 2H , J = 8.94 Hz, ArH ), 7.78 (dd, 2H, J = 7.84 Hz, ArH), 8.50
13
(s, 1H, ArH), 10.02 (s, 1H, CHO); C NMR (CDCl3, 100 MHz) δ121.05 (2 × CH),
121.41, 122.74, 128.77 (2 × CH), 128.89 (2 × CH), 129.40, 130.76, 131.06, 132.72 (2
× CH), 137.95, 154.93, 185.03; IR (KBr): 3124, 3064, 2833, 1677, 1527, 1213, 823
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cm–1; MS (EI): 328.0(98), 327.0(81), 326.0(100), 299.0(10), 218.1(16), 156.9(14),
154.9(14), 115(10), 77.0(17); HRMS: Calcd. for C16H11BrN2O: 326.0055. Found:
326.0050.
1-(4-Methoxyphenyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (3i): Orange solid;
1
mp 110–114 °C; H NMR (CDCl3, 400 MHz) δ 3.75 (s, 3H, CH3), 6.90 (d, 2H, J =
9.00 Hz, ArH), 7.38–7.47 (m, 3H, ArH), 7.61 (d, 2H, J = 9.00 Hz, ArH), 7.79 (d, 2H,
J = 7.96, 1.44 Hz, ArH), 8.35 (s, 1H, ArH), 9.96 (s, 1H, CHO); 13C NMR (CDCl3, 100
MHz) δ 55.30, 114.41 (2 × CH), 120.93 (2 × CH), 121.95, 128.46 (2 × CH), 128.70 (2
× CH), 128.93, 130.76, 131.23, 132.25, 154.07, 158.95, 184.76; IR (KBr): 3124, 2838,
1672, 1528, 1251, 1043, 830 cm–1; MS (EI): 279.1(17), 278.1(100), 277.1(44),
77.0(15); HRMS: Calcd. for C17H14N2O2: 278.1055. Found: 278.1053.
1-Phenyl-3-(p-tolyl)-1H-pyrazole-4-carbaldehyde (3j): Brown solid; mp 119–123
°C; 1H NMR (CDCl3, 400 MHz) δ 2.41 (s, 3H, CH3), 7.29 (d, 2H, J = 7.84 Hz, ArH),
7.35–7.39 (m, 1H, ArH), 7.47–7.51 (m, 2H, ArH), 7.69 (d, 2H, J = 8.12 Hz, ArH),
13
7.77 (dd, 2H, J = 8.56, 1.02 Hz, ArH), 8.50 (s, 1H, ArH), 10.03 (s, 1H, CHO); C
NMR (CDCl3, 100 MHz) δ 21.33, 119.72 (2 × CH), 122.45, 127.87, 128.44, 128.82 (2
× CH), 129.44 (2 × CH), 129.63 (2 × CH), 130.82, 139.04, 139.32, 154.87, 185.30; IR
(KBr): 3124, 3029, 2924, 2838, 1671, 1520, 1219, 755 cm–1; MS (EI): 263.2(17),
262.2(100), 261.1(42), 247.1(36), 233.1(12), 77.0(24); HRMS: Calcd. for C17H14N2O:
262.1106. Found: 262.1099.
3-(4-Chlorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3k): Orange brown
1
solid; mp 91–95 °C; H NMR (CDCl3, 400 MHz) δ 7.39 (t, 1H, J = 7.40 Hz, ArH),
7.44–7.52 (m, 4H, ArH), 7.76 (d, 2H, J = 7.75 Hz, ArH), 7.81 (d, 2H, J = 8.62 Hz,
ArH), 8.51 (s, 1H, ArH), 10.01 (s, 1H, CHO); 13C NMR (CDCl3, 100 MHz) δ 119.72
(2 × CH), 122.50, 128.09, 128.91 (2 × CH), 129.71 (2 × CH), 129.83, 130.17 (2 ×
CH), 131.98, 135.42, 138.88, 153.18, 184.42; IR (KBr): 3124, 3069, 2828, 1671,
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1523, 1228, 1090, 835 cm–1; MS (EI): 284.1(33), 283.1(39), 282.1(100), 281.1(63),
247.1(17), 104.1(15), 77.0(34); HRMS: Calcd. for C16H11ClN2O: 282.0560. Found:
282.0552.
3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3l): Light brown
solid; mp 111–115 °C; 1H NMR (CDCl3, 400 MHz) δ 3.85 (s, 3H, CH3), 7.00 (d, 2H,
J = 8.88 Hz, ArH), 7.36 (t, 1H, J = 7.46 Hz, ArH), 7.48 (t, 2H, J = 8.00 Hz, ArH),
13
7.75–7.79 (m, 4H, ArH), 8.49 (s, 1H, ArH), 10.02 (s, 1H, CHO); C NMR (CDCl3,
100 MHz) δ 55.34, 114.16 (2 × CH), 119.66 (2 × CH), 122.32, 123.82, 127.82, 129.62
(2 × CH), 130.22 (2 × CH), 131.17, 139.02, 154.43, 160.52, 185.10; IR (KBr): 3124,
3079, 2833, 1672, 1520, 1250, 1175, 840 cm–1; MS (EI): 279.1(18), 278.1(100),
277.1(24), 235.1(19), 77.0(23); HRMS: Calcd. for C17H14N2O2: 278.1055. Found:
278.1056.
ACKNOWLEDGMENTS
We are grateful to the Tsuzuki Institute for Traditional Medicine and the Ministry
of Science and Technology of the Republic of China (MOST 107-2113-M-039-006)
for financial support.
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