Suzuki-Miyaura reactions of N-protected tribromopyrazoles. Efficient and site-selective synthesis of 3,4,5-triaryl-pyrazoles, 3,5-diaryl-4-bromopyrazoles and 5-aryl-3,4-dibromopyrazoles

Article abstract of DOI:10.1016/j.tet.2011.05.036

Suzuki-Miyaura reactions of N-protected tribromopyrazoles were studied. The reactions proceed with excellent site-selectivity. The first attack occurs at position 5, while the second and third attack occur at positions 3 and 4, respectively. A variety of 3,4,5-triaryl-pyrazoles, 3,5-diaryl-4-bromopyrazoles, and 5-aryl-3,4-dibromopyrazoles were efficiently prepared. The products are not readily available by other methods.

Full text of DOI:10.1016/j.tet.2011.05.036

Tetrahedron 67 (2011) 5244e5253
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
SuzukieMiyaura reactions of N-protected tribromopyrazoles. Efficient and
site-selective synthesis of 3,4,5-triaryl-pyrazoles, 3,5-diaryl-4-bromopyrazoles
and 5-aryl-3,4-dibromopyrazoles
,
,
,
,e
Rasheed Ahmad Khera a b, Asad Ali a c, Hummera Rafique a d, Munawar Hussain a, Jovana Tatar a
,
Aamer Saeed d, Alexander Villinger a, Peter Langer a
,f,
*
a
€
€
Universitat Rostock, Institut fur Chemie, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Governmental College University, Faisalabad, Pakistan
c University of Mardan, Mardan, N.W.F.P., Pakistan
d Quaid-i-Azam University, Islamabad, Pakistan
e University of Belgrade, Belgrade, Serbia
f
€
€
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
SuzukieMiyaura reactions of N-protected tribromopyrazoles were studied. The reactions proceed with
excellent site-selectivity. The first attack occurs at position 5, while the second and third attack occur at
positions 3 and 4, respectively. A variety of 3,4,5-triaryl-pyrazoles, 3,5-diaryl-4-bromopyrazoles, and
5-aryl-3,4-dibromopyrazoles were efficiently prepared. The products are not readily available by other
methods.
Received 25 February 2011
Received in revised form 27 April 2011
Accepted 9 May 2011
Available online 14 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoles
Catalysis
SuzukieMiyaura reaction
Regioselectivity
Palladium
1. Introduction
a,b
-unsaturated ketones.12 The reaction of hydrazines with 4-aryl-
2,4-dioxoesters afforded 5-arylpyrazole-3-carboxylates which
were transformed into potent and selective COX-1 and COX-2 in-
hibitors.13 Pyrazoles have also been prepared by cyclization of
Pyrazoles are of considerable importance in medicinal chemis-
try and are also used as synthetic building blocks.1e6 Pyrazole
derivatives, specifically 1-phenylpyrazole derivatives, are known to
have a broad spectrum of biological activities. For example,
4-amino-N-(1-phenyl-1H-pyrazol-5-yl)benzensulfonamide (sulfa-
phenazole) derived from 5-amino-1-phenylpyrazole is a potent
antibacterial drug,7 while 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-
yl)benzamide (CDPPD) has been identified as a positive allosteric
metabotropic modulator of the glutamate receptor (Fig. 1).8
Nonsteroidal anti-inflammatory drugs, such as lonazolac are (1,3-
diphenyl-1H-pyrazol-4-yl)acetic acid derivatives.9 The anti-
inflammatory activity is also typical for (1,4-diphenylpyrazol-3-yl)
acetic acid and related compounds.10 A number of synthetic
approaches to pyrazoles have been reported. They have been
prepared by 1,3-dipolar cycloaddition of diazoalkanes with
alkynes,11 by cyclization of hydrazines with 1,3-diketones and
dilithiated hydrazones with esters, acid chlorides, nitriles,
a-hal-
oketones, propiolates, Weinreb amides and diethyl oxalate.14
In recent years, site-selective cross-coupling reactions of poly-
halogenated heterocycles have gained increasing importance.15,16
Site-selective SuzukieMiyaura (SeM) reactions of tribromopy-
rroles have been previously reported.17 A modular approach to
various trisubstituted pyrazoles has been reported which is based
on sequential direct lithiation of the 3- and 5-positions of the
pyrazole ring and their conversion into pyrazolylboronic acids.18a
The latter was reacted in SeM reactions. Another very interesting
synthesis relies on the combination of CeH activation and SeM
reactions of monobrominated SEM-protected pyrazoles.18b While
site-selective metalehalide exchange reactions of N-protected
tribromopyrazoles are known,19 palladium catalyzed transforma-
tions were unknown until our recent short communication in
this field.20 Herein, we report full details of SuzukieMiyaura re-
actions of N-protected tribromopyrazoles. These reactions provide
* Corresponding author. E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.036

R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
5245
The SuzukieMiyaura reaction of 2aec with arylboronic acids
3aen (1.1 equiv) afforded the 5-aryl-3,4-dibromopyrazoles 4aen in
66e81% yield (Table 1, Scheme 2). The reactions were carried out
using Pd(PPh3)4 (3 mol %) as the catalyst. Potassium phosphate
(1.5 equiv) was employed as the base. The stoichiometry played an
important role (use of 1.0 equiv of the arylboronic acid). The re-
actions were carried out in a 4:1 mixture of dioxane and water
because of the low solubility of the boronic acids in toluene. The
employment of PdCl2(PPh3)2 or of Pd(OAc)2 in the presence of
XPhos, a biaryl ligand developed by Buchwald and Billingsley,23
gave lower yields. The reaction mixtures were stirred at 100 ꢀC
for 12 h. The conversion was not complete when the reaction time
was shortened or when the temperature was decreased.
Scheme 2. Synthesis of 5-aryl-3,4-dibromopyrazoles 4aen. Reagents and conditions:
i, 2aec (1.0 equiv), ArB(OH)2 (1.1 equiv), 2 M K2CO3, Pd(PPh2)Cl2 (3 mol %), 1,4-dioxane/
H2O (4:1), 60 ꢀC, 4 h.
Fig. 1. Some pharmaceuticals bearing a pyrazole moiety.
Table 1
Synthesis of 4aen
a convenient approach to triaryl-pyrazoles, 3,5-diaryl-4-bromop-
yrazoles and 5-aryl-3,4-dibromo-pyrazoles, which are of consid-
erable pharmacological relevance.21 The products are not readily
available by other methods.
3,4
2
R
Ar
% (4)a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
a
a
a
a
a
a
a
b
b
b
b
c
Me
Me
Me
Me
Me
Me
Me
Vinyl
Vinyl
Vinyl
Vinyl
Benzyl
Benzyl
Benzyl
4-MeC6H4
4-EtC6H4
76
79
81
73
71
75
71
66
69
73
71
74
71
76
4-tBuC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
2. Results and discussion
4-(MeO)C6H4
4-MeC6H4
2-(MeO)C6H4
4-(MeO)C6H4
2,6-(MeO)2C6H3
3,5-Me2C6H3
4-FC6H4
N-Methyl-tribromopyrazole (2a) was prepared by reaction of
commercially available tribromopyrazole (1) with methyl iodide
(Scheme 1). N-Benzyl-tribromopyrazole (2c) was prepared fol-
lowing a known procedure, which was slightly modified.22 Instead
of benzylchloride, benzylbromide was used. N-Vinyl-tribromopyr-
azole (2b) was prepared by reaction of 1 with dibromoethane.
c
c
4-(MeO)C6H4
a
Yields of isolated compounds.
The formation of 4aen proceeded with excellent site-selectivity
in favour of position 5. Inspection of the crude product mixture
showed that a small amount of pyrazole derived from double and
triple Suzuki reaction were formed. In addition, some biaryl for-
mation (by dimerization of the boronic acid) was detected. A good
yield was obtained even for product 4k derived from a sterically
hindered arylboronic acid. No clear dependence of the yields from
the electronic nature of the arylboronic acid was observed.
The configuration of the products was unambiguously con-
firmed by 2D NMR experiments (NOESY, HMQC). For example, the
regioselectivity of compound 4a was established unambiguously by
2D NMR using 1He1H NOESY and HMQC experiments. The methyl
protons (NMe) at
with the phenyl protons at
4-methylphenyl group is attached to C-5 of the pyrazole moiety
(Fig. 2).
d
¼3.70 show a clear correlation through space
d
¼7.24, which confirm that the
Likewise, the structure of compound 4j was established by 2D
NMR. The vinylic proton attached to carbon C-129.7 showed a clear
correlation through space with the phenyl proton located at d 7.30,
which confirmed that the 4-methoxyphenyl is attached at C-5 of
the pyrazole moiety (Fig. 3).
Scheme 1. Synthesis of 2aec. Reagents and conditions: (i) 1 (1.0 equiv), methyl iodide
(1.0 equiv), NEt3 (1.1 equiv), CH2Cl2 (5 mL per mmol of 1), 20 ꢀC, 8 h. (ii) 1 (1.0 equiv),
1,2-dibromoethane (1.2 equiv), NEt3 (5 mL per mmol), CH3CN (5 mL per mmol of 1),
70 ꢀC, 7 h. (iii) 1 (1.0 equiv), benzylbromide (1.0 equiv), NEt3 (1.1 equiv), CH2Cl2, 20 ꢀC,
4 h.
The structure of 4n was independently confirmed by an X-ray
crystal structure analysis (Fig. 4).24

5246
R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
Scheme 3. Synthesis of 5-aryl-3,4-dibromopyrazoles 5aed. Reagents and conditions:
i, 2aec (1.0 equiv), ArB(OH)2 (2.2 equiv),
2 M K2CO3, Pd(PPh2)Cl2 (5 mol %),
1,4-dioxane/H2O (4:1), 80 ꢀC, 6 h.
Table 2
Synthesis of 5aed
Fig. 2. 2D NMR correlations (HMQC and NOSEY) of 4a.
5
3
R
Ar
4-(MeO)C6H4
3,5-Me2C6H3
4-(MeO)C6H4
4-FC6H4
% (5)a
a
b
c
g
l
g
f
Me
60
62
60
66
Vinyl
Vinyl
Benzyl
d
a
Yields of isolated compounds.
Suzuki reactions of N-protected tribromopyrazoles with
3.3 equiv of arylboronic acids were next studied. As a test reaction
for the optimization studies, the synthesis of 6a was investigated.
Initially, it was found that mixtures of products were formed when
Pd(PPh3)4 (3 mol %) or Pd(PPh3)2Cl2 were used as the catalysts. In
contrast, good yields of pure triarylated products were obtained
when Pd(OAc)2 (5 mol %) in the presence of XPhos (10 mol %) was
used as the catalyst (dioxane, 90 ꢀC, 6 h) (entry 4, Table 3). The best
yields were obtained when Pd(OAc)2 (5 mol %) was used in the
presence of SPhos (10 mol %) in an aqueous solution of K2CO3 (2 M)
(entry 3, Table 3).
Fig. 3. 2D NMR correlations (HMQC and NOSEY) of 4j.
The SuzukieMiyaura reaction of 2aec with an excess of aryl-
boronic acids 3aec,eeg,l,m (3.5 equiv) afforded the 3,4,5-triaryl-
pyrazoles 6aem in 66e91% yield (Table 4, Scheme 4). The yields of
the products derived from methyl derivative 2a were generally
higher than those of 2b and 2c, which might be explained by the
high stability of the methyl group. No clear trend was observed for
the dependence of the yields from the type of arylboronic acid
employed. Inspection of the crude product mixture showed that
a small amount of biaryls were formed.
The reaction of 5-aryl-3,4-dibromopyrazoles 4 with arylboronic
acids 3a,b,d,g,o afforded the 3,4,5-triaryl-pyrazoles 7aei in
Scheme 4. Synthesis of 3,4,5-triaryl-pyrazoles 6aem. Reagents and conditions: i, 1
(1.0 equiv), ArB(OH)2 (3.3 equiv), 2 M K2CO3,, Pd(OAc)2 (5 mol %), SPhos (10 mol %), 1,4-
dioxane/H2O (4:1), 100 ꢀC, 8 h.
Fig. 4. ORTEP plot of 4n (50% probability level).
The SuzukieMiyaura reaction of 2aec with arylboronic acids
3f,g,l (2.2 equiv) afforded the 3,5-diaryl-4-bromopyrazoles 5aed in
60e66% yield (Table 2, Scheme 3). During the optimization, it
proved to be important to slightly increase the amount of the cat-
alyst (5 mol %) and to use exactly 2 equiv of the boronic acid and
3.0 equiv of base. The yields decreased when Pd(OAc)2/XPhos or
PdCl2(PPh3)2 were employed. Reduced yields were also obtained
when the temperature was decreased or when the reaction time
was shortened. A small amount of monoarylated and triarylated
pyrazole was formed as side product (inspection of the crude
product mixture). The structure of 5c was previously confirmed by
an X-ray crystal structure analysis.20
Table 3
Optimization of the synthesis of 1-methyl-3,4,5-tri(4-methylphenyl)pyrazole (6a)
Entry
Conditions
% (6a)a
1
2
3
4
5
6
7
Pd(PPh3)2Cl2 (5 mol %), aq K2CO3 (2 M)
Pd(PPh3)4 (5 mol %), aq K2CO3 (2 M)
42
28
91
80
Decomp.
Traces
20
Pd(OAc)2 (5 mol %), SPhos (10 mol %), aq K2CO3 (2 M)
Pd(OAc)2 (5 mol %), XPhos (10 mol %), aq K2CO3 (2 M)
Pd(OAc)2 (5 mol %), (EtOH)3N, K2CO3 (2 M)
Pd(OAc)2 (5 mol %), (EtO)2PPh, K2CO3 (2 M)
Pd(OAc)2 (5 mol %), (nBu)3P, K2CO3 (2 M)
a
Yields of isolated compounds.

R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
5247
Table 4
Synthesis of 6aem
6
3
R
Ar
% (6)a
a
b
c
d
e
f
g
h
i
a
b
c
l
m
g
b
c
l
e
f
a
b
Me
Me
Me
Me
Me
Me
Vinyl
Vinyl
Vinyl
Benzyl
Benzyl
Benzyl
Benzyl
4-MeC6H4
4-EtC6H4
4-tBuC6H4
3,5-Me2C6H3
4-FC6H4
91
89
86
84
87
81
66
73
71
76
78
81
84
4-(MeO)C6H4
4-EtC6H4
4-tBuC6H4
3,5-Me2C6H3
4-ClC6H4
j
k
l
4-FC6H4
4-MeC6H4
4-EtC6H4
m
a
Yields of isolated compounds.
74e92% yield (Scheme 5, Table 5). The best yields were obtained
when Pd(OAc)2 (5 mol %)/SPhos (10 mol %) was used as the
catalyst.
Scheme 5. Synthesis of 7aei. Reagents and conditions: (i) 4 (1.0 equiv), ArB(OH)2
(2.2 equiv), K2CO3 (2 M, 1 mL), Pd(OAc)2 (5 mol %), SPhos (10 mol %), 1,4-dioxane/H2O
(4:1), 100 ꢀC, 6 h.
Fig. 5. ORTEP plot of 7a (50% probability level).
Table 5
Synthesis of 7aei
7
3
Ar1
Ar2
% (7)a
(10 mol %), at 20 ꢀC under argon atmosphere. After stirring for
30 min, the arylboronic acid (2 M aqueous solution of K2CO3) was
added. The mixture was heated for 6e8 h at 60e100 ꢀC. After
cooling to 20 ꢀC, the mixture was diluted with H2O, extracted with
CH2Cl2 (3ꢁ25 mL), dried (Na2SO4) and filtered. The solvent of the
filtrate was concentrated in vacuo and the residue was purified by
column chromatography (heptanes/EtOAc).
a
b
c
d
e
f
g
h
i
o
g
o
d
g
o
b
a
g
4-MeC6H4
4-MeC6H4
4-EtC6H4
4-EtC6H4
4-EtC6H4
4-ClC6H4
4-ClC6H4
4-(MeO)C6H4
4-(MeO)C6H4
C6H5
4-(MeO)C6H4
C6H5
3-ClC6H5
4-(MeO)C6H4
C6H5
4-EtC6H4
4-MeC6H4
3-ClC6H4
92
84
89
82
86
79
81
83
74
3.1.1. 3,4-Dibromo-1-methyl-5-p-tolyl-1H-pyrazole
(4a). Starting
a
Yields of isolated products.
with 2a (159 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg, 3 mol %), K2CO3
(H2O, 2 M, 0.5 mL) and p-tolylboronic acid (75 mg, 0.55 mmol), 4a
was isolated as a white solid (125 mg, 76%). Mp¼56e57 ꢀC. 1H NMR
The structure of 7a was independently confirmed by X-ray
crystal structure (Fig. 5).24
(300 MHz, CDCl3):
d
¼2.35 (s, 3H, CH3), 3.70 (s, 3H, NCH3), 7.19
(d, 2H, J¼8.5 Hz, ArH), 7.24 (d, 2H, J¼8.5 Hz, ArH). 13C NMR
In conclusion, we have reported site-selective SuzukieMiyaura
reactions of N-protected tribromopyrazoles. The first attack occurs
at position 5, while the second and third attack occur at positions 3
and 4, respectively. The higher reactivity of carbon atoms C-3 and
C-5 compared to C-4 can be explained by their location next to the
nitrogen atom and, thus, more electron deficient character. The
higher reactivity of position 5 compared to 3 is surprising because
position 5 is sterically more hindered than position 3. The selec-
tivity might again be explained by electronic reasons. A variety of
3,4,5-triaryl-pyrazoles, 3,5-diaryl-4-bromopyrazoles and 5-aryl-
3,4-dibromopyrazoles were efficiently prepared which are not
readily available by other methods.
(75.5 MHz, CDCl3):
d¼21.4 (CH3), 38.5 (NCH3), 96.2, 125.0, 127.1 (C),
129.5, 129.6 (CH), 139.9, 143.3 (C). IR (KBr): v¼2948, 2918, 2852 (w),
1484, 1361, 1273, 995 (m), 823 (s), 720 (w), 575 (m) cmꢂ1. GCeMS
(EI, 70 eV): m/z (%)¼330 ([M, 81Br, 79Br]þ, 100), 328 ([M, 79Br2]þ, 51),
170 (10),169 (10). HRMS (EI, 70 eV): calcd for C11H10N2Br2 (Mþ, 81Br,
79Br]): 329.91848; found 329.919092.
3.1.2. 3,4-Dibromo-5-(4-ethylphenyl)-1-methyl-1H-pyrazole
(4b). Starting with 2a (159 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-ethylphenylboronic acid
(82 mg, 0.55 mmol), 4b was isolated as a white solid (136 mg, 79%).
Mp¼61 ꢀC. 1H NMR (300 MHz, CDCl3):
¼1.20 (t, J¼7.4 Hz, CH3),
d
3. Experimental section
3.1. General procedure
2.63 (q, J¼7.6 Hz, CH2), 3.69 (s, 3H, NCH3), 7.20 (d, J¼8.4 Hz, 2H,
ArH), 7.25 (d, J¼8.4 Hz, 2H, ArH). 13C NMR (75.5 MHz, CDCl3):
d
¼15.2 (CH3), 28.7 (CH2), 38.5 (NCH3), 96.2, 125.1, 127.1 (C), 128.3,
129.5 (CH), 143.3, 146.0 (C). IR (KBr): v¼2963 (m), 2929, 2848 (w),
1613 (m), 1485 (m), 1363 (s), 1274, 1117, 1004 (m) 994, 837 (s), 791,
613 (w), 577 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼344 ([M, 81Br,
To a 1,4-dioxane solution (4 mL) of 2a,b,c (0.5 mmol) were
added Pd(PPh3)4 (3e5 mol %) or Pd(OAc)2 (5 mol %) and SPhos

5248
R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
79Br]þ, 100), 342 ([M, 79Br2]þ, 51), 331 (37), 329 (75), 327 (38).
HRMS (ESIþ): calcd for C12H13Br2N2 ([MþH]þ, 79Br2): 342.9440;
found 342.9442.
CH3), 3.78 (s, 3H, CH3), 6.93 (d, J¼8.8 Hz, 2H, ArH), 7.23 (d, J¼8.8 Hz,
2H, ArH). 13C NMR (62.9 MHz, CDCl3):
¼37.5 (NCH3), 54.3 (OCH3),
d
95.2 (C), 113.2 (CH), 118.9, 126.0 (C), 129.9 (CH), 142.1, 159.5 (C). IR
(KBr): v¼3012, 2922, 2839 (w), 1607, 1539, 1481, 1366, 1257, 1176,
1025, 991 (m), 831 (s), 803 (m), 765, 687, 613, 573 (m) cmꢂ1. GCeMS
(EI, 70 eV): m/z (%)¼346 ([M, 81Br, 79Br]þ,100), 344 ([M, 79Br2]þ, 51),
333 (11), 331 (23), 329 (11). HRMS (ESIþ): calcd for C11H11Br2N2
([MþH]þ, 79Br2): 344.9233; found 344.9234.
3.1.3. 3,4-Dibromo-5-(4-tert-butylphenyl)-1-methyl-1H-pyrazole
(4c). Starting with 2a (159 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-tert-butylphenylboronic
acid (98 mg, 0.55 mmol), 4c was isolated as a white solid (151 mg,
81%). Mp¼61 ꢀC. 1H NMR (300 MHz, CDCl3):
¼1.29 (s, 9H, 3CH3),
d
3.72 (s, 3H, NCH3), 7.25 (d, J¼7.1 Hz, 2H, ArH), 7.44 (d, J¼6.9 Hz, 2H,
3.1.8. 3,4-Dibromo-5-p-tolyl-1-vinyl-1H-pyrazole (4h). Starting with
2b (165 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg, 3 mol %), K2CO3 (H2O,
2 M, 0.5 mL) and p-tolylboronic acid (75 mg, 0.55 mmol), 4h was
isolated as a white solid (112 mg, 66%). Mp¼67 ꢀC. 1H NMR
ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼31.2 (CH3), 34.8 (C), 38.6
(NCH3), 96.2, 124.9 (C), 125.7 (CH), 127.2 (C), 129.2 (CH), 143.3, 152.8
(C). IR (KBr): v¼3031, 2954, 2865 (w), 1680 (m), 1363 (m), 1266 (s),
1109 (m), 994, 839 (s), 694 (m), 587 (s) cmꢂ1. GCeMS (EI, 70 eV): m/z
(%)¼372 ([M, 81Br, 79Br]þ, 48), 370 ([M, 79Br2]þ, 27), 359 (45), 358
(11), 357 (100), 356 (13), 355 (54), 329 (18), 164 (17). HRMS (ESIþ):
calcd for C14H17Br2N2 ([MþH]þ, 79Br2): 370.9753; found 370.9751.
(300 MHz, CDCl3):
d
¼2.34 (s, 3H, CH3), 4.76 (d, 1H, J¼8.1 Hz, vinyl),
5.70 (d, 1H, J¼15.0 Hz, vinyl), 6.71 (dd, 1H, J¼15.1, 8.7 Hz, vinyl CH),
7.20 (d, 2H, J¼8.4 Hz, ArH), 7.23 (d, 2H, J¼8.6 Hz, ArH). 13C NMR
(75.5 MHz, CDCl3):
d¼21.3 (CH3), 97.1 (C), 101.8 (CH2), 114.1 (CH),
125.1, 127.1 (C), 129.3, 128.5 (CH), 138.8, 145.2 (C). IR (KBr): v¼3032,
2987, 2948, 2917, 2850 (w), 1486, 1364, 1276, 993 (m), 827 (s), 726
(w), 579 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼340 ([M, 79Br2]þ,
100), 170 (10). HRMS (EI, 70 eV): calcd for C12H10N2Br2 (Mþ, [79Br2]):
340.81848; found 340.819092.
3.1.4. 3,4-Dibromo-5-(3-chlorophenyl)-1-methyl-1H-pyrazole
(4d). Starting with 2a (159 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 3-chlorophenylboronic acid
(86 mg, 0.55 mmol), 4d was isolated as a white solid (129 mg, 73%).
Mp¼67 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.73 (s, 3H, NCH3),
7.20e7.23 (m, 1H, ArH), 7.31e7.33 (m, 1H, ArH), 7.38 (s, 1H, ArH),
3.1.9. 3,4-Dibromo-5-(2-methoxyphenyl)-1-vinyl-1H-pyrazole
(4i). Starting with 2b (165 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 2-methoxyphenylboronic
acid (83 mg, 0.55 mmol), 4i was isolated as a white solid
7.39e7.40 (m, 1H, ArH). 13C NMR (75.5 MHz, CDCl3):
d
¼38.7 (NCH3),
96.8, 125.7, 127.4 (C), 127.8, 129.6, 129.9, 130.2 (CH), 134.8, 141.8 (C).
IR (KBr): v¼3059, 2945, 2926, 2850 (w), 1600, 1565, 1461, 1366,
1272, 1080, 996, 897 (m), 784 (s), 686 (s), 593 (m) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼350 ([M, 81Br, 79Br]þ, 100), 348 ([M, 79Br2]þ, 45),
147 (10). HRMS (ESIþ): calcd for C10H8Br2ClN2 ([MþH]þ, 79Br2):
348.8737; found 348.874.
(122 mg, 69%). Mp¼58e59 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.78
d
(s, 3H, OCH3), 4.78 (d, 1H, J¼8.7 Hz, vinyl), 5.74 (d, 1H, J¼15.2 Hz,
vinyl), 6.72 (dd, 1H, J¼15.2, 8.6 Hz, vinyl CH), 6.94e6.98 (m, 2H,
ArH), 7.29e7.31 (m, 1H, ArH), 8.31e8.33 (m, 1H, ArH). 13C NMR
(75.5 MHz, CDCl3):
d¼55.3 (OCH3), 97.9 (C), 102.8 (CH2), 114.5 (CH),
3.1.5. 3,4-Dibromo-5-(4-chlorophenyl)-1-methyl-1H-pyrazole
(4e). Starting with 2a (159 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-chlorophenylboronic acid
(86 mg, 0.55 mmol), 4e was isolated as a white solid (125 mg, 71%).
119.1 (C), 121.7 (CH), 122.3 (C), 131.5 (CH), 131.7, 152.1 (C). IR (KBr):
v¼3012, 2933,1741 (w), 1645 (m),1554 (w),1468 (s), 1422 (m), 1382
(w), 1345 (m), 1322 (s), 1280 (m), 1239 (s), 1186 (w), 1172 (s), 1101
(m), 1027 (s), 983 (s), 887 (m), 832 (s), 602, 550 (m) cmꢂ1. GCeMS
(EI, 70 eV): m/z (%)¼358 ([M, 81Br, 79Br]þ,100), 356 ([M, 79Br2]þ, 70),
343 (13), 327 (22), 277 (39), 246 (22), 198 (23). HRMS (EI, 70 eV):
calcd for C12H10N2Br2O [M, 79Br2]þ: 355.81523; found 355.815343.
Mp¼52e53 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.69 (s, 3H, NCH3),
d
7.26 (d, J¼8.5 Hz, 2H, ArH), 7.42 (d, J¼8.5 Hz, 2H, ArH). 13C NMR
(62.9 MHz, CDCl3):
d
¼38.6 (NCH3), 96.6,126.3,127.3 (C),129.2,130.9
(CH), 136.0, 142.1 (C). IR (KBr): v¼3028, 2952, 2851 (w), 1473, 1359,
1264, 1089 (m), 996, 836 (s), 775, 715, 644, 574 (m) cmꢂ1. GCeMS
(EI, 70 eV): m/z (%)¼350 ([M, 81Br, 79Br]þ,100), 348 ([M, 79Br2]þ, 45),
147 (11). HRMS (ESIþ): calcd for C10H8Br2ClN2 ([MþH]þ, 79Br2):
348.8736; found 348.873.
3.1.10. 3,4-Dibromo-5-(4-methoxyphenyl)-1-vinyl-1H-pyrazole
(4j). Starting with 2b (165 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-methoxyphenylboronic
acid (83 mg, 0.55 mmol), 4j was isolated as a white solid
(130 mg, 73%). Mp¼68e69 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.80
d
3.1.6. 3,4-Dibromo-5-(4-fluorophenyl)-1-methyl-1H-pyrazole
(4f). Starting with 2a (159 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-fluorophenylboronic acid
(77 mg, 0.55 mmol), 4f was isolated as a white solid (125 mg, 75%).
(s, 3H, OCH3), 4.77 (d, 1H, J¼8.7 Hz, vinyl), 5.72 (d, 1H, J¼15.2 Hz,
vinyl), 6.70 (dd, 1H, J¼15.2, 8.5 Hz, vinyl CH), 6.95 (d, 2H, J¼8.8 Hz,
ArH), 7.25 (d, 2H, J¼8.8 Hz, ArH). 13C NMR (75.5 MHz, CDCl3):
d¼55.4 (OCH3), 98.2 (C), 102.7 (CH2), 114.3 (CH), 119.0 (C), 129.7
Mp¼55e56 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.71 (s, 3H, NCH3),
(CH), 130.5 (C), 131.5 (CH), 142.4, 160.7 (C). IR (KBr): v¼3002, 2936,
2835, 1730 (w), 1641 (m), 1574 (w), 1488 (s), 1432 (m), 1392 (w),
1355 (m), 1332 (s), 1290 (m), 1249 (s), 1196 (w), 1174 (s), 1110 (m),
1030 (s), 984 (s), 888 (m), 833 (s), 801 (m), 725 (w), 602 (m), 551
(m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼358 ([M, 81Br, 79Br]þ, 100),
356 ([M, 79Br2]þ, 70), 353 (13), 327 (22), 277 (39), 246 (22),198 (23).
HRMS (EI, 70 eV): calcd for C12H10N2Br2O [M, 79Br2]þ: 355.91544;
found 355.915354.
7.13e7.19 (m, 2H, ArH), 7.28e7.34 (m, 2H, ArH). 19F NMR
(282.4 MHz, CDCl3):
d
¼ꢂ110.1. 13C NMR (62.9 MHz, CDCl3):
¼38.5
d
(NCH3), 96.6 (C), 116.1 (d, JF,C¼21.8 Hz, CH), 123.9 (d, JF,C¼3.2 Hz, C),
127.2 (C), 131.6 (d, JF,C¼10.8 Hz, CH), 142.3 (C), 163.4 (d,
JF,C¼244.7 Hz, CeF). IR (KBr): v¼3038, 2951, 2855 (w), 1730 (w),
1606, 1541 (m), 1484, 1361, 1219 (s), 1159, 997 (m), 839 (s), 816, 721,
611, 575 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼334 ([M, 81Br,
79Br]þ, 100), 332 ([M, 79Br2]þ, 79), 174, 136 (11), 131 (12). HRMS
(ESIþ): calcd for C10H8Br2FN2 ([MþH]þ, 81Br, 79Br): 334.9013; found
334.9016.
3.1.11. 3,4-Dibromo-5-(2,6-dimethoxyphenyl)-1-vinyl-1H-pyrazole
(4k). Starting with 2b (165 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 2,6-dimethoxyphenyl-
boronic acid (100 mg, 0.55 mmol), 4k was isolated as a white
solid (139 mg, 71%). Mp¼60e61 ꢀC. 1H NMR (300 MHz, CDCl3):
3.1.7. 3,4-Dibromo-5-(4-methoxyphenyl)-1-methyl-1H-pyrazole
(4g). Starting with 2a (159 mg, 0.5 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-methoxyphenylboronic
acid (83 mg, 0.55 mmol), 4g was isolated as a white solid
d
¼3.69 (s, 6H, 2OCH3), 4.65 (d, 1H, J¼8.6 Hz, vinyl), 5.66 (d, 1H,
J¼15.2 Hz, vinyl), 6.47 (dd, 1H, J¼15.2, 8.6 Hz, vinyl CH), 6.57 (d, 2H,
(123 mg, 71%). Mp¼73 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.67 (s, 3H,
d
J¼8.8 Hz, ArH), 7.33e7.39 (m, 1H, ArH). 13C NMR (75.5 MHz, CDCl3):

R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
5249
d
¼55.9 (2OCH3), 100.0 (C), 101.2 (CH2), 103.9 (CH), 104.3, 130.0 (C),
578 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼374 ([M, 81Br]þ,100), 372
([M, 79Br]þ, 51), 265 (15),107 (07), 281 (13), 207 (100). HRMS (ESIþ):
calcd for [MþH, 79Br]þ: 372.13462; found 385.13464.
130.2, 132.5 (CH), 137.0, 158.8 (C). IR (KBr): v¼3093, 2928, 2838,
1726 (w), 1643 (m), 1537 (w), 1474 (s), 1431 (m), 1389 (w), 1356 (m),
1332 (s), 1297 (w), 1253 (s), 1187, 1173 (w), 1253 (s), 1150 (w), 1107
(s), 1030 (w), 985 (s), 886 (w), 763 (m), 588 (w) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼388 ([M, 81Br, 79Br]þ, 100), 386 ([M, 79Br2]þ, 77),
276 (26), 265 (13), 228 (42). HRMS (ESIþ): calcd for C13H13N2Br2O2
[(MþH), 81Br, 79Br]þ: 388.9918; found 388.9326.
3.1.16. 4-Bromo-3,5-bis(3,5-dimethylphenyl)-1-vinyl-1H-pyrazole
(5b). Starting with 2b (165 mg, 0.50 mmol), Pd(PPh3)2Cl2 (17 mg,
5 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 2,6-dimethylphenylboronic
acid (165 mg, 1.1 mmol), 5b was isolated as a white solid (118 mg,
62%). Mp¼89 ꢀC. 1H NMR (300 MHz, CDCl3):
¼2.31 (s, 6H, 2CH3),
d
3.1.12. 1-Benzyl-3,4-dibromo-5-(3,5-dimethylphenyl)-1H-pyrazole
(4l). Starting with 2c (197 mg, 0.50 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 3,5-dimethylphenylboronic
acid (82 mg, 0.55 mmol), 4l was isolated as a white solid (155 mg,
2.32 (s, 6H, 2CH3), 4.74 (d, 1H, J¼9.1 Hz, vinyl), 5.78 (d, 1H,
J¼15.3 Hz, vinyl), 6.79 (dd, 1H, J¼9.1, 15.3 Hz, vinyl CH), 6.90e6.93
(m, 2H, ArH), 6.91e7.06 (m, 4H, ArH). 13C NMR (75.5 MHz, CDCl3):
d¼21.3, 21.4 (CH3), 94.3 (C), 101.6 (CH2), 125.9 (CH), 126.1, 127.6 (C),
74%). Mp¼73e74 ꢀC. 1H NMR (250 MHz, CDCl3):
d¼2.23 (s, 6H,
127.7, 128.1, 129.8, 130.3 (CH), 131.6, 138.6, 142.6, 149.8 (C). IR (KBr):
v¼3080, 2992, 2824, 1729 (w), 1618 (m), 1575 (w), 1489 (s), 1446
(m), 1205 (m), 1240, 1174 (s), 1151, 1109 (m), 1019 (s), 965 (s), 933
(m), 844 (s), 775 (w), 625 (w), 518 (m) cmꢂ1. GCeMS (EI, 70 eV):
m/z (%)¼380 (M, 79Br, 100]), 275 (17), 105 (13), 135 (4). HRMS
(ESIþ): calcd for C21H22N2Br [MþH, 79Br]þ: 380.94368; found
380.94367.
OCH3), 5.11 (s, 2H, CH2), 6.76 (s, 2H, ArH), 6.97 (s, 2H, ArH),
7.19e7.23 (m, 5H, ArH). 13C NMR (62.9 MHz, CDCl3):
d¼21.2 (s, 6H,
2CH3), 54.7 (CH2), 96.8, 125.3 (C), 127.3, 127.4, 127.7 (CH), 128.0 (C),
128.6, 131.4 (CH), 136.3, 138.4, 143.9 (C). IR (KBr): v¼3029, 2918,
2853 (w), 1603, 1495, 1453 (m), 1356 (s), 1275, 1193, 1077, 1029 (m),
999 (s), 905, 861, 848, 785 (m), 727, 696 (s), 576 (m) cmꢂ1. GCeMS
(EI, 70 eV): m/z (%)¼418 ([M, 79Br2]þ, 100), 234 (10), 143 (11), 91
(54), 65 (11). HRMS (ESIþ): calcd for C18H17Br2N2 ([MþH]þ, 79Br2):
418.9753; found 418.9751.
3.1.17. 4-Bromo-3,5-bis(4-methoxyphenyl)-1-vinyl-1H-pyrazole
(5c). Starting with 2b (165 mg, 0.5 mmol), Pd(PPh3)2Cl2 (17 mg,
5 mol %), K2CO3 (H2O, 2 M,1 mL) and 4-methoxyphenylboronic acid
(167 mg, 1.1 mmol), 5c was isolated as a white solid (116 mg, 60%).
3.1.13. 1-Benzyl-3,4-dibromo-5-(4-fluorophenyl)-1H-pyrazole
(4m). Starting with 2c (197 mg, 0.62 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-fluorophenylboronic acid
(77 mg, 0.55 mmol), 4m was isolated as a white solid (144 mg, 71%).
Mp¼86 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.79 (s, 3H, OCH3), 3.81 (s,
d
3H, OCH3), 4.75 (d, 1H, J¼8.5 Hz, vinyl), 5.75 (d, 1H, J¼15.4 Hz, vi-
nyl), 6.78 (dd, 1H, J¼8.8, 15.3 Hz, vinyl CH), 6.92 (d, 2H, J¼8.9 Hz,
ArH), 6.96 (d, 2H, J¼8.8 Hz, ArH), 7.30 (d, 2H, J¼8.8 Hz, ArH), 7.86 (d,
Mp¼71e72 ꢀC. 1H NMR (300 MHz, CDCl3):
¼5.11 (s, 2H, CH2),
d
7.12e7.15 (m, 2H, 2H, ArH), 7.18e7.23 (m, 5H, ArH), 7.29e7.33 (m,
2H, J¼8.9 Hz, ArH). 13C NMR (75.5 MHz, CDCl3):
d
¼55.3, 55.4
2H, 2H, ArH). 19F NMR (282.4 MHz, CDCl3):
(62.9 MHz, CDCl3):
d
¼ꢂ112.1. 13C NMR
(OCH3), 94.2 (C), 101.6 (CH2), 113.7, 114.2 (CH), 120.1, 124.5 (C), 129.4,
130.3, 131.7 (CH), 142.2, 149.3, 159.9, 160.4 (C). IR (KBr): v¼3090,
2996, 2834, 1789 (w), 1638 (m), 1574 (w), 1489 (s), 1436 (m), 1307
(w), 1207 (m), 1250, 1178 (s), 1161, 1111 (m), 1029 (s), 1114 (m), 975
d
¼96.4 (C), 118.1 (d, JF,C¼22.5 Hz, CH), 122.2 (d,
JF,C¼3.2 Hz, C), 124.2 (C), 128.5, 129.1, 129.6 (CH), 131.4 (d,
JF,C¼10.0 Hz, CH), 141.3, 144.2 (C), 165.4 (d, JF,C¼244.7 Hz, C). IR
(KBr): v¼3033, 3001, 2951, 2901, 2855 (w),1730 (w),1607,1543 (m),
1482, 1357, 1229 (s), 1149, 990 (m), 849 (s), 826, 731, 609, 585
(m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼408 ([M, 79Br2]þ, 100), 174
(13), 136 (12), 131 (10). HRMS (ESIþ): calcd for C16H12Br2FN2
([MþH]þ, 79Br2): 408.8012; found 408.8013.
(s), 943 (m), 834 (s), 795 (w), 736 (m), 635 (w), 528 (m) cmꢂ1
.
GCeMS (EI, 70 eV): m/z (%)¼384 ([M, 79Br]þ, 100), 365 (08), 332
(07), 281 (13), 207 (100), 175 (9), 135 (4). HRMS (ESIþ): calcd for
C19H18 N2BrO2 [MþH, 79Br]þ: 385.05462; found 385.05434.
3.1.18. 1-Benzyl-4-bromo-3,5-bis(4-fluorophenyl)-1H-pyrazole
(5e). Starting with 2c (197 mg, 0.5 mmol), Pd(PPh3)2Cl2 (17 mg,
5 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-fluorophenylboronic acid
(154 mg, 1.1 mmol), 5e was isolated as a white solid (140 mg, 66%).
3.1.14. 1-Benzyl-3,4-dibromo-5-(4-methoxyphenyl)-1H-pyrazole
(4n). Starting with 2c (197 mg, 0.50 mmol), Pd(PPh3)2Cl2 (10 mg,
3 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-methoxyphenylboronic
acid (83 mg, 0.55 mmol), 4n was isolated as a white solid
Mp¼102e103 ꢀC. 1H NMR (300 MHz, CDCl3):
¼5.20 (s, 2H, CH2),
d
(161 mg, 76%). Mp¼84 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.75 (s, 3H,
6.95e6.98 (m, 2H, ArH), 7.03e7.09 (m, 4H, ArH), 7.17e7.23 (m, 5H,
OCH3), 5.12 (s, 2H, CH2), 6.86 (d, J¼7.1 Hz, 2H, ArH), 6.94 (d,
ArH), 7.84e7.89 (m, 2H, ArH). 19F NMR (300 MHz, CDCl3):
d
¼ꢂ113.5,
J¼7.0 Hz, ArH), 7.09e7.20 (m, 5H, ArH). 13C NMR (62.9 MHz, CDCl3):
ꢂ110.8. 13C NMR (62.9 MHz, CDCl3):
d
¼53.9 (CH2), 114.3 (d,
d
¼54.5 (CH2), 55.3 (OCH3), 97.0 (C), 114.3 (CH), 120.0 (C), 127.1 (CH),
JF,C¼21.5 Hz, CH), 115.0 (d, JF,C¼21.8 Hz, CH), 123.7 (CH), 1123.9 (C),
126.8 (CH), 127.5 (d, JF,C¼8.1 Hz, CH), 128.6 (CH), 126.8 (C), 131.9 (d,
JF,C¼8.4 Hz, CH), 135.6, 141.3, 146.6, 160.3 (C), 163.7 (d, JF,C¼249.0 Hz,
CeF), 164.3 (d, JF,C¼248.6 Hz, CeF). IR (KBr): v¼3061, 2956, 1900,
1667, 1590 (w), 1486 (s), 1446 (m), 1348 (w), 1222 (s), 1177 (w), 1156
(s), 1012 (m), 948 (w), 840 (s), 787 (m), 722 (s), 650 (m), 575
(w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼424 ([M]þ, 79Br, 49), 329 (11),
225 (38), 91 (100). HRMS (EI, 70 eV): calcd for C22H15N2BrF2
[M, 79Br]þ: 424.03812; found 424.037441.
127.8 (C), 127.9, 128.7, 131.1 (CH), 136.3, 143.5, 160.6 (C). IR (KBr):
v¼3031, 3002, 2957, 2917, 2833 (w), 1608, 1540, 1482, 1447, 1367,
1357 (m), 1248, 1174 (s), 1029, 998 (s), 833 (m), 726 (s), 562
(m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼420 ([M, 79Br2]þ, 45), 234
(10), 143 (11), 91 (100), 65 (11). HRMS (ESIþ): calcd for
C17H15Br2N2O ([MþH]þ, 79Br2): 420.9546; found 420.9543.
3.1.15. 4-Bromo-3,5-bis(4-methoxyphenyl)-1-methyl-1H-pyrazole
(5a). Starting with 2a (159 mg, 0.50 mmol), Pd(PPh3)2Cl2 (17 mg,
5 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and 4-methoxyphenylboronic
acid (167 mg, 1.1 mmol), 5a was isolated as a white solid (112 mg,
3.1.19. 1-Methyl-3,4,5-tri-(p-tolyl)-1H-pyrazole (6a). Starting with
2a (159 mg, 0.5 mmol), Pd(OAc)2 (7 mg, 5 mol %), SPhos (25 mg,
10 mol %), K2CO3 (H2O, 2 M, 1 mL) and p-tolylboronic acid (224 mg,
1.65 mmol), 6a was isolated as a white solid (160 mg, 91%).
60%). Mp¼91e92 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.76, 3.83, 3.87
d
(CH3), 6.87 (d, J¼8.4 Hz, 2H, CH), 6.90 (d, J¼8.1 Hz, 2H, CH), 7.29 (d,
J¼8.6 Hz, 2H, CH), 7.71 (d, J¼8.3 Hz, 2H, CH). 13C NMR (75.5 MHz,
Mp¼147 ꢀC. 1H NMR (300 MHz, CDCl3):
¼2.20 (s, 3H, CH3), 2.24 (s,
d
CDCl3):
d¼38.8 (NCH3), 55.2, 55.3 (OCH3), 93.6 (C),101.6 (CH2),113.8,
3H, CH3), 2.28 (s, 3H, CH3), 3.76 (s, 3H, NCH3), 6.84 (d, J¼8.3 Hz, 2H,
ArH), 6.89 (d, J¼8.3 Hz, 2H, ArH), 6.99 (d, J¼8.3 Hz, 2H, ArH), 7.03 (d,
J¼8.3 Hz, 2H, ArH), 7.09 (d, J¼7.8 Hz, 2H, ArH), 7.27 (d, J¼8.1 Hz, 2H,
113.9 (CH),115.6,121.5,123.3,124.9(C),128.6,130.6(CH),147.9,158.2,
158.7 (C). IR (KBr): v¼3002, 2923, 2831(w), 1613, 1550, 1494, 1437,
1362, 1290 (m), 1248, 1177 (s), 1028, 1029, 975, 755, 742, 685, 605,
ArH). 13C NMR (62.9 MHz, CDCl3):
d¼21.1, 21.2, 21.3 (CH3), 37.2

5250
R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
(NCH3), 118.7, 127.3 (C), 127.9, 128.7, 128.9, 129.1 (CH), 129.3 (C),
130.0, 130.2 (CH), 130.7, 135.6, 136.8, 138.2, 142.1, 148.4 (C). IR (KBr):
v¼3018, 2919, 2872 (w), 1579, 1523, 1440, 1315, 1277, 1182, 1112,
1005, 975 (m), 818 (s), 750, 723, 657, 613 (m) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼352 ([M]þ, 100), 351 (36). HRMS (ESIþ): calcd for
C25H25N2 [MþH]þ: 353.2012; found 353.2012.
CDCl3):
d
¼37.3 (NCH3), 115.2 (d, JF,C¼21.4 Hz, CH), 115.4 (d,
JF,C¼21.4 Hz, CH), 115.8 (d, JF,C¼21.6 Hz, CH), 118.1 (C), 125.7 (d,
JF,C¼3.6 Hz, C),129.0 (d, JF,C¼3.2 Hz, C),129.2 (d, JF,C¼3.2 Hz, C),129.6
(d, JF,C¼8.1 Hz, CH), 131.8 (d, JF,C¼8.0 Hz, CH), 131.9 (d, JF,C¼8.1 Hz,
CH), 159.7, 160.3, 160.8, 163.6, 164.3, 164.7 (C). IR (KBr): v¼3003,
2915, 2857, 1738 (w), 1600 (s), 1444, 1358, 1261, 1152, 1036, 912 (m),
848 (s), 789, 733, 694, 651 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼
364([M]þ, 100), 393 (26). HRMS (ESIþ): calcd for C22H16F3N2
(MþH): 365.126; found 365.1263.
3.1.20. 3,4,5-Tris(4-ethylphenyl)-1-methyl-1H-pyrazole
(6b). Starting with 2a (159 mg, 0.5 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
4-ethylphenylboronic acid (247 mg, 1.65 mmol), 6b was isolated as
a white solid (175 mg, 89%). Mp¼134 ꢀC. 1H NMR (300 MHz, CDCl3):
3.1.24. 3,4,5-Tris(4-methoxyphenyl)-1-methyl-1H-pyrazole
(6f). Starting with 2a (159 mg, 0.5 mmol), Pd(OAc)2 (7 mg, 5 mol %),
SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and 4-methoxy-
phenylboronic acid (251 mg, 1.65 mmol), 6f was isolated as
a white solid (162 mg, 81%). Mp¼161 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼1.09e1.20 (m, 9H, 3CH3), 2.46e2.63 (m, 6H, 3CH2), 3.76 (s, 3H,
NCH3), 6.89 (d, J¼8.2 Hz, 2H, ArH), 6.92 (d, J¼8.4 Hz, 2H, ArH), 7.02
(d, J¼8.0 Hz, 2H, ArH), 7.06 (d, J¼8.3 Hz, 2H, ArH), 7.10 (d, J¼8.7 Hz,
2H, ArH), 7.30 (d, J¼8.2 Hz, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼3.66 (s, 3H, CH3), 3.69 (s, 3H, CH3), 3.71 (s, 3H, CH3), 3.74 (s, 3H,
d
¼14.1, 14.2, 14.3 (CH3), 27.3, 27.5, 27.6 (CH2), 36.2 (NCH3), 117.6 (C),
CH3), 6.63 (d, J¼8.8 Hz, 2H, ArH), 6.72 (d, J¼8.8 Hz, 2H, ArH), 6.79
(d, J¼8.8 Hz, 2H, ArH), 6.88 (d, J¼8.8 Hz, 2H, ArH), 7.06 (d, J¼8.5 Hz,
2H, ArH), 7.31 (d, J¼8.5 Hz, 2H, ArH). 13C NMR (75.4 MHz, CDCl3):
126.4, 126.5 (CH), 126.6 (C), 126.8, 126.9, 129.0, 129.2 (CH), 129.7,
130.0, 140.8, 141.1, 142.0, 143.3, 147.4 (C). IR (KBr): v¼3019, 2961,
2871 (w), 1573, 1521, 1440, 1358, 1260, 1114, 1047, 1006, 976 (m),
833 (s), 753, 657, 615 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼394
([M]þ, 100), 379 (29). HRMS (ESIþ): calcd for C28H31N2 (MþH):
395.2482; found 395.24.86.
d¼37.2 (NCH3), 55.0 (OCH3), 55.1 (OCH3), 55.2 (OCH3), 113.6, 113.7,
113.9 (CH), 118.1, 122.5, 126.0, 126.3, 126.7 (C), 129.2, 131.4, 131.5
(CH), 141.8, 148.1, 158.0, 158.8, 159.9 (C). IR (KBr): v¼3019, 2961,
2871 (w), 1573, 1521, 1440, 1358, 1260, 1114, 1047, 1006, 976 (m),
833 (s), 753, 657, 615 cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼400 ([M]þ,
100), 399 (13), 385 (20). HRMS (ESI, 70 eV): calcd for C25H25N2O3
(MþH): 401.186; found 401.1868.
3.1.21. 3,4,5-Tris(4-tert-butylphenyl)-1-methyl-1H-pyrazole
(6c). Starting with 2a (159 mg, 0.5 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
4-tert-butylphenylboronic acid (293 mg, 1.65 mmol), 6c was iso-
lated as a white solid (205 mg, 86%). Mp¼123 ꢀC. 1H NMR (250 MHz,
3.1.25. 3,4,5-Tris(4-ethylphenyl)-1-vinyl-1H-pyrazole (6g). Starting
with 2b (165 mg, 0.5 mmol), Pd(OAc)2 (7 mg, 5 mol %), SPhos
(25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and 4-ethylphenyl-
boronic acid (247 mg, 1.65 mmol), 6g was isolated as a white
solid (134 mg, 66%). Mp¼133 ꢀC. 1H NMR (250 MHz, CDCl3):
CDCl3):
d
¼1.20 (s, 9H, 3CH3), 1.22 (s, 9H, 3CH3), 1.25 (s, 9H, 3CH3),
3.75 (s, 3H, NCH3), 6.93 (d, J¼8.4 Hz, 2H, ArH), 7.08 (d, J¼8.5 Hz, 2H,
ArH), 7.10 (d, J¼7.3 Hz, 2H, ArH), 7.18 (d, J¼8.2 Hz, 2H, ArH), 7.28 (d,
J¼8.2 Hz, 2H, ArH), 7.33 (d, J¼8.5 Hz, 2H, ArH). 13C NMR (62.9 MHz,
d
¼1.08e1.19 (m, 9H, 3CH3), 2.44e2.61 (m, 6H, 3CH2), 4.71 (d, 1H,
CDCl3):
d
¼31.2, 31.3, 31.4 (CH3), 37.3 (NCH3), 118.6 (C), 124.8, 125.0,
J¼8.0 Hz, vinyl), 5.76 (d, 1H, J¼15.1 Hz, vinyl), 6.82 (d, J¼15.2 Hz,
vinyl), 6.87 (d, J¼8.4 Hz, 2H, ArH), 6.91 (d, J¼8.3 Hz, 2H, ArH), 7.01
(d, J¼8.1 Hz, 2H, ArH), 7.04 (d, J¼8.4 Hz, 2H, ArH), 7.06 (d, J¼8.4 Hz,
2H, ArH), 7.27 (d, J¼7.9 Hz, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
125.2 (CH), 126.2 (C), 127.5, 129.8, 130.0 (CH), 130.4, 130.8, 142.1,
148.3, 148.8, 149.9, 151.2 (C). IR (KBr): v¼3029, 2959, 2867 (w),
1525, 1436, 1362, 1264, 1201, 1128, 1016, 975 (m), 838 (s), 799, 727,
656, 550 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼478 ([M]þ, 96), 464
(37), 463 (100), 224 (14). HRMS (ESI, 70 eV): calcd for C34H42N2
(MþH): 478.33425; found 478.334253.
d
¼14.3, 14.4, 14.5 (CH3), 27.1, 27.2, 27.3 (CH2), 118.3 (C), 126.9 (C),
127.2, 127.4, 127.7, 127.9, 129.3, 129.5 (CH), 129.9, 130.2, 140.9, 141.3,
142.2, 143.5, 147.7 (C). IR (KBr): v¼3023, 2951, 2861 (w), 1572, 1520,
1443, 1359, 1262, 1116, 1049, 976 (m), 832 (s), 753, 657 (m) cmꢂ1
.
3.1.22. 3,4,5-Tris(3,5-dimethylphenyl)-1-methyl-1H-pyrazole
(6d). Starting with 2a (159 mg, 0.5 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
3,5-dimethylphenylboronic acid (247 mg, 1.65 mmol), 6d was iso-
lated as a white solid (165 mg, 84%). Mp¼167 ꢀC. 1H NMR (250 MHz,
GCeMS (EI, 70 eV): m/z (%)¼406 ([M]þ, 100), 259 (14), 196 (12), 105
(14). HRMS (EI, 70 eV): calcd for C29H30N2 [M]þ: 406.14080; found:
406.140571.
3.1.26. 3,4,5-Tris(4-tert-butylphenyl)-1-vinyl-1H-pyrazole
(6h). Starting with 2b (165 mg, 0.5 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
4-tert-butylphenylboronic acid (293 mg, 1.65 mmol), 6h was iso-
lated as a white solid (178 mg, 73%). Mp¼129 ꢀC. 1H NMR (300 MHz,
CDCl3):
d
¼2.06 (s, 6H, 2CH3), 2.14 (s, 6H, 2CH3), 2.20 (s, 6H, 2CH3),
3.74 (s, 3H, NCH3), 6.61 (s, 2H, ArH), 6.69 (s, 1H, ArH), 6.74 (s, 1H,
ArH), 6.79 (s, 2H, ArH), 6.89 (s, 1H, ArH), 7.04 (s, 2H, ArH). 13C NMR
(62.9 MHz, CDCl3):
d
¼21.1, 21.2, 21.3 (6CH3), 37.3 (NCH3), 123.3 (C),
125.8, 127.8, 127.9, 128.2, 128.8, 130.0 (CH), 130.2, 133.2, 133.4, 136.9,
137.3, 138.0, 142.3, 148.3 (C). IR (KBr): v¼3003, 2915, 2857, 1738 (w),
1600 (s), 1444, 1358, 1261, 1152, 1036, 912 (m), 848 (s), 789, 733,
694, 651 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼394 ([M]þ, 100),
393 (26). HRMS (ESIþ): calcd for C28H31N2 (MþH): 395.2482; found
395.2483.
CDCl3):
d¼1.21 (s, 9H, 3CH3), 1.23 (s, 9H, 3CH3), 1.25 (s, 9H, 3CH3),
4.70 (d, 1H, J¼8.7 Hz, vinyl), 5.79 (d, 1H, J¼15.3 Hz, vinyl), 6.84 (d,
J¼15.3 Hz, vinyl), 6.92e6.95 (m, 2H, ArH), 7.10e7.13 (m, 2H, ArH),
7.18e7.22 (m, 4H, ArH), 7.27e7.30 (m, 2H, ArH), 7.37e7.39 (m, 2H,
ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼31.1, 31.2, 31.3 (CH3), 34.4,
34.5, 34.6 (C), 100.3 (CH2), 120.5 (C), 124.5, 124.8, 125.5 (CH), 126.2,
126.6 (C), 127.7 (CH), 128.1, 129.8 (CH), 129.9 (C), 130.0 (CH), 130.3,
133.3, 135.7, 146, 152.2 (C). IR (KBr): v¼3014, 2905, 2852 (w), 1640
(m), 1600 (s), 1540 (w), 1442 (m), 1363 (s), 1238 (s), 1203, 1154, 1110,
1090 (m), 996, 900, 883 (w), 847 (s), 788 (w), 690 (m), 541
(m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼490 ([M]þ, 100), 433 (26),
357 (10). HRMS (EI, 70 eV): calcd for C35H42N2 [M]þ: 490.53480;
found: 490.534711.
3.1.23. 3,4,5-Tris(4-fluorophenyl)-1-methyl-1H-pyrazole
(6e). Starting with 2a (159 mg, 0.5 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
4-fluorophenylboronic acid (231 mg, 1.65 mmol), 6e was isolated as
a white solid (158 mg, 87%). Mp¼121 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼3.76 (s, 3H, NCH3), 6.81 (d, J¼8.6 Hz, 2H, ArH), 6.87 (d, J¼7.8 Hz,
2H, ArH), 6.92 (d, J¼8.7 Hz, 2H, ArH), 7.00 (d, J¼8.5 Hz, 2H, ArH),
7.13 (d, J¼8.6 Hz, 2H, ArH), 7.33 (d, J¼8.7 Hz, 2H, ArH). 19F NMR
3.1.27. 3,4,5-Tris(3,5-dimethylphenyl)-1-vinyl-1H-pyrazole
(6i). Starting with 2b (165 mg, 0.5 mmol), Pd(OAc)2 (7 mg,
(282 MHz, CDCl3):
d
¼ꢂ111.9, ꢂ114.5, ꢂ115.5. 13C NMR (62.9 MHz,

R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
5251
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and 3,
5-dimethylphenylboronic acid (247 mg, 1.65 mmol), 6i was iso-
lated as a white solid (144 mg, 71%). Mp¼128e129 ꢀC. 1H NMR
(%)¼428 ([M]þ, 100), 427(57), 337 (15), 309 (18), 91 (16). HRMS
(EI, 70 eV): calcd for C31H28N2 [M]þ: 428.22470; found
428.224038.
(300 MHz, CDCl3):
d¼2.06 (s, 6H, 2CH3), 2.10 (s, 6H, 2CH3), 2.15 (s,
6H, 2CH3), 4.69 (d, 1H, J¼8.7 Hz, vinyl), 5.78 (d, 1H, J¼15.3 Hz,
3.1.31. 1-Benzyl-3,4,5-tris(4-ethylphenyl)-1H-pyrazole
(6m). Starting with 2c (197 mg, 0.5 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
4-ethylphenylboronic acid (247 mg, 1.65 mmol), 6m was isolated as
a white solid (197 mg, 84%). Mp¼169 ꢀC. 1H NMR (300 MHz, CDCl3):
vinyl), 6.61e6.90 (m, 8H), 7.09 (br s, 2H, ArH). 13C NMR (75 MHz,
CDCl3):
d
¼21.1, 21.2, 21.3 (CH3), 100.5 (CH2), 120.5 (C), 126.2, 128.1,
128.2, 128.5 (CH), 129.2 (C), 129.3, 130.3, 130.4 (CH), 132.6, 133.0,
137.0, 137.4, 137.8, 141.8, 150.4 (C). IR (KBr): v¼3002, 2915, 2859
(w), 1738, 1642 (m), 1600 (s), 1550 (w), 1444 (m), 1373 (s), 1303,
1268 (w), 1237 (s), 1203, 1154, 1110, 1096 (w), 1093 (m), 996, 900,
881 (w), 848 (s), 789 (w), 691 (m), 542 (w) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼406 ([M]þ, 100), 391 (26), 375 (02), 259 (04), 203
(03), 180 (02), 132 (04). HRMS (EI, 70 eV): calcd for C29H30N2 [M]þ:
406.24090; found: 406.240571.
d
¼1.08e1.17 (m, 9H, 3CH3), 2.46e2.58 (m, 6H, 3CH2), 5.20 (s, 2H,
CH2), 689e7.05 (m, 12H, ArH), 7.13e7.19 (m, 3H, ArH), 7.33e7.36 (m,
2H, ArH). 13C NMR (62.9 MHz, CDCl3):
¼15.1, 15.2, 15.4 (CH3), 28.4,
d
28.5, 28.6, 53.2 (CH2), 127.1, 127.3, 127.4 (CH), 127.5(C), 127.6(CH),
127.8(C), 128.1, 128.4, 130.2, 130.3 (CH), 130.7, 131.1, 137.8, 141.8,
142.4, 143.1, 144.4, 148.9 (C). IR (KBr): v¼3063 (w), 2962 (m), 2871,
1910, 1524 (w), 1494, 1452 (s), 1373 (m), 1253, 1155, 1062, 981 (w),
957 (m), 837 (s), 792 (m), 724, 694 (s), 595, 536 (w) cmꢂ1. GCeMS
(EI, 70 eV): m/z (%)¼470 ([M]þ, 02), 446 (16), 366 (100), 351 (08),
289 (12), 261 (12). HRMS (EI, 70 eV): calcd for C34H34N2 [M]þ:
470.27215; found 470.27208.
3.1.28. 1-Benzyl-3,4,5-tris(4-chlorophenyl)-1H-pyrazole
(6j). Starting with 2c (197 mg, 0.5 mmol), Pd(OAc)2 (7 mg, 5 mol %),
SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and 4-
chlorophenylboronic acid (257 mg, 1.65 mmol), 6j was isolated as
a white solid (186 mg, 76%). Mp¼167 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼5.20 (s, 2H, CH2), 684e6.87 (m, 2H, ArH), 6.92e6.95 (m, 2H, ArH),
3.1.32. 1-Methyl-3,4-diphenyl-5-p-tolyl-1H-pyrazole (7a). Starting
with 4a (100 mg, 0.30 mmol), Pd(OAc)2 (7 mg, 5 mol %), SPhos
(25 mg, 10 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and phenylboronic acid
(80 mg, 0.66 mmol), 7a was isolated as a white solid (89 mg, 92%).
7.00e7.08 (m, 4H, ArH), 7.17e7.22 (m, 7H, ArH), 7.31e7.34 (m, 2H,
ArH). 13C NMR (75 MHz, CDCl3):
¼53.2 (CH2), 127.1, 127.7 (CH),
d
128.0 (C), 128.6, 128.8, 128.9, 129.0, 129.5 (CH), 130.9, 131.2, 131.4
(C), 131.5, 131.9 (CH), 132.7, 133.6, 135.1, 136.9, 141.4, 147.8 (C). IR
(KBr): v¼3089, 3031, 1913, 1601, 1496 (w), 1441 (m), 1391, 1268 (w),
1152 (m), 1089 (s), 1031 (w), 1008, 980 (s), 956 (w), 841 (s), 784 (w),
734 (s), 609 (w), 542 (s) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼488 ([M,
35Cl3]þ, 100), 343 (13), 327 (22), 277 (39), 246 (22), 198 (23). HRMS
(EI, 70 eV): calcd for C28H19N2Cl3 [M, 35Cl3]þ: 488.91544; found
488.915354.
Mp¼147 ꢀC. 1H NMR (300 MHz, CDCl3):
¼2.28 (s, 3H, CH3), 3.78 (s,
d
3H, NCH3), 6.95e6.98 (m, 2H, ArH), 7.03e7.05 (m, 1H, ArH),
7.07e7.10 (m, 4H, ArH), 7.06e7.09 (m, 2H, ArH), 7.15e7.22 (m, 4H,
ArH), 7.37e7.40 (m, 1H, ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼21.3,
37.3 (NCH3), 118.9 (C), 126.2, 128.0, 129.2, 130.0, 130.4 (CH), 122.5
(C), 127.9, 128.8, 128.9, 130.2 (CH), 130.4, 133.4, 138.3, 142.3, 148.4
(C). IR (KBr): v¼3051, 2921, 2850 (w), 1600, 1519 (w), 1483, 1356,
1232, 1006, 831 (m), 760, 694 (s), 626, 566 (m) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼324 ([M]þ, 100), 323 (53). HRMS (ESIþ): calcd for
C23H21N2 ([MþH]þ): 325.1699; found 325.1703.
3.1.29. 1-Benzyl-3,4,5-tris(4-fluorophenyl)-1H-pyrazole
(6k). Starting with 2c (197 mg, 0.62 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
4-fluorophenylboronic acid (231 mg,1.65 mmol), 6k was isolated as
a white solid (171 mg, 78%). Mp¼151 ꢀC. 1H NMR (250 MHz, CDCl3):
3.1.33. 3,4-Bis(4-methoxyphenyl)-1-methyl-5-p-tolyl-1H-pyrazole
(7b). Starting with 4a (100 mg, 0.30 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and
4-methoxyphenylboronic acid (100 mg, 0.66 mmol), 7b was iso-
lated as a white solid (97 mg, 84%). Mp¼159e160 ꢀC. 1H NMR
d
¼5.21 (s, 2H, CH2), 6.76e6.81 (m, 2H, ArH), 6.87e6.90 (m, 3H,
ArH), 6.92e6.94 (m, 2H, ArH), 6.97e7.03 (m, 4H, ArH), 7.18e7.22 (m,
4H, ArH), 7.34e7.39 (m, 2H, ArH). 19F NMR (282 MHz, CDCl3):
d
¼ꢂ111.8, ꢂ114.5, ꢂ115.6. 13C NMR (62.9 MHz, CDCl3):
d¼53.5
(300 MHz, CDCl3):
d
¼2.28 (s, 3H, CH3), 3.68 (s, 3H, CH3), 3.71 (s, 3H,
(CH2), 115.2 (d, JF,C¼21.2 Hz, CH), 115.3 (d, JF,C¼21.3 Hz, CH), 115.8 (d,
JF,C¼22.9 Hz, CH), 118.5 (C), 127.0, 127.6, 128.6 (CH), 128.8, 128.9,
129.4 (C), 129.8 (d, JF,C¼7.9 Hz, CH), 131.8 (d, JF,C¼8.0 Hz, CH), 132.1
(d, JF,C¼7.9 Hz, CH),137.1,141.4,147.9,159.7,160.4,164.8 (C). IR (KBr):
v¼3063, 2953, 2924, 2851 (w), 1604, 1593, 1491, 1443 (m), 1223,
CH3), 3.76 (s, 3H, CH3), 6.63e6.66 (m, 3H, ArH), 6.72e6.75 (m, 3H,
ArH), 6.87e6.90 (m, 3H, ArH), 7.02e7.10 (m, 5H, ArH), 7.30e7.33 (m,
2H, ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼21.3 (CH3), 37.2 (NCH3),
55.0, 55.1 (OCH3), 113.5, 113.6 (CH), 118.1, 125.9, 126.2, 127.3 (C),
129.1, 129.2, 130.0, 131.4 (CH), 138.1, 142.0, 148.1, 157.9, 158.8 (C). IR
(KBr): v¼3011, 2923, 2832, 1611 (w), 1520, 1432, 1283 (m), 1241 (s),
1172 (s), 1033, 837, 807 (m), 755, 612, 530 (m) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼384 ([M]þ, 100), 341 (13), 327 (22), 277 (39), 246
(22),198 (23). HRMS (ESIþ): calcd for C25H25N2O2 [MþH]: 385.1911;
found 385.1914.
1156 (s), 1094, 975, 908 (m), 838, 816 (s), 720, 601, 530 (m) cmꢂ1
.
GCeMS (EI, 70 eV): m/z (%)¼440 ([M]þ, 100), 345 (15), 321 (11), 91
(48). HRMS (ESIþ): calcd for C28H19N2 (MþH): 441.126; found
441.1263.
3.1.30. 1-Benzyl-3,4,5-tri-p-tolyl-1H-pyrazole (6l). Starting with 2c
(197 mg, 0.5 mmol), Pd(OAc)2 (7 mg, 5 mol %), SPhos (25 mg,
10 mol %), K2CO3 (H2O, 2 M, 1 mL) and 4-methylphenylboronic
acid (224 mg, 1.65 mmol), 6l was isolated as a white solid
3.1.34. 5-(4-Ethylphenyl)-1-methyl-3,4-diphenyl-1H-pyrazole
(7c). Starting with 4b (103 mg, 0.3 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 1 mL) and
phenylboronic acid (80 mg, 0.66 mmol), 7c was isolated as a white
(173 mg, 81%). Mp¼174 ꢀC. 1H NMR (300 MHz, CDCl3):
¼2.18 (s,
d
3H, CH3), 2.24 (s, 3H, CH3), 2.25 (s, 3H, CH3), 5.20 (s, 2H, CH2),
6.84e6.87 (m, 4H, ArH), 6.91e6.94 (m, 2H, ArH), 6.98e7.02 (m,
2H, ArH), 7.03e7.05 (m, 2H, ArH), 7.16e7.19 (m, 3H, 3CH3). 13C
solid (90 mg, 89%). Mp¼153 ꢀC. 1H NMR (300 MHz, CDCl3):
¼1.18
d
(t, J¼7.5 Hz, 3H, CH3), 2.59 (q, J¼7.6 Hz, 2H, CH2), 3.79 (s, 3H, NCH3),
6.96e6.99 (m, 2H, ArH), 7.05e7.10 (m, 5H, ArH), 7.17e7.21 (m, 5H,
NMR (62.9 MHz, CDCl3):
d
¼21.1, 21.2, 21.3 (CH3), 53.1 (CH2), 115.1,
ArH), 7.37e7.40 (m, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼15.1
119.0 (C), 127.1 (CH), 127.3 (C), 128.1, 128.4, 128.7, 128.8, 129.1
(CH), 129.9 (C), 130.1, 130.2 (CH), 130.4, 130.8, 135.6, 136.9, 137.7,
138.2, 142.4, 148.9 (C). IR (KBr): v¼3065, 3018, 2918, 2862 (w),
1494, 1452 (s), 1361 (m), 1309, 1294, 1185, 1113, 1028, 973, 852,
829 (m), 815, 733, 721 (m), 693 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z
(CH3), 28.5 (CH2), 37.3 (NCH3), 125.5 (C), 126.2, 127.2, 127.9, 128.0,
128.1 (CH), 128.5, 128.7 (C), 130.0, 130.4 (CH), 133.5, 142.3, 144.5,
148.4 (C). IR (KBr): v¼3051, 2959, 2924, 2848, 1603, 1519, 1454,
1361, 1277, 1117, 1058, 1007, 973, 916 (w), 841 (m), 761, 696 (s), 627,
536 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼338 ([M]þ, 100),

5252
R.A. Khera et al. / Tetrahedron 67 (2011) 5244e5253
337 (45). HRMS (EI, 70 eV): calcd for C24H23N2 [MþH]: 339.1856;
1007 (m), 835 (s), 755, 675, 628, 604, 538 (m) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼400 ([M, 35Cl]þ, 100). HRMS (ESIþ): calcd for
C26H26ClN2 [MþH]þ: 401.1779; found 401.178.
found 339.1861.
3.1.35. 3,4-Bis(3-chlorophenyl)-5-(4-ethylphenyl)-1-methyl-1H-pyr-
azole (7d). Starting with 4b (103 mg, 0.3 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and
3-chlorophenylboronic acid (99 mg, 0.66 mmol), 7d was isolated as
a white solid (100 mg, 82%). Mp¼148 ꢀC. 1H NMR (300 MHz, CDCl3):
3.1.39. 5-(4-Methoxyphenyl)-1-methyl-3,4-di-p-tolyl-1H-pyrazole
(7h). Starting with 4g (104 mg, 0.3 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and
p-tolylboronic acid (90 mg, 0.66 mmol), 7h was isolated as a white
solid (92 mg, 83%). Mp¼157e159 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼1.18 (t, J¼7.5 Hz, 3H, CH3), 2.59 (q, J¼7.6 Hz, 2H, CH2), 3.79 (s, 3H,
NCH3), 6.96e6.99 (m, 2H, ArH), 7.05e7.10 (m, 5H, ArH), 7.17e7.21
d
¼2.20 (s, 3H, CH3), 2.24 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.75 (s, 3H,
(m, 3H, ArH), 7.37e7.40 (m, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
CH3), 6.80 (d, J¼7.1 Hz, 2H, ArH), 6.84 (d, J¼8.3 Hz, 2H, ArH), 6.90 (d,
J¼8.0 Hz, 2H, ArH), 7.00 (d, J¼7.9 Hz, 2H, ArH), 7.08 (d, J¼7.0 Hz, 2H,
ArH), 7.28 (d, J¼8.0 Hz, 2H, ArH). 13C NMR (75.4 MHz, CDCl3):
d
¼15.1 (CH3), 28.6 (CH2), 37.4 (NCH3),117.8 (C),126.2 (CH),126.5 (C),
126.7, 127.3, 127.5, 127.9, 128.1, 128.6 (CH), 128.7 (C), 129.4, 129.9,
130.1 (CH), 133.9, 134.2, 135.1, 142.7, 145.0, 147.0 (C). IR (KBr):
v¼3063, 2961, 2872 (w), 1596, 1455, 1409, 1359, 1304, 1257, 1111,
d¼21.1, 21.2 (CH3), 37.2 (NCH3), 55.2 (OCH3), 113.9 (CH), 118.6, 122.5
(C), 127.9, 128.8, 128.9, 130.2 (CH), 130.6, 130.8 (C), 131.4 (CH), 135.6,
136.8, 141.9, 148.4, 159.5 (C). IR (KBr): v¼2951, 2920, 2851 (w), 1612,
1529, 1492, 1353, 1286 (m), 1243, 1178 (s), 1107 (m), 1034 (s), 1020,
845 (m), 824 (s), 800, 755, 721, 614, 530 (m) cmꢂ1. GCeMS (EI,
70 eV): m/z (%)¼368 ([M]þ, 100). HRMS (ESIþ): calcd for C25H25N2O
[MþH]þ: 369.1961; found 369.1962.
1076, 997, 880, 847 (w), 786, 759, 697 (s), 635, 556 (m) cmꢂ1
.
GCeMS (EI, 70 eV): m/z (%)¼406 ([M]þ, 100), 405 (26), 391 (10).
HRMS (EI, 70 eV): calcd for C24H21Cl2N2 [MþH]: 407.1076; found
407.1074.
3.1.36. 5-(4-Ethylphenyl)-3,4-bis(4-methoxyphenyl)-1-methyl-1H-
pyrazole (7e). Starting with 4b (103 mg, 0.3 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and
4-methoxyphenylboronic acid (100 mg, 0.66 mmol), 7e was iso-
lated as a white solid (102 mg, 86%). Mp¼169 ꢀC. 1H NMR (300 MHz,
3.1.40. 3,4-Bis(3-chlorophenyl)-5-(4-methoxyphenyl)-1-methyl-1H-
pyrazole (7i). Starting with 4g (104 mg, 0.3 mmol), Pd(OAc)2 (7 mg,
5 mol %), SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and
3-chlorophenylboronic acid (103 mg, 0.66 mmol), 7i was isolated as
a white solid (102 mg, 83%). Mp¼171 ꢀC. 1H NMR (300 MHz, CDCl3):
CDCl3):
d
¼1.17 (t, J¼7.5 Hz, 3H, CH3), 2.58 (q, J¼7.6 Hz, 2H, CH2),
3.68 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.76 (s, 3H, NCH3), 6.64 (d,
J¼8.8 Hz, 2H, ArH), 6.73 (d, J¼9.0 Hz, 2H, ArH), 6.89 (d, J¼8.8 Hz, 2H,
ArH), 7.07 (d, J¼8.2 Hz, 2H, ArH), 7.11 (d, J¼8.2 Hz, 2H, ArH), 7.32 (d,
d
¼3.75 (s, 3H, CH3), 3.76 (s, 3H, CH3), 6.81e6.82 (m, 4H, ArH), 6.85
(s, 1H, ArH), 6.94 (s, 1H, ArH), 7.03e7.08 (m, 4H, ArH), 711e7.15 (m,
2H, ArH). 13C NMR (62.9 MHz, CDCl3):
d¼37.3 (NCH3), 55.2 (OCH3),
J¼9.1 Hz, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
d¼15.1 (CH3), 28.5
114.1 (CH), 117.7, 121.4 (C), 126.2, 126.7, 127.5, 127.9, 128.5, 129.4,
130.0, 130.1, 131.3 (CH), 133.9, 134.2, 135.0, 135.1, 142.4, 146.9, 159.8
(C). IR (KBr): v¼3057, 2926, 2835 (w), 1611, 1597, 1469, 1358, 1290
(m), 1247 (s), 1174, 1077, 1032, 998, 846 (m), 784, 730, 698 (s), 604
(m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼408 ([M, 35Cl2]þ, 100). HRMS
(CH2), 37.2 (NCH3), 55.0, 55.1 (OCH3), 113.5, 113.6 (CH), 118.1, 125.9,
126.2, 127.4 (C), 127.9, 129.2, 130.0, 131.4 (CH), 142.1, 144.3, 148.1,
157.9, 158.8 (C). IR (KBr): v¼3010, 2961, 2925, 2832 (w), 1612, 1578,
1547,1520,1463,1433,1354,1283 (m),1242,1171 (s),1110,1034, 973
(m), 833 (s), 809, 756, 608, 544 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z
(%)¼398 ([M]þ, 100), 397 (12), 383 (18). HRMS (ESIþ): calcd for
C26H27N2O2 [MþH]: 399.2067; found 399.2071.
(ESIþ): calcd for C23H19Cl2N2O [MþH]þ
(
35Cl2): 409.0869; found
409.0867.
Acknowledgements
3.1.37. 5-(4-Chlorophenyl)-1-methyl-3,4-diphenyl-1H-pyrazole
(7f). Starting with 4e (105 mg, 0.3 mmol), Pd(OAc)2 (7 mg, 5 mol %),
SPhos (25 mg, 10 mol %), K2CO3 (H2O, 2 M, 0.5 mL) and phenyl-
boronic acid (80 mg, 0.66 mmol), 7f was isolated as a white solid
Financial support from the State of Pakistan (HEC scholarships
for M.H., R.A.K. and H.R.), from the DAAD (scholarships for R.A.K.
and A.A.), from the State of Mecklenburg-Vorpommern (scholar-
ships for M.H., R.A.K. and J.T.) and from the Friedrich-Irmgard-
Harms-Stiftung (scholarships for A.A. and R.A.K.) is gratefully
acknowledged. Partial financial support by the Ministry of Science
of the Republic of Serbia, Grant No. 142007, is gratefully
acknowledged.
(82 mg, 79%). Mp¼157 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.85 (s, 3H,
d
NCH3), 6.99e7.02 (m, 2H, ArH), 7.09e7.12 (m, 2H, ArH), 7.22e7.25
(m, 3H, ArH), 7.28e7.34 (m, 2H, ArH), 7.38e7.42 (m, 3H, ArH),
7.50e7.54 (m, 2H, ArH). 13C NMR (75.5 MHz, CDCl3):
d
¼37.5 (NCH3),
119.2 (C), 127.0 (CH), 127.1 (C), 127.2, 128.1, 128.2, 128.3, 128.8, 130.4,
130.5 (CH), 133.4, 133.5, 140.2, 141.1, 141.9, 148.5 (C). IR (KBr):
v¼3011, 2923, 2832, 1611 (w), 1520, 1432, 1283 (m), 1241 (s), 1172
(s), 1033, 837, 807 (m), 755, 612, 530 (m) cmꢂ1. GCeMS (EI, 70 eV):
m/z (%)¼346 ([M, 37Cl]þ, 100), 344 ([M, 35Cl]þ, 99). HRMS (EI,
70 eV): calcd for (Mþ, [35Cl]): 344.91324; found 344.9133.
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¼1.12e1.17 (m, 6H, 2CH3), 2.49e2.59 (m, 4H, ArH), 3.75 (s, 3H,
CH3), 6.86 (d, J¼8.0 Hz, 2H, ArH), 6.93 (d, J¼7.3 Hz, 2H, ArH), 7.02 (d,
J¼8.0 Hz, 2H, ArH), 7.09 (d, J¼8.1 Hz, 2H, ArH), 7.26 (d, J¼8.3 Hz, 2H,
ArH), 7.30 (d, J¼8.0 Hz, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼14.1, 14.3 (CH3), 28.4, 28.5 (CH2), 36.3 (NCH3), 118.1, 125.9 (C),
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v¼2960, 2913, 2871, 2848 (w), 1525, 1453, 1360, 1259, 1183, 1091,

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