Palladium-catalysed direct diarylations of pyrazoles with aryl bromides: A one step access to 4,5-diarylpyrazoles

Article abstract of DOI:10.1016/j.tetlet.2014.01.079

The palladium-catalysed direct arylation of pyrazoles with aryl halides, using PdCl(C₃H₅)(dppb)/KOAc catalyst, reveals a similar reactivity of C4 and C5 CH bonds of pyrazoles, whereas the C3 CH bond is almost unreactive, and gives ac

Full text of DOI:10.1016/j.tetlet.2014.01.079

Accepted Manuscript
Palladium-Catalysed Direct Diarylations of Pyrazoles with Aryl Bromides: A
One Step Access to 4,5-Diarylpyrazoles
Abdelilah Takfaoui, Liqin Zhao, Rachid Touzani, Pierre H. Dixneuf, Henri
Doucet
PII:
S0040-4039(14)00113-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.079
TETL 44112
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 December 2013
13 January 2014
17 January 2014
Please cite this article as: Takfaoui, A., Zhao, L., Touzani, R., Dixneuf, P.H., Doucet, H., Palladium-Catalysed
Direct Diarylations of Pyrazoles with Aryl Bromides: A One Step Access to 4,5-Diarylpyrazoles, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.079
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Graphical Abstract
Palladium-Catalysed Direct Diarylations of
Pyrazoles with Aryl Bromides: A One Step
Access to 4,5-Diarylpyrazoles
Leave this area blank for abstract info.
Abdelilah Takfaoui, Liqin Zhao, Rachid Touzani,* Pierre H. Dixneuf, and Henri Doucet*
The similar reactivity of C4 and C5 C-H bonds of pyrazoles
allows a one step access to 4,5-diarylpyrazoles
R1
H
R2
R2
PdCl(C3H5)(dppb) 2 mol%
KOAc, DMA, 150 °C, 72 h
Br
N
+
R1
H
N
R3
N
R1 = CN, NO2, CHO, COEt, CO2Et, CF3, Cl, F, Me
N
R3
R2 = H, Me
R3 = Me, Ph
R1

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Palladium-Catalysed Direct Diarylations of Pyrazoles with Aryl Bromides: A One
Step Access to 4,5-Diarylpyrazoles
Abdelilah Takfaoui,a,b Liqin Zhao,a Rachid Touzani,b,c* Pierre H. Dixneuf,a and Henri Douceta*
aInstitut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes
"Organométalliques: Matériaux et Catalyse", Campus de Beaulieu, 35042 Rennes, France.
bLaboratoire de Chimie Appliquée et Environnement (LCAE-URAC18), Faculté des Sciences, Université Mohamed Premier,
Oujda, Maroc.
cFaculté Pluridisciplinaire de Nador, Université Mohammed Premier, BP: 300, Selouane 62700, Nador, Maroc
ARTICLE INFO
ABSTRACT
Article history:
Received
.
Received in revised form
Accepted
The palladium-catalysed direct arylation of pyrazoles with aryl halides, using
PdCl(C3H5)(dppb)/KOAc catalyst, reveals the similar reactivity of C4 and C5 C-H bonds of
pyrazoles, whereas C3 C-H bond is almost unreactive, and gives access in one step to a variety
of 4,5-diarylpyrazoles. This C–H bond functionalisation reaction tolerates a variety of
substituents on the aryl bromide such as nitro, cyano, formyl, propionyl, ester, chloro, fluoro or
trifluoromethyl groups. 2009 Elsevier Ltd. All rights reserved
Available online
Keywords:
Pyrazoles
Aryl bromides
C-H activation
Catalysis
Palladium
Among heterocycles, several (di)arylpyrazoles display
attractive compared to classical palladium-catalysed couplings
such as Stille, Suzuki or Negishi reactions as they avoid the
preliminary synthesis of organometallic derivatives. The direct
catalytic arylations of sp2C-H bonds provide only HX associated
to a base as by-product and therefore are offer advantages both in
terms of atom-economy and inert wastes. However, there are
still limitations for these reactions to reach large substrate scope.
Only a few examples of palladium-catalysed direct arylations of
pyrazoles have been reported to date.9-12 This is due to the lack
of regioselectivity observed in the course of these couplings.9
Sames and co-workers have established the regioselectivity of the
catalytic C–H arylation of pyrazoles (Fig. 2).9a SEM-pyrazole
important biological properties. For example, Celecoxib is an
antiinflammatory drug, Ruxolitinib is employed for the treatment
of myelofibrosis, Ipazilide has antiarrhythmic properties and
Fezolamine is an antidepressant agent (Fig. 1).
H
N
F3C
N
N
N
N
N
N
N
N
N
O
N
NC
HN
NEt2
SO2NH2
(SEM
=
2-(trimethylsilyl)ethoxymethyl), reacted with
NEt2
Fezolamine
bromobenzene using 5 mol% of Pd(OAc)2 associated to 7.5
mol% of P(nBu)(Ad)2 as the catalyst, gave a mixture of products,
which indicated the higher reactivity of the 5-position relative to
the 4-position, and very low reactivity of the 3-position (Fig 2).
Ipazilide
Celecoxib
Ruxolitinib
Fig. 1 Examples of bioactive pyrazoles
The synthesis of such arylpyrazoles can be performed
using classical palladium-catalysed cross-coupling reactions such
as Suzuki, Negishi or Stille couplings.1-5 However, these
methods are not very convenient as usually stoichiometric
amounts of two organometallic derivatives have to be prepared
for the cross-coupling reactions. Moreover, they are not
environmentally attractive as they provide an organometallic or a
H
Ph
PhBr +
1.5 equiv.
N
N
+
Ph
H
N
N
Pd(OAc)2 5 mol%
P(n-Bu)(Ad)2 7.5 mol%
H
SEM
SEM
a
b
K2CO3, PivOH 25 mol%,
DMAc, 140 °C, 12 h
N
H
N
Ph
+
SEM
salt (MX) as by-product.
Therefore, to overcome these
N
Ph
N
1 equiv.
limitations, the discovery of more straightforward methods for
the functionalisation of pyrazoles is highly desirable.
c
SEM
Ratio a:b:c 10:2.5:7.5
SEM = Me3SiCH2CH2OCH2
The palladium-catalysed direct arylation of several
(hetero)aromatics via a C–H bond activation using aryl halides
Fig. 2 Regioselectivity of palladium-catalysed direct arylation of
pyrazoles
has led to successes in recent years.6-8 Such couplings are very
———
∗ Corresponding author. Tel.: 00-33-2-23-23-63-84; fax: 00-33-2-23-23-69-39; e-mail: henri.doucet@univ-rennes1.fr

2
Tetrahedron Letters
In the course of this reaction, the 5-phenylpyrazole a
NC
N
was obtained in 40% yield, and the 4-phenylpyrazole b in only
10% yield. Moreover, the formation of an important amount of
4,5-diarylated pyrazole c (30%) was also observed.
N
NC
H
H
2b
2a
N
N
According to Gorelsky calculations, in the concerted
metallation deprotonation (CMD) process, the carbon 5 of 1-
methylpyrazole should be slightly more reactive than carbon 4
(energies of activation: 27.3 vs 28.5); whereas carbon 3 has an
higher energy of activation of 31.3 (Fig. 3).13 This minor
difference of energy of activation between positions 4 and 5
explains the poor regioselectivity observed for Pd-catalysed
arylations of pyrazoles which proceed via a CMD process.
H
N
N
[Pd] 1-2 mol%
base
NC
NC
CN
1
+
NC
Br
N
N
N
N
NC
NC
2d
2c
Scheme
bromobenzonitrile
1
Arylation of 1-methylpyrazole
1
with 4-
Gibbs free energies of activation (∆G298K) of
H
H
31.3
28.5
the cleavage of C-H bonds for
Table 1. Influence of the reaction conditions for palladium-
catalysed direct arylation of 4-bromobenzonitrile with 1-
methylpyrazole 1 (Scheme 1).14,15
N
1-methylpyrazole in the CMD process using
the [Pd(C6H5)(PMe3)(OAc)] catalyst.
H
N
27.3
Me
Entry
Catalyst (mol%)
Base (eq.) Time (h) Ratio
Yield in
2a+2b:2c
2c (%)
Fig. 3 1-Methylpyrazole Gibbs free energies of activation for
CMD process13
1
2
3
4
5
6
7
8
PdCl(C3H5)(dppb) (1)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (1)
PdCl(C3H5)(dppb) (1)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
Pd(OAc)2 (2)
KOAc (4)
K2CO3 (4)
NaOAc (4)
CsOAc (4)
KOAc (6)
KOAc (6)
KOAc (6)
KOAc (6)
20
20
20
20
20
48
72
20
58:42
75:25
70:30
48:52
53:47
42:58
33:67
27:73
To our knowledge, the palladium-catalysed direct
diarylation of pyrazoles to produce 4,5-diarylpyrazoles has not
been investigated, although it would allow a one step access to
useful compounds. Here, taking advantage of relatively similar
reactivities of C4-H and C5-H bonds vs C3 position, we report on
effective conditions for the direct 4,5-diarylations of pyrazoles
using a variety of aryl bromides.
30
35
60
59
Conditions: 4-bromobenzonitrile (3 equiv.), 1-methylpyrazole 1 (1 equiv.),
DMA, under argon, 150 °C.
We had previously observed that the use of
PdCl(C3H5)(dppb) as catalyst, KOAc as the base and DMA as
solvent are effective conditions for the direct arylation of aryl
bromides with several heteroaromatics.8b For this study, we
initially employed 1 mol% of PdCl(C3H5)(dppb) as the catalyst, 4
equiv. of KOAc and DMA at 150 °C during 20 h for the coupling
of 1-methylpyrazole 1 with 3 equiv. of 4-bromobenzonitrile
(Scheme 1, table 1). However, these conditions resulted in the
formation of a mixture of the two mono-arylated pyrazoles 2a
and 2b, whereas the desired diarylated product 2c was only
obtained in 42% selectivity and the triarylated product 2d was
not detected (Table 1, entry 1). Lower selectivities in 2c were
observed in the presence of K2CO3 or NaOAc as bases (Table 1,
entries 2 and 3). CsOAc base allowed to increase the selectivity
in 2c to 52%; however, the formation of several unidentified
side-products was also observed (Table 1, entry 4). This might
be due to the partial degradation of the nitrile function with this
Then, we examined the scope of the coupling of 1-
methylpyrazole 1 with a variety of aryl bromides using 2 mol%
PdCl(C3H5)(dppb) catalyst, 6 equiv. of KOAc as base in DMA
during 72 h (Scheme 2, Tables 2 and 3).
From 4-
bromonitrobenzene, 4-bromobenzaldehyde and ethyl 4-
bromobenzoate, the diarylation products 3c-5c were selectively
produced in 38-41% yields (Table 2, entries 1, 4 and 7). Better
results were obtained in the presence of 4-bromopropiophenone,
4-bromochlorobenzene and 4-bromofluorobenzene as the desired
products 6c-8c were isolated in 54-64% yields (Table 2, entries 9,
11 and 12). In the presence of the electron-rich 4-bromotoluene,
the desired coupling product 10c was only obtained in 34% yield
due to the formation of an important amount of mono-arylation
products (Table 2, entry 14). A few reactions were also
performed using 2 mol% Pd(OAc)2 catalyst; however, similar or
lower yields than in the presence of PdCl(C3H5)(dppb) catalyst
were obtained (Table 2, entries 2, 5, 8, 10). Next, we studied the
reactivity of meta- and ortho-substituted aryl bromides in the
presence of 1-methylpyrazole 1. Quite similar results than with
stronger and more soluble base.
The use of 2 mol%
PdCl(C3H5)(dppb) and 6 equiv. of KOAc as base also allowed to
increase the selectivity in 2c to 47% (Table 1, entry 5). Then we
employed longer reaction times, and we observed that after 48 h,
2c was formed in 58% selectivity (Table 1, entry 6). The best
selectivity was obtained using a reaction time of 72h, with an
isolated yield of 2c of 60% (Table 1, entry 7). The use of
Pd(OAc)2 catalyst without ligand was also very effective for this
coupling, as the desired product 2c was produced in 73%
selectivity and in 59% isolated yield after only 20h (Table 1,
entry 8). It should be noted that, in all cases, no significant
amount of triarylation product 2d was detected by GC/MS
analysis of the crude mixtures.
para-substituted aryl bromides were obtained.
Again,
regioselective diarylations at C4 and C5 positions were observed
in most cases. In the presence of 3-bromobenzonitrile, 3-
(trifluoromethyl)bromobenzene or 2-bromonaphthalene, 11c-13c
were isolated in 44%, 65% and 61% yields, respectively (Table
2, entries 15-17). Even the more congested aryl bromides, 2-
bromobenzonitrile and 1-bromonaphthalene led to the desired
coupling products 14c and 15c in 81% and 51% yields,
respectively (Table 2, entries 18 and 19).
From 2-
fluorobromobenzene and 1 as the coupling partner, 16c was also
isolated in 60% (Table 2, entry 20). For all these reactions, no
trace of unreacted 1 was detected by GC analysis of the crude
mixtures.
R
H
H
PdCl(C3H5)(dppb)
2 mol%
R
N
+
Br
H
N
KOAc, DMA,
150 °C, 72 h
N
N
1
R
2c-20c
Scheme 2 Palladium-catalysed diarylation of 1-methylpyrazole 1
with aryl bromides.

3
2.1 and 4 equiv. of this aryl bromide. In the presence of only
2.1 of the aryl bromide, the 4,5-diarylated pyrazole 17c was
obtained in 46% yield, whereas with 4 equiv. of aryl bromide,
17d was isolated in 67% yield.
Table 2. Palladium-catalysed diarylation of 1-methylpyrazole 1
with substituted aryl bromides (Scheme 2).14,15
Entr
Product
RatioYieldEntry
a+b:c (%)
Product
RatioYield
a+b: (%)
CF3
H
H
Me
O2N
N
F3C
F3C
H
N
PdCl(C3H5)(dppb)
2 mol%
1
1 equiv.
+
N
KOAc, DMA,
150 °C, 72 h
N
N
N
1
2
3
33:67 41 14
33:67 42a
38:62 30b
61:39 34
N
N
F3C
Me
O2N
10c
F3C
3c
17c
CF3
Br
CF3
O
F3C
F3C
F3C
CF3
NC
NC
ArBr
(equiv.)
2.1
3
Ratio
17c:17d (%)
Yield
N
N
N
62:38
33:67
17:83
46 of 17c
4
5
6
39:61 38 15
40:60 37a
38:62 28b
48:52 44
N
N
N
O
11c
4
4c
67 of 17d
F3C
17d
EtO2C
Scheme 3 Palladium-catalysed di- and tri-arylation of 1-
methylpyrazole 1 with 3,5-bis(trifluoromethyl)bromobenzene.
F3C
F3C
We also studied the reactivity of three heteroaryl bromides
containing coordinating atoms (Table 3).
N
N
7
8
38:62 40 16
a
59:41 34
5:95 65c
N
N
From 3-
EtO2C
12c
5c
bromopyridine, 3-bromoquinoline and 4-bromoisoquinoline the
desired diarylation products 18c-20c were obtained in moderate
yields.
Et
O
Table 3. Palladium-catalysed diarylation of 1-methylpyrazole 1
with heteroaryl bromides (Scheme 2).14,15
Ratio
a+b:
9
10
29:71 64 17
51:49 32a
29:71 61
13c
N
N
N
Product
Ratio
a+b
N
O
Entry
Product
Entry
Et
6c
Cl
N
N
CN
1
37:63
3
34:66
N
N
N
N
N
N
N
N
N
11
30:70 60 18
9:91 81
N
Cl
7c
CN
14c
18c 48%
20c 53%
F
N
12
40:60 54 19
38:62 51
N
N
N
2
N
N
N
40:60
N
F
8c
15c
19c 42%
F
Conditions: PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (3 mmol.), 1-
methylpyrazole 1 (1 mmol.), KOAc (6 mmol.), DMA (6 mL), 72 h, 150 °C,
isolated yields.
13
39:61 52 20
30:70 60
N
N
N
Finally, the reactivity of two 1-phenylpyrazoles was evaluated
(Scheme 4). The presence of phenyl substituent on nitrogen
atom or of a methyl substituent at C3 does not significantly
modify the reactivity of pyrazoles. From 1 equiv. of 1-
phenylpyrazole 21 or 1-phenyl-3-methylpyrazole 23, and 3
equiv. of 4-bromobenzonitrile, the target products 22c and 24c
were obtained in similar yields of 40% and 43%, respectively.
A high yield of 78% in 25c was obtained in the presence of 3,5-
bis(trifluoromethyl)bromobenzene and 23 as the coupling
partners.
N
F
16c
9c
Conditions: PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (3 mmol.), 1-
methylpyrazole 1 (1 mmol.), KOAc (6 mmol.), DMA (6 mL), 72 h, 150 °C,
c
a
isolated yields. Pd(OAc)2 (0.02 mmol), 20 h.
b
CsOAc (6 mmol.).
Formation of triarylated pyrazole was also observed by GC/MS analysis in <
10% yield.
The reactivity of 3,5-bis(trifluoromethyl)bromobenzene was
found to be very different to other aryl bromides, as in the
presence of 3 equiv. of this reactant the formation of a large
amount of 3,4,5-triarylated pyrazole 17d was observed with a
ratio 17c:17d of 33:67 (Scheme 3). In order to obtain higher
selectivities, we performed two other coupling reactions using

4
Tetrahedron Letters
4. For synthesis of arylpyrazoles using Kumada coupling: (a)
H
R
Felding, J.; Kristensen, J.; Bjerregaard, T.; Sander, L.; Vedso, P.;
Begtrup, M. J. Org. Chem. 1999, 64, 4196-4198; (b) Ichikawa, H.;
Ohno, Y.; Usami, Y.; Arimoto, M. Heterocycles 2006, 68, 2247-
2252.
R
R
PdCl(C3H5)(dppb)
2 mol%
N
H
N
+
Br
N
N
R
KOAc, DMA,
150 °C, 72 h
5. For synthesis of arylpyrazoles using Stille coupling: (a) Elguero,
J.; Jaramillo, C.; Pardo, C. Synthesis 1997, 563-566; (b) Jeon, S.-
L.; Choi, J. H.; Kim, B. T.; Jeong, I. H. J. Fluorine Chem. 2007,
128, 1191-1197.
R
R
H
Me
3 equiv.
21
23
1 equiv.
6. (a) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200-205; (b)
Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007,
40, 35-41; (c) Seregin, I. V.; Gevoryan, V. Chem. Soc. Rev. 2007,
36, 1173-1193; (d) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008,
949-957; (e) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269-
10310; (f) Ackermann, L.; Vincente, R.; Kapdi, A. R. Angew.
Chem. Int. Ed. 2009, 48, 9792-9826; (g) Roger, J.; Gottumukkala,
A. L.; Doucet, H. ChemCatChem 2010, 2, 20-40; (h) Fischmeister,
C.; Doucet, H. Green Chem. 2011, 13, 741-753; (i) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem.
Int. Ed. 2012, 51, 10236-10254; (j) Yamaguchi, J.; Yamaguchi, A.
D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960-9009; (k)
Wencel-Delord, J.; Glorius, F. Nature Chem. 2013, 5, 369-375; (l)
Kuzhushkov, S. I.; Potukuchi, H. K.; Ackermann, L. Catal. Sci.
Technol. 2013, 3, 562-571; (m) Yuan, K.; Doucet H.
ChemCatChem 2013, 5, 3495-3496.
CF3
NC
NC
F3C
F3C
Me
Me
N
N
N
N
N
N
NC
NC
F3C
25c 78%
22c 40%
24c 43%
Scheme 4 Palladium-catalysed diarylation of 1-phenylpyrazoles
21 and 23 with aryl bromides.
In summary, taking advantage of the relatively similar
energies of activation of positions C4 and C5 of pyrazoles vs C3
7. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.;
Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990,
31, 1951-1958.
for
palladium-catalysed
couplings
via
C-H
bonds
activation/functionalisation reactions, we have shown here that a
range of (hetero)aryl bromides react similarly at both C4 and C5
positions of pyrazoles, but without arylation at C3, except by
using 3,5-bis(trifluoromethyl)bromobenzene, to give in only one
step 4,5-diarylpyrazoles. It should be noted that this protocol,
which employs a moderate loading of an air stable catalyst and an
inexpensive base, is compatible with a range of functions,
including electron-withdrawing reactive ones, such as chloro,
formyl, propionyl, ester, nitrile or nitro on the aryl bromide
allowing further transformations. The major by-products of these
couplings are KBr/AcOH instead of metallic salts with more
classical coupling procedures. For these reasons, this process
gives a simpler and greener access to these diarylpyrazoles.
8. For recent contributions on direct arylations or vinylations of
(hetero)aromatics from our laboratory: (a) Beydoun, K.; Zaarour,
M.; Williams, J. A. G.; Doucet, H.; Guerchais, V. Chem.
Commun. 2012, 48, 1260-1262; (b) Zhao, L.; Bruneau, C.;
Doucet, H. ChemCatChem 2013, 5, 255-262; (c) Yuan, K.;
Doucet, H. Chem. Sci. 2014, 5, 392-396.
9. For studies on the regioselectivity of the intermolecular direct
arylation of pyrazoles: (a) Goikhman, R.; Jacques, T. L.; Sames,
D. J. Am. Chem. Soc. 2009, 131, 3042-3048; (b) Beladhria, A.;
Beydoun, K.; Ben Ammar, H.; Ben Salem, R.; Doucet, H.
Synthesis 2011, 2553-2560.
10. For examples of Pd-catalysed direct intermolecular 5-arylations of
pyrazoles: (a) Rene, O.; Fagnou, K. Adv. Synth. Catal. 2010, 352,
2116-2120; (b) Mateos, C.; Mendiola, J.; Carpintero, M.;
Minguez, J. M. Org. Lett. 2010, 12, 4924-4927; (c) Gaulier, S. M.;
McKay, R.; Swain, N. A. Tetrahedron Lett. 2011, 52, 6000-6002;
(d) Yang, Y.; Kuang, C.; Jin, H.; Yang, Q.; Zhang, Z. Beil. J. Org.
Chem. 2011, 1656-1662; (e) Yan, T.; Chen, L.; Bruneau, C.;
Dixneuf, P. H.; Doucet, H. J. Org. Chem. 2012, 77, 7659-7664;
For examples of Pd-catalysed direct intramolecular 5-arylations of
pyrazoles: (f) Choi, Y. L.; Lee, H.; Kim, B. T.; Choi, K.; Heo, J.-
N. Adv. Synth. Catal. 2010, 352, 2041-2049.
Acknowledgments
We thank the Centre National de la Recherche Scientifique,
“Rennes Metropole”, the Université Mohamed Premier and
“Faculté des Sciences d’Oujda” for providing financial support.
References and notes
11. For examples of palladium-catalysed direct intermolecular 4-
arylations of 5-substituted pyrazoles: (a) Fall, Y.; Doucet, H.;
Santelli, M. Synthesis 2010, 127-135; (b) Derridj, F.; Roger, J.;
Djebbar, S.; Doucet, H. Adv. Synth. Catal. 2012, 354, 747-750;
see also ref 10e.
1. a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry,
Pergamon: Amsterdam, 2000; b) Negishi, E. Ed. Handbook of
Organopalladium Chemistry for Organic Synthesis; Wiley-
Interscience: New York, 2002; Part III, p 213.
2.
For synthesis of arylpyrazoles using Suzuki coupling: (a) Walker,
S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871-1876; (b) Liu, B.; Moffett, K. K.;
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12. For an example of triarylation of a pyrazole: Shibahara, F.;
Yamaguchi, E.; Murai, T. J. Org. Chem. 2011, 76, 2680-2693.
13. Gorelsky, S. I. Coord. Chem. Rev. 2013, 257, 153-164.
14. General procedure for the direct diarylation of 1-methylpyrazole
1, 1-phenylpyrazole 21 and 3-methyl-1-phenylpyrazole 23: In a
typical experiment, the aryl bromide (3 mmol), heteroaromatic 1,
21 or 23 (1 mmol), KOAc (0.588 g,
6 mmol) and
PdCl(C3H5)(dppb)16 (0.012 g, 0.02 mmol) were dissolved in DMA
(4 mL) under an argon atmosphere. The reaction mixture was
stirred at 150 °C for 72 h. Then, the solvent was evaporated and
the product was purified by silica gel column chromatography.
15. All new compounds gave satisfactory 1H, 13C and elementary
analysis. 4-(2-Methylpyrazol-3-yl)-benzonitrile (2a):9b 1H (400
MHz, CDCl3) δ = 7.79 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz,
2H), 7.55 (d, J = 1.8 Hz, 1H), 6.39 (d, J = 1.8 Hz, 1H), 3.92 (s,
3H). 4-(1-Methylpyrazol-4-yl)-benzonitrile (2b):9b 1H (400
MHz, CDCl3) δ = 7.82 (s, 1H), 7.71 (s, 1H), 7.69 (d, J = 8.5 Hz,
2H), 7.62 (d, J = 8.5 Hz, 2H), 3.99 (s, 3H). 1-Methyl-4,5-bis[(4-
cyanophenyl)]-pyrazole (2c):9b 1H (400 MHz, CDCl3) δ= 7.81 (d,
J = 8.5 Hz, 2H), 7.79 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.45 (d, J =
8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 3.83 (s, 3H).
3. For synthesis of arylpyrazoles using Negishi coupling: (a) Balle,
T.; Andersen, K.; Vedso, P. Synthesis 2002, 1509-1512; (b) Milne,
J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028-13032.
16. Cantat, T.; Génin, E.; Giroud, C.; Meyer, G.; Jutand, A. J.
Organomet. Chem. 2003, 687, 365-376.