Pd-catalyzed cross-coupling reactions of halogenated 1-phenylpyrazol-3-ols and related triflates

Article abstract of DOI:10.1016/j.tet.2009.07.017

1-Phenyl-1H-pyrazol-3-ol was used as a versatile synthon for the preparation of various 1-phenyl-1H-pyrazole derivatives substituted at C-3 and C-4 of the pyrazole nucleus and at the phenyl ring para-position. Treatment of 1-phenyl-1H-pyrazol-3-ol with tr

Full text of DOI:10.1016/j.tet.2009.07.017

Tetrahedron 65 (2009) 7817–7824
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd-catalyzed cross-coupling reactions of halogenated 1-phenylpyrazol-3-ols
and related triflates
a
a
b
b
,
a,
*
*
ˇ
ˇ
ˇ
Egle Arbaciauskiene , Gyte Vilkauskaite , Gernot A. Eller , Wolfgang Holzer , Algirdas Sackus
˙
˙
˙
˙
a Institute of Synthetic Chemistry, Kaunas University of Technology Radvilenu pl. 19, LT-50254 Kaunas, Lithuania
b Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2009
Received in revised form 3 July 2009
Accepted 4 July 2009
Available online 9 July 2009
1-Phenyl-1H-pyrazol-3-ol was used as a versatile synthon for the preparation of various 1-phenyl-1H-
pyrazole derivatives substituted at C-3 and C-4 of the pyrazole nucleus and at the phenyl ring para-
position. Treatment of 1-phenyl-1H-pyrazol-3-ol with triflic anhydride in the presence of base gave
3-trifloyloxy pyrazole, while bromination and iodination yielded the corresponding halogenated de-
rivatives. The obtained scaffolds were used in carbon–carbon bond forming Pd-catalyzed cross-coupling
reactions to yield (het)aryl- and carbo-functionally substituted 1-phenyl-1H-pyrazoles.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
method is the catalyzed N-arylation of the 1H-pyrazole unit.12
However, in the case of unsymmetrical pyrazoles, this route faces
Pyrazoles are common motifs in material,1 agricultural,2
and pharmaceutical3 sciences. More specifically, 1-phenyl-
pyrazole derivatives are known to have a broad spectrum of
biological activities. For example, 4-amino-N-(1-phenyl-1H-pyr-
azol-5-yl)benzensulfonamide (Sulfaphenazole) derived from
5-amino-1-phenylpyrazole is a potent antibacterial drug,4 while
a similar problem of regioselectivity because pyrazole can act as an
ambident nucleophile due to tautomerism.13
Cl
F3C
COOH
O
O
N
N
S
3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
(CDPPD)
Me
N
N
N
N
N
N
O
N
N
H
H
NH2
has been identified as a positive allosteric metabotropic modu-
lator of the glutamate receptor.5 Nonsteroidal anti-inflammatory
drugs such as Lonazolac are (1,3-diphenyl-1H-pyrazol-4-yl)acetic
acid derivatives (Fig. 1).6 The anti-inflammatory activity is also
characteristic of (1,4-diphenylpyrazol-3-yl)acetic, -propionic, and
-butyric acids.7 The widely prescribed COX-2 inhibitor Celecoxib
carries a trifluoromethyl substituent at the C-3 of the pyrazole
nucleus and a partial sulfonamide structure at the N-phenyl ring.8
1,3-Diphenylpyrazoles containing heterocyclic moieties such as
pyrimidine, 1,3,4-oxadiazole or 1,2,4-triazole at the C-4 have been
tested for their antimicrobial, antifungal, and antiviral activities.9
4-Alkyl-1,2,5-tris(4-hydroxyphenyl)pyrazoles have been studied
as estrogen receptor-selective agonists.10
CN
SO2NH2
CDPPB
Sulfaphenazole
Lonazolac
Celecoxib
Figure 1. Some pharmaceuticals bearing the N-phenylpyrazole moiety.
In order to develop an efficient synthetic approach to the var-
ious 3- and 4-substituted 1-phenyl-1H-pyrazoles, we chose to
explore the palladium-catalyzed coupling reactions for in-
corporating the desired substituents to the fully assembled core.
There have been several literature reports on the palladium-cata-
lyzed cross-coupling reactions of halo- and pseudohalo-
substituted pyrazoles. Most of these studies report the Suzuki
cross-couplings of 4(5)-bromo-, 4(5)-iodo or 5-trifloyloxy-1H-
pyrazoles with arylboronic acids,14 and, correspondingly, 4(5)-
(1,3,2-dioxaborolan-2-yl)-1H-pyrazoles or 4(5)-pyrazoleboronic
acids with haloarenes.15 Collins et al. utilized a Suzuki cross-cou-
pling of 3(5)-pyrazolyl nonaflates for regioselective synthesis of
3,5-diaryl-1-methyl-1H-pyrazoles.16 Wang et al. performed Suzuki,
Sonogashira, and Stille cross-couplings on 1-aryl-5-bromo-1H-
pyrazoles for the preparation of 1-aryl-1H-pyrazoles substituted at
the C-5 position.17
Many methods have been described in the literature for the
synthesis of substituted 1-phenylpyrazoles. The most common
approach is based on the cyclocondensation of N-arylhydrazines
with 1,3-dicarbonyl compounds; unfortunately, asymmetric 1,3-
diketones often give a mixture of two regioisomers.11 An alternative
* Corresponding authors. Tel.: þ43 1 4277 55623; fax: þ43 1 4277 9556.
E-mail addresses: wolfgang.holzer@univie.ac.at (W. Holzer), algirdas.sackus@
ˇ
ˇ
ktu.lt (A. Sackus).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.017

ˇ
E. Arbaciauskiene˙ et al. / Tetrahedron 65 (2009) 7817–7824
7818
A survey of the literature has shown that Pd-catalyzed cross-
was treated with iodine and potassium hydroxide in DMF, 4-
iodo-1-phenyl-1H-pyrazol-3-ol (6) was formed in good yield
(Scheme 1). The dibrominated pyrazole 7 was obtained by
refluxing compound 2 with 3 equiv of Br2 in CHCl3 (simulta-
neously introducing a bromo atom into both the phenyl and the
pyrazole moieties) as we have described previously.23 Treatment
of 4-bromopyrazole 4 and 4,40-dibromopyrazole 7 with triflic
anhydride in the presence of triethylamine afforded multiply
coupling reactions remain one of the most efficient methods for the
functionalization of 1H-pyrazoles. Although this method has found
many applications in synthesizing novel pyrazoles, there is still
a great deal of work remaining to enable the development of effi-
cient protocols for structurally different compounds and to make
these reactions more practical by using inexpensive and easily
available starting materials.
halogenated and pseudohalogenated substrates
respectively.
5 and 8,
2. Results and discussion
The use of O-triflated variants in cross-coupling strategies rep-
resents an efficient approach for installing various heterocycles into
complex molecules.24 Having successfully prepared 3-trifloyloxy-
1H-pyrazole 3, we examined its ability to participate in Heck,
Sonogashira and Suzuki cross-coupling reactions (Scheme 2).
We chose 1-phenylpyrazol-3-ol (2) as a starting material for
the synthesis of 3- and 4-substituted 1-phenyl-1H-pyrazoles.
Compound 2 was obtained by oxidation of the commercially
available 1-phenylpyrazolidin-3-one (1) according to a pre-
viously described method.18 The second step in our synthetic
sequence was the preparation of substrates suitable for Pd-
catalyzed cross-coupling reactions by introducing substituents
such as halogen atoms and the triflic group into the pyrazole
core.
The general method for the preparation of O-triflates is treat-
ment of hydroxylic substrates with triflic anhydride in the presence
of non-nucleophilic tertiary amines or inorganic bases.14c,d,19 We
easily introduced the triflate group at C-3 of the pyrazole nucleus by
reaction of compound 2 with triflic anhydride in the presence of
triethylamine in methylene chloride to give the 3-trifloyloxy-1H-
pyrazole 3. No formation of an unwanted mixture of N- and O-tri-
flated products was found, in contrast to an observation reported
earlier regarding the low regioselectivity of a similar triflation of 1-
substituted pyrazol-5-ones.14c
TfO
R
9a R= 2-(tert-butoxycarbonyl)ethenyl, 74%
9b R=phenylethynyl, 55%
9c R= phenyl, 65%
i, ii or iii
N
N
N
N
9d R=3-thienyl, 60%
Ph
Ph
9e R=2-thienyl, 53%
3
9a-e
Scheme 2. Reagents and conditions: (i) H2C]CHCO2-t-Bu, Pd(PPh3)2Cl2, TEA, DMF,
120 ꢀC, 16 h (for 9a); (ii) CH^CPh, Pd(PPh3)2Cl2, CuI, TEA, DMF, 55 ꢀC, 5 days (for 9b);
(iii) arylboronic acid, Pd(PPh3)4, K3PO4, KBr, dioxane, reflux, 6–17 h (for 9c–e).
Under the Heck reaction conditions,25 3-trifloylpyrazole 3 was
successfully coupled with tert-butyl acrylate using Pd(PPh3)2Cl2 as
a catalyst in DMF containing TEA to give product 9a at a 74% yield.
The standard Sonogashira reaction conditions26 (Pd(PPh3)2Cl2, CuI,
triethylamine) were applied to obtain the cross-coupling product
9b (55%) from triflate 3 and phenylacetylene. The Suzuki reaction27
was used for the cross-coupling of triflate 3 with various boronic
acids (phenyl-, 2-thiophene-, 3-thiophene-) to give 9c–e, re-
spectively, in good yields. In this case, Pd(PPh3)4 was used as
a catalyst, and the reaction was carried out in the presence of KBr,
which prevents the decomposition of the catalyst as reported
elsewhere.14c,27b The Suzuki reaction of compound 3 was also ex-
amined with 2-furylboronic acid under the conditions described
above. However, this coupling did not give a positive result as
a complex reaction mixture was obtained (Scheme 3) with full
consumption of the starting compound 3.
Further, we investigated the cross-coupling reactions of the
halogenated compounds 4 and 6, which possess the hydroxyl
functionality at the C-3 position. The presence of electron-do-
nating groups on the aromatic ring of arylhalides is known to
often decrease the rate of the cross-coupling reaction rate.27b
More specifically, the reactivity of phenol halides can also be
substantially lowered if the hydroxylate donor group forms under
the influence of base.28 However, formation of unwanted pheno-
lates can be avoided by protecting the hydroxyl groups, for ex-
ample, by their transformation to the corresponding ethers or
esters.29
The selective monobromination at C-4 of 2 was performed
with 1 equiv of Br2 in chloroform at room temperature, similarly
to
a
previously described procedure,20 yielding 4-bromo-1-
phenyl-1H-pyrazol-3-ol (4). There are several methods known
for the preparation of 4-iodo-1H-pyrazoles, including green io-
dination with iodine/hydrogen peroxide in water.21 However,
due to the low solubility of compound 2 in such a solvent, we
have instead used a procedure described by Roy et al. for the
iodination of indole at the C-3 position.22 When compound 2
TfO
N
N
Ph
3, 79%
ii
O
HO
TfO
Br
HO
Br
i
iii
ii
HN
N
N
N
N
Ph
1
N
N
N
Ph
Ph
Ph
2, 70%
4, 75%
5, 78%
iv
v
HO
I
Thus, 4-bromopyrazol-3-ol (4) was coupled with tert-butyl ac-
rylate under Heck reaction conditions to afford product 10a at
a moderate yield of 50%. Employing 4-iodopyrazol-3-ol 6 as the
starting material under analogous reaction conditions, only a 20%
yield of 10a was obtained.
HO
Br
TfO
Br
ii
N
N
N
N
N
N
Ph
6, 63%
Both 4-halopyrazol-3-ols 4 and 6 were also tested under Sono-
gashira reaction conditions using the Pd(PPh3)2Cl2/CuI catalytic
system in DMF. However, in this case only the iodinated pyrazole 6
gave the desired product 10b, which was subsequently hydroge-
nated to give 11 (Scheme 3). The Sonogashira coupling was also
examined with but-3-yn-1-ol, but no target product was formed
under the above-mentioned conditions. Under Stille coupling
Br
7, 82%
Br
8, 79%
Scheme 1. Reagents and conditions: (i) FeCl3, HCl (aq), EtOH, reflux, 1 h or FeCl3, DMF,
80 ꢀC, 4 days; (ii) Tf2O, TEA, DCM, rt, 2 h (for 3, 5, and 8); (iii) 1 equiv Br2, CHCl3, rt,
20 h; (iv): I2, KOH, DMF, rt, 20 h; (v) 3 equiv Br2, CCl4, reflux, 19 h.

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E. Arbaciauskiene˙ et al. / Tetrahedron 65 (2009) 7817–7824
7819
conditions30 (Pd(PPh3)2Cl2 as a catalyst in DMF), 4-bromopyrazol-
3-ol 4 was successfully coupled with phenyltributyltin to give 10c
(Scheme 3).
and 13b were easily removed under standard conditions (1 N NaOH
in MeOH) to give pyrazol-3-ols 10c and 14.
Pd-catalyzed cross-coupling reactions of multiply halogenated
heterocycles are widely used in the construction of highly func-
tionalized organic compounds.33 It is known that the main factors
determining regioselectivity in cross-coupling reactions of het-
erocycles multiply substituted by identical halogen atoms include
various electronic and steric effects and the coordinating features of
ring heteroatoms.33 When the halogen atoms are different, the
regioselectivity is mainly due to the bond dissociation energies of
the respective carbon–halogen bonds.34 Therefore, the bromine
atom might be expected to undergo substitution more readily than
the TfO group, as the relative bond dissociation energy of the C–Br
bond is lower than that of the C–O bond.35 In our case, this ex-
pectation was corroborated by the cross-coupling reaction of 4-
bromo-3-trifloyloxy-1H-pyrazole (5). Treatment of the latter with
phenylboronic acid under Suzuki reaction conditions afforded
a mixture of products 15, 16, and 17, indicating that substitution at
the 4-position of the pyrazole nucleus is preferred (Scheme 4). In
order to achieve full consumption of the starting compound 5, we
used a threefold excess of phenylboronic acid. In this case, the ratio
of products 15, 16, and 17 (established by both 1H NMR analysis of
the crude mixture and the relative yields of purified products) was
1:2.7:1. When using 4 equiv of phenylboronic acid and refluxing the
reaction mixture for 20 h, only 1,3,4-triphenyl-1H-pyrazole 17 was
obtained, in a 70% yield. Synthesis of the latter has previously been
described in the literature.36
Ph
HO
R
HO
i, ii or iii
iv
4, 6
N
N
11, 50%
N
N
Ph
Ph
10a R=2-(tert-butoxycarbonyl)ethenyl, 50%
10b R=phenylethynyl, 55%
10c R=phenyl (iii: 61%; vii: 95%)
v
vii
Cl
HO
AcO
X
AcO
R
vi
vii
N
N
N
N
N
N
Ph
Ph
Ph
12a, b
13a-c
14, 60%
12a X=Br, 92%
12b X=I, 76%
13a R=phenyl, 45%
13b R=2-chlorophenyl, 30%
13c R=3-thienyl, 35%
Scheme 3. Reagents and conditions: (i) H2C]CHCO2-t-Bu, Pd(PPh3)2Cl2, TEA, DMF,
120 ꢀC, 5 h (for 10a); (ii) CH^CPh, Pd(PPh3)2Cl2, CuI, TEA, DMF, 55 ꢀC, 8 h (for 10b); (iii)
SnBu3Ph, Pd(PPh3)2Cl2, DMF, 80 ꢀC, 12 h (for 10c); (iv) H2, Pd/C, rt, 50 bar, 1 day; (v)
Ac2O, reflux, 30 min; (vi) arylboronic acid, Pd(PPh3)4, K3PO4, KBr, dioxane, reflux,
3–6 h; (vii) 1 N NaOH, MeOH, 60 ꢀC, 2 h.
TfO
Br
Ph
Br
TfO
Ph
Ph
Ph
3 equiv PhB(OH)2
N
N
N
N
N
Pd(PPh3)4, K3PO4, KBr
dioxane, reflux, 5 h
N
N
N
However, the efforts to perform Suzuki couplings with the
4-halopyrazoles 4 and 6 and phenylboronic acid using Pd(PPh3)4 as
a catalyst and employing various conditions reported in the liter-
ature31 (Na2CO3 in DME/H2O; NaOH in toluene/H2O; K3PO4 in
toluene/H2O; Bu4NF in toluene; K3PO4 in toluene) failed, and only
dehalogenated pyrazole was obtained. Thus, we next examined
whether the protection of the hydroxyl group could influence the
outcome of the Suzuki reaction. It was recently reported that
4-halo-1-phenyl-1H-pyrazoles with the 3-hydroxyl moiety pro-
tected by alkylation easily underwent Suzuki cross-coupling with
arylboronic acids.14e However, the conditions used in that work for
the subsequent cleavage of the 3-alkoxy group and liberation of the
hydroxyl functionality were rather harsh, and in principle not
compatible with many functional groups. In our case, ‘blocking’ of
the hydroxyl functionality was achieved by treatment of pyrazol-3-
ols 4 and 6 with boiling acetic anhydride,32 allowing us to obtain
the esters 12a and 12b, respectively (Scheme 3).
+
+
Ph
Ph
Ph
Ph
5
15, 19%
16, 52%
17, 20%
Scheme 4. Reagents and conditions: (i) phenylboronic acid, Pd(PPh3)4, K3PO4, KBr,
dioxane, reflux, 6 h.
A
regiospecific construction of different 3,4-disubstituted
1-phenyl-1H-pyrazoles could be achieved by employing the suc-
cessfully prepared adducts 10 and 11 as the intermediates for
a second cross-coupling reaction. Thus, transformation of the pyr-
azol-3-ols 10c and 11 into the triflates 16 and 18, respectively,
yielded effective electrophiles that easily participated in Suzuki
cross-coupling with phenylboronic acid to afford the trisubstituted
pyrazoles 19a and 19b, respectively (Scheme 5).
TfO
R
R1
R
ii
i
10c, 11
Having in hand the ‘protected’ scaffolds 12a and 12b, a brief
study of the Suzuki reaction with phenylboronic acid was un-
dertaken (Table 1), indicating a preference for bromopyrazole 12a
as a substrate in the cross-coupling protocol (Scheme 3).
N
N
N
N
Ph
Ph
16 R=Ph, 90%
18 R=(2-phenylethyl), 78%
19a R=Ph, R1=3-thienyl, 84%
19b R=(2-phenylethyl), R1=phenyl, 88%
Table 1
Scheme 5. Reagents and conditions: (i) Tf2O, TEA, DCM, rt, 2 h; (ii) arylboronic acid,
Conditions for the Suzuki reactions of 12a,
b with phenylboronic acid using
Pd(PPh3)4, K3PO4, KBr, dioxane, reflux, 4 h.
Pd(PPh3)4 as a catalyst
Starting compound
Base and solvent (reflux)
Time, h
Yield, %
Recently, an efficient protocol for the arylation of 1-phenyl-
pyrazole in 2-position of the phenyl ring has been published.37 We
performed a related coupling by reacting 3-acyloxy-4,40-dibromo-
pyrazole 20 with phenylboronic acid (3 equiv) using Pd(PPh3)4 as
the catalyst (Scheme 6). The reaction afforded product 21 in good
yield, in which both bromo atoms of reactant 20 were replaced by
phenyl rings. Furthermore, treatment of the dibrominated 3-tri-
floyloxy pyrazole 8 with 6 equiv of phenylboronic acid for 24 h
under the same reaction conditions afforded the trisubstitution
product 22 in a 40% yield (Scheme 6).
12b
12b
12a
12a
Na2CO3, DME/H2O
K3PO4, Toluene
K3PO4, Toluene
22
20
16
5
d
8
40
60
K3PO4, KBr, 1,4-dioxane
After optimizing the reaction conditions, we performed Suzuki
couplings with other boronic acids: 2-chlorophenyl- and 3-thio-
pheneboronic acids to obtain the desired functionalized pyrazoles
13b and 13c (Scheme 3). In the next step, the acetyl groups of 13a

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7820
The reaction mixture was poured into water (15 mL) and extracted
with ethyl acetate (3ꢂ20 mL). Organic layers were combined,
washed with brine, and dried over sodium sulfate. The solvent was
evaporated and the residue was purified by column chromatogra-
phy (SiO2, eluent ethyl acetate/hexane, 1:4 v/v).
HO
Br
AcO
Br
AcO
Ph
N
N
N
N
N
i
ii
N
4.2.1.1. 1-Phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate 3. Yield
690 mg, 79%; colorless oil; 1H NMR (300 MHz, CDCl3):
d 6.35 (d,
Br
Br
Ph
3J¼2.6 Hz, 1H, H-4), 7.34 (m, 1H, Ph H-4), 7.47 (m, 2H, Ph H-3,5),
20, 81%
21, 71%
7
7.63 (m, 2H, Ph H-2,6), 7.87 (d, 3J¼2.6 Hz, 1H, H-5); 13C NMR
(75 MHz, CDCl3):
d
98.5 (C-4, 1J¼185.2 Hz, 2J(C4,H5)¼8.1 Hz,
TfO
Br
Ph Ph
5J(C4,CF3)¼0.6 Hz), 118.7 (CF3, 1J¼321.1 Hz), 119.1 (Ph C-2,6), 127.4
(Ph C-4),128.7 (C-5,1J¼190.7 Hz, 2J(C5,H4)¼7.8 Hz),129.6 (Ph C-3,5),
N
N
ii
139.2 (Ph C-1), 153.7 (C-3, 2J(C3,H4)¼1.1 Hz, 3J(C3,H5)¼11.9 Hz); 15
N
N
N
NMR (50 MHz, CDCl3):
d
ꢃ174.3 (N-1), ꢃ98.9 (N-2); IR (KBr): 3158
(CHarom), 1601, 1531, 1448, 1430, 1250, 1224, 1056, 1011 cmꢃ1; MS
m/z (%): 292 (Mþ, 34), 159 ([MꢃCF3SO2]þ, 100), 77 (C6Hþ5 , 95). Anal.
Calcd for C10H7F3N2O3S: C, 41.10; H, 2.41; N, 9.59. Found: C, 41.37; H,
2.40; N, 9.64.
Br
Ph
8
22, 40%
Scheme 6. Reagents and conditions: (i) Ac2O, reflux, 30 min; (ii) phenylboronic acid,
Pd(PPh3)4, K3PO4, KBr, dioxane, reflux, 5–24 h.
4.2.1.2. 4-Bromo-1-phenyl-1H-pyrazol-3-yl trifluoro methanesulfo-
nate 5. Yield 864 mg, 78%; white solid; mp 36–37 ꢀC; 1H NMR
(300 MHz, CDCl3):
d 7.37 (m, 1H, Ph H-4), 7.48 (m, 2H, Ph H-3,5),
7.59 (m, 2H, Ph H-2,6), 7.92 (s, 1H, H-5); 13C NMR (75 MHz, CDCl3):
3. Conclusions
d
87.2 (C-4, 2J(C4,H5)¼5.3 Hz), 118.6 (CF3, 1J¼321.3 Hz), 118.9 (Ph C-
2,6), 127.9 (Ph C-4), 129.1 (C-5, 1J¼195.9 Hz), 129.7 (Ph C-3,5), 138.8
In conclusion, we have developed a general approach for the
preparation of (het)aryl- and carbo-functionally substituted
1-phenyl-1H-pyrazoles via Pd(0)-catalyzed cross-coupling re-
actions starting from 1-phenylpyrazol-3-ol.38
(Ph C-1), 151.6 (C-3, 3J(C3,H5)¼10.3 Hz); 15N NMR (50 MHz, CDCl3):
d
ꢃ174.5 (N-1), N-2 was not found; IR (KBr): 3151 (CHarom), 1451,
1422, 1244, 1232, 1137, 1073, 757, 729, 608, 514 cmꢃ1; MS m/z (%):
372/370 (Mþ, 9), 239/237 ([MꢃCF3SO2]þ, 39), 77 (C6Hþ5 , 100). Anal.
Calcd for C10H5Br2F3N2O3S: C, 32.36; H, 1.62; N, 7.55. Found: C,
32.70; H, 1.60; N, 7.30.
4. Experimental
4.1. General
4.2.1.3. 4-Bromo-1-(4-bromophenyl)-1H-pyrazol-3-yl trifluoro methane-
sulfonate 8. Yield 1.07 g, 79%; white solid; mp 55–56 ꢀC; 1H NMR
Melting points were determined on a Reichert–Kofler hot-
stage microscope or Melt-Temp (Capillary Melting point Appa-
ratus) and are uncorrected. Mass spectra were obtained on
a Shimadzu QP 1000 instrument (EI, 70 eV), on a Waters ZQ 2000
(APCIþ, 20 V) instrument and on a Finnigan MAT 8230 in-
strument (EI, 70 eV, HRMS). IR spectra were recorded on a Per-
kin–Elmer FTIR 1605 spectrophotometer or on a Perkin–Elmer
FTIR spectrum 1000 spectrometer. Elemental analyses (C, H, and
N) were performed at the Microanalytical Laboratory, University
of Vienna, and were in good agreement (ꢁ0.4%) with the calcu-
lated values. 1H and 13C NMR spectra were recorded on a Varian
UnityPlus 300 spectrometer at 28 ꢀC (299.95 MHz for 1H,
75.43 MHz for 13C) or on a Bruker Avance 500 spectrometer at
293 K (500.13 MHz for 1H, 125.77 MHz for 13C). The center of the
signal was used as an internal standard, which was related to
(300 MHz, CDCl3):
d
7.48 (m, 2H, Ph-3,5), 7.60 (m, 2H, Ph H-2,6),
87.8 (C-4), 118.6 (CF3,
7.90 (s, 1H, H-5); 13C NMR (75 MHz, CDCl3):
d
1J¼321.2 Hz), 120.3 (Ph C-2,6), 121.4 (Ph C-4), 129.0 (C-5), 132.8
(Ph C-3,5), 137.8 (Ph C-1), 151.8 (C-3); IR (KBr): 3101 (CHarom),
1494, 1451, 1428, 1238, 1135, 1080, 1060, 834, 605, 656 cmꢃ1; MS
m/z (%): 452/450/448 (Mþ, 19/37/18), 319/317/315 ([MꢃCF3SO2]þ,
57/100/51), 157/155 ([C6H4Br]þ, 72/68). Anal. Calcd for
C10H5Br2F3N2O3S: C, 26.69; H, 1.12; N, 6.22. Found: C, 27.08; H,
1.11; N, 5.83.
4.2.1.4. 1,4-Diphenyl-1H-pyrazol-3-yl trifluoromethane sulfonate
16. Yield 994 mg, 90%; white solid; mp 58–60 ꢀC; 1H NMR
(300 MHz, CDCl3):
NMR (75 MHz, CDCl3):
d
7.34–7.70 (m, 10H, Ph), 8.06 (s, 1H, H-5); 13C
d
118.8 (NPh C-2,6), 119.9 (CF3,
1J¼321.4 Hz), 125.9, 127.0, 127.4, 127.9, 128.4, 128.6, 129.0, 129.6,
139.0, 139.6, 142.3; IR (KBr): 3121 (CHarom), 1599, 1506, 1426, 1222,
1133, 767, 753 cmꢃ1; MS m/z (%): 369 ([MþH]þ, 5), 301 (25), 242
(100). Anal. Calcd for C16H11F3N2O3S: C, 52.17; H, 3.01; N, 7.61.
Found: C, 51.97; H, 3.16; N, 7.22.
TMS with
d
d
7.26 ppm (1H in CDCl3),
d
2.49 ppm (1H in DMSO-d6),
77.0 ppm (13C in CDCl3), and
d
39.5 ppm (13C in DMSO-d6). 15N
NMR spectra were obtained on a Bruker Avance 500 instrument
with a ‘directly’ detecting broadband observation probe, and
were referenced against external nitromethane. Digital resolu-
tions were 0.25 Hz/data point in the 1H spectra and 0.4 Hz/data
point in the 13C NMR spectra.
4.2.1.5. 1-Phenyl-4-(2-phenylethyl)-1H-pyrazol-3-yl trifluoromethane
sulfonate 18. Yield 741 mg, 78%, colorless liquid; 1H NMR (300 MHz,
CDCl3):
(m, 6H, Ar–H), 7.41–7.57 (m, 5H, Ar–H); 13C NMR (75 MHz, CDCl3):
23.9 (CH2–CH2–Ph), 35.6 (CH2–Ph), 113 (C-4), 118.6 (CF3,
d 2.84 (m, 2H, CH2–CH2–Ph), 2.95 (m, 2H, CH2–Ph), 7.20–7.35
4.2. Synthetic procedures
d
4.2.1. General procedure for pyrazole triflation (compounds 3, 5, 8,
16, and 18)
The appropriate pyrazole (2, 4, 10c or 11) (3 mmol), tri-
fluormethanesulfonic anhydride (889 mg, 3.15 mmol), and trie-
thylamine (0.5 mL, 3.6 mmol) were dissolved in dichloromethane
(10 mL), and the mixture was stirred at room temperature for 1 h.
1J¼321.2 Hz), 118.6 (NPh C-2,6), 126.3, 127.0, 128.5 (CPh C-2,3,5,6),
129.5 (NPh C-3,5), 139.2 (NPh C-1), 140.6 (CPh C-1), 152.1 (C-3); IR
(KBr): 3065, 3030 (CHarom), 2930, 2862 (CHaliph), 1601, 1504, 1427,
1217, 1136, 756, 700 cmꢃ1; MS m/z (%): 397 ([MþH]þ, 100), 264
([MꢃCF3SO2þH]þ, 85). Anal. Calcd for C, 54.54; H, 3.81; N, 7.07.
Found: C, 54.76; H, 3.80; N, 6.95.

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E. Arbaciauskiene˙ et al. / Tetrahedron 65 (2009) 7817–7824
7821
4.2.2. Iodination reaction: synthesis of 4-iodo-1-phenyl-1H-
pyrazol-3-ol 6
4.2.4. General procedure for the Sonogashira reaction (compounds
9b and 10b)
A solution of 2 (992 mg, 6.2 mmol), iodine (2.39 g, 9.4 mmol),
and KOH (0.9 g, 16 mmol) in dimethylformamide (10 mL) was
stirred at room temperature for 20 h. Then, the mixture was poured
into a sodium thiosulfate solution (1.0 g in 7 mL of water) and
extracted with diethyl ether (3ꢂ20 mL). Organic layers were com-
bined and dried over sodium sulfate, and the solvent was evapo-
rated. The residue was recrystallized from 50% aqueous ethanol to
give pure 6. Yield 1.12 g, 63%; yellowish crystals; mp 169–171 ꢀC; 1H
Triethylamine (0.42 mL, 3 mmol), phenylacetylene (0.32 mL,
3 mmol), Pd(PPh3)2Cl2 (140 mg, 0.2 mmol), and CuI (38 mg,
0.2 mmol) were added to a solution of the appropriate pyrazole (3
or 6) (2 mmol) in dry dimethylformamide (20 mL) under an argon
atmosphere. The reaction mixture was stirred at 55 ꢀC under an
argon atmosphere for the given time. Then, the mixture was filtered
over Celite, the solvent was evaporated, and the residue was puri-
fied by column chromatography.
NMR (500 MHz, DMSO-d6):
d
7.18 (m, J¼7.5 Hz,1H, Ph H-4), 7.41 (m,
2H, Ph H-3,5), 7.67 (m, 2H, Ph H-2,6), 8.40 (s, 1H, H-5), 10.89 (s, 1H,
4.2.4.1. 1-Phenyl-3-(phenylethynyl)-1H-pyrazole 9b. The reaction
mixture was stirred for 5 days and purified by column chroma-
tography (SiO2, eluent ethyl acetate/hexane, 1:20 v/v). Yield
244 mg, 50%; beige crystals; mp 130–135 ꢀC; 1H NMR (300 MHz,
OH); 13C NMR (125 MHz, DMSO-d6):
d
49.0 (C-4, 2J(C4,H5)¼6.3 Hz),
116.8 (Ph C-2,6), 125.2 (Ph C-4), 129.4 (Ph C-3,5), 132.5 (C-5,
1J¼193.8 Hz), 139.3 (Ph C-1), 162.7 (C-3, 3J(C3,H5)¼9.4 Hz); 15N
NMR (50 MHz, DMSO-d6):
d
ꢃ181.9 (N-1), ꢃ118.1 (N-2); IR (KBr):
CDCl3):
d
6.67 (d, J¼2.56 Hz, 1H, H-4), 7.29–7.74(m, 10H, Ph), (d,
3047 (OH) cmꢃ1; MS m/z (%): 287 ([Mþ1]þ, 11), 286 ([Mþ, 100), 77
(C6Hþ5 , 87). Anal. Calcd for C9H7IN2O: C, 37.79; H, 2.47; N, 9.79.
Found: C, 37.94; H, 2.57; N, 9.72.
J¼2.56 Hz, 1H, H-5); 13C NMR (75 MHz, CDCl3):
d 82.0 (C^CPh),
90.6 (C^CPh), 111.7 (C-4), 119.3 (N–Ph C-2,6), 126.9, 127.3, 128.3,
128.6, 129.4, 131.7, 136.6 (N–Ph C-1), 139.7 (C-3); IR (KBr): 3147
(CHarom),1598,1517,1343, 756, 691 cmꢃ1; MS m/z (%): 246 ([Mþ2]þ,
10), 245 ([MþH]þ, 100). Anal. Calcd for C17H12N2$0.2H2O: C, 82.37;
H, 5.04; N, 11.30. Found: C, 82.61; H, 5.21; N, 10.97.
4.2.3. General procedure for the Heck reaction (compounds 9a
and 10a)
Triethylamine (0.21 mL, 1.5 mmol), CH2CHCOO-t-Bu (0.3 mL,
2 mmol), and Pd(PPh3)2Cl2 (70 mg, 0.1 mmol) were added to a so-
lution of the appropriate pyrazole (3 or 4) (1 mmol) in dry dime-
thylformamide (4 mL) under argon atmosphere. Then, the reaction
mixture was stirred at 120 ꢀC under an argon atmosphere for the
given time. After cooling, the mixture was filtered over Celite,10 mL
of water was added, and extraction was done with dichloro-
methane (3ꢂ20 mL). Organic layers were combined, washed with
brine, dried over sodium sulfate, and evaporated under reduced
pressure. The residue was purified by column chromatography
(SiO2, eluent ethyl acetate/hexane, 1:6 v/v).
4.2.4.2. 1-Phenyl-4-(phenylethynyl)-1H-pyrazol-3-ol 10b. The re-
action mixture was stirred for 8 h and purified by column
chromatography (SiO2, eluent dichloromethane/methanol, 100:1
v/v). Yield 286 mg, 55%; beige solid; mp 145–146 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d 7.23 (m, 1H, NPh H-4), 7.38 (m, 1H, CPh H-
4), 7.40 (m, 2H, CPh H-3,5), 7.45 (m, 2H, NPh H-3,5), 7.47 (m, 2H, CPh
H-2,6), 7.72 (m, 2H, NPh H-2,6), 8.64 (s, 1H, H-5), 11.01 (s, 1H, OH);
13C NMR (75 MHz, DMSO-d6):
d
80.4 (PhC^C, 3J(C,H5)¼1.7 Hz), 91.3
(C-4, 2J(C4,H5)¼6.8 Hz), 91.6 (PhC^C), 117.2 (NPh C-2,6), 122.9 (CPh
C-1), 125.4 (NPh C-4), 128.2 (CPh C-4), 128.7 (CPh C-3,5), 129.4 (NPh
C-3,5), 130.7 (C-5, 1J¼192.6 Hz), 130.9 (CPh C-2,6), 139.1 (NPh C-1),
162.7 (C-3, 3J(C3,H5)¼9.1 Hz); 15N NMR (50 MHz, DMSO-d6):
4.2.3.1. tert-Butyl (2E)-3-(1-phenyl-1H-pyrazol-3-yl)acrylate 9a. The
reaction mixture was stirred for 16 h. Yield 180 mg, 74%; colorless
d
ꢃ186.9 (N-1), ꢃ120.3 (N-2); IR (KBr): 3129 (OH), 1535, 1503, 1212,
substance; mp 125–130 ꢀC; 1H NMR (300 MHz, CDCl3):
d
1.54 (s, 9H,
1063, 761, 692 cmꢃ1; MS m/z (%): 283 ([MþNa]þ, 100), 261
([MþH]þ, 5). Anal. Calcd for C17H12N2O: C, 78.44; H, 4.65; N, 10.76.
Found: C, 75.40; H, 4.80; N, 10.69.
CH3), 6.42 (d, 3Jtrans¼16.1 Hz, 1H, COCH]CH), 6.67 (d,
3J(H4,H5)¼2.5 Hz, 1H, H-4), 7.30 (m, 1H, Ph H-4), 7.46 (m, 2H, Ph H-
3,5), 7.66 (d, 3Jtrans¼16.1 Hz, 1H, COCH]CH), 7.69 (m, 2H, Ph H-2,6),
7.89 (d, 3J(H5,H4)¼2.5 Hz,1H, H-5); 13C NMR (75 MHz, CDCl3):
d
28.2
4.2.5. Stille coupling: synthesis of 1,4-diphenyl-1H-pyrazol-3-ol 10c
Under inert and anhydrous conditions, 6 (100 mg, 0.42 mmol)
was dissolved in dimethylformamide (5 mL). Pd(PPh3)2Cl2 (14 mg,
0.02 mmol) and phenyltributyltin (0.16 mL, 0.5 mmol) were added
to the solution, which was stirred at 80 ꢀC for 12 h. DMF was re-
moved under reduced pressure, the mixture was diluted with
dichloromethane (50 mL), washed with potassium fluoride (aq)
(30 mL), and dried over sodium sulfate, and the solvent was
evaporated. The residue was purified by column chromatography
(SiO2, eluent dichloromethane). Yield 60 mg, 61%; white solid; mp
189–196 ꢀC (lit. mp 202–204 ꢀC);39 1H NMR (300 MHz, CDCl3):
(CH3,1J¼126.8 Hz, 3J(CH3,CH3)¼4.0 Hz, 80.4 (C(CH3)3), 2J(C,CH3)¼4.0 Hz),
106.6 (C-4, 1J¼177.2 Hz, 2J(C4,H5)¼8.1 Hz, 3J(C4, ]CH)¼4.3 Hz),
119.2 (Ph C-2,6), 122.2 (COCH, 1J¼162.3 Hz, 2J¼3.4 Hz, 126.9 (Ph C-4),
128.1 (C-5, 1J¼188.0 Hz, 2J(C5,H4)¼8.9 Hz), 129.5 (Ph C-3,5), 135.2
(COCH]CH, 1J¼159.3 Hz), 139.8 (Ph C-1), 149.8 (C-3, 2J(C3,
]CH)¼1.2 Hz, 2J(C3,H4)¼4.9 Hz, 3J(C3,H5)¼8.7 Hz, 3J(C3,COCH)
¼6.3 Hz), 166.0 (C]O, 2J(CO,COCH)¼2.7 Hz, 3J(CO, ]CH)¼6.7 Hz);
15N NMR (50 MHz, CDCl3):
d
ꢃ161.0 (N-1), ꢃ77.0 (N-2); IR (KBr):
3137 (CHarom), 2980 (CHaliph), 1699, 1638, 1517, 1311, 1254, 1152 (C–O),
773, 755 cmꢃ1; ms: m/z 293 ([MþNa]þ, 30), 271 ([MþH]þ, 3). Anal.
Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 71.21; H,
6.68; N, 10.09.
d
7.25 (m, 1H, Ph H-4), 7.30 (m, 1H, NPh H-4), 7.41 (m, 2H, Ph H-3,5),
7.50 (m, 2H, NPh H-3,5), 7.61 (m, 2H, NPh H-2,6), 7.78 (m, 2H, Ph H-
2,6), 7.99 (s, 1H, H-5), 12.00 (br, 1H, OH); 13C NMR (75 MHz, CDCl3):
4.2.3.2. tert-Butyl (2E)-3-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acry-
late 10a. The reaction mixture was stirred for 5 h. Yield 143 mg,
50%; yellow crystals; mp 189–190 ꢀC; 1H NMR (300 MHz, CDCl3):
d
109.3 (C-4), 118.6 (NPh C-2,6), 125.7 (C-5, 1J¼185.5 Hz), 126.0 (Ph
C-2,6), 126.3 (NPh C-4), 126.5 (Ph C-4), 128.7 (Ph C-3,5), 129.7 (NPh
C-3,5), 131.3 (Ph C-1), 139.3 (NPh C-1), 161.1 (C-3, 3J(C3,5-
H)¼9.6 Hz); IR (KBr): 2961 (OH), 1600, 1536, 1505, 1250, 1215, 753,
692 cmꢃ1; MS m/z (%): 236 (Mþ, 100), 77 (C6Hþ5 , 92). Anal. Calcd for
C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C, 76.21; H, 5.22; N,
11.79.
d
1.31 (s, 9H, Me), 4.27 (br, 1H, OH), 6.20 (d, Jtrans¼15.8 Hz, 1H,
COCH]CH), 7.04 (m, 1H, Ph H-4), 7.21 (m, 1H, Ph H-3,5), 7.27 (d,
Jtrans¼15.8 Hz, 1H, COCH]CH), 7.36 (m, 2H, Ph H-2,6), 7.76 (s, 1H, H-
5); 13C NMR (75 MHz, CDCl3):
d 27.6 (Me), 80.0 (CMe3), 105.7 (C-4),
117.5 (Ph C-2,6), 125.7 (Ph C-4), 127.7, 128.9, 129.0, 132.9, 138.9, 161.4
(C-3), 167.7 (C]O); IR (KBr): 3101 (OH), 2974 (CHaliph), 1698 (C]O),
1638, 1510, 1415, 1314 ,1215, 1151 (C–O), 751, 685 cmꢃ1; MS m/z (%):
309 ([MþNa]þ, 62). Anal. Calcd for C16H18N2O3$2H2O: C, 59.61; H,
6.88; N, 8.69. Found: C, 59.61; H, 6.54; N, 8.84.
4.2.6. General procedure for the Suzuki cross-coupling reaction
(compounds 9c–e, 13a–c, 15–17, 19a, b, 21, and 22)
Anhydrous K3PO4 (636 mg, 3 mmol), an appropriate arylboronic
acid, Pd(PPh3)4 (92 mg, 0.08 mmol), and KBr (131 mg, 1.1 mmol)

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E. Arbaciauskiene˙ et al. / Tetrahedron 65 (2009) 7817–7824
7822
were added to a solution of the pyrazole (3, 5, 8, 12a, 16, 18 or 20)
(1 mmol) in 1,4-dioxane (10 mL) under an argon atmosphere. After
refluxing under an argon atmosphere for the appropriate reaction
time, the mixture was diluted with water (10 mL) and extracted
with ethyl acetate (3ꢂ20 mL). The combined organic layers were
washed with brine, dried over sodium sulfate, and evaporated
under reduced pressure. The residue was purified by column
chromatography.
(SiO2, eluent dichloromethane). Yield 167 mg, 60%; white solid; mp
94–95 ꢀC; 1H NMR (300 MHz, CDCl3):
2.35 (s, 3H, CH3), 7.30 (m,
d
1H, NPh H-4), 7.30 (m, 1H, CPh H-4), 7.40 (m, 2H, CPh H-3,5), 7.46
(m, 2H, NPh H-3,5), 7.49 (m, 2H, CPh H-2,6), 7.68 (m, 2H, NPh H-
2,6), 8.05 (s, 1H, H-5); 13C NMR (75 Hz, CDCl3):
d 20.8 (CH3,
1J¼130.4 Hz), 114.9 (C-4, 2J(C4,H5)¼7.1 Hz, 3J(C4, Ph H-2,6)¼4.1 Hz),
118.7 (NPh C-2,6), 125.6 (C-5, 1J¼187.5 Hz), 126.6 (CPh C-2,4,6),
127.1 (NPh C-4), 128.9 (CPh C-3,5), 129.4 (NPh C-3,5), 130.4 (CPh
C-1), 139.6 (NPh C-1), 153.3 (C-3, 3J(C3,H5)¼9.9 Hz), 168.4 (CO,
2J(CO,CH3)¼7.1 Hz); IR (KBr): 3113 (CHarom), 1759 (C]O), 1594,
1509, 1408, 1211, 1180, 761, 754, 701, 691 cmꢃ1; MS m/z (%): 278
(Mþ, 4), 236 (100), 77 (C6Hþ5 , 28). Anal. Calcd for
C17H14N2O2$0.4H2O: C, 71.51; H, 5.22; N, 9.81. Found: C, 71.39; H,
4.88; N, 9.76.
4.2.6.1. 1,3-Diphenyl-1H-pyrazole 9c. The coupling was performed
with phenylboronic acid (366 mg, 3 mmol). The mixture was
refluxed for 6 h and purified by column chromatography (SiO2, el-
uent ethyl acetate/petrol ether, 1:8 v/v). Yield 143 mg, 65%; white
solid; mp 81–83 ꢀC (lit. mp 82–84 ꢀC);40 1H NMR (300 MHz, DMSO-
d6):
d 7.05 (s, 1H, 4-H), 7.32–7.94 (m, 10H, Ph), 8.58 (s, 1H, H-5); IR
(KBr): 3136, 1600, 1527, 1506, 1455, 756, 686 cmꢃ1; MS m/z (%): 221
([MþH]þ, 16), 220 (Mþ, 100), 219 ([M–H]þ, 68), 77 (C6Hþ5 , 34). Anal.
Calcd for C15H12N2: C, 81.79; H, 5.49; N, 12.72. Found: C, 81.80; H,
5.49; N, 12.71.
4.2.6.5. 4-(2-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl acetate 13b. The
coupling was performed with 2-chlorophenylboronic acid (469 mg,
3 mmol), a reaction time of 3 h and purification by column chroma-
tography (SiO2, eluent ethyl acetate/petrol ether, 1:8 v/v). Yield 92 mg,
30%; white crystals; 1H NMR (300 MHz, CDCl3):
d 2.26 (s, 3H, CH3),
4.2.6.2. 1-Phenyl-3-(thiophen-3-yl)-1H-pyrazole 9d. The coupling
was performed with thiophene-3-boronic acid (384 mg, 3 mmol),
a reaction time of 17 h and purification by column chromatography
(SiO2, eluent ethyl acetate/petrol ether, 1:8 v/v). Yield 136 mg, 60%;
7.71–7.28 (m, 9H, Ph), 8.14 (s, 1H, H-4); MS m/z (%): 314/312 (Mþ, 0.2/
0.6), 272/270 (6/21), 160 (61), 77 (C6Hþ5 , 72), 43 (CH3COþ, 100). The
material was immediately converted into compound 14.
yellowish solid; mp 83–87 ꢀC; 1H NMR (500 MHz, CDCl3):
d
6.66 (d,
4.2.6.6. 1-Phenyl-4-(thiophen-3-yl)-1H-pyrazol-3-yl acetate 13c. The
coupling was performed with thiophene-3-boronic acid (384 mg,
3 mmol), a reaction time of 6 h and purification by column chro-
matography (SiO2, eluent ethyl acetate/hexane, 1:10 v/v). Yield
100 mg, 35%; white solid; mp 110 ꢀC; 1H NMR (300 MHz, CDCl3):
J¼2.5 Hz, 1H, H-4), 7.29 (m, 1H, Ph H-4), 7.38 (dd, 3J(H5,H4)¼5.0 Hz,
4J(H5,H2)¼3.0 Hz, 1H, Th H-5), 7.47 (m, 2H, Ph H-3,5), 7.59 (dd,
3J(H4,H5)¼5.0 Hz, 4J(H4,H2)¼1.3 Hz, 1H, Th H-4), 7.68 (dd,
4J(H2,H4)¼1.3 Hz, 4J(H2,H5)¼3.0 Hz, 1H, Th H-2), 7.76 (m, 2H, Ph
H-2,6), 7.92 (d, 3J(H5,H4)¼2.5 Hz, 1H, H-5); 13C NMR (125 MHz,
d
2.42 (s, 3H, CH3), 6.66 (m, 1H, H-4), 7.24–7.50 (m, 5H, Ar–H), 7.69
CDCl3):
d
105.4 (C-4, 1J¼176.3 Hz, 2J(C4,H5)¼8.3 Hz), 119.0 (Ph C-
(m, 2H, Ph H-2,6), 8.06 (s, 1H, H-5); 13C NMR (75 MHz, CDCl3):
d
20.8
2,6), 121.0 (Th C-2), 125.9 (Th C-5), 126.1 (Th C-4), 126.3 (Ph C-4),
127.7 (C-5, 1J¼186.9 Hz, 2J(C5,H4)¼9.0 Hz), 129.4 (Ph C-3,5), 135.0
(Th C-3), 140.2 (Ph C-1), 149.3 (C-3); 15N NMR (50 MHz, CDCl3):
(CH3), 110.6 (C-4), 118.6, 120.2, 125.2, 126.2, 126.5, 129.4, 130.2, 139.4,
153.1, 168.4 (C]O); IR (KBr): 3107 (CHarom), 1758 (C]O), 1594, 1518,
1209, 759, 692 cmꢃ1; MS m/z (%): 308 ([MþNaþH]þ, 10), 307
([MþNa]þ, 46]), 285 ([MþH]þ, 10), 243 (100). Anal. Calcd for
C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.75; H, 4.49; N,
10.28.
d
ꢃ166.6 (N-1), N-2 was not found; IR (KBr): 3092 (CHarom), 1599,
1497, 788, 754 cmꢃ1; MS m/z (%): 227 ([MþH]þ, 18), 226 (Mþ, 100),
225 ([MꢃH]þ, 51), 77 (C6H5þ, 23). Anal. Calcd for C13H10N2S: C,
69.00; H, 4.45; N, 12.38. Found: C, 68.84; H, 4.53; N, 11.95.
4.2.6.7. General procedure for the synthesis of 15–17. The coupling
was performed with phenylboronic acid (366 mg, 3 mmol), a re-
action time of 5 h and purification by column chromatography
(SiO2, eluent ethyl acetate/hexane, 1:10 v/v) to give 15, 16, and 17 in
separate fractions.
4.2.6.3. 1-Phenyl-3-(thiophen-2-yl)-1H-pyrazole 9e. The coupling
was performed with thiophene-2-boronic acid (384 mg, 3 mmol),
a reaction time of 15 h and purification by column chromatography
(SiO2, eluent ethyl acetate/petrol ether, 1:8 v/v). Yield 120 mg, 53%;
yellowish solid; mp 63–65 ꢀC (lit. mp 52–53 ꢀC);40 1H NMR
4.2.6.7.1. 4-Bromo-1,3-diphenyl-1H-pyrazole 15. Yield 56 mg,
(500 MHz, CDCl3):
d
6.68 (d, 3J(H4,H5)¼2.5 Hz, 1H, H-4), 7.09 (dd,
19%; colorless liquid; 1H NMR (300 MHz, CDCl3):
d
7.30–7.50 (m, 6H,
Ph), 7.73 (m, 2H, NPh H-2,6), 8.01 (m, 2H, CPh H-2,6), 8.03 (s, 1H, H-
5); 13C NMR (75 MHz, CDCl3):
94.4 (C-4), 118.8 (NPh C-2,6), 126.9,
3J(H4,H3)¼3.6 Hz, 3J(H4,H5)¼5.1 Hz, 1H, Th H-4), 7.29 (m, 1H, Ph H-
4), 7.29 (dd, 3J(H5,H4)¼5.1 Hz, 4J(H5,H3)¼1.2 Hz, 1H, Th H-5), 7.42
(dd, 3J(H3,H4)¼3.6 Hz, 4J(H3,H5)¼1.2 Hz, 1H, Th H-3), 7.46 (m, 2H,
Ph H-3,5), 7.74 (m, 2H, Ph H.2,6), 7.92 (d, 3J(H5,H4)¼2.5 Hz, 1H, H-
d
127.8, 128.4, 128.5, 128.8, 129.5, 131.7, 139.8, 150.0 (C-3); IR (KBr):
3139, 3061 (CHaliph), 1600, 1511, 754, 687 cmꢃ1; MS m/z (%): 300/
298 (Mþ, 22/24), 77 (C6H5þ, 100). Anal. Calcd for C15H11BrN2: C,
60.22; H, 3.71; N, 9.36. Found: C, 59.65; H, 3.86; N, 8.86.
4.2.6.7.2. 1,4-Diphenyl-1H-pyrazol-3-yl trifluoro methanesulfo-
nate 16. Yield 191 mg, 52%.
5); 13C NMR (125 MHz, CDCl3):
d
105.1 (C-4, 1J¼177.4 Hz,
2J(C4,H5)¼8.3 Hz), 119.0 (Ph C-2,6), 124.2 (Th C-3, 1J¼166.5 Hz,
2J(C3,H4)¼5.9 Hz, 3J(C3,H5)¼9.4 Hz), 124.9 (Th C-5, 1J¼185.9 Hz,
2J(C5,H4)¼6.8 Hz, 3J(C5,H3)¼10.6 Hz), 126.4 (Ph C-4), 127.4 (Th C-4,
1J¼167.8 Hz, 2J(C4,H3)¼5.4 Hz, 2J(C4,H5)¼3.7 Hz), 128.0 (C-5,
1J¼187.4 Hz, 2J(C5,H4)¼8.9 Hz), 129.4 (Ph C-3,5), 136.3 (Th C-2),
4.2.6.7.3. 1,3,4-Triphenyl-1H-pyrazole 17. Yield 60 mg, 20%,
white solid; mp 90–91 ꢀC (lit. mp 92–93 ꢀC);41 1H NMR (CDCl3):
139.9 (Ph C-1), 148.2 (C-3); 15N NMR (50 MHz, CDCl3):
d
ꢃ165.3
d d 118.9
7.30–7.84 (m, 15H, Ph), 8.04 (s, 1H, H-5); 13C NMR (CDCl3):
(N1), N-2 was not found; IR (KBr): 1598,1507,1374 (C]C, C–N), 760,
688 (CH]CH of monosubstituted benzene) cmꢃ1; MS m/z (%): 227
([MþH]þ, 18), 226 (Mþ, 100), 225 ([MꢃH]þ, 34), 77 (C6Hþ5 , 23). Anal.
Calcd for C13H10N2S$0.4H2O: C, 66.87; H, 4.66; N, 12.00. Found: C,
67.19; H, 4.47; N, 11.60. HRMS Calcd for C13H10N2S: 226.0565.
Found: 226.0563.
(N–Ph C-2,6), 122.9 (C-4), 126.4, 126.6, 126.9, 127.8, 128.3, 128.4,
128.5, 128.6, 129.4, 132.8, 133.1, 139.9 (N-Ph C-1), 150.4 (C-3); IR
(KBr): 3047 (CHarom), 1598, 1501, 767, 956, 698, 692 cmꢃ1; MS m/z
(%): 298 ([Mþ2]þ, 25), 297 ([MþH]þ, 100). Anal. Calcd for
C21H16N2$0.3H2O: C, 83.42; H, 5.56; N, 9.26. Found: C, 83.74; H,
5.49; N, 9.21.
4.2.6.4. 1,4-Diphenyl-1H-pyrazol-3-yl acetate 13a. The coupling
was performed with phenylboronic acid (366 mg, 3 mmol), a re-
action time of 5 h and purification by column chromatography
4.2.6.8. 1,4-Diphenyl-3-(thiophen-3-yl)-1H-pyrazole 19a. The cou-
pling was performed with thiophene-3-boronic acid (384 mg,
3 mmol), a reaction time of 4 h and purification by column

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E. Arbaciauskiene˙ et al. / Tetrahedron 65 (2009) 7817–7824
7823
chromatography (SiO2, acetate/hexane, 1:20 v/v). Yield 254 mg,
84%; colorless liquid; 1H NMR (300 MHz, CDCl3):
7.28–7.51 (m,
11H, Ar–H), 7.79 (m, 2H, NPh H-2,6), 7.98 (s, 1H, 5-H); 13C NMR
(75 MHz, CDCl3): 118.8 (NPh C-2,6), 119.0, 123.0, 125.1 (NPh C-4),
126.4, 126.5, 127.2, 127.5, 128.5, 129.0, 129.4 (NPh C-3,5), 132.8 (CPh
C-1), 133.9 (Th C-1), 139.8 (NPh C-1), 146.4 (C-3); IR (KBr): 3107,
3052 (CHarom), 1600, 1505, 1406, 1335, 792, 756, 724, 700,
690 cmꢃ1; MS m/z (%): 303 ([MþH]þ, 100). Anal. Calcd for C, 75.47;
H, 4.67; N, 9.26. Found: C, 75.07; H, 4.67; N, 9.45.
(CPh C-4), 129.4 (NPh C-3,5), 129.6 (CPh C-3), 130.2 (CPh C-1), 131.3
(CPh C-6), 131.7 (CPh C-2), 139.5 (NPh C-1), 160.0 (C-3,
d
3J(C3,H5)¼9.6 Hz); 15N NMR (50 MHz, DMSO-d6):
d
ꢃ188.3 (N-1),
d
ꢃ121.8 (N-2); IR (KBr): 3058 (OH), 1609, 1538, 1507, 1068, 1013, 742,
689 cmꢃ1; MS m/z (%): 272/270 (Mþ, 33/100), 235 (50), 77 (C6Hþ5 ,
31). Anal. Calcd for C15H11ClN2O$0.4H2O: C, 64.82; H, 4.28; N, 10.08.
Found: C, 64.44; H, 4.02; N, 10.06.
4.2.8. 1-Phenyl-4-(2-phenylethyl)-1H-pyrazol-3-ol 11
Compound 10b (260 mg, 1 mmol) was dissolved in absolute
methanol (5 mL) and Pd/C (13 mg, 10%) was added under an argon
atmosphere. The mixture was stirred for 1 day under a 50 bar hy-
drogen atmosphere at room temperature. The mixture was then
filtered over Celite and the solvent was evaporated. The residue was
purified by column chromatography (SiO2, eluent ethyl acetate/
hexane, 1:3 v/v). Yield 211 mg, 80%; beige solid; mp 145–146 ꢀC; 1H
4.2.6.9. 1,3-Diphenyl-4-(2-phenylethyl)-1H-pyrazole 19b. The cou-
pling was performed with phenylboronic acid (366 mg, 3 mmol),
a reaction time of 4 h and purification by column chromatography
(SiO2, eluent ethyl acetate/hexane, 1:20 v/v). Yield 285 mg, 88%;
white crystals; mp 68–70 ꢀC; 1H NMR (300 MHz, CDCl3):
d
2.98 (m,
2H, CH2–CH2–Ph), 3.08 (m, 2H, CH2–Ph), 7.24–7.53 (m, 12H, Ar–H),
7.75–7.81 (m, 4H, Ar–H); 13C NMR (75 MHz, CDCl3):
26.7 (CH2–
d
NMR (300 MHz, CDCl3): d 2.80 (m, 2H, CH2–CH2–Ph), 2.96 (m, 2H,
CH2–Ph), 36.4 (CH2–Ph), 118.7 (NPh C-2,6), 119.0, 118.7, 126.0, 126.1,
126.2,127.7,127.8,128.4,128.4,128.5,129.3,133.7,141.1,141.5,151.43
(C-3); IR (KBr): 3061, 3028 (CHarom), 2948, 2924 (CHaliph),1600,1505,
1402, 763, 747, 695 cmꢃ1; MS m/z (%): 325 ([MþH]þ,100). Anal. Calcd
for C, 85.15; H, 6.21; N, 8.63. Found: C, 84.82; H, 6.17; N, 8.85.
CH2–Ph), 7.21 (m, 1H, NPh H-4), 7.23 (m, 1H, CPh H-4), 7.25 (m, 2H,
CPh H-2,6), 7.28 (m, 2H, CPh H-3,5), 7.36 (s, 1H, H-5), 7.45 (m, 4H,
NPh H-2,3,5,6), 11.70 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d
24.2 (CH2–CH2–Ph), 35.7 (CH2–Ph), 108.1 (C-4), 118.0 (NPh C-2,6),
125.3 (NPh C-4), 125.9 (CPh C-4), 126.9 (C-5), 128.3 (CPh C-3,5),
128.6 (CPh C-2,6), 129.5 (NPh C-3,5), 139.6 (NPh C-1), 141.8 (CPh C-
1), 162.3 (C-3); IR (KBr): 3136 (OH), 1561, 1506, 1320, 1252, 751,
688 cmꢃ1; MS m/z (%): 264 (Mþ, 12), 173 ([MꢃBn]þ, 100), 91 (16), 77
(21). Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C,
76.87; H, 6.35; N, 11.00.
4.2.6.10. 1-(Biphenyl-4-yl)-4-phenyl-1H-pyrazol-3-yl acetate 21. The
coupling was performed with phenylboronic acid (488 mg,
4 mmol), a reaction time of 5 h and purification by column
chromatography (SiO2, eluent ethyl acetate/hexane, 1:10 v/v). Yield
250 mg, 71%; white solid; mp 101–104 ꢀC; 1H NMR (300 MHz,
CDCl3):
NMR (75 MHz, CDCl3):
d
2.26 (CH3), 7.16–7.64 (m, 14H, Ph), 8.04 (s, 1H, H-5); 13C
20.3 (CH3), 118.7 (NPh C-2,6), 125.7, 126.2,
4.2.9. Acetylation: synthesis of 4-iodo-1-phenyl-1H-pyrazol-3-yl
acetate 12b
d
126.6, 127.0, 127.3, 127.7, 127.78, 128.6, 130.0, 138.3, 139.3, 139.4,
153.0, 168.6 (C]O); IR (KBr): 3036 (CHarom), 1768 (C]O), 1373,
1203, 1183, 833, 763, 693 cmꢃ1; MS m/z (%): 377 ([MþNa]þ, 15), 340
(25), 339 ([MꢃCH3]þ, 100). Anal. Calcd for C23H18N2O2: C, 77.95; H,
5.12; N, 7.90. Found: C, 77.69; H, 5.26; N, 8.00.
Compound 6 (500 mg, 1.75 mmol) and an excess of acetic anhy-
dride (6 mL) were heated to reflux for 30 min. Then, 10 mL of water
wereadded and the solutionwas stirred for 30 min at rt. The mixture
was poured into ice-water (30 mL), and after 30 min of stirring the
precipitate was collected by filtration, washed with water, and dried.
Yield 434 mg, 76%; white crystals; mp 94–96 ꢀC; 1H NMR (300 MHz,
4.2.6.11. 1-(Biphenyl-4-yl)-3,4-diphenyl-1H-pyrazole 22. The cou-
pling was performed with phenylboronic acid (732 mg, 6 mmol),
a reaction time of 24 h and purification by column chromatography
(SiO2, eluent ethyl acetate/hexane, 1:10 v/v). Yield 150 mg, 40%;
CDCl3): d 2.38 (s, 3H, CH3), 7.30 (m, 1H, Ph H-4), 7.44 (m, 2H, Ph H-
3,5), 7.59 (m, 2H, Ph H-2,6), 7.90 (s, 1H, H-5); 13C NMR (75 MHz,
CDCl3):
d
20.5 (CH3,1J¼130.7 Hz), 52.6 (C-4, 2J(C4,H5)¼6.2 Hz),118.7
(Ph C-2,6), 127.1 (Ph C-4), 129.5 (Ph C-3,5), 132.7 (C-5, 1J¼194.0 Hz),
yellowish solid; mp 170–172 ꢀC; 1H NMR (300 MHz, CDCl3):
d
7.34–
7.90 (m, 19H, Ph), 8.06 (s, 1H, H-5); 13C NMR (75 MHz, CDCl3):
119.1 (NPh C-2,6), 123.0, 125.1, 126.5, 126.9, 127.4, 127.9, 128.0,
139.3 (Ph C-1), 157.7 (C-3, 3J(C3,H5)¼9.7 Hz), 167.7 (CO,
2J(CO,CH3)¼7.1 Hz); 15N NMR (50 MHz, CDCl3):
d
ꢃ171.7 (N1), N-2
d
was not found; IR (KBr): 3139 (CHarom),1759 (C]O),1531,1457,1225,
1190, 887, 761, 689 cmꢃ1; MS m/z (%): 328 (Mþ, 5), 286 (100), 77
(C6Hþ5 , 53). Anal. Calcd for C11H9IN2O2: C, 40.27; H, 2.76; N, 8.54.
Found: C, 40.19; H, 2.70, N, 8.39.
128.3, 128.4, 128.5, 128.7, 128.8, 132.8, 139.0, 139.2, 140.1 (C-3); IR
(KBr): 3052 (CHarom), 1527, 1493, 841, 762, 698 cmꢃ1; MS m/z (%):
374 ([MþH]þ, 33), 373 (Mþ, 100). Anal. Calcd for C23H18
N2O2$0.2H2O: C, 86.23; H, 5.47; N, 7.45. Found: C, 85.88; H, 5.59;
N, 7.47.
References and notes
4.2.7. General procedure for the deacetylation (compounds 10c
and 14)
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DMSO-d6): 7.22 (m, 1H, NPh H-4), 7.29 (m, 1H, CPh H-4), 7.36 (m,
14. Yield
d
1H, CPh H-5), 7.45 (m, 2H, NPh H-3,5), 7.52 (m, 1H, CPh H-3), 7.63
(m, 1H, CPh H-6), 7.75 (m, 2H, NPh H-2,6), 8.52 (s, 1H, H-5), 10.78 (s,
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d 106.1 (C-4), 116.2 (NPh C-
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