Formyl substituent at C-4 of pyrazoles: A temporary protecting group for regioselective palladium-catalyzed direct arylation at C-5

Article abstract of DOI:10.1002/ejoc.201301593

Pyrazoles with an aldehyde function at C-4 underwent a palladium-catalyzed direct arylation reaction to provide a regioselective approach to 5-aryl-substituted pyrazoles. The reaction proceeds in moderate to high yields with a variety of aryl bromides in the presence of 2 mol-% of Pd(OAc) ₂ as the catalyst. The use of an aldehyde function at C-4 of the pyrazoles presents several advantages: (1) 4-formylpyrazoles are easily prepared from hydrazine derivatives, ketones, and N,N-dimethylformamide (DMF), (2) the control of the regioselectivity of the arylation at C-5 of the pyrazole, (3) the aldehyde substituent can easily be transformed into a wide variety of other substituents, and (4) the formyl group can be considered a temporary protecting group, as it can be removed by a straightforward reaction. Copyright

Full text of DOI:10.1002/ejoc.201301593

FULL PAPER
DOI: 10.1002/ejoc.201301593
Formyl Substituent at C-4 of Pyrazoles: A Temporary Protecting Group for
Regioselective Palladium-Catalyzed Direct Arylation at C-5
Imen Smari,[a,b] Chiraz Youssef,[c] Kedong Yuan,[b] Anissa Beladhria,[b,c]
Hamed Ben Ammar,*[a,c] Bechir Ben Hassine,[a] and Henri Doucet*[b]
Keywords: Nitrogen heterocycles / Palladium / C–H activation / Regioselectivity / Homogeneous catalysis
Pyrazoles with an aldehyde function at C-4 underwent a pal-
ladium-catalyzed direct arylation reaction to provide a re-
gioselective approach to 5-aryl-substituted pyrazoles. The re-
action proceeds in moderate to high yields with a variety of
aryl bromides in the presence of 2 mol-% of Pd(OAc)2 as the
catalyst. The use of an aldehyde function at C-4 of the pyr-
azoles presents several advantages: (1) 4-formylpyrazoles are
easily prepared from hydrazine derivatives, ketones, and
N,N-dimethylformamide (DMF), (2) the control of the re-
gioselectivity of the arylation at C-5 of the pyrazole, (3) the
aldehyde substituent can easily be transformed into a wide
variety of other substituents, and (4) the formyl group can be
considered a temporary protecting group, as it can be re-
moved by a straightforward reaction.
In recent years, the palladium-catalyzed direct arylation
of heteroaromatic compounds has emerged as a very
powerful tool for simple access to a wide variety of (hetero)-
arylated heteroaromatic compounds.[1–3] However, there are
still limitations to these reactions in terms of their scope of
substrates. Only a few examples of palladium-catalyzed di-
rect arylations of pyrazoles have been reported to date.[4–8]
This is because of the lack of regioselectivity that is ob-
served in the course of these coupling reactions.[4,5] Sames
and co-workers determined the regioselectivity of the cata-
lytic C–H arylation of pyrazoles (see Scheme 1, top).[4] The
SEM-substituted pyrazole [SEM = 2-(trimethylsilyl)ethoxy-
methyl] was treated with bromobenzene using 5 mol-% of
Pd(OAc)2 and 7.5 mol-% of the electron-rich and congested
phosphine Pd(nBu)(Ad)2 as the catalyst (Ad = adamantyl)
to give a mixture of products. These results indicated a
higher reactivity at the 5-position relative to the 4-position
and a very low reactivity at the 3-position.
Introduction
Among heterocycle derivatives, (hetero)aryl-substituted
pyrazoles display important biological properties. For ex-
ample, rimonabant is an antiobesity agent, celecoxib is an
anti-inflammatory agent, and regadenoson a vasodilator
(see Figure 1).
In the course of this reaction, 5-phenylpyrazole a was
obtained in 40% yield, and 4-phenylpyrazole b was pro-
duced in only 10% yield. Moreover, the formation of a sig-
nificant amount of 4,5-diarylated pyrazole c (30%) was also
observed. Our studies of the arylation of 1-methylpyrazole
with various aryl bromides confirmed that the regioselective
control of such reactions is very challenging, as in all cases,
Figure 1. Examples of bioactive pyrazoles.
[a] Laboratoire de Synthèse Asymétrique et Catalyse Homogène
(UR 11ES56), Université de Monastir, Faculté des Sciences de
Monastir,
Avenue de l’environnement, Monastir 5000, Tunisie
E-mail: hamed_benammar@yahoo.fr
[b] Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS – we obtained mixtures of 4- and 5-arylated pyrazoles.[5] As
Université de Rennes “Organométalliques: Matériaux et
a consequence, only a few examples of selective 5-arylations
Catalyse”, Campus de Beaulieu,
of pyrazoles have been described.[6,7] In several cases of
35042 Rennes, France
E-mail: henri.doucet@univ-rennes1.fr
intermolecular coupling reactions, the C-4 position was
blocked by a chloro substituent to control the regioselectiv-
ity (see Scheme 1, middle).[6b,6d]
The reaction between hydrazine derivatives, N,N-dimeth-
ylformamide (DMF), ketones, and POCl3 is a well-known
approach to access a wide variety of 4-formylpyrazoles and
http://scienceschimiques.univ-rennes1.fr/catalyse/
personal%20web%20pages/page%20web%20Doucet.pdf
[c] Laboratoire de Chimie Organique Physique (UR11ES74),
Université de Sfax, Faculté des Sciences de Sfax,
Route de la Soukra, 3038 Sfax, Tunisie
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301593.
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Regioselective Palladium-Catalyzed Direct Arylation
Figure 2. Reactivity of 4-formylpyrazoles.
and air-stable catalyst, (2) the influence of substituents on
the arene ring at C-3 of the pyrazole, and (3) the subsequent
decarbonylation of the prepared 4-formyl-5-arylpyrazoles
(see Scheme 1, bottom).
Results and Discussion
Scheme 1. Regioselectivity of palladium-catalyzed direct arylation
of pyrazoles (Piv = pivaloyl, DMA = N,N-dimethylacetamide,
NMP = N-methylpyrrolidone).
We started our investigation with the C–H functionaliza-
tion of 1,3-diphenylpyrazole-4-carbaldehyde (1) using 4-
bromobenzaldehyde as the coupling partner. The reaction
that employed 2 mol-% of PdCl(C3H5)(dppb) as the catalyst
[dppb = 1,4-bis(diphenylphosphino)butane] and KOAc as
the base at 150 °C in DMAproceeded towards completion
in 24 h to afford 2 in 54% yield (see Table 1, Entry 1). In
the course of this reaction, the formation of a small amount
of a decarbonylated compound was also observed by GC–
MS analysis of the crude mixture. This side reaction was
expected, as the palladium-catalyzed decarbonylation of 4-
formylpyrrole has already been described.[11] A slightly
higher yield of 2 was obtained in the presence of 2 mol-%
of Pd(OAc)2 as the catalyst (see Table 1, Entry 3). Next, the
influence of a few different bases was examined. CsOAc
gave a mixture of 2 and the decarbonylated product in a
low yield (see Table 1, Entry 5). In the presence of NaOAc,
a large amount of the decarbonylated product was pro-
duced, and only a trace amount of 2 was observed (see
generally gives the desired heteroarenes in high yields (see
Scheme 2).[9] Moreover, the 4-formylpyrazole units are im-
portant building blocks in organic synthesis. The formyl
substituent can be easily transformed into other useful
functional groups such as alcohols, imines, and thiocarbon-
yls (see Figure 2).[10] In the presence of Pd catalysts and by
using specific reaction conditions, their decarbonylation is
also possible, which can make the formyl substituent a tem-
porary protecting group.[11]
Scheme 2. Synthesis of 4-formylpyrazoles.
To the best of our knowledge, no examples have been Table 1, Entry 6). 1,3-Diphenylpyrazole-4-carbaldehyde (1)
reported to date of a palladium-catalyzed direct arylation was recovered unreacted when we employed Cs2CO3 as the
of pyrazoles that contain a formyl substituent at C-4. Such base (see Table 1, Entry 7). The influence of a few different
direct arylations would allow: (1) control of the regioselec- solvents was then examined. NMP and DMF led to a trace
tivity of the arylation, and (2) access to a wide scope of amount of 2, but a large amount of decarbonylated product
pyrazole derivatives. Therefore, the discovery of an effective was formed (see Table 1, Entries 8 and 9).
method for the direct selective coupling at C-5 of 4-formyl-
Next, we studied the scope of this reaction with various
pyrazole derivatives with aryl halides, especially using an (hetero)aryl bromides, 2 mol-% of Pd(OAc)2 as the catalyst,
affordable catalyst and base as well as simple reaction con- KOAc as the base, and DMA as the solvent (see Scheme 3
ditions, would be attractive for synthetic chemists. We now and Tables 2, 3, and 4). Very high yields of 3 and 4 were
report: (1) the conditions for the palladium-catalyzed direct obtained for the coupling reactions of 1 with 4-bromo-
arylation of 4-formylpyrazoles with a series of (hetero)aryl benzonitrile and 4-bromonitrobenzene, respectively (see
bromides using an inexpensive base and an easily accessible Table 2, Entries 1 and 2). Good results were also obtained
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Table 1. Influence of the reaction conditions on the palladium-cata-
lyzed direct arylation of 1,3-diphenylpyrazole-4-carbaldehyde (1)
with 4-bromobenzaldehyde.[a]
Table 2. Palladium-catalyzed direct arylations of 1,3-diphenylpyr-
azole-4-carbaldehyde (1) with para-substituted aryl bromides (see
Scheme 3).[a]
Entry Catalyst (mol-%)
Base Solvent % Yield 2
1
2
3
4
5
6
7
8
9
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (0.5) KOAc DMA
KOAc DMA
54[b]
41[b]
60[b]
21[b]
19[b]
11[c]
0
Pd(OAc)2 (2)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
KOAc DMA
KOAc DMA
CsOAc DMA
NaOAc DMA
Cs2CO3 DMA
KOAc NMP
KOAc DMF
3[c]
4[c]
[a] Reagents and conditions: 4-bromobenzaldehyde (1.0 equiv.),
pyrazole derivative (1.5 equiv.), base (2.0 equiv.), solvent, 16 h,
150 °C. [b] Ͻ10% decarbonylated product was also observed.
[c] Ͼ20% decarbonylated product was also observed.
by using 4-bromoacetophenone and methyl 4-bromobenzo-
ate as the coupling partners, as the desired coupling prod-
ucts 5 and 6 were obtained in 78 and 77% yield, respectively
(see Table 2, Entries 3 and 4). In the presence of 4-chloro-
bromobenzene, 7 was isolated in 68% yield without the
cleavage of the C–Cl bond, which will allow for further
transformations (see Table 2, Entry 5). Even bromobenzene
was reactive under these conditions to produce 9 in 68%
yield, whereas electron-rich 4-bromoanisole gave 10 in only
41% yield (Table 2, Entries 7–9). The oxidative addition of
this aryl bromide appears to be quite slow under these con-
ditions. The use of PdCl(C3H5)(dppb) as a catalyst for this
reaction did not improve the yield.
[a] Reagents and conditions: Pd(OAc)2 (0.02 equiv.), aryl bromide
(1.0 equiv.), pyrazole derivative (1.5 equiv.), KOAc (2.0 equiv.),
DMA, 16 h, 150 °C. [b] PdCl(C3H5)(dppb) (0.02 equiv.) was used
as a catalyst.
The pyridine motif is found in many bioactive com-
pounds. Therefore, the introduction of the pyridine, quin-
olone, or pyrimidine motifs into the pyrazole structure
would also be very useful. We observed that the coupling
Scheme 3.
To enlarge the scope of substrates for this reaction, we reactions between 3-bromopyridine, 3-bromoquinoline, and
also performed the arylations with meta- and ortho-substi- 5-bromopyrimidine with 1,3-diphenylpyrazole-4-carb-
tuted aryl bromides (see Table 3). Aryl bromides that con- aldehyde (1) by again using 2 mol-% of Pd(OAc)2 also pro-
tained nitrile, nitro, acetyl, formyl, or chloro groups in the ceeded nicely to give 19–21 in 60–83% yield (see Table 4).
meta position were successfully coupled with 1,3-di-
We then studied the influence of a substituted benzene
phenylpyrazole-4-carbaldehyde (1) to provide 11–15 in 55– ring at the C-3 position of the pyrazole (see Scheme 4). Six
91% yield (see Table 3, Entries 1–5). By using 3,5-bis(tri- aryl bromides were treated with 3-(4-nitrophenyl)-1-phenyl-
fluoromethyl)bromobenzene and 4-bromo-1-nitro-2-(tri- pyrazole-4-carbaldehyde (22, see Scheme 4, top). A nitro
fluoromethyl)benzene as the coupling partners, the ex- group on the benzene ring appears to have a minor influ-
pected products 16 and 17 were also obtained in the high ence on the reaction, as in all cases the target products 23–
yields of 94 and 80%, respectively (see Table 3, Entries 6 28 were obtained in good to excellent yields. The best re-
and 7). A lower yield of 58% was obtained for 18 by em- sults were obtained by using 4-chlorobromobenzene and
ploying the more congested 2-bromobenzonitrile (see 3,5-bis(trifluoromethyl)bromobenzene as the coupling part-
Table 3, Entry 8).
ners, as 23 and 26 were isolated in 91 and 93% yields,
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Regioselective Palladium-Catalyzed Direct Arylation
Table 3. Palladium-catalyzed direct arylations of 1,3-diphenylpyr- respectively. Lower yields of 62 and 66% of 27 and 28 were
azole-4-carbaldehyde (1) with meta- or ortho-substituted aryl brom-
obtained by employing 3-bromopyridine and 5-bromopyr-
ides (see Scheme 3).[a]
imidine, respectively.
[a] Reagents and conditions: Pd(OAc)2 (0.02 equiv.), aryl bromide
(1.0 equiv.), pyrazole derivative (1.5 equiv.), KOAc (2.0 equiv.),
DMA, 16 h, 150 °C.
Table 4. Palladium-catalyzed direct arylations of 1,3-diphenylpyr-
azole-4-carbaldehyde (1) with heteroaryl bromides (see
Scheme 3).[a]
Scheme 4.
A chloro-substituted benzene ring at C-3 of the pyrazole
was also tolerated. By starting from 29 and 4-bromobenzo-
nitrile and 3,5-bis(trifluoromethyl)bromobenzene, the de-
sired products 30 and 31 were obtained in 88 and 86%
yield, respectively (see Scheme 4, middle). In these cases, no
cleavage of the C–Cl bond was observed. On the other
hand, the presence of a methoxy substituent on the benzene
[a] Reagents and conditions: Pd(OAc)2 (0.02 equiv.), aryl bromide
(1.0 equiv.), pyrazole derivative (1.5 equiv.), KOAc (2.0 equiv.),
DMA, 16 h, 150 °C.
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H. Ben Ammar, H. Doucet et al.
FULL PAPER
lytical grade (99%) was not distilled before use. NaOAc (99+%),
KOAc (99+%), CsOAc (99+%), and Cs2CO3 (99%) were used. 4-
Formylpyrazoles were prepared according to a reported pro-
cedure.[9] Flash chromatography was performed with silica gel
(230–400 mesh). Thin layer chromatography was carried out with
Merck silica gel GF254 plates. Chromatograms were recorded with
a SHIMADZU GC–MS-GP2010S gas chromatograph mass spec-
ring at C-3 of the pyrazole led to low to moderate yields of
33 and 34. Finally, the C-5 arylated products 36, 37, 39,
and 40 were also obtained in good yields from 1-phenylpyr-
azole-4-carbaldehyde (35) and 3-methyl-1-phenylpyrazole-
4-carbaldehyde (38). No arylation at C-3 of 35 was detected
by GC–MS analysis of the crude mixture (see Scheme 4,
bottom).
1
trometer. The H and 13C NMR spectroscopic data were recorded
The decarbonylation of (hetero)arenes in the presence of
a catalytic amount of Pd(OAc)2 and molecular sieves in cy-
with a Bruker Avance-300 or -400 spectrometer. The chemical shifts
are reported in ppm (δ) relative to CDCl3 (1H NMR, 7.26 ppm;
clohexane was recently reported by Maiti and co- 13C NMR, 77.0 ppm).
workers.[11] To further demonstrate that 4-formyl substitu-
Representative Procedure for the Arylation of 4-Formylpyrazoles
ents of pyrazoles can be considered as temporary protecting
groups, we studied the decarboxylation of three different 5-
aryl-substituted pyrazoles. Using quite similar reaction con-
ditions to those reported by Maiti, the decarbonylations of
6, 9, and 11 proceeded nicely to afford 41–43 in 69–90%
yield (see Scheme 5).
without Decarbonylation: The aryl bromide (1 mmol), 1,3-di-
phenylpyrazole-4-carbaldehyde (0.372 g, 1.5 mmol), and KOAc
(0.196 g, 2 mmol) in the presence of Pd(OAc)2 (4.4 mg, 0.02 mmol)
or PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) (see Tables 1, 2, 3, and
4) were dissolved in DMA (4 mL) under argon. The reaction mix-
ture was stirred in a preheated oil bath at 150 °C for 16 h. After
the reaction mixture was cooled to room temperature, the evapora-
tion of the solvent and chromatography on a silica gel column af-
forded the coupling product.
5-(4-Formylphenyl)-1,3-diphenyl-pyrazole-4-carbaldehyde (2): 4-
Bromobenzaldehyde (0.185 g, 1 mmol) and 1,3-diphenylpyrazole-4-
carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 2
1
(0.211 g, 60% yield). H NMR (400 MHz, CDCl3): δ = 10.06 (s, 1
H), 9.95 (s, 1 H), 7.90 (d, J = 8.0 Hz, 2 H), 7.87 (d, J = 8.0 Hz, 2
H), 7.54 (d, J = 8.0 Hz, 2 H), 7.52–7.47 (m, 3 H), 7.36–7.25 (m, 5
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.4, 185.4, 154.9,
146.2, 138.4, 136.7, 133.8, 131.4, 131.1, 129.6, 129.4, 129.3, 129.2,
128.7, 128.6, 125.5, 118.9 ppm. C23H16N2O2 (352.39): calcd. C
78.39, H 4.58; found C 78.48, H 4.69.
Scheme 5.
4-(4-Formyl-2,5-diphenylpyrazol-3-yl)-benzonitrile (3): 4-Bromo-
benzonitrile (0.182 g, 1 mmol) and 1,3-diphenylpyrazole-4-carbal-
dehyde (0.372 g, 1.5 mmol) were employed to afford 3 (0.314 g,
Conclusions
1
90% yield). H NMR (400 MHz, CDCl3): δ = 9.88 (s, 1 H), 7.76
(d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.45–7.38 (m, 5 H),
7.32–7.28 (m, 2 H), 7.20–7.15 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 185.3, 155.2, 144.9, 138.2, 132.6, 132.1, 131.4, 130.9,
129.4, 129.3, 129.2, 128.9, 128.7, 125.5, 118.8, 118.1, 113.5 ppm.
C23H15N3O (349.38): calcd. C 79.07, H 4.33; found C 78.88, H
4.19.
In summary, we have demonstrated that the presence of
a formyl substituent at C-4 of a pyrazole allows the regiose-
lective control of the palladium-catalyzed direct arylation
with aryl bromides. The desired 5-aryl-4-formylpyrazoles
were obtained in good to excellent yields by using 2 mol-%
of Pd(OAc)2 as the catalyst and KOAc as the base. This
method tolerates several functional groups, both on the aryl
bromide and on the benzene ring at C-3 of the pyrazole.
This protocol employs a moderate loading of a phosphine-
free air-stable catalyst and an inexpensive base. In addition,
the major byproducts of these coupling reactions are KBr
and AcOH instead of the metallic salts that are produced by
more classical coupling procedures. This makes this process
economically viable and environmentally attractive. More-
over, the formyl substituent can easily be removed by using
a Pd catalyst, and, therefore, can be considered a temporary
protecting group.
5-(4-Nitrophenyl)-1,3-diphenylpyrazole-4-carbaldehyde
(4):
4-
Bromonitrobenzene (0.202 g, 1 mmol) and 1,3-diphenylpyrazole-4-
carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 4
1
(0.339 g, 92% yield). H NMR (400 MHz, CDCl3): δ = 9.98 (s, 1
H), 8.23 (d, J = 8.2 Hz, 2 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.56 (d, J
= 8.0 Hz, 2 H), 7.53–7.48 (m, 3 H), 7.40–7.25 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 185.4, 155.4, 148.3, 144.4, 138.1,
134.5, 131.7, 130.8, 129.5, 129.4, 129.3, 129.0, 128.7, 125.5, 123.5,
119.0 ppm. C22H15N3O3 (369.37): calcd. C 71.54, H 4.09; found C
71.41, H 4.35.
5-(4-Acetylphenyl)-1,3-diphenylpyrazole-4-carbaldehyde
(5):
4-
Bromoacetophenone (0.199 g, 1 mmol) and 1,3-diphenylpyrazole-
4-carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 5
1
(0.285 g, 78% yield). H NMR (400 MHz, CDCl3): δ = 9.93 (s, 1
H), 7.97 (d, J = 8.0 Hz, 2 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.52–7.47
(m, 5 H), 7.36–7.25 (m, 5 H), 2.63 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 197.9, 186.0, 155.3, 147.3, 139.1, 138.4,
133.1, 131.8, 131.6, 130.0, 129.9, 129.3, 129.2, 129.0, 126.1, 119.6,
27.3 ppm. C24H18N2O2 (366.41): calcd. C 78.67, H 4.95; found C
78.80, H 5.11.
Experimental Section
General Methods: All the reactions were performed under argon
with a Schlenk tube apparatus and predried glassware. All chemical
reactants, except the 4-formylpyrazoles, were obtained from com-
mercial sources and used without further purification. DMAc ana-
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Regioselective Palladium-Catalyzed Direct Arylation
Methyl 4-(4-Formyl-2,5-diphenylpyrazol-3-yl)benzoate (6): Methyl
4-bromobenzoate (0.215 g, 1 mmol) and 1,3-diphenylpyrazole-4-
carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 6
5-(3-Acetylphenyl)-1,3-diphenylpyrazole-4-carbaldehyde (13): 3-
Bromoacetophenone (0.199 g, 1 mmol) and 1,3-diphenylpyrazole-
4-carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 13
1
1
(0.294 g, 77% yield). H NMR (400 MHz, CDCl3): δ = 9.92 (s, 1
(0.282 g, 77% yield). H NMR (400 MHz, CDCl3): δ = 9.94 (s, 1
H), 8.06 (d, J = 8.2 Hz, 2 H), 7.89 (d, J = 8.0 Hz, 2 H), 7.51–7.40 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.89 (s, 1 H), 7.87 (d, J = 8.0 Hz, 1
(m, 5 H), 7.33–7.20 (m, 5 H), 3.94 (s, 3 H) ppm. 13C NMR H), 7.56 (d, J = 8.0 Hz, 1 H), 7.54–7.30 (m, 10 H), 2.52 (s, 3
(100 MHz, CDCl3): δ = 184.3, 165.3, 153.5, 146.0, 137.4, 131.3, H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.0, 185.4, 154.7,
130.3, 130.2, 129.7, 128.7, 128.3, 128.2, 127.5, 127.4, 124.4, 117.8,
51.4 ppm. C24H18N2O3 (382.41): calcd. C 75.38, H 4.74; found C
75.24, H 4.61.
146.8, 138.4, 137.2, 134.9, 131.2, 130.7, 129.4, 129.3 (2 C), 129.2,
128.9, 128.6, 128.5, 128.4, 125.6, 118.7, 26.6 ppm. C24H18N2O2
(366.41): calcd. C 78.67, H 4.95; found C 78.54, H 5.17.
5-(4-Chlorophenyl)-1,3-diphenylpyrazole-4-carbaldehyde (7): 4-
Bromochlorobenzene (0.191 g, 1 mmol) and 1,3-diphenylpyrazole-
4-carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 7
5-(3-Formylphenyl)-1,3-diphenylpyrazole-4-carbaldehyde (14): 3-
Bromobenzaldehyde (0.185 g, 1 mmol) and 1,3-diphenylpyrazole-4-
carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 14
1
1
(0.243 g, 68% yield). H NMR (400 MHz, CDCl3): δ = 9.91 (s, 1
(0.260 g, 74% yield). H NMR (400 MHz, CDCl3): δ = 9.98 (s, 1
H), 7.89 (d, J = 8.0 Hz, 2 H), 7.50–7.25 (m, 12 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.4, 154.5, 146.9, 138.5, 136.1, 131.9,
131.2, 129.3, 129.2, 129.1, 128.9, 128.5, 128.4, 126.2, 125.5,
118.7 ppm. C22H15ClN2O (358.82): calcd. C 73.64, H 4.21; found
C 73.48, H 4.37.
H), 9.94 (s, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.89–7.87 (m, 2 H),
7.62 (d, J = 8.0 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.52–7.25 (m,
9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.2, 185.4, 154.8,
146.1, 138.3, 136.5, 136.2, 131.9, 131.1, 130.5, 129.4, 129.3 (m),
129.2, 129.1, 128.7, 128.6, 125.5, 118.8 ppm. C23H16N2O2 (352.39):
calcd. C 78.39, H 4.58; found C 78.27, H 4.39.
5-(4-Fluorophenyl)-1,3-diphenylpyrazole-4-carbaldehyde (8): 4-
Bromofluorobenzene (0.175 g, 1 mmol) and 1,3-diphenylpyrazole-
4-carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 8
5-(3-Chlorophenyl)-1,3-diphenylpyrazole-4-carbaldehyde (15): 3-
Bromochlorobenzene (0.191 g, 1 mmol) and 1,3-diphenylpyrazole-
4-carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 15
1
(0.243 g, 71% yield). H NMR (400 MHz, CDCl3): δ = 9.80 (s, 1
H), 7.88 (d, J = 8.0 Hz, 2 H), 7.45–7.17 (m, 12 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 184.5, 162.9 (d, J = 253.0 Hz), 153.3, 146.3,
137.5, 131.6, 131.5, 130.3, 128.2, 128.1 (d, J = 8.7 Hz), 127.4, 124.4,
122.7 (J = 3.4 Hz), 117.6, 114.8 (J = 21.6 Hz) ppm. C22H15FN2O
(342.37): calcd. C 77.18, H 4.42; found C 77.01, H 4.27.
1
(0.325 g, 91% yield). H NMR (400 MHz, CDCl3): δ = 9.90 (s, 1
H), 7.90 (d, J = 8.0 Hz, 2 H), 7.52–7.20 (m, 12 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.3, 154.3, 146.8, 138.4, 134.6, 131.2,
130.6, 130.0, 129.8, 129.6, 129.3, 129.2, 128.8, 128.6, 128.5, 128.4,
125.4, 118.8 ppm. C22H15ClN2O (358.82): calcd. C 73.64, H 4.21;
found C 73.80, H 4.07.
1,3,5-Triphenylpyrazole-4-carbaldehyde
(9):[12]
Bromobenzene
(0.157 g, 1 mmol) and 1,3-diphenylpyrazole-4-carbaldehyde
(0.372 g, 1.5 mmol) were employed to afford 9 (0.220 g, 68% yield).
1H NMR (400 MHz, CDCl3): δ = 9.82 (s, 1 H), 7.82 (d, J = 8.0 Hz,
2 H), 7.45–7.10 (m, 11 H), 7.01 (t, J = 7.8 Hz, 2 H) ppm.
5-[3,5-Bis(trifluoromethylphenyl)]-1,3-diphenylpyrazole-4-carb-
aldehyde (16): 3,5-Bis(trifluoromethyl)bromobenzene (0.293 g,
1 mmol) and 1,3-diphenylpyrazole-4-carbaldehyde (0.372 g,
1.5 mmol) were employed to afford 16 (0.432 g, 94% yield). 1H
NMR (400 MHz, CDCl3): δ = 9.99 (s, 1 H), 7.89 (s, 1 H), 7.81 (s,
2 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.52–7.20 (m, 8 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.4, 155.7, 143.1, 137.8, 131.7 (q, J =
34.0 Hz), 130.9 (m), 130.7, 130.1, 129.5, 129.4, 129.3, 129.2, 128.8,
123.2 (m), 122.5 (q, J = 273.0 Hz), 118.7 ppm. C24H14F6N2O
(460.37): calcd. C 62.61, H 3.07; found C 62.41, H 3.00.
5-(4-Methoxyphenyl)-1,3-diphenylpyrazole-4-carbaldehyde (10): 4-
Bromoanisole (0.187 g) and 1,3-diphenylpyrazole-4-carbaldehyde
(0.372 g, 1.5 mmol) were employed to afford 10 (0.145 g, 41%
1
yield). H NMR (400 MHz, CDCl3): δ = 9.80 (s, 1 H), 7.87 (d, J
= 7.8 Hz, 2 H), 7.45–7.20 (m, 10 H), 6.85 (d, J = 7.8 Hz, 2 H), 3.77
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.8, 160.7,
153.9, 149.0, 138.9, 132.0, 131.6, 129.2, 129.1, 129.0, 128.3, 128.1,
125.4, 119.6, 118.5, 114.1, 55.3 ppm. C23H18N2O2 (354.40): calcd.
C 77.95, H 5.12; found C 77.78, H 5.21.
5-(4-Nitro-3-trifluoromethylphenyl)-1,3-diphenylpyrazole-4-carb-
aldehyde (17): 4-Bromo-1-nitro-2-trifluoromethylbenzene (0.270 g,
1 mmol) and 1,3-diphenylpyrazole-4-carbaldehyde (0.372 g,
1.5 mmol) were employed to afford 17 (0.350 g, 80% yield). 1H
NMR (400 MHz, CDCl3): δ = 10.03 (s, 1 H), 7.88 (d, J = 8.0 Hz,
1 H), 7.82–7.75 (m, 4 H), 7.60–7.20 (m, 8 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.8, 156.4, 148.3, 142.3, 138.0, 135.6,
133.2, 130.8 (m), 129.8 (m), 129.2, 128.4, 127.1, 126.6, 126.0, 125.5,
125.3, 125.1, 121.5 (q, J = 274.2 Hz), 119.2 ppm. C23H14F3N3O3
(437.37): calcd. C 63.16, H 3.23; found C 63.02, H 3.42.
3-(4-Formyl-2,5-diphenylpyrazol-3-yl)-benzonitrile (11): 3-Bromo-
benzonitrile (0.182 g, 1 mmol) and 1,3-diphenylpyrazole-4-carbal-
dehyde (0.372 g, 1.5 mmol) were employed to afford 11 (0.307 g,
1
88% yield). H NMR (400 MHz, CDCl3): δ = 9.86 (s, 1 H), 7.75
(d, J = 8.0 Hz, 2 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.56 (s, 1 H), 7.53
(d, J = 8.0 Hz, 1 H), 7.45–7.38 (m, 4 H), 7.32–7.16 (m, 5 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 184.3, 154.1, 143.5, 137.0, 133.8,
132.9, 132.1, 129.9, 128.5, 128.3 (m, 4 C), 127.9, 127.6, 124.5, 117.8,
116.8, 111.9 ppm. C23H15N3O (349.38): calcd. C 79.07, H 4.33;
found C 78.97, H 4.50.
2-(4-Formyl-2,5-diphenylpyrazol-3-yl)-benzonitrile (18): 2-Bromo-
benzonitrile (0.182 g, 1 mmol) and 1,3-diphenylpyrazole-4-carbal-
dehyde (0.372 g, 1.5 mmol) were employed to afford 18 (0.202 g,
5-(3-Nitrophenyl)-1,3-diphenylpyrazole-4-carbaldehyde (12): 3-
Bromonitrobenzene (0.202 g, 1 mmol) and 1,3-diphenylpyrazole-4-
carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 12
1
58% yield). H NMR (400 MHz, CDCl3): δ = 9.99 (s, 1 H), 7.85
(d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.63 (t, J = 8.0 Hz,
1 H), 7.55–7.25 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
185.3, 155.1, 142.6, 138.2, 133.3, 132.6, 132.4, 131.8, 130.9, 130.1,
129.4, 129.3, 129.2, 128.8, 128.7, 125.4, 119.8, 116.8 ppm.
C23H15N3O (349.38): calcd. C 79.07, H 4.33; found C 78.99, H
4.41.
1
(0.203 g, 55% yield). H NMR (400 MHz, CDCl3): δ = 9.99 (s, 1
H), 8.28 (d, J = 8.0 Hz, 1 H), 8.24 (s, 1 H), 7.83 (d, J = 8.0 Hz, 2
H), 7.70 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 1 H), 7.55–7.25
(m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.4, 155.3,
148.0, 144.1, 138.0, 136.5, 130.8, 129.8, 129.5, 129.4, 129.3, 129.2,
129.0, 128.7, 125.7, 125.6, 124.5, 118.9 ppm. C22H15N3O3 (369.37):
calcd. C 71.54, H 4.09; found C 71.27, H 4.01.
1,3-Diphenyl-5-pyridin-3-ylpyrazole-4-carbaldehyde (19): 3-Bromo-
pyridine (0.158 g, 1 mmol) and 1,3-diphenylpyrazole-4-carbal-
Eur. J. Org. Chem. 2014, 1778–1786
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1783

H. Ben Ammar, H. Doucet et al.
FULL PAPER
dehyde (0.372 g, 1.5 mmol) were employed to afford 19 (0.256 g,
79% yield). 1H NMR (400 MHz, CDCl3): δ = 9.96 (s, 1 H), 8.65
(d, J = 3.2 Hz, 1 H), 8.57 (s, 1 H), 7.86 (d, J = 8.0 Hz, 2 H), 7.75
(d, J = 8.2 Hz, 1 H), 7.55–7.20 (m, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 185.4, 155.3, 149.5, 149.1, 143.1, 139.3, 138.0, 130.9,
dehyde (0.439 g, 1.5 mmol) were employed to afford 26 (0.470 g,
93% yield). H NMR (400 MHz, CDCl3): δ = 9.90 (s, 1 H), 8.32
(d, J = 8.5 Hz, 2 H), 8.09 (d, J = 8.5 Hz, 2 H), 7.94 (s, 1 H), 7.79
(s, 2 H), 7.44–7.22 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 184.1, 152.1, 148.3, 145.4, 137.4, 137.2, 132.2 (q, J = 34.1 Hz),
1
129.5 (m), 129.3, 129.0, 128.7, 125.7, 125.1, 123.6, 119.1 ppm. 130.8 (m), 130.1, 129.6, 129.5, 129.4, 125.6, 123.7, 122.5 (q, J =
C21H15N3O (325.36): calcd. C 77.52, H 4.65; found C 77.38, H
4.48.
273.5 Hz), 119.3 ppm. C24H13F6N3O3 (505.37): calcd. C 57.04, H
2.59; found C 56.88, H 2.60.
1,3-Diphenyl-5-quinolin-3-ylpyrazole-4-carbaldehyde (20): 3-Bromo-
quinoline (0.208 g), and 1,3-diphenylpyrazole-4-carbaldehyde
(0.372 g, 1.5 mmol) were employed to afford 20 (0.311 g, 83 %
yield). 1H NMR (400 MHz, CDCl3): δ = 9.93 (s, 1 H), 8.68 (s, 1
H), 8.27 (s, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.84–7.70 (m, 5 H),
7.57 (t, J = 8.0 Hz, 1 H), 7.46–7.40 (m, 4 H), 7.20–7.15 (m, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.4, 155.3, 150.0,
147.3, 143.9, 138.9, 138.2, 131.2, 131.0, 129.5, 129.4, 129.3, 129.1,
3-(4-Nitrophenyl)-1-phenyl-5-pyridin-3-ylpyrazole-4-carbaldehyde
(27): 3-Bromopyridine (0.158 g, 1 mmol) and 3-(4-nitrophenyl)-1-
phenylpyrazole-4-carbaldehyde (0.439 g, 1.5 mmol) were employed
1
to afford 27 (0.229 g, 62% yield). H NMR (400 MHz, CDCl3): δ
= 9.87 (s, 1 H), 8.74 (br. s, 1 H), 8.63 (br. s, 1 H), 8.34 (d, J =
8.5 Hz, 2 H), 8.19 (d, J = 8.5 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 1 H),
7.48–7.25 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 183.4,
150.5, 149.7, 149.4, 147.2, 145.3, 137.1, 136.8, 136.5, 129.1, 128.5,
128.9, 128.6, 128.3, 127.7, 126.9, 125.6, 121.4, 119.2 ppm. 128.2, 124.5, 122.6, 118.6 ppm. C21H14N4O3 (370.36): calcd. C
C25H17N3O (375.42): calcd. C 79.98, H 4.56; found C 80.17, H
4.69.
68.10, H 3.81; found C 68.24, H 3.60.
3-(4-Nitrophenyl)-1-phenyl-5-pyrimidin-5-ylpyrazole-4-carbaldehyde
1,3-Diphenyl-5-pyrimidin-5-ylpyrazole-4-carbaldehyde (21): 5- (28): 5-Bromopyrimidine (0.159 g, 1 mmol) and 3-(4-nitrophenyl)-
Bromopyrimidine (0.159 g, 1 mmol) and 1,3-diphenylpyrazole-4-
1-phenylpyrazole-4-carbaldehyde (0.439 g, 1.5 mmol) were em-
ployed to afford 28 (0.245 g, 66 % yield). 1H NMR (400 MHz,
CDCl3): δ = 9.98 (s, 1 H), 9.27 (s, 1 H), 8.75 (s, 2 H), 8.37 (d, J =
carbaldehyde (0.372 g, 1.5 mmol) were employed to afford 21
1
(0.196 g, 60% yield). H NMR (400 MHz, CDCl3): δ = 10.04 (s, 1
H), 9.22 (s, 1 H), 8.75 (s, 2 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.55–7.20 8.5 Hz, 2 H), 8.09 (d, J = 8.5 Hz, 2 H), 7.48–7.25 (m, 5 H) ppm.
(m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 184.5, 157.7, 13C NMR (100 MHz, CDCl3): δ = 184.0, 159.1, 157.7, 152.6, 148.4,
156.7, 155.0, 138.5, 136.7, 129.6, 128.7, 128.5, 128.4, 128.3, 127.8,
124.8, 118.2 ppm. C20H14N4O (326.35): calcd. C 73.61, H 4.32;
found C 73.40, H 4.19.
141.6, 137.4, 137.1, 130.1, 129.8, 129.7, 125.7, 123.9, 122.7,
119.7 ppm. C20H13N5O3 (371.35): calcd. C 64.69, H 3.53; found C
64.79, H 3.41.
5-(4-Chlorophenyl)-3-(4-nitrophenyl)-1-phenylpyrazole-4-carb- 4-[5-(4-Chlorophenyl)-4-formyl-2-phenylpyrazol-3-yl]-benzonitrile
aldehyde (23): 4-Bromochlorobenzene (0.191 g, 1 mmol) and 3-(4- (30): 4-Bromobenzonitrile (0.182 g, 1 mmol) and 3-(4-chloro-
nitrophenyl)-1-phenylpyrazole-4-carbaldehyde (0.439 g, 1.5 mmol) phenyl)-1-phenylpyrazole-4-carbaldehyde (0.423 g, 1.5 mmol) were
1
were employed to afford 23 (0.367 g, 91 % yield). 1H NMR
(400 MHz, CDCl3): δ = 9.82 (s, 1 H), 8.32 (d, J = 8.5 Hz, 2 H), 8.21
(d, J = 8.5 Hz, 2 H), 7.45–7.25 (m, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 184.8, 151.0, 149.3, 148.1, 138.1, 137.8, 136.7, 131.9,
employed to afford 30 (0.337 g, 88% yield). H NMR (400 MHz,
CDCl3): δ = 9.88 (s, 1 H), 7.84 (d, J = 8.0 Hz, 2 H), 7.69 (d, J =
8.0 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 4 H), 7.40–7.25 (m, 5 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 184.8, 153.5, 145.9, 138.0, 135.6,
130.1, 129.4, 129.3, 128.9, 125.5, 125.3, 123.5, 119.2 ppm. 132.3, 132.2, 131.3, 130.5, 129.5, 129.4, 129.0, 128.8, 125.4, 118.9,
C22H14ClN3O3 (403.82): calcd. C 65.43, H 3.49; found C 65.59, H 117.9, 113.8 ppm. C23H14ClN 3.77.
3.28.
5-[3,5-Bis(trifluoromethylphenyl)]-3-(4-chlorophenyl)-1-phenylpyr-
5-(4-Fluorophenyl)-3-(4-nitrophenyl)-1-phenylpyrazole-4-carb- azole-4-carbaldehyde (31): 3,5-Bis(trifluoromethyl)bromobenzene
aldehyde (24): 4-Bromofluorobenzene (0.175 g, 1 mmol) and 3-(4-
(0.293 g, 1 mmol) and 3-(4-chlorophenyl)-1-phenylpyrazole-4-carb-
nitrophenyl)-1-phenylpyrazole-4-carbaldehyde (0.439 g, 1.5 mmol) aldehyde (0.423 g, 1.5 mmol) were employed to afford 31 (0.425 g,
1
were employed to afford 24 (0.306 g, 79 % yield). 1H NMR
(400 MHz, CDCl3): δ = 9.82 (s, 1 H), 8.32 (d, J = 8.5 Hz, 2 H),
8.23 (d, J = 8.5 Hz, 2 H), 7.42–7.22 (m, 7 H), 7.14 (t, J = 8.0 Hz,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 184.6, 163.8 (d, J =
252.7 Hz), 150.3, 149.3, 147.8, 137.8, 137.5, 132.3 (d, J = 8.7 Hz),
129.7, 129.0, 128.5, 125.0, 123.2, 122.7, 118.8, 116.0 (d, J =
21.6 Hz) ppm. C22H14FN3O3 (387.36): calcd. C 68.21, H 3.64;
found C 68.34, H 3.50.
86% yield). H NMR (400 MHz, CDCl3): δ = 9.88 (s, 1 H), 7.85
(s, 1 H), 7.74 (s, 2 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz,
2 H), 7.35–7.15 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
184.7, 154.0, 144.0, 137.7, 135.7, 131.9 (q, J = 34.0 Hz), 130.9 (m),
130.6, 129.9, 129.5, 129.3, 129.2, 129.0, 125.6, 123.4 (m), 123.0 (q,
J = 273.0 Hz), 118.8 ppm. C24H13ClF6N2O (494.82): calcd. C
58.26, H 2.65; found C 58.04, H 2.84.
5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-1-phenylpyrazole-4-carb-
5-(4-Phenyl)-3-(4-nitrophenyl)-1-phenylpyrazole-4-carbaldehyde aldehyde (33): 4-Bromochlorobenzene (0.191 g, 1 mmol) and 3-(4-
(25): Bromobenzene (0.157 g, 1 mmol) and 3-(4-nitrophenyl)-1-
methoxyphenyl)-1-phenylpyrazole-4-carbaldehyde (0.417 g,
1.5 mmol) were employed to afford 33 (0.136 g, 35% yield). 1H
NMR (400 MHz, CDCl3): δ = 9.87 (s, 1 H), 7.86 (d, J = 8.5 Hz, 2
H), 7.40–7.22 (m, 9 H), 7.01 (d, J = 8.5 Hz, 2 H), 3.87 (s, 3 H) ppm.
phenylpyrazole-4-carbaldehyde (0.439 g, 1.5 mmol) were employed
1
to afford 25 (0.266 g, 72% yield). H NMR (400 MHz, CDCl3): δ
= 9.81 (s, 1 H), 8.32 (d, J = 8.5 Hz, 2 H), 8.27 (d, J = 8.5 Hz, 2
H), 7.50–7.25 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13C NMR (100 MHz, CDCl3): δ = 185.5, 160.5, 154.1, 147.2, 138.5,
185.3, 151.1, 150.6, 148.1, 138.4, 138.1, 130.6, 130.3, 130.1, 129.2,
128.9, 128.7, 127.0, 125.3, 123.4, 119.2 ppm. C22H15N3O3 (369.37):
calcd. C 71.54, H 4.09; found C 71.41, H 4.29.
136.1, 131.9, 130.6, 129.2, 128.9, 128.4, 126.3, 125.4, 123.7, 118.6,
113.9, 55.3 ppm. C23H17ClN2O2 (388.85): calcd. C 71.04, H 4.41;
found C 70.88, H 4.19.
5-[3,5-Bis(trifluoromethylphenyl)]-3-(4-nitrophenyl)-1-phenylpyr-
azole-4-carbaldehyde (26): 3,5-Bis(trifluoromethyl)bromobenzene
(0.293 g, 1 mmol) and 3-(4-nitrophenyl)-1-phenylpyrazole-4-carbal-
5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-1-phenylpyrazole-4-carb-
aldehyde (34): 4-Bromofluorobenzene (0.175 g, 1 mmol) and 3-(4-
methoxyphenyl)-1-phenylpyrazole-4-carbaldehyde (0.417 g,
1784
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1778–1786

Regioselective Palladium-Catalyzed Direct Arylation
1.5 mmol) were employed to afford 34 (0.231 g, 62% yield). 1H
NMR (400 MHz, CDCl3): δ = 9.87 (s, 1 H), 7.78 (d, J = 8.5 Hz, 2
H), 7.35–7.22 (m, 7 H), 7.10 (t, J = 8.0 Hz, 2 H), 7.01 (d, J =
1,3,5-Triphenylpyrazole (42):[13] 1,3,5-Triphenylpyrazole-4-carbal-
dehyde (9, 0.324 g, 1 mmol) was employed to afford 42 (0.204 g,
63% yield). H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.5 Hz,
1
8.5 Hz, 2 H), 3.87 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 2 H), 7.70 (m, 1 H), 7.52 (m, 1 H), 7.47–7.25 (m, 11 H), 6.83 (s, 1
= 184.5, 164.0 (d, J = 252.7 Hz), 159.5, 152.9, 146.6, 137.6, 131.6 H) ppm.
(d, J = 8.7 Hz), 129.6, 128.1, 127.3, 124.4, 122.8 (d, J = 3.4 Hz),
3-(2,5-Diphenylpyrazol-3-yl)benzonitrile (43): 3-(4-Formyl-2,5-di-
122.7, 117.5, 114.8 (d, J = 21.9 Hz), 112.8, 54.3 ppm. C23H17FN2O2
phenylpyrazol-3-yl)benzonitrile (11, 0.349 g, 1 mmol) was em-
(372.39): calcd. C 74.18, H 4.60; found C 74.04, H 4.69.
ployed to afford 43 (0.289 g, 90 % yield). 1H NMR (400 MHz,
4-(4-Formyl-2-phenylpyrazol-3-yl)-benzonitrile (36): 4-Bromobenzo-
nitrile (0.182 g, 1 mmol) and 1-phenylpyrazole-4-carbaldehyde
(0.258 g, 1.5 mmol) were employed to afford 36 (0.227 g, 83 %
yield). 1H NMR (400 MHz, CDCl3): δ = 9.81 (s, 1 H), 8.26 (s, 1
H), 7.69 (d, J = 8.2 Hz, 2 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.40–7.33
(m, 3 H), 7.24–7.20 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 184.3, 144.1, 141.6, 138.1, 132.4, 132.2, 131.0, 129.4, 128.9,
125.3, 122.8, 117.8, 113.8 ppm. C17H11N3O (273.29): calcd. C
74.71, H 4.06; found C 74.84, H 4.00.
CDCl3): δ = 7.83 (d, J = 8.0 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 1 H),
7.59 (s, 1 H), 7.50–7.30 (m, 10 H), 6.88 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 151.3, 140.9, 138.5, 131.8, 131.5, 130.9,
130.7, 128.4, 128.2, 127.7, 127.3, 127.1, 124.8, 124.3, 117.1, 111.9,
104.8 ppm. C22H15N3 (321.37): calcd. C 82.22, H 4.70; found C
82.34, H 4.81.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of new compounds.
5-[3,5-Bis(trifluoromethylphenyl)]-1-phenylpyrazole-4-carbaldehyde
(37): From 3,5-bis(trifluoromethyl)bromobenzene (0.293 g,
1 mmol) and 1-phenylpyrazole-4-carbaldehyde (0.258 g, 1.5 mmol)
were employed to afford 37 (0.299 g, 78 % yield). 1H NMR
(400 MHz, CDCl3): δ = 9.88 (s, 1 H), 8.28 (s, 1 H), 7.92 (s, 1 H),
7.75 (s, 2 H), 7.44–7.20 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 183.9, 142.5, 142.2, 137.7, 132.2 (q, J = 32.2 Hz), 130.4
(m), 129.8, 129.5, 129.3, 125.5, 123.4 (m), 122.7, 122.6 (q, J =
273.0 Hz) ppm. C18H10F6N2O (384.28): calcd. C 56.26, H 2.62;
found C 56.07, H 2.85.
Acknowledgments
I. S. is grateful to UTIQUE for a grant. The authors thank the
Centre National de la Recherche Scientifique (CNRS), the Rennes
Metropole, and the Scientific Ministry of Higher Education and
Research of Tunisia for providing financial support.
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3-Methyl-5-(4-nitrophenyl)-1-phenylpyrazole-4-carbaldehyde (39): 4-
Bromonitrobenzene (0.202 g, 1 mmol) and 3-methyl-1-phenylpyr-
azole-4-carbaldehyde (0.279 g, 1.5 mmol) were employed to afford
1
39 (0.209 g, 68% yield). H NMR (400 MHz, CDCl3): δ = 9.84 (s,
1 H), 8.24 (d, J = 8.2 Hz, 2 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.40–
7.33 (m, 3 H), 7.24–7.17 (m, 2 H), 2.64 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.0, 152.0, 148.4, 145.3, 138.1, 134.1,
131.4, 129.4, 128.7, 125.3, 123.8, 120.0, 13.3 ppm. C17H13N3O3
(307.30): calcd. C 66.44, H 4.26; found C 66.21, H 4.52.
5-[3,5-Bis(trifluoromethylphenyl)}-3-methyl-1-phenylpyrazole-4-
carbaldehyde (40): 3,5-Bis(trifluoromethyl)bromobenzene (0.293 g,
1 mmol) and 3-methyl-1-phenylpyrazole-4-carbaldehyde (0.279 g,
1.5 mmol) were employed to afford 40 (0.302 g, 76% yield). 1H
NMR (400 MHz, CDCl3): δ = 9.87 (s, 1 H), 7.92 (s, 1 H), 7.72 (s,
1 H), 7.40–7.34 (m, 3 H), 7.26–7.16 (m, 3 H), 2.64 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 184.7, 152.2, 144.1, 137.7, 132.2
(q, J = 32.2 Hz), 130.4 (m), 130.0, 129.4, 129.0, 125.5, 123.6 (m),
122.2 (q, J = 273.0 Hz), 119.8 ppm. C19H12F6N2O (398.30): calcd.
C 57.29, H 3.04; found C 57.35, H 2.89.
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Representative Procedure for Deformylation: The pyrazole deriva-
tive (1 mmol) and Pd(OAc)2 (11 mg, 0.05 mmol) were dissolved in
xylene (3 mL) in the presence of molecular sieves (4 Å, 300 mg)
under argon. The reaction mixture was stirred in a preheated oil
bath at 140 °C for 22 h. After cooling the reaction mixture to room
temperature, the evaporation of the solvent and chromatography
on a silica gel afforded the coupling product.
Methyl 4-(2,5-Diphenylpyrazol-3-yl)benzoate (41): Methyl 4-(4-
formyl-2,5-diphenylpyrazol-3-yl)benzoate (6, 0.382 g, 1 mmol) was
1
employed to afford 41 (0.269 g, 76% yield). H NMR (400 MHz,
CDCl3): δ = 7.98 (d, J = 8.2 Hz, 2 H), 7.92 (d, J = 8.0 Hz, 2 H),
7.45–7.35 (m, 10 H), 6.90 (s, 1 H), 3.92 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.5, 151.2, 142.3, 138.9, 133.9, 131.8,
128.7, 128.1, 127.7, 127.6, 127.1, 126.8, 124.8, 124.3, 104.7,
51.2 ppm. C23H18N2O2 (354.40): calcd. C 77.95, H 5.12; found C
78.09, H 4.98.
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5 arylations of pyrazoles, see: Y. L. Choi, H. Lee, B. T. Kim,
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Eur. J. Org. Chem. 2014, 1778–1786
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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H. Ben Ammar, H. Doucet et al.
FULL PAPER
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Received: October 24, 2013
Published Online: January 14, 2014
1786
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1778–1786