Palladium-catalyzed direct arylation of pyrazole derivatives: A green access to 4-arylpyrazoles

Article abstract of DOI:10.1055/s-0029-1217075

1,3,5-Trisubstituted pyrazoles were found to be suitable partners for palladium-catalyzed direct arylation via C-H activation/functionalization using aryl bromides. The reaction conditions and the catalyst have a determining influence on the yields. The system using palladium(II) acetate as the catalyst, potassium acetate as the base, and N,N-dimethylacetamide as the solvent promotes selective 4-arylations in moderate to high yields. Several aryl and heteroaryl bromide derivatives have been employed successfully; their electronic properties have a decisive influence on the yields of coupling products. Electron-poor aryl bromides gave satisfactory results, whereas the electron-rich ones gave lower yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217075

PAPER
127
Palladium-Catalyzed Direct Arylation of Pyrazole Derivatives:
A Green Access to 4-Arylpyrazoles
P
alladium-Catalyz
a
e
d
D
irect
A
c
rylation of
o
Pyrazole
D
e
u
rivatives b Fall,a Henri Doucet,*b Maurice Santelli*a
a
Laboratoire de Synthèse Organique (Equipe Chirosciences, Associée au CNRS, UMR 6263), Faculté des Sciences de Saint Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
E-mail: m.santelli@univ-cezanne.fr
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes ‘Catalyse et Organometalliques’, Campus de Beaulieu,
35042 Rennes, France
b
Fax +33(2)23236939; E-mail: henri.doucet@univ-rennes1.fr
Received 3 September 2009
Since the discovery by Ohta and co-workers of the palla-
dium-catalyzed coupling of aryl halides with heteroaryl
derivatives via C–H bond activation,6 very exciting results
for the coupling of a variety of heteroaryl derivatives with
Abstract: 1,3,5-Trisubstituted pyrazoles were found to be suitable
partners for palladium-catalyzed direct arylation via C–H activa-
tion/functionalization using aryl bromides. The reaction conditions
and the catalyst have a determining influence on the yields. The sys-
tem using palladium(II) acetate as the catalyst, potassium acetate as aryl iodides, bromides, and even chlorides have been re-
ported by several groups.7–15 On the other hand, to our
knowledge, the direct coupling of pyrazoles with aryl ha-
the base, and N,N-dimethylacetamide as the solvent promotes selec-
tive 4-arylations in moderate to high yields. Several aryl and het-
eroaryl bromide derivatives have been employed successfully; their
lides via C–H bond activation/functionalization has at-
electronic properties have a decisive influence on the yields of cou-
tracted much less attention.16–18 An intramolecular version
pling products. Electron-poor aryl bromides gave satisfactory re-
of this reaction with the activation of the C–H bond in po-
sition C3 of a pyrazole has been reported.16 Using a 4-sub-
stituted pyrazole, and palladium(II) acetate as the catalyst,
the intramolecular cyclization produces a tetracyclic com-
pound in 75% yield. Recently, Sames and co-workers
have established the regioselectivity of the catalytic C–H
arylation of pyrazoles.17 [2-(Trimethylsilyl)ethoxymeth-
yl]pyrazole (SEM-pyrazole) reacted with bromobenzene
using palladium(II) acetate (5 mol%) and an electron-rich
and congested phosphine di-1-adamantylbutylphosphine
[Bu(Ad)2P, 7.5 mol%] 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. The arylation of 1-SEM-5-phenylpyra-
zole was quite selective, taking place at the 4-position to
afford 1-SEM-4,5-diphenylpyrazole in 51% yield.
sults, whereas the electron-rich ones gave lower yields.
Key words: pyrazoles, palladium catalysis, C–H arylation, aryl
bromide
Heteroaryl derivatives, including arylpyrazoles, are im-
portant building blocks in organic synthesis due to their
biological properties. The coupling reactions of pyrazoles
with aryl halides provides an efficient method for the
preparation of these compounds.1 One of the classical
methods to perform such coupling reactions is to employ
an aryl halide with an organometallic pyrazole derivative
or a halopyrazole with an organometallic aryl derivative
using a palladium catalyst (Scheme 1). However, these re-
actions require the preliminary preparation of organome-
tallic derivatives, such as ArB(OR)2,2 ArZnX,3 ArMgX,4
or ArSnR3,5 and provide either an organometallic or a salt
(MX) as the byproduct.
If an example of palladium-catalyzed intermolecular di-
rect 4-arylation of a pyrazole has been described, to the
best of our knowledge, the influence of the reaction con-
ditions, palladium source, and loading and also the effect
of the nature of the substituents on the aryl halides or on
the pyrazole derivatives have not been reported. Here, we
wish to report on the palladium-catalyzed 4-arylation of a
set of 1,3,5-trisubstituted pyrazoles using of a wide vari-
ety of aryl bromides.
R2M
X
R3
N
N
N
R1
+
[Pd]
[Pd]
N
R1
+
(base)
(base)
N
N
R3
R3
R1
MR2
Our first goal was to determine the most suitable reaction
conditions for the direct coupling of 4-bromoacetophe-
none with 1,3,5-trimethylpyrazole (1) (Table 1). We have
already reported the direct 4-arylation of a range of pyr-
roles, furans, or thiophene derivatives using ligand-less
palladium catalysts.15 Based on these results, the first re-
actions were performed at 140–150 °C under argon in the
presence 0.01–0.05 mol% palladium(II) acetate as the cat-
alyst using several bases and solvents. The formation of
product 2a was observed in most cases, however, we ob-
X
+
R2MX/base
R2M = ZnX, MgX, B(OR)2, SnBu3
Scheme 1
SYNTHESIS 2010, No. 1, pp 0127–0135
x
x
.
x
x
.2
0
0
9
Advanced online publication: 22.10.2009
DOI: 10.1055/s-0029-1217075; Art ID: Z18409SS
© Georg Thieme Verlag Stuttgart · New York

128
Y. Fall et al.
PAPER
served that the reaction conditions and the nature of the pling with Pd(OAc)2, PdCl2(PhCN)2, PdCl2, Pd2(dba)3, or
base, solvent, and catalyst have a determining influence [PdCl(C3H5)]2 without added ligand (Table 1, entries 5–
on the reaction yield. N,N-Dimethylacetamide (DMAc) as 9). The best yield was obtained using palladium(II) ace-
solvent and using potassium acetate as the base gave the tate as the catalyst precursor. For this reaction, the pres-
coupling product 2a in 92% yield, whereas N-methylpyr- ence of monodentate or bidentate phosphine ligands, such
rolidin-2-one, N,N-dimethylformamide, or dimethyl sul- as triphenylphoshine, tricyclohexylphosphine, or 1,2-
foxide led to partial conversions of 4-bromoacetophenone bis(diphenylphosphino)ethane, did not increase the yield
and to moderate yields of 2a (Table 1, entries 1–4). More- of 2a (Table 1, entries 14–16).
over, with N,N-dimethylacetamide, high selectivity in fa-
vor of the formation of 2a was observed. Then, we
examined the influence of the base for this reaction. Potas-
Then, we tried to evaluate the scope and limitations of this
procedure using palladium(II) acetate as the catalyst, po-
tassium acetate as the base, and N,N-dimethylacetamide
sium carbonate and cesium carbonate led to the formation
as the solvent at 150 °C with several 1,3,5-trisubstituted
of 2a in 7% and 17% yields, respectively (Table 1, entries
pyrazole derivatives and aryl bromides (Scheme 2,
Tables 2– 6). para-Substituted aryl bromides reacted with
1,3,5-trimethylpyrazole (1) to give satisfactory results in
most cases (Scheme 2, Table 2). Electron-poor aryl bro-
10 and 12). In the presence of palladium(II) acetate (0.5
mol%) as the catalyst, the most suitable base appears to be
potassium acetate which gave 2a in 75% yield, whereas
sodium acetate gave 2a in only 25% yield (Table 1, en-
mides such as 4-bromobenzophenone, 4-bromobenzoni-
tries 9 and 13). Then, we examined the influence of the
trile, or 1-bromo-4-(trifluoromethyl)benzene gave the 4-
catalyst precursor on this reaction. We performed the cou-
arylated pyrazoles 2b–f,h in 71–84% yields (Table 2, en-
Table 1 Influence of the Reaction Conditions for Palladium-Catalyzed Coupling of 4-Bromoacetophenone with 1,3,5-Trimethylpyrazole
O
O
[Pd]
+
N
Br
base
N
Me
N
N
1
2a
Me
Entry
Catalysta
Ratio substrate/ Solvent
catalyst
Base
Temp. (°C)
Conv.b
Yieldc (%)
1
2
Pd(OAc)2
100
100
100
100
100
200
200
100
200
200
200
200
200
200
200
200
NMP
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
NaHCO3
Cs2CO3
NaOAc
KOAc
KOAc
KOAc
140
140
140
140
140
140
150
150
150
150
150
150
150
150
150
150
85
90
70
100
100
100
75
63
90
10
0
40
51
31
92
62
51
65
50
75
7
Pd(OAc)2
DMF
3
Pd(OAc)2
DMSO
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
4
Pd(OAc)2
5
PdCl2(PhCN)2
0.5 [PdCl(C3H5)]2
PdCl2
6
7
8
0.5 Pd2(dba)3
Pd(OAc)2
9
10
11
12
13
14
15
16
Pd(OAc)2
Pd(OAc)2
–
Pd(OAc)2
22
35
82
84
60
17
25
60
64
45
Pd(OAc)2
Pd(OAc)2, 2 Ph3P
Pd(OAc)2, 2 Cy3P
Pd(OAc)2, dppe
a Reagents and conditions: 4-bromoacetophenone (1 mmol), 1,3,5-trimethylpyrazole (1, 1.5 mmol), base (2 mmol), 20 h.
b Conversion of 4-bromoacetophenone determined by GC and NMR analysis.
c Isolated yield.
Synthesis 2010, No. 1, 127–135 © Thieme Stuttgart · New York

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Palladium-Catalyzed Direct Arylation of Pyrazole Derivatives
129
Table 3 Palladium-Catalyzed Reaction of meta- or ortho-Substitut-
ed Aryl Bromides with 1,3,5-Trimethylpyrazole (1) (Scheme 2)a
tries 1–5 and 7). A lower yield was obtained in the pres-
ence of 1-bromo-4-nitrobenzene due to the formation of
side products (Table 2, entry 6). Slightly deactivated aryl
bromides, 1-bromo-4-tert-butylbenzene or 4-bromotolu-
ene were also found to give the desired coupling products
2i,j in good yields (Table 2, entries 8 and 9). On the other
hand, 4-bromoanisole and especially 1-bromo-4-(dimeth-
ylamino)benzene gave the expected compounds 2k,l in
low to moderate yields (Table 2, entries 10 and 11). The
oxidative addition of the aryl bromides to palladium
seems to be the rate-limiting step of the reaction in the
presence of this ligand-less catalyst.
Entry
Ar
Product
3a
Yieldb (%)
1
2
3
4
5
6
3,5-(F3C)2C6H3
3-OHCC6H4
6-methoxy-2-naphthyl
2-OHCC6H4
2-NCC6H4
80
74
78c
79
80
76
3b
3c
3d
3e
1-naphthyl
3f
a Reagents and conditions: Pd(OAc)2 (0.005 mmol), ArBr (1 mmol),
Ar
Pd(OAc)2
1,3,5-trimethylpyrazole (1, 1.5 mmol), KOAc (2 mmol), DMAc, 150
ArBr
+
N
N
°C, 20 h
N
b Isolated yields.
c Pd(OAc)2 (0.01 mmol).
KOAc, DMAc, 150 °C, 20 h
N
Me
2–4
Me
1
lated on C4 using sterically congested aryl bromide, 1-
bromonaphthalene, as the coupling partner (Table 3, entry
6).
Scheme 2
Table 2 Palladium-Catalyzed Reaction of para-Substituted Aryl
Bromides with 1,3,5-Trimethylpyrazole (1) (Scheme 2)a
Pyridines, quinolines, and pyrimidines are p-electron de-
ficient heterocycles, therefore, their oxidative addition to
palladium is generally easy. We observed that the reaction
of 1,3,5-trimethylpyrazole (1) with 3- or 4-bromopy-
ridines or 3-bromoquinoline gave 4a–c in 73–80% yields
(Scheme 2, Table 4, entries 1–3). Congested heteroaryl
bromide, 4-bromoisoquinoline gave 4d in 78% isolated
yield (Table 4, entry 4). 5-Bromopyrimidine also led to
the desired 4-arylated pyrazole 4e in high yield (Table 4,
entry 5).
Entry
Ar
Product
2b
2c
Yieldb (%)
82
1
2
4-OHCC6H4
4-BzC6H4
4-MeO2CC6H4
4-NCC6H4
4-F3CC6H4
4-O2NC6H4
4-FC6H4
80
3
2d
2e
71
4
84
5
2f
80
Next, the reactivity of 3,5-dimethyl-1-phenylpyrazole (5)
was examined (Table 5). To our knowledge, the direct 4-
arylation of 1-arylpyrazole has not been reported so far.
Such arylations should be useful as some of these com-
pounds, such as Isofezolac or Pyrazolac, have biological
properties (nonsteroidal anti-inflammatory drugs). 3,5-
Dimethyl-1-phenylpyrazole (5) appears to be slightly less
reactive than 1,3,5-trimethylpyrazole (1). This reactant
gave the expected 4-arylated 1-phenylpyrazoles 6a–g in
6
2g
41c
7
2h
2i
78c
8
4-t-BuC6H4
4-MeC6H4
4-MeOC6H4
4-Me2NC6H4
77c
9
2j
74c
10
11
2k
2l
55c
11c
a Reagents and conditions: Pd(OAc)2 (0.005 mmol), ArBr (1 mmol),
1,3,5-trimethylpyrazole (1, 1.5 mmol), KOAc (2 mmol), DMAc, 150
Table 4 Palladium-Catalyzed Reaction of Heteroaryl Bromides
with 1,3,5-Trimethylpyrazole (1) (Scheme 2)a
°C, 20 h.
b Isolated yields.
c Pd(OAc)2 (0.01 mmol).
Entry
Ar
Product
4a
Yieldb (%)
1
2
3
4
5
3-pyridyl
80
73d
75
78
80
4-pyridylc
quinolin-3-yl
isoquinolin-4-yl
pyrimidin-5-yl
4b
Next, we examined the reactivity of meta- or ortho-substi-
tuted aryl bromides (Scheme 2, Table 3). As expected, 1-
bromo-3,5-bis(trifluoromethyl)benzene or 3-bromobenz-
aldehyde gave the coupling products 3a,b in good yields
(Table 3, entries 1 and 2). ortho-Substituents on aryl bro-
mides generally have a more important effect on the rates
and yields of palladium-catalyzed reactions due to their
steric or coordination properties. However, we observed
that 2-bromobenzaldehyde or 2-bromobenzonitrile, also
gave high yields of products 3d,e (Table 3, entries 4 and
5). 1,3,5-Trimethylpyrazole (1) was also successfully ary-
4c
4d
4e
a Reagents and conditions: Pd(OAc)2 (0.005 mmol), ArBr (1 mmol),
1,3,5-trimethylpyrazole (1, 1.5 mmol), KOAc (2 mmol), DMAc, 150
°C, 20 h.
b Isolated yields.
c From 4-bromopyridine hydrochloride.
d Pd(OAc)2 (0.01 mmol).
Synthesis 2010, No. 1, 127–135 © Thieme Stuttgart · New York

130
Y. Fall et al.
PAPER
58–80% yields. However, the reaction is limited to elec-
tron-deficient aryl bromides such as 2- or 4-bromoben-
zonitrile or 4-bromobenzaldehyde and to bromopyridine
derivatives. When we employed 4-bromoanisole as the
coupling partner, no formation of 4-arylation product was
detected.
Table 6 Palladium-Catalyzed Reaction of Aryl Bromides with 1-
tert-Butyl-3,5-dimethylpyrazole (7)a
Ar
Pd(OAc)2
N
N
+
ArBr
N
N
KOAc, DMAc, 150 °C, 20 h
Table 5 Palladium-Catalyzed Reaction of Aryl Bromides with 3,5-
Dimethyl-1-phenylpyrazole (5)a
7
8
Yieldb (%)
Ar
Entry
Ar
Product
Pd(OAc)2
N
+
1
2
3
4
5
6
4-NCC6H4
8a
8b
8c
8d
8e
8f
79
74
77
73
78
79
ArBr
N
N
N
KOAc, DMAc, 150 °C, 20 h
4-OHCC6H4
4-BzC6H4
Ph
5
Ph
6
Entry
Ar
Product
Yieldb (%)
2-NCC6H4
1
2
3
4
5
6
7
4-OHCC6H4
4-BzC6H4
6a
6b
6c
6d
6e
6f
58
70
80
66
69c
64c
80
quinolin-3-yl
pyrimidin-5-yl
a Reagents and conditions: Pd(OAc)2 (0.005 mmol), ArBr (1 mmol),
1-tert-butyl-3,5-dimethylpyrazole (7, 1.5 mmol), KOAc (2 mmol),
DMAc, 150 °C, 20 h.
4-NCC6H4
2-NCC6H4
3-pyridyl
b Isolated yields.
quinolin-3-yl
pyrimidin-5-yl
N
6g
N
Pd(OAc)2 (2 mol%)
Bu(Ad)2P (5 mol%)
a Reagents and conditions: Pd(OAc)2 (0.01 mmol), ArBr (1 mmol),
3,5-dimethyl-1-phenylpyrazole (5, 1.5 mmol), KOAc (2 mmol),
DMAc, 150 °C, 20 h.
Br
N
+
DMAc, KOAc,
150 °C, 20 h
O
b Isolated yields.
N
O
N
c Pd(OAc)2 (0.02 mmol).
EtO
Me
N
EtO
Me
25% 10
We also studied the reactivity of commercially available
1-tert-butyl-3,5-dimethylpyrazole (7) for such couplings
(Table 6). The use of this reactant, which has not been em-
ployed so far for direct arylations, should be very useful
in organic synthesis, as the tert-butyl substituent can be
removed under acidic conditions to give the free N–H
pyrazole.19 The reactions performed in the presence of this
pyrazole derivative were found to be very clean using our
ligand-less palladium procedure. Both para- and ortho-
substituted aryl bromides and also heteroaryl bromides
gave the target compounds 8a–f in good yields. For these
couplings only 0.5 mol% palladium(II) acetate was em-
ployed as the catalyst.
9
Scheme 3
NC
NC
Br
Pd(OAc)2 (2 mol%)
Bu(Ad)2P (5 mol%)
+
DMAc, KOAc,
150 °C, 20 h
O
O
N
N
N
N
EtO
EtO
Me
Me
22% 11
9
Scheme 4
Finally, we examined the reactivity of a pyrazole deriva-
tive substituted on position 5 by an ester (Schemes 3
and 4). When using the palladium ligand-less procedure,
no formation of products 10 or 11 was detected. On the
other hand, in the presence of palladium(II) acetate/di-1-
adamantylbutylphosphine as the catalyst, the 4-arylated
products 10 and 11 were obtained in low yields. In the
course of these two reactions, an important amount of the
aryl bromide homocoupling products was formed. The
presence of such electron-withdrawing function on the
pyrazole ring seems to slow down the arylation rate.
In summary, 1,3,5-trisubstituted pyrazoles are useful re-
actants in palladium-catalyzed direct arylation using aryl
bromides. The use of 0.5–1 mol% palladium(II) acetate
with potassium acetate as the base and N,N-dimethylacet-
amide as the solvent generally led to high yields of the 4-
arylated pyrazoles. The electronic properties of the aryl
bromides have a determining influence on the reaction
yields. If the electron-withdrawing substituents support
the reactions, on the other hand, electron-donating substit-
uents are unfavorable. A wide variety of substituents such
Synthesis 2010, No. 1, 127–135 © Thieme Stuttgart · New York

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Palladium-Catalyzed Direct Arylation of Pyrazole Derivatives
Methyl 4-(1,3,5-Trimethylpyrazol-4-yl)benzoate (2d)
131
as acetyl, formyl, ester, nitrile, nitro, fluoro, or trifluoro-
methyl on the aryl bromide are tolerated. This procedure
is economically attractive due to the easy access to several
pyrazole derivatives and to aryl bromides, to the use of a
relatively low loading of a commercially available cata-
lyst, and also to the reduction of number of steps to pre-
pare these compounds. Moreover, with this ligand-less
procedure, there is no need to eliminate phosphine deriv-
atives at the end of the reaction.
Following the typical procedure using methyl 4-bromobenzoate
(0.215 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 173 mg (71%).
1H NMR (300 MHz): d = 8.05 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.5
Hz, 2 H), 3.92 (s, 3 H), 3.78 (s, 3 H), 2.25 (s, 6 H).
13C NMR (75 MHz): d = 167.1, 145.1, 139.2, 136.5, 129.7, 129.1,
127.7, 118.4, 52.1, 36.0, 12.6, 10.3.
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60. Found: C, 68.69; H,
6.60.
All reactions were run under argon using vacuum lines and oven-
dried Schlenk tubes. Commercial pyrazoles, aryl bromides, analyt-
ical grade DMAc, Pd(OAc)2, and KOAc (99%) were employed
without purification. 1H (300 MHz), 13C (75 MHz) spectra were re-
corded for CDCl3 solns relative to residual CHCl3 (1H, d = 7.25 and
13C, d = 77.0 ppm). Flash chromatography was performed on silica
gel (230–400 mesh).
4-(1,3,5-Trimethylpyrazol-4-yl)benzonitrile (2e)
Following the typical procedure using 4-bromobenzonitrile (0.182
g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 177 mg (84%).
1H NMR (300 MHz): d = 7.64 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.5
Hz, 2 H), 3.75 (s, 3 H), 2.23 (s, 3 H), 2.21 (s, 3 H).
13C NMR (75 MHz): d = 144.8, 139.3, 136.6, 132.1, 129.6, 118.9,
117.6, 109.4, 35.9, 12.4, 10.2.
4-Arylpyrazoles 2–4, 6, and 8; General Procedure
The aryl bromide (1 mmol), pyrazole derivative (1.5 or 1.25 mmol),
KOAc (0.196 g, 2 mmol), and Pd(OAc)2 (see Tables 2– 6) were dis-
solved in DMAc (3 mL) under an argon atmosphere. The mixture
was stirred at 150 °C for 20 h. The solvent was removed in vacuo
and then the crude product was purified by column chromatography
(silica gel).
Anal. Calcd for C13H13N3: C, 73.91; H, 6.20. Found: C, 73.97; H,
6.30.
4-(4-Trifluoromethylphenyl)-1,3,5-trimethylpyrazole (2f)
Following the typical procedure using 1-bromo-4-(trifluorometh-
yl)benzene (0.225 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2
(1.1 mg, 0.005 mmol); yield: 203 mg (80%).
1H NMR (300 MHz): d = 7.65 (d, J = 8.5 Hz, 2 H), 7.36 (d, J = 8.5
Hz, 2 H), 3.79 (s, 3 H), 2.26 (s, 6 H).
13C NMR (75 MHz): d = 144.9, 138.1, 136.5, 129.4, 128.0 (q,
J = 32.7 Hz), 125.2 (q, J = 4.0 Hz), 124.1 (q, J = 271.4 Hz), 117.9,
35.9, 12.4, 10.2.
4-(1,3,5-Trimethylpyrazol-4-yl)acetophenone (2a)
Following the typical procedure using 4-bromoacetophenone
(0.199 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 171 mg (75%).
1H NMR (300 MHz): d = 7.97 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.5
Hz, 2 H), 3.76 (s, 3 H), 2.60 (s, 3 H), 2.24 (s, 6 H).
13C NMR (75 MHz): d = 197.7, 145.1, 139.6, 136.6, 134.9, 129.3,
128.6, 118.3, 36.1, 26.6, 12.6, 10.4.
Anal. Calcd for C13H13F3N2: C, 61.41; H, 5.15. Found: C, 61.52; H,
5.31.
Anal. Calcd for C14H16N2O: C, 73.66; H, 7.06. Found: C, 73.81; H,
7.14.
4-(4-Nitrophenyl)-1,3,5-trimethylpyrazole (2g)
Following the typical procedure using 1-bromo-4-nitrobenzene
(0.202 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg,
0.01 mmol); yield: 95 mg (41%).
1H NMR (300 MHz): d = 8.25 (d, J = 8.5 Hz, 2 H), 7.38 (d, J = 8.5
Hz, 2 H), 3.80 (s, 3 H), 2.29 (s, 3 H), 2.26 (s, 3 H).
4-(1,3,5-Trimethylpyrazol-4-yl)benzaldehyde (2b)
Following the typical procedure using 4-bromobenzaldehyde
(0.185 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 176 mg (82%).
1H NMR (300 MHz): d = 10.00 (s, 1 H), 7.90 (d, J = 8.5 Hz, 2 H),
7.38 (d, J = 8.5 Hz, 2 H), 3.77 (s, 3 H), 2.26 (s, 3 H), 2.25 (s, 3 H).
13C NMR (75 MHz): d = 145.8, 145.0, 141.4, 136.8, 129.5, 123.7,
117.3, 36.0, 12.5, 10.3.
13C NMR (75 MHz): d = 191.7, 145.1, 141.0, 136.6, 134.1, 129.8,
129.6, 118.2, 36.0, 12.6, 10.3.
Anal. Calcd for C12H13N3O2: C, 62.33; H, 5.67. Found: C, 62.47; H,
5.48.
Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59. Found: C, 73.01; H,
6.47.
4-(4-Fluorophenyl)-1,3,5-trimethylpyrazole (2h)2e
Following the typical procedure using 1-bromo-4-fluorobenzene
(0.175 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg,
0.01 mmol); yield: 159 mg (78%).
1H NMR (300 MHz): d = 7.18 (dd, J = 8.2, 5.7 Hz, 2 H), 7.07 (t,
J = 8.2 Hz, 2 H), 3.76 (s, 3 H), 2.20 (s, 6 H).
4-(1,3,5-Trimethylpyrazol-4-yl)benzophenone (2c)
Following the typical procedure using 4-bromobenzophenone
(0.261 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 232 mg (80%).
1H NMR (300 MHz): d = 7.82 (d, J = 8.5 Hz, 2 H), 7.79 (d, J = 8.5
Hz, 2 H), 7.50 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.31 (d,
J = 8.5 Hz, 2 H), 3.74 (s, 3 H), 2.25 (s, 3 H), 2.24 (s, 3 H).
13C NMR (75 MHz): d = 196.0, 144.8, 138.8, 137.6, 136.4, 134.9,
132.0, 130.2, 129.7, 128.8, 128.1, 118.1, 35.8, 12.4, 10.2.
4-(4-tert-Butylphenyl)-1,3,5-trimethylpyrazole (2i)
Following the typical procedure using 1-bromo-4-tert-butylben-
zene (0.213 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (2.2
mg, 0.01 mmol); yield: 187 mg (77%).
1H NMR (300 MHz): d = 7.41 (d, J = 8.2 Hz, 2 H), 7.16 (d, J = 8.2
Hz, 2 H), 3.77 (s, 3 H), 2.25 (s, 3 H), 2.24 (s, 3 H), 1.35 (s, 9 H).
Anal. Calcd for C19H18N2O: C, 78.59; H, 6.25. Found: C, 78.64; H,
6.40.
13C NMR (75 MHz): d = 148.8, 145.0, 136.1, 131.1, 128.9, 125.2,
118.9, 35.9, 34.4, 31.3, 12.5, 10.3.
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Anal. Calcd for C16H22N2: C, 79.29; H, 9.15. Found: C, 79.40; H,
9.21.
1H NMR (300 MHz): d = 7.78 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 8.5
Hz, 1 H), 7.63 (s, 1 H), 7.40 (dd, J = 8.5, 1.7 Hz, 1 H), 7.25–7.15
(m, 2 H), 3.95 (s, 3 H), 3.82 (s, 3 H), 2.33 (s, 3 H), 2.29 (s, 3 H).
4-(4-Methylphenyl)-1,3,5-trimethylpyrazole (2j)
Following the typical procedure using 4-bromotoluene (0.171 g, 1
mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg, 0.01 mmol);
yield: 148 mg (74%).
1H NMR (300 MHz): d = 7.23 (d, J = 8.5 Hz, 2 H), 7.15 (d, J = 8.5
Hz, 2 H), 3.79 (s, 3 H), 2.40 (s, 3 H), 2.26 (s, 3 H), 2.25 (s, 3 H).
13C NMR (75 MHz): d = 157.5, 145.1, 136.2, 132.9, 129.4, 129.1,
129.0, 128.4, 127.6, 126.6, 119.1, 118.8, 105.6, 55.2, 35.9, 12.4,
10.2.
Anal. Calcd for C17H18N2O: C, 76.66; H, 6.81. Found: C, 76.81; H,
6.59.
13C NMR (75 MHz): d = 144.9, 136.0, 135.7, 131.1, 129.2, 129.0,
2-(1,3,5-Trimethylpyrazol-4-yl)benzaldehyde (3d)
Following the typical procedure using 2-bromobenzaldehyde
(0.185 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 169 mg (79%).
1H NMR (300 MHz): d = 9.87 (s, 1 H), 8.01 (d, J = 8.5 Hz, 1 H),
7.62 (t, J = 7.8 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.25 (d, J = 8.4
Hz, 1 H), 3.80 (s, 3 H), 2.11 (s, 6 H).
119.0, 35.9, 21.1, 12.4, 10.2.
Anal. Calcd for C13H16N2: C, 77.96; H, 8.05. Found: C, 77.99; H,
8.31.
4-(4-Methoxyphenyl)-1,3,5-trimethylpyrazole (2k)2e
Following the typical procedure using 4-bromoanisole (0.187 g, 1
mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg, 0.01 mmol);
yield: 119 mg (55%).
1H NMR (300 MHz): d = 7.15 (d, J = 8.5 Hz, 2 H), 6.94 (d, J = 8.5
Hz, 2 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 2.22 (s, 3 H), 2.21 (s, 3 H).
13C NMR (75 MHz): d = 192.6, 145.8, 137.7, 137.6, 134.4, 133.8,
132.1, 127.5, 127.4, 114.9, 36.1, 12.1, 10.0.
Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59. Found: C, 72.81; H,
6.46.
4-[4-(Dimethylamino)phenyl]-1,3,5-trimethylpyrazole (2l)
Following the typical procedure using 1-bromo-4-(dimethylami-
no)benzene (0.200 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2
(2.2 mg, 0.01 mmol); yield: 25 mg (11%).
1H NMR (300 MHz): d = 7.11 (d, J = 8.5 Hz, 2 H), 7.78 (d, J = 8.5
Hz, 2 H), 3.76 (s, 3 H), 2.97 (s, 6 H), 2.23 (s, 3 H), 2.21 (s, 3 H).
2-(1,3,5-Trimethylpyrazol-4-yl)benzonitrile (3e)
Following the typical procedure using 2-bromobenzonitrile (0.182
g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 169 mg (80%).
1H NMR (300 MHz): d = 7.72 (d, J = 8.5 Hz, 1 H), 7.60 (t, J = 7.8
Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 8.5 Hz, 1 H), 3.78 (s,
3 H), 2.18 (s, 3 H), 2.17 (s, 3 H).
13C NMR (75 MHz): d = 148.9, 145.1, 135.9, 130.2, 122.2, 119.1,
112.5, 40.6, 35.9, 12.4, 10.2.
13C NMR (75 MHz): d = 145.3, 138.2, 137.4, 133.1, 132.5, 131.6,
127.1, 118.5, 116.1, 113.5, 36.0, 12.2, 10.5.
Anal. Calcd for C14H19N3: C, 73.33; H, 8.35. Found: C, 73.41; H,
8.38.
Anal. Calcd for C13H13N3: C, 73.91; H, 6.20. Found: C, 73.99; H,
6.14.
4-[3,5-Bis(trifluoromethyl)phenyl]-1,3,5-trimethylpyrazole (3a)
Following the typical procedure using 3,5-bis(trifluoromethyl)bro-
mobenzene (0.293 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2
(1.1 mg, 0.005 mmol); yield: 258 mg (80%).
1H NMR (300 MHz): d = 7.80 (s, 1 H), 7.69 (s, 2 H), 3.82 (s, 3 H),
2.28 (s, 3 H), 2.27 (s, 3 H).
13C NMR (75 MHz): d = 144.9, 136.7 (d, J = 9.8 Hz), 131.7 (q,
J = 32.6 Hz), 129.1, 129.0, 123.0 (q, J = 274.0 Hz), 119.8 (q,
J = 4.5 Hz), 116.8, 36.1, 12.3, 10.1.
1,3,5-Trimethyl-4-(naphthalen-1-yl)pyrazole (3f)
Following the typical procedure using 1-bromonaphthalene (0.207
g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 180 mg (76%).
1H NMR (300 MHz): d = 7.90 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.5
Hz, 1 H), 7.65 (d, J = 8.5 Hz, 1 H), 7.55–7.35 (m, 3 H), 7.30 (d,
J = 8.5 Hz, 1 H), 3.84 (s, 3 H), 2.06 (s, 3 H), 2.05 (s, 3 H).
13C NMR (75 MHz): d = 146.2, 137.4, 133.8, 132.8, 131.7, 128.4,
128.3, 127.4, 126.1, 125.8, 125.6, 125.4, 117.3, 36.0, 12.3, 10.2.
Anal. Calcd for C14H12F6N2: C, 52.18; H, 3.75. Found: C, 52.01; H,
3.80.
Anal. Calcd for C16H16N2: C, 81.32; H, 6.82. Found: C, 81.40; H,
6.78.
3-(1,3,5-Trimethylpyrazol-4-yl)benzaldehyde (3b)
Following the typical procedure using 3-bromobenzaldehyde
(0.185 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 159 mg (74%).
1H NMR (300 MHz): d = 10.01 (s, 1 H), 7.75 (d, J = 8.5 Hz, 1 H),
7.71 (s, 1 H), 7.53 (t, J = 7.7 Hz, 1 H), 7.47 (d, J = 8.5 Hz, 1 H), 3.75
(s, 3 H), 2.21 (s, 6 H).
3-(1,3,5-Trimethylpyrazol-4-yl)pyridine (4a)
Following the typical procedure using 3-bromopyridine (0.158 g, 1
mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005 mmol);
yield: 150 mg (80%).
1H NMR (300 MHz): d = 8.48 (m, 2 H), 7.52 (dt, J = 7.7, 2.1 Hz, 1
H), 7.32 (dd, J = 7.7, 4.9 Hz, 1 H), 3.76 (s, 3 H), 2.22 (s, 3 H), 2.21
(s, 3 H).
13C NMR (75 MHz): d = 192.2, 144.8, 136.6, 136.3, 135.3, 135.2,
130.2, 129.0, 127.5, 117.9, 35.9, 12.3, 10.1.
13C NMR (75 MHz): d = 150.1, 147.2, 145.2, 136.7, 136.5, 130.2,
123.3, 115.6, 36.0, 12.3, 10.2.
Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59. Found: C, 72.80; H,
6.49.
Anal. Calcd for C11H13N3: C, 70.56; H, 7.00. Found: C, 70.47; H,
6.98.
4-(6-Methoxynaphthalen-2-yl)-1,3,5-trimethylpyrazole (3c)
Following the typical procedure using 2-bromo-6-methoxynaphtha-
lene (0.237 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (2.2
mg, 0.01 mmol); yield: 208 mg (78%).
4-(1,3,5-Trimethylpyrazol-4-yl)pyridine (4b)
Following the typical procedure using 4-bromopyridine hydrochlo-
ride (0.194 g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (2.2
mg, 0.01 mmol); yield: 137 mg (73%).
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1H NMR (300 MHz): d = 8.59 (m, 2 H), 7.19 (d, J = 5.7 Hz, 2 H),
13C NMR (75 MHz): d = 196.2, 147.0, 139.5, 138.4, 137.6, 136.7,
3.78 (s, 3 H), 2.28 (s, 3 H), 2.26 (s, 3 H).
135.3, 132.2, 130.4, 129.9, 129.1, 129.0, 128.2, 127.6, 124.9, 119.9,
12.7, 11.9.
13C NMR (75 MHz): d = 148.9, 145.2, 143.0, 137.1, 124.0, 116.5,
36.0, 12.5, 10.4.
Anal. Calcd for C24H20N2O: C, 81.79; H, 5.72. Found: C, 81.59; H,
5.99.
Anal. Calcd for C11H13N3: C, 70.56; H, 7.00. Found: C, 70.49; H,
6.92.
4-(3,5-Dimethyl-1-phenylpyrazol-4-yl)benzonitrile (6c)
Following the typical procedure using 4-bromobenzonitrile (0.182
g, 1 mmol), 5 (0.258 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg, 0.01
mmol); yield: 219 mg (80%).
1H NMR (300 MHz): d = 7.74 (d, J = 8.5 Hz, 2 H), 7.50–7.40 (m, 7
H), 2.36 (s, 3 H), 2.33 (s, 3 H).
3-(1,3,5-Trimethylpyrazol-4-yl)quinoline (4c)
Following the typical procedure using 3-bromoquinoline (0.208 g,
1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 178 mg (75%).
1H NMR (300 MHz): d = 8.79 (d, J = 1.5 Hz, 1 H), 8.06 (d, J = 8.5
Hz, 1 H), 7.90 (d, J = 1.5 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.62
(t, J = 7.8 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 3.74 (s, 3 H), 2.23 (s,
3 H), 2.22 (s, 3 H).
13C NMR (75 MHz): d = 146.9, 139.4, 138.9, 136.8, 132.3, 129.8,
129.1, 127.8, 125.0, 119.3, 119.0, 109.8, 12.7, 11.8.
Anal. Calcd for C18H15N3: C, 79.10; H, 5.53. Found: C, 79.22; H,
5.57.
13C NMR (75 MHz): d = 151.6, 146.4, 145.2, 136.8, 134.9, 129.0,
128.9, 127.9, 127.4, 127.3, 126.6, 115.5, 35.9, 12.2, 10.1.
2-(3,5-Dimethyl-1-phenylpyrazol-4-yl)benzonitrile (6d)
Following the typical procedure using 2-bromobenzonitrile (0.182
g, 1 mmol), 5 (0.258 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg, 0.01
mmol); yield: 180 mg (66%).
1H NMR (300 MHz): d = 7.79 (d, J = 8.5 Hz, 1 H), 7.67 (t, J = 7.7
Hz, 1 H), 7.60–7.30 (m, 7 H), 2.30 (s, 3 H), 2.28 (s, 3 H).
Anal. Calcd for C15H15N3: C, 75.92; H, 6.37. Found: C, 76.01; H,
6.22.
4-(1,3,5-Trimethylpyrazol-4-yl)isoquinoline (4d)
Following the typical procedure using 4-bromoisoquinoline (0.208
g, 1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 185 mg (78%).
1H NMR (300 MHz): d = 9.25 (s, 1 H), 8.32 (s, 1 H), 8.04 (d, J = 8.0
Hz, 1 H), 7.70-7.45 (m, 3 H), 3.83 (s, 3 H), 2.06 (s, 3 H), 2.04 (s, 3
H).
13C NMR (75 MHz): d = 147.2, 139.5, 137.8, 137.7, 133.2, 132.6,
131.7, 129.1, 127.7, 127.4, 125.0, 118.5, 117.8, 113.6, 12.4, 11.9.
Anal. Calcd for C18H15N3: C, 79.10; H, 5.53. Found: C, 79.20; H,
5.64.
13C NMR (75 MHz): d = 151.0, 146.4, 143.1, 137.9, 135.6, 130.8,
128.1, 127.4, 124.9, 113.3, 35.9, 12.1, 10.1.
3-(3,5-Dimethyl-1-phenylpyrazol-4-yl)pyridine (6e)
Following the typical procedure using 3-bromopyridine (0.158 g, 1
mmol), 5 (0.258 g, 1.5 mmol), and Pd(OAc)2 (4.4 mg, 0.02 mmol);
yield: 172 mg (69%).
Anal. Calcd for C15H15N3: C, 75.92; H, 6.37. Found: C, 75.81; H,
6.30.
5-(1,3,5-Trimethylpyrazol-4-yl)pyrimidine (4e)
Following the typical procedure using 5-bromopyrimidine (0.159 g,
1 mmol), 1 (0.165 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 151 mg (80%).
1H NMR (300 MHz): d = 9.03 (s, 1 H), 8.56 (s, 2 H), 3.72 (s, 3 H),
2.19 (s, 3 H), 2.17 (s, 3 H).
1H NMR (300 MHz): d = 8.59 (s, 1 H), 8.54 (d, J = 4.9 Hz, 1 H),
7.63 (d, J = 7.9 Hz, 1 H), 7.50–7.30 (m, 6 H), 2.32 (s, 3 H), 2.29 (s,
3 H).
13C NMR (75 MHz): d = 150.3, 147.6, 147.2, 139.6, 136.9, 136.6,
129.7, 129.1, 127.7, 125.0, 123.4, 117.3, 12.1, 11.3.
Anal. Calcd for C16H15N3: C, 77.08; H, 6.06. Found: C, 77.01; H,
6.14.
13C NMR (75 MHz): d = 156.4, 156.2, 145.1, 137.0, 128.3, 111.9,
36.0, 12.2, 10.1.
3-(3,5-Dimethyl-1-phenylpyrazol-4-yl)quinoline (6f)
Following the typical procedure using 3-bromoquinoline (0.208 g,
1 mmol), 5 (0.258 g, 1.5 mmol), and Pd(OAc)2 (4.4 mg, 0.02
mmol); yield: 192 mg (64%).
1H NMR (300 MHz): d = 8.93 (d, J = 2.0 Hz, 1 H), 8.13 (d, J = 8.5
Hz, 1 H), 8.05 (d, J = 1.9 Hz, 1 H), 7.84 (d, J = 8.5 Hz, 1 H), 7.75–
7.30 (m, 7 H), 2.38 (s, 3 H), 2.34 (s, 3 H).
Anal. Calcd for C10H12N4: C, 63.81; H, 6.43. Found: C, 63.89; H,
6.54.
4-(3,5-Dimethyl-1-phenylpyrazol-4-yl)benzaldehyde (6a)
Following the typical procedure using 4-bromobenzaldehyde
(0.185 g, 1 mmol), 5 (0.258 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg,
0.01 mmol); yield: 160 mg (58%).
1H NMR (300 MHz): d = 10.06 (s, 1 H), 7.97 (d, J = 8.5 Hz, 2 H),
13C NMR (75 MHz): d = 151.7, 147.4, 146.7, 139.6, 137.1, 135.3,
129.3, 129.2, 129.1, 128.0, 127.7, 127.6, 127.0, 126.9, 124.9, 117.4,
12.6, 11.7.
7.55–7.40 (m, 7 H), 2.39 (s, 3 H), 2.35 (s, 3 H).
13C NMR (75 MHz): d = 191.8, 147.0, 140.5, 139.5, 136.8, 134.3,
129.9, 129.7, 129.1, 127.8, 125.0, 119.8, 12.8, 11.9.
Anal. Calcd for C20H17N3: C, 80.24; H, 5.72. Found: C, 80.30; H,
5.94.
Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84. Found: C, 78.30; H,
5.75.
5-(3,5-Dimethyl-1-phenylpyrazol-4-yl)pyrimidine (6g)
Following the typical procedure using 5-bromopyrimidine (0.159 g,
1 mmol), 5 (0.258 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg, 0.01
mmol); yield: 200 mg (80%).
1H NMR (300 MHz): d = 9.18 (s, 1 H), 8.76 (s, 2 H), 7.50–7.30 (m,
5 H), 2.36 (s, 3 H), 2.33 (s, 3 H).
4-(3,5-Dimethyl-1-phenylpyrazol-4-yl)benzophenone (6b)
Following the typical procedure using 4-bromobenzophenone
(0.261 g, 1 mmol), 5 (0.258 g, 1.5 mmol), and Pd(OAc)2 (2.2 mg,
0.01 mmol); yield: 247 mg (70%).
1H NMR (300 MHz): d = 7.82 (d, J = 8.5 Hz, 2 H), 7.78 (d, J = 8.5
Hz, 2 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.52–7.40 (m, 9 H), 2.41 (s, 3 H),
2.36 (s, 3 H).
13C NMR (75 MHz): d = 156.7, 156.6, 147.1, 139.3, 137.3, 129.2,
128.2, 128.0, 125.0, 113.7, 12.5, 11.6.
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5-(1-tert-Butyl-3,5-dimethylpyrazol-4-yl)pyrimidine (8f)
Following the typical procedure using 5-bromopyrimidine (0.159 g,
1 mmol), 7 (0.228 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 182 mg (79%).
1H NMR (300 MHz): d = 9.10 (s, 1 H), 8.59 (s, 2 H), 2.36 (s, 3 H),
2.18 (s, 3 H), 1.64 (s, 9 H).
13C NMR (75 MHz): d = 157.1, 156.3, 143.3, 136.2, 128.6, 114.1,
60.0, 30.1, 13.2, 12.3.
Anal. Calcd for C15H14N4: C, 71.98; H, 5.64. Found: C, 71.79; H,
5.80.
4-(1-tert-Butyl-3,5-dimethylpyrazol-4-yl)benzonitrile (8a)
Following the typical procedure using 4-bromobenzonitrile (0.182
g, 1 mmol), 7 (0.228 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 200 mg (79%).
1H NMR (300 MHz): d = 7.68 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.5
Hz, 2 H), 2.39 (s, 3 H), 2.21 (s, 3 H), 1.68 (s, 9 H).
Anal. Calcd for C13H18N4: C, 67.80; H, 7.88. Found: C, 67.64; H,
7.98.
13C NMR (75 MHz): d = 142.9, 139.6, 135.6, 132.0, 130.3, 119.8,
119.0, 109.4, 59.7, 30.1, 13.2, 12.5.
Anal. Calcd for C16H19N3: C, 75.85; H, 7.56. Found: C, 75.80; H,
7.47.
Ethyl 1,3-Dimethyl-4-(quinolin-3-yl)pyrazole-5-carboxylate
(10)
3-Bromoquinoline (0.208 g, 1 mmol), ethyl 1,3-dimethylpyrazole-
5-carboxylate (9, 0.210 g, 1.25 mmol), KOAc (0.196 g, 2 mmol),
Bu(Ad)2P (18 mg, 0.05 mmol), and Pd(OAc)2 (4.4 mg, 0.02 mmol)
were dissolved in DMAc (3 mL) under an argon atmosphere. The
mixture was stirred at 150 °C for 20 h. The solvent was removed in
vacuo, then the crude product was purified by column chromatog-
raphy (silica gel) to give 10; yield: 74 mg (25%).
1H NMR (300 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H), 8.10 (d, J = 8.5
Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 7.70
(t, J = 7.8 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 4.17 (s, 3 H), 4.10 (q,
J = 7.5 Hz, 2 H), 2.20 (s, 3 H), 0.94 (t, J = 7.5 Hz, 3 H).
4-(1-tert-Butyl-3,5-dimethylpyrazol-4-yl)benzaldehyde (8b)
Following the typical procedure using 4-bromobenzaldehyde
(0.185 g, 1 mmol), 7 (0.228 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 190 mg (74%).
1H NMR (300 MHz): d = 10.01 (s, 1 H), 7.89 (d, J = 8.2 Hz, 2 H),
7.37 (d, J = 8.2 Hz, 2 H), 2.39 (s, 3 H), 2.22 (s, 3 H), 1.66 (s, 9 H).
13C NMR (75 MHz): d = 191.9, 143.1, 141.3, 135.7, 134.1, 130.3,
129.7, 120.3, 59.7, 30.2, 13.4, 12.6.
Anal. Calcd for C16H20N2O: C, 74.97; H, 7.86. Found: C, 74.81; H,
7.80.
13C NMR (75 MHz): d = 159.8, 152.3, 146.8, 146.3, 136.0, 130.4,
129.3, 129.2, 127.6, 127.4, 126.7, 126.5, 121.5, 60.9, 39.8, 13.6,
11.9.
4-(1-tert-Butyl-3,5-dimethylpyrazol-4-yl)benzophenone (8c)
Following the typical procedure using 4-bromobenzophenone
(0.261 g, 1 mmol), 7 (0.228 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg,
0.005 mmol); yield: 256 mg (77%).
Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80. Found: C, 69.30; H,
5.71.
1H NMR (300 MHz): d = 7.88 (d, J = 8.2 Hz, 2 H), 7.85 (d, J = 8.2
Hz, 2 H), 7.59 (t, J = 7.8 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 2 H), 7.36 (d,
J = 8.2 Hz, 2 H), 2.44 (s, 3 H), 2.27 (s, 3 H), 1.69 (s, 9 H).
13C NMR (75 MHz): d = 196.0, 144.8, 138.8, 137.6, 136.4, 134.9,
132.0, 130.2, 129.7, 128.8, 128.1, 118.1, 35.8, 12.4, 10.2.
Ethyl 4-(4-Cyanophenyl)-1,3-dimethylpyrazole-5-carboxylate
(11)
4-Bromobenzonitrile (0.182 g, 1 mmol), ethyl 1,3-dimethylpyra-
zole-5-carboxylate (9, 0.210 g, 1.25 mmol), KOAc (0.196 g, 2
mmol), Bu(Ad)2P (18 mg, 0.05 mmol), and Pd(OAc)2 (4.4 mg, 0.02
mmol) were dissolved in DMAc (3 mL) under an argon atmosphere.
The mixture was stirred at 150 °C for 20 h. The solvent was re-
moved in vacuo, then the crude product was purified by column
chromatography (silica gel) to give 11; yield: 59 mg (22%).
1H NMR (300 MHz): d = 7.68 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0
Hz, 2 H), 4.18 (q, J = 7.5 Hz, 2 H), 4.16 (s, 3 H), 2.16 (s, 3 H), 1.07
(t, J = 7.5 Hz, 3 H).
Anal. Calcd for C22H24N2O: C, 79.48; H, 7.28. Found: C, 79.58; H,
7.37.
2-(1-tert-Butyl-3,5-dimethylpyrazol-4-yl)benzonitrile (8d)
Following the typical procedure using 2-bromobenzonitrile (0.182
g, 1 mmol), 7 (0.228 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 185 mg (73%).
1H NMR (300 MHz): d = 7.73 (d, J = 8.5 Hz, 1 H), 7.58 (t, J = 7.8
Hz, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 8.5 Hz, 1 H), 2.31 (s,
3 H), 2.13 (s, 3 H), 1.66 (s, 9 H).
13C NMR (75 MHz): d = 143.4, 138.6, 136.6, 133.0, 132.4, 131.9,
127.0, 118.5, 118.3, 113.9, 59.8, 30.1, 13.6, 12.3.
13C NMR (75 MHz): d = 159.7, 145.5, 138.4, 131.5, 130.9, 130.1,
123.5, 118.8, 110.8, 61.0, 39.7, 13.6, 11.8.
Anal. Calcd for C15H15N3O2: C, 66.90; H, 5.61. Found: C, 67.01; H,
5.57.
Anal. Calcd for C16H19N3: C, 75.85; H, 7.56. Found: C, 75.91; H,
7.49.
References
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3-(1-tert-Butyl-3,5-dimethylpyrazol-4-yl)quinoline (8e)
Following the typical procedure using 3-bromoquinoline (0.208 g,
1 mmol), 7 (0.228 g, 1.5 mmol), and Pd(OAc)2 (1.1 mg, 0.005
mmol); yield: 218 mg (78%).
1H NMR (300 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H), 8.08 (d, J = 8.5
Hz, 1 H), 7.92 (d, J = 2.0 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.64
(t, J = 7.8 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 1 H), 2.37 (s, 3 H), 2.22 (s,
3 H), 1.64 (s, 9 H).
13C NMR (75 MHz): d = 152.2, 146.4, 143.4, 135.9, 135.5, 129.0,
128.8, 127.9, 127.6, 127.4, 126.6, 117.7, 59.6, 30.0, 13.2, 12.4.
Anal. Calcd for C18H21N3: C, 77.38; H, 7.58. Found: C, 77.32; H,
7.39.
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Synthesis 2010, No. 1, 127–135 © Thieme Stuttgart · New York