4-Arylation of 3-alkoxypyrazoles

Article abstract of DOI:10.1016/j.tet.2009.01.109

Following the study of the alkoxypyrazoles nitrogen's reactivity toward arylation or alkylation reactions, we report here our results on the introduction of various aryl groups on carbon 4 position of 3-alkoxypyrazoles. This was achieved from the correspo

Full text of DOI:10.1016/j.tet.2009.01.109

Tetrahedron 65 (2009) 3529–3535
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Tetrahedron
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4-Arylation of 3-alkoxypyrazoles
,
Sandrine Guillou a, Olivier Nesmes a, Mikhail S. Ermolenko b, Yves L. Janin a
*
a Institut Pasteur, URA 2128 CNRS – Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France
b Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Following the study of the alkoxypyrazoles nitrogen’s reactivity toward arylation or alkylation reactions,
we report here our results on the introduction of various aryl groups on carbon 4 position of 3-alkoxy
pyrazoles. This was achieved from the corresponding 4-halogeno derivatives via a Suzuki–Miyaura aryl–
aryl coupling reaction. The unexpected difficulties (lack of reactivity or unwanted halogen reduction)
encountered in the C-4 arylation of NH-free 4-halogenopyrazoles led us to design solutions to this re-
current problem. The cleavage of the 3-alkoxy group was also investigated using hydrogen bromide in
acetic acid or boron tribromide in dichloromethane. This led, in one case, to the observation of a re-
markable neighboring group-assisted electrophilic aryl boronylation. This second part of our work paves
the way to the synthesis of many original chemical libraries featuring 3-alkoxy 1,4-diaryl pyrazoles as
well as the corresponding 1,4-diaryl pyrazol-3-ones.
Received 21 November 2008
Received in revised form 23 January 2009
Accepted 28 January 2009
Available online 14 February 2009
Keywords:
3-Alkoxypyrazole
C-Arylation
Suzuki–Miyaura
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
approach would provide a quicker method for the fine-tuning of
any structure–activity relationship study undertaken in these
Inexhaustible interest in the synthesis of arylated heterocyclic
compounds is sustained by their value to medicinal chemistry. For
instance, pyrazol-3-one is present in many organic compounds of
biological interest. A data base survey points out that more than
76,790 derivatives featuring this nucleus were prepared, which led
(from 1891 up to October 2008) to 15,593 patents. Interestingly,
about half of these patents are less than 20 years old. These figures,
better than anything, convey the fact that this heterocycle is
a popular scaffold used in the design of many compounds of
pharmaceutical or agricultural interest. The starting point of this
work stems from our simple preparation of a vast array of 3-
alkoxypyrazoles such as 1.1 From these compounds, the two general
chemical pathways described in Scheme 1 were investigated. In the
preceding paper,2 we have described the 3-alkoxypyrazole nitro-
gens reactivity toward alkylation or arylation reactions leading to
compound 2. We report here the results of our investigation on the
palladium-catalyzed arylation of the pyrazole ring to give 4-aryl
derivatives such as 3 as well as the subsequent 3-alkoxy hydrolysis
to provide an access to the 4-arylpyrazol-3-ones of the general
formula 5. Most of the C4-arylated pyrazol-3-ones have so far been
usually prepared per item by condensation between hydrazines and
various 1,3-dicarbonyl precursors.3–10 As the introduction of the
aryl moiety follows the construction of the pyrazole ring, our
series.
Scheme 1. General pathways investigated.
2. Results and discussion
The palladium-catalyzed coupling reaction of halogenated
heterocycles featuring an NH component appears to be one of the
few possibly limiting parameters of the Suzuki–Miyaura aryl–aryl
cross-coupling reaction.11–14 A short literature survey points out
that this reaction has been found problematic in the case of 2-
bromoindole,15 some 4-iodopyrazoles,16,17 or even worse from 4-
bromopyrazole in comparison with N-benzyl-4-bromopyrazole.18
The same phenomenon is actually seen when comparing the
* Corresponding author.
E-mail address: yves.janin@pasteur.fr (Y.L. Janin).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.109

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S. Guillou et al. / Tetrahedron 65 (2009) 3529–3535
coupling reaction between 3-iodo-7-methyl-1,8-naphthyridin-
4(1H)-one and its N-alkyl homologue.19 We started scouting the
routes for the Suzuki–Miyaura cross-coupling from 4-halogenated
pyrazoles 6 and 7,2 and representative phenylboronic acids. A
number of catalysts (Pd[PPh3]4, PdCl2(PPh)3, PdCl2dppe,
PdCl2dppp, PdCl2dppb, PEPPSIÔ-IPr catalyst, and several more) in
the presence of various bases (K3PO4, K2CO3, Cs2CO3) in different
aqueous solvents (THF, dioxane, propanol) appeared ineffective
for the cross-coupling of 7 and phenylboronic acid. On the other
hand, the reaction in the presence of [1,10-bis(diphenylphosphi-
no)ferrocene] dichloropalladium as a catalyst and cesium car-
bonate as a base in aqueous dioxane20 provided the expected
arylated product 8a, albeit in moderate and fluctuating yields.
Addition of lithium chloride has been reported to improve a few
palladium-catalyzed aryl coupling reaction involving halogenated
heterocycles with an NH component.15,17,21,22 This turned out to be
also true in our case, as the yields, in the presence of LiCl, became
reproducible. Little or no improvements were observed when we
switched from dioxane to propanol as a solvent for this reaction.
We also noted that the 4-iodo-pyrazole 7 is more reactive in this
reaction, as compared to its 4-bromo homologue 6. Furthermore,
the reaction time was shortened by the use of a microwave irra-
diation. Under these conditions, 4-chlorophenylpyrazole 8b could
also be synthesized. On the other hand, from 7 and the electron-
rich 3-methoxyphenylboronic acid, a host of unidentified prod-
uct(s) along with a very low yield of the coupling product 8c were
observed. Even worse, only traces of the coupling product 8d were
detected by LC/MS with the more sterically demanding
2-methoxyphenylboronic acid. These results led us to suggest that
the problems encountered in this palladium-catalyzed aryl–pyr-
azole coupling reaction are due to the trapping of active catalytic
species by NH-bearing pyrazole derivatives.
We thus resorted to the transient protection of the 3-alkoxy
pyrazole nitrogens by a mesylation reaction. This gave a 1/4 pro-
portion of the two possible mesyl-bearing isomers 9 and 10. No
attempt was made to separate them or to elucidate the regiose-
lectivity of this reaction. This proportion seems actually quite
variable upon the solvent used for the reaction. The palladium-
catalyzed coupling of these isomers with 2 and 3-methoxy
phenylboronic acids was then followed in situ by the basic hydro-
lysis of the mesylate group using potassium hydroxide. This
allowed the preparation of compounds 8c and 8d in, respectively,
32% and 55% overall yield.
Somehow logically, from the N-methylated and N-arylated iodo
derivatives 11 and 12, much less problems were encountered. In-
deed, without the recourse neither to lithium chloride nor, in early
cases, to a microwave oven, consistent (and better) yields of the
arylation products 13a–d and 14a–d were obtained from 11 and 12
and the corresponding arylboronates. We suggest that the differ-
ence in coupling efficiency seen between the N-methyl and the
N-phenyl compounds 11 and 12 is due to their relative stability
toward the reaction conditions (Scheme 2).
Scheme 2. (i) ArB(OH)2, PdCl2dppf, Cs2CO3, LiCl, dioxane–H2O, 130 ꢀC, MW. (ii) MeS-
O2Cl, NEt3, AcOEt. (iii) ArB(OH)2, PdCl2dppf, Cs2CO3, LiCl, propanol–H2O, 130 ꢀC, MW
then KOH, 90 ꢀC. (iv) ArB(OH)2, PdCl2dppf, Cs2CO3, dioxane–H2O, 90 ꢀC.
characterized and upon arylation reaction conditions followed by
the treatment with hydrochloric acid, the bis-arylated compound
18 was then obtained in an unoptimized 59% yield. A trial with
compound 7 also pointed out the efficiency of this approach in
that case. This fruitful use of a 1-ethoxyethyl group is reminiscent
of the pyran moiety reported recently as an efficient protecting
group in pyrazole chemistry;25–27 previous work has also reported
the use of a trityl protecting group.16 In our case, this 1-ethoxy-
ethyl significantly improved the Suzuki–Miyaura aryl–pyrazole
cross-coupling reaction. Further work in this domain is in
progress.
In order to increase the chemical diversity attainable from
these pyrazoles, we also applied the reported coupling of pyridine
N-oxide28 (20) to our halogenated pyrazoles 11 and 12. From the
4-iodo derivative 12, under microwave irradiation, none of
the expected arylation product was obtained. A slow reduction of
the 4-iodopyrazole to the parent compound was the sole trans-
formation we could monitor by LC/MS. On the other hand, from
the 4-bromopyrazole 21,2 the coupling reaction proceeded in
a 61% yield to give compound 22. Unfortunately, much less
C4-arylated product could be obtained from the N-methyl ana-
logue of 21 and none from the NH-bearing compounds 6 and 7
(with or without lithium chloride added). Compound 22 was
further catalytically reduced to the corresponding 2-pyridyl
derivative 23 using ammonium formate as a source of hydrogen in
boiling ethanol (Scheme 3).
The N-arylation of compound 8a, by the copper-mediated
method previously used,2 was also studied. From this compound,
the N-1 arylation product 14a could be isolated in 83% yield along
with traces amount (4%) of the N-2 arylation product 15. The 4-
iodo-5-phenylpyrazole 17 was easily prepared by iodination of the
readily available1 pyrazole 16. The 4-arylation reaction of this
hindered 4-iodo-5-phenylpyrazole under the conditions de-
scribed above led to the bis-arylated compound 18 although in
only a 20% yield along with large amount (50%) of the reduced
material 16. Further work aiming at avoiding this was undertaken.
The reported23,24 use of 1-ethoxyethyl as a pyrazole protecting
group prompted us to treat compound 17 with vinylethylether and
an acid catalyst. This led to a mixture of the 1-ethoxyethyl-pro-
tected regioisomers 19. These products were not further
In order to complete this synthetic exploration, we undertook
the cleavage of the ethyl or isopropyl ether protecting the oxygen
moiety of these compounds. This cleavage was best achieved using
hydrogen bromide acetic acid in a sealed tube at high temperature
and under argon atmosphere to prevent oxidative bromination of

S. Guillou et al. / Tetrahedron 65 (2009) 3529–3535
3531
Scheme 4. (i) HBr–AcOH, 140 ꢀC. (ii) BBr3, CH2Cl2, reflux. (iii) HCl, 37% reflux.
Scheme 3. (i) Cu(OAc)2, PheB(OH)2, pyridine, 4 Å molecular sieves, CH2Cl2, air, 25 ꢀC.
(ii) I2, NaI, K2CO3, EtOH, H2O, 25 ꢀC. (iii) PheB(OH)2, PdCl2dppf, Cs2CO3, LiCl, PrOH–H2O,
120 ꢀC, MW. (iv) APTS, dichloromethane. (v) PheB(OH)2, PdCl2dppf, Cs2CO3, PrOH–H2O,
120 ꢀC, MW then HCl, 12 N. (vi) PBu2Me–HBF4, Pd(OAc)2, K2CO3, toluene, 170 ꢀC, MW.
(vii) 10% Pd–C, NH3–HCO2H, ethanol reflux.
In summary, the introduction of a halogen atom at C-4 position of
3-alkoxypyrazole ring system followed by the Suzuki–Miyaura cross-
coupling reaction with arylboronic acids allowed preparation of
arylpyrazoles in satisfactory yields. This work encountered the re-
current problem of achieving a Suzuki–Miyaura coupling reaction
with a halogenated substrate bearing exchangeable hydrogen. The
addition of lithium chloride15,17,21,22 to the reaction mixture
answered this problem only partially. Accordingly, we developed the
use of the mesyl and 1-ethoxyethyl as transient protecting groups for
this heterocycle, which allowed a greater scope for the Suzuki–
Miyaura reaction. The use of [1,10-bis(diphenylphosphino)ferrocene]
dichloropalladium as a precatalyst afforded the cross-coupling
productsinreasonableyieldsandinshortreactiontime, whichcanbe
furtherreducedbythemicrowaveirradiation. Thecleavageofethylor
isopropyl ether group protecting theoxygenof the3-alkoxypyrazoles
moiety can be achieved by treatment with HBr/AcOH at elevated
temperature. Alternatively, the cleavage of some of these ethers is
also possible with boron tribromide in boiling dichloromethane. On
the new chemical entities aspect, we hope that the present work will
provide an easier access to 4-arylated-3-alkoxypyrazoles and related
pyrazol-3-ones of potential biological interest that have been over-
looked inthe past. Effortsaimingatfurther refinementof thereaction
sequence leading to these challenging molecules are in progress.
These results, as well as the biological evaluation of the corre-
sponding chemical libraries, will be communicated in due course.
some of the substrates. As mentioned in the proceeding report,2
stronger structural assignment was obtained by the deprotection of
the isomers2 24 and 25 into the corresponding pyrazol-3-ones 26
and 27 in 74 and 76% yield, respectively. As only the isomer 27 can
display methylenic 1H and 13C signals, this lifted any doubt on
structures of compounds 24 and 25. A more thorough NMR study of
the behavior of compound 27 has actually been reported recently.29
The use of boron tribromide in boiling dichloromethane to depro-
tect compound 24 also led to compound 26 although in a lower
yield. On the other hand, a remarkable process took place when
trying to deprotect compound 25 with this reagent. Indeed, the sole
product we could isolate from this trial was the boronic ester
resulting from a boronylation of the proximate phenyl moiety. This
reaction product was actually characterized as the citric acid ether
derivative 28, which precipitates from the reaction mixture upon
addition of citric acid. Further work on this original electrophilic
boronylation reaction is in progress. By using hydrogen bromide in
acetic acid at 140 ꢀC, many other pyrazol-3-ones were obtained
such as compounds 29a and 29b from compounds 8a and 18 in 45%
and 73% yield, respectively, or compound 30 from 13a and com-
pound 31 from 14a in 76% and 92% yield, respectively. Under these
conditions, the 3-methoxyphenyl derivative 322 underwent full
cleavage of the ether residues to give compound 33 in a 64% yield. A
selective deprotection of 3-alkoxypyrazole moiety of 32 to 3-
methoxyphenyl pyrazole-3-one 34 could be achieved in boiling
hydrochloric acid in 43% yield. All these deprotected compounds
are depicted in their ‘oxo’ tautomeric form. However, depending on
their substituent these compounds often exist in their ‘hydroxy’
tautomeric form in solution (Scheme 4).30
3. Experimental part
3.1. General
A Biotage Initiator 2 microwave oven was used for reactions
requiring microwave irradiations. The 1H NMR and 13C NMR spectra

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S. Guillou et al. / Tetrahedron 65 (2009) 3529–3535
were recorded on a Bruker Avance 400 spectrometer at 400 MHz
and 100 MHz, respectively. Unless otherwise noted, CDCl3 was the
2.28 (s, 1/5 of 3H), 2.54 (s, 4/5 of 3H), 3.23 (s, 4/5 of 3H), 3.24 (s, 1/5
of 3H), 5.02 (m, 1H).
solvent used. Shifts (d) are given in parts per million with respect to
the TMS signal and coupling constants (J) are given in hertz. Col-
umn chromatography was performed either with Merck silica gel
60 (0.035–0.070 mm) or neutral alumina containing a suitable
proportion of water, using a solvent pump operating at pressure
between 2 and 7 bar (25–50 mL/mn) and an automated collecting
system driven by a UV detector set to 254 nm unless stated other-
wise (i.e., if ethyl acetate was used then it would be set to 280 nm).
Sample deposition was always carried out by absorption of the
mixture to be purified on a small amount of the solid phase fol-
lowed by its deposition of the top of the column. The low resolution
mass spectra were obtained on an Agilent 1100 series LC/MSD
system using an atmospheric electrospray ionization system and
the high resolution mass spectroscopy spectra (HRMS) were
obtained using a Waters Micromass Q-Tof with an electrospray ion
source.
3.4. Palladium-catalyzed C-arylation of the mixture of
compounds 9 and 10, preparation of 8c and 8d
In a Biotage 10 mL tube a mixture of the considered pyrazole
(1.1 mmol); the relevant boronic acid (1.45 mmol), cesium car-
bonate (2.8 mmol), lithium chloride (2.24 mmol) in propanol
(5 mL), and water (5 mL) were degassed with a slow stream of
argon for ten minutes. Following this, [1,10-bis(diphenylphosphino)-
ferrocene] dichloropalladium complexed with dichloromethane
(0.044 mmol) was added, the tube was sealed and heated at
120 ꢀC for 60 min in the microwave oven. After cooling to room
temperature, potassium hydroxide (5 mmol) was added and the
tube heated in an oil bath at 90 ꢀC for 2 h. This was diluted in
water, extracted with ethyl acetate, the organic layer was washed
with brine and dried over sodium sulfate and concentrated to
dryness. The residue was purified by chromatography on silica gel
as described below.
3.2. Palladium-catalyzed C-arylation of compound 7;
preparation of 8a and 8b
3.4.1. 3-Isopropoxy-4-(3-methoxyphenyl)-5-methyl-1H-pyrazole 8c
Obtained as an oil in a 32% yield after a chromatography
over neutral alumina containing 1.5% of water (cyclohexane–
ethyl acetate 7/3). 1H (CDCl3): 1.39 (d, 6H, J¼6.1 Hz), 2.37 (s,
3H), 3.85 (s, 3H), 4.93 (sept, 1H, J¼6.1 Hz), 6.80 (m, 1H), 7.08 (m,
1H), 7.12 (m, 1H), 7.30 (m, 1H), 9.10 (br s, 1H). 13C (CDCl3): 11.7,
22.2, 55.1, 71.6, 105.0, 111.2, 113.7, 120.5, 129.2, 133.9, 137.5,
159.5, 160.2. HRMS: Calcd for C14H18N2O2þH: 247.1447. Found:
m/z, 247.1387.
In a Biotage 10 mL tube a mixture of the considered pyrazole
(1 mmol), the relevant boronic acid (1.3 mmol), cesium carbonate
(2.5 mmol), lithium chloride (2.1 mmol) in dioxane (4 mL), and
water (4 mL) was degassed with a slow stream of argon for 10 min.
Following this, [1,10-bis(diphenylphosphino)ferrocene] dichloro-
palladium complexed with dichloromethane (0.05 mmol) was
added, the tube was sealed and heated at 120 ꢀC for 30 min in the
microwave oven. After cooling to room temperature, the reaction
mixture was diluted in water and extracted with ethyl acetate. The
organic phase was dried over sodium sulfate and concentrated to
dryness. The residue was purified by chromatography on silica gel
as described below.
3.4.2. 3-Isopropoxy-4-(2-methoxyphenyl)-5-methyl-1H-pyrazole 8d
Obtained as an oil in a 53% yield after a chromatography
over neutral alumina containing 1.5% of water (cyclohexane–
ethyl acetate 7/3) followed by a second chromatography over
silica gel (dichloromethane–ethanol 98.5/1.5). 1H (CDCl3): 1.35
(d, 6H, J¼6.1 Hz), 2.20 (s, 3H), 3.83 (s, 3H), 4.86 (sept, 1H,
J¼6.1 Hz), 7.01 (m, 2H), 7.28 (m, 2H), 7.40 (br s, 1H). 13C (CDCl3):
11.5, 22.2, 55.3, 102.2, 110.0, 120.4, 120.8, 128.2, 132.0, 139.2,
156.9, 160.5. HRMS: Calcd for C14H18N2O2þH: 247.1447. Found:
m/z, 247.1398.
3.2.1. 3-Isopropoxy-5-methyl-4-phenyl-1H-pyrazole 8a
Obtained as an oil that slowly solidified in a 50% yield after
a chromatography over silica gel (cyclohexane–dichloromethane
2/8). Mp¼86 ꢀC. 1H (CDCl3): 1.47 (d, 6H, J¼6.1 Hz), 2.38 (s, 3H), 5.00
(sept,1H, J¼6.1 Hz), 7.30 (m,1H), 7.44 (m, 2H), 7.57 (m, 2H),10.5 (br s,
1H).13C (CDCl3): 11.9, 22.8, 72.2,105.4,126.0,128.6,128.7,133.1,138.1,
160.5. HRMS: Calcd for C13H16N2OþH: 217.1341. Found: m/z,
217.1348.
3.5. Palladium-catalyzed C-arylation of compounds 11 and 12
3.2.2. 4-(4-Chlorophenyl)-3-isopropoxy-5-methyl-1H-pyrazole 8b
Obtained as a solid in a 59% yield after a chromatography over
silica gel (dichloromethane–ethanol 99/1). Mp¼145 ꢀC. 1H (CDCl3):
1.27 (d, 6H, J¼6.1 Hz), 2.20 (s, 3H), 4.79 (sept, 1H, J¼6.1 Hz), 7.23 (m,
2H), 7.29 (m, 2H), 9.00 (br s, 1H). 13C (CDCl3): 11.7, 22.4, 71.9, 104.1,
In a 60 mL round-bottomed thick glass tube fitted with a PTFE-
faced screw-cap, a mixture of the considered pyrazole (1.14 mmol),
the relevant boronic acid (2.27 mmol), cesium carbonate
(2.27 mmol) in dioxane (4 mL), and water (1 mL) was degassed
with a slow stream of argon for 10 min. Following this, [1,10-bis
(diphenylphosphino)ferrocene] dichloropalladium complexed with
dichloromethane (0.057 mmol) was added, the tube was closed
tightly and heated at 90 ꢀC overnight. After cooling to room tem-
perature, the reaction mixture was diluted in water and extracted
with ethyl acetate. The organic phase was dried over sodium sulfate
and concentrated to dryness. The residue was purified by chro-
matography on silica gel as described below.
128.5, 129.3, 131.1, 131.3, 137.6, 160.1. HRMS: Calcd for
35
C13
H
ClN2OþH: 251.0951. Found: m/z, 251.0978.
15
3.3. Preparation of the mixture of 4-iodo-5-isopropoxy-3-
methyl-1-(methylsulfonyl)-1H-pyrazole and 4-iodo-3-
isopropoxy-5-methyl-1-(methylsulfonyl)-1H-pyrazole 9 and 10
Compound 7 (2.31 g, 8.68 mmol) was dissolved in ethyl acetate
(90 mL), triethylamine (1.9 mL,13.8 mmol, dried over 4 Å molecular
sieves) was added followed by mesyl chloride (1 mL, 13.0 mmol).
The solution was protected from moisture by a calcium chloride
guard and stirred for 2 h at room temperature. This was washed
with 2 N potassium carbonate, 0.5 N hydrochloric acid and brine,
dried over sodium sulfate, and concentrated to dryness to yield the
1/4 mixture of compounds 9 and 10 as a dark oil (2.84 g, 95%). 1H
(CDCl3): 1.40 (d, 4/5 of 6H, J¼6.1 Hz), 1.42 (d, 1/5 of 6H, J¼6.1 Hz),
3.5.1. 3-Isopropoxy-1,5-dimethyl-4-phenyl-1H-pyrazole 13a
This compound was obtained as an oil in a 61% yield from 11
after a chromatography over neutral alumina containing 1.5% of
water (dichloromethane–cyclohexane 1/4). 1H (CDCl3): 1.36 (d, 6H,
J¼6.1 Hz), 2.31 (s, 3H), 3.71 (s, 3H), 4.88 (sept,1H, J¼6.1 Hz), 7.23 (m,
1H), 7.41 (m, 4H). 13C (CDCl3): 10.7, 22.3, 35.7, 71.4, 105.8, 125.5,
128.2, 128.6, 133.0, 136.6, 158.6. HRMS: Calcd for C14H18N2OþH:
231.1497. Found: m/z, 231.1528.

S. Guillou et al. / Tetrahedron 65 (2009) 3529–3535
3533
3.5.2. 4-(4-Chlorophenyl)-3-isopropoxy-1,5-dimethyl-1H-pyrazole 13b
This compound was obtained as a yellow solid in a 67% yield
from 11 after a chromatography over neutral alumina containing
1.5% of water (dichloromethane–cyclohexane 1/9). Mp¼86 ꢀC. 1H
(CDCl3): 1.35 (d, 6H, J¼6.1 Hz), 2.29 (s, 3H), 3.70 (s, 3H), 4.88 (sept,
1H, J¼6.1 Hz), 7.34 (m, 4H). 13C (CDCl3): 10.7, 22.2, 35.7, 71.4, 104.7,
1.47 (d, 6H, J¼6.1 Hz), 2.29 (s, 3H), 3.90 (s, 3H), 5.12 (sept, 1H,
J¼6.1 Hz), 7.08 (m, 2H), 7.35 (m, 2H), 7.47 (m, 3H), 7.61 (m, 2H).
13C (CDCl3): 12.7, 22.3, 55.4, 71.2, 104.9, 111.2, 120.5, 121.1,
121.4, 124.4, 126.5, 128.2, 128.7, 132.3, 138.2, 140.1, 157.1, 160.5.
HRMS: Calcd for C19H19N235ClOþH: 293.1654. Found: m/z,
293.1672.
128.3, 129.7, 131.1, 131.5, 136.6, 158.4. HRMS: Calcd for
35
C14H
ClN2OþH: 265.1108. Found: m/z, 265.1037.
3.6. Preparation of 14a and 15 by the copper-catalyzed N-
arylation of 8a
17
3.5.3. 3-Isopropoxy-4-(3-methoxyphenyl)-1,5-dimethyl-1H-
pyrazole 13c
Compound 8a (0.16 g, 0.74 mmol), phenylboronic acid (0.1 g,
0.81 mmol), pyridine (0.12 mL, 1.48 mmol, dried over 4 Å molecular
sieves), copper(II) acetate hydrate (0.22 g, 1.11 mmol), and 4 Å
molecular sieves (0.3 g) were stirred in open air for 48 h in
dichloromethane (50 mL). The resulting suspension was absorbed
on a small amount of silica gel and purified by a chromatography
over silica gel (dichloromethane–cyclohexane 5/5 to 7/3) to yield
compound 14a (0.18 g, 83% as described above) and then com-
pound 15 (0.01 g, 4%).
This compound was obtained as an oil in a 43% yield from 11
after a chromatography over silica gel (cyclohexane–ethyl acetate
97/3). 1H (CDCl3): 1.38 (d, 6H, J¼6.1 Hz), 2.31 (s, 3H), 3.69 (s, 3H),
3.84 (s, 3H), 4.91 (sept, 1H, J¼6.1 Hz), 6.80 (m,1H), 7.05 (m, 2H), 7.30
(m, 1H). 13C (CDCl3): 10.8, 22.2, 35.6, 55.1, 71.4, 105.6, 111.1, 114.2,
129.4, 134.3, 136.8, 158.6, 159.5. HRMS: Calcd for C15H20N2O2þH:
261.1603. Found: m/z, 261.1553.
3.5.4. 3-Isopropoxy-4-(2-methoxyphenyl)-1,5-dimethyl-1H-
pyrazole 13d
3.6.1. 5-Isopropoxy-3-methyl-1,4-diphenyl-1H-pyrazole 15
Obtained as an oil 1H (CDCl3): 1.03 (d, 6H, J¼6.1 Hz), 2.39
(s, 3H), 4.06 (sept, 1H, J¼6.1 Hz), 7.30 (m, 2H), 7.45 (m, 4H),
7.51 (m, 2H), 7.78 (m, 2H). 13C (CDCl3): 14.3, 22.6, 77.8, 108.6,
123.1, 127.0, 128.6, 128.8, 129.1, 129.3, 133.1, 139.3, 147.4, 149.9.
HRMS: Calcd for C19H20N2OþH: 293.1654. Found: m/z,
293.1665.
This compound was obtained as an oil in a 41% yield from 11
after a chromatography over neutral alumina containing 1.5% of
water (dichloromethane–cyclohexane 1/9). 1H (CDCl3): 1.34 (d,
6H, J¼6.1 Hz), 2.13 (s, 3H), 3.71 (s, 3H), 3.83 (s, 3H), 4.85 (sept,
1H, J¼6.1 Hz), 6.98 (m, 2H), 7.28 (m, 2H). 13C (CDCl3): 10.9, 22.3,
35.7, 55.3, 71.1, 102.1, 110.9, 120.4, 121.4, 127.8, 132.1, 138.1, 156.9,
158.7. HRMS: Calcd for C15H20N2O2þH: 261.1603. Found: m/z,
261.1531.
3.6.2. 3-Ethoxy-4-iodo-5-phenyl-1H-pyrazole 17
Compound 161 (1.6 g, 8.51 mmol), potassium carbonate
(3.52 g, 25.53 mmol), sodium iodide (1.27 g, 8.51 mmol) were
dissolved in 80 mL of a water ethanol mixture 4–6. To this was
added iodine (3.2 g, 12.76 mmol). The solution was stirred for
1 h dispersed in water (300 mL) and the resulting precipitate
was filtered, washed with water, and dried under high vacuum
to yield compound 17 as a slightly yellow powder (2.02 g, 75%).
Mp¼128 ꢀC. 1H (CDCl3): 1.38 (t, 3H, J¼7.0 Hz), 4.21 (q, 2H,
J¼7.0 Hz), 7.48 (m, 3H), 7.66 (m, 2H), 10.53 (s(br), H). 13C
(CDCl3): 14.8, 45.1, 65.2, 126.6 (two signals), 128.8, 129.3, 144.5,
163.8. HRMS: Calcd for C11H11IN2OþH: 314.9994. Found: m/z,
315.0020.
3.5.5. 3-Isopropoxy-5-methyl-1,4-diphenyl-1H-pyrazole 14a
This compound was obtained as an oil in a 90% yield from 12
after a chromatography over neutral alumina containing 1.5% of
water (dichloromethane–cyclohexane 1/4). 1H (CDCl3): 1.42 (d,
6H, J¼6.1 Hz), 2.39 (s, 3H), 5.06 (sept, 1H, J¼6.1 Hz), 7.27 (m,
1H), 7.34 (m, 1H), 7.47 (m, 8H). 13C (CDCl3): 13.0, 22.7, 71.8,
108.5, 125.2, 126.2, 127.2, 128.6, 129.1, 129.4, 132.9, 137.2, 140.4,
160.6. HRMS: Calcd for C19H20N2OþH: 293.1654. Found: m/z,
293.1672.
3.5.6. 4-(4-Chlorophenyl)-3-isopropoxy-5-methyl-1-phenyl-1H-
pyrazole 14b
This compound was obtained as a white solid in a 79% yield from
12 after a chromatography over silica gel (dichloromethane–cy-
clohexane 2/8). Mp¼92 ꢀC. 1H (CDCl3): 1.43 (d, 6H, J¼6.1 Hz), 2.38
(s, 3H), 5.08 (sept, 1H, J¼6.1 Hz), 7.38 (m, 3H), 7.50 (m, 6H). 13C
(CDCl3): 12.6, 22.3, 71.5,107.0,124.8,126.9,128.4, 129.0, 129.9,131.0,
131.6, 136.7, 139.9, 160.0. HRMS: Calcd for C19H19N325ClOþH:
293.1654. Found: m/z, 293.1672.
3.6.3. 3-Ethoxy-4,5-diphenyl-1H-pyrazole 18
In
a 10 mL Biotage glass tube compound 17 (0.29 g,
9.2 mmol), phenylboronic acid (0.14 g, 1.20 mmol), cesium car-
bonate (0.75 g, 2.30 mmol), lithium chloride (0.078 g, 1.84 mmol)
in propanol (2.5 mL), and water (2.5 mL) was degassed with
a slow stream of argon for 10 min. Following this, [1,10-bis(di-
phenylphosphino)ferrocene] dichloropalladium complexed with
dichloromethane (0.038 g, 0.046 mmol) was added, the tube was
sealed and heated at 120 ꢀC for 30 min in the microwave oven.
After cooling to room temperature, the reaction mixture was
diluted in water and extracted with dichloromethane. The or-
ganic phase was dried over sodium sulfate and concentrated to
dryness. The residue was purified first by chromatography over
silica gel (dichloromethane–ethanol 98/2) and the fractions
containing compounds 17 and 18 were further purified by
a second chromatography over alumina containing 1.5% water
(dichloromethane and then dichloromethane–ethanol 99/1) to
yield, in this order, compound 18 (0.05 g, 20%) and then the
reduced compound 17 (0.09 g, 52%). Mp¼151 ꢀC (lit.31¼157–
158 ꢀC). 1H (CDCl3): 1.42 (t, 3H, J¼7.0 Hz), 4.34 (q, 2H, J¼7.0 Hz),
7.20 (m, 1H), 7.32 (m, 2H), 7.37 (m, 7H), 9.67 (s(l), 1H). 13C
(CDCl3): 15.0, 64.1, 104.6, 126.1, 127.8, 128.2, 128.7, 128.9, 129.1,
130.3, 131.6, 141.2, 161.6. HRMS: Calcd for C17H16N2OþH:
265.1341. Found: m/z, 265.1292.
3.5.7. 3-Isopropoxy-4-(3-methoxyphenyl)-5-methyl-1-phenyl-1H-
pyrazole 14c
This compound was obtained as an oil in a 80% yield from 12
after a chromatography over neutral alumina containing 1.5% of
water (dichloromethane–cyclohexane 1/9). 1H (CDCl3): 1.45 (d, 6H,
J¼6.1 Hz), 2.43 (s, 3H), 3.89 (s, 3H), 5.11 (sept,1H, J¼6.1 Hz), 6.88 (m,
1H), 7.16 (m, 2H), 7.36 (m, 2H), 7.50 (m, 4H). 13C (CDCl3): 12.7, 22.3,
55.1, 71.3, 107.9, 111.6, 114.4, 121.1, 125.0, 126.8, 128.7, 128.9, 133.8,
136.9, 140.0, 159.6, 160.2. HRMS: Calcd for C19H19N325ClOþH:
293.1654. Found: m/z, 293.1672.
3.5.8. 3-Isopropoxy-4-(2-methoxyphenyl)-5-methyl-1-phenyl-1H-
pyrazole 14d
This compound was obtained as an oil in a 71% yield from
12 after a chromatography over neutral alumina containing
1.5% of water (dichloromethane–cyclohexane 2/8). 1H (CDCl3):

3534
S. Guillou et al. / Tetrahedron 65 (2009) 3529–3535
3.7. Alternative preparation of 18 via 19
1H), 7.13 (m, 1H), 7.37 (m, 1H), 7.48 (d, 1H, J¼8.0 Hz), 7.59 (d, 1H,
J¼7.4 Hz). 13C (DMSO-d6): 12.1, 41.0, 43.6, 76.3, 91.4, 111.2, 119 (very
weak signal), 125.6, 128.5, 133.6, 136.2, 148.1, 155.0, 170.9, 171.3,
178.1. HRMS: Calcd for C10H9BN2O2ꢁH: 199.0681. Found: m/z,
199.0639 and (much weaker signal), Calcd for C16H15BN2O8ꢁH:
373.0846. Found: m/z, 373.0785.
Compound 17 (0.5 g, 1.59 mmol) was dissolved in dichloro-
methane (20 mL); ethylvinylether (0.9 mL, 9.5 mmol) and p-tolue-
nesulfonic acid (0.015 g, 0.08 mmol) were added and the solution
was stirred for 45 min at room temperature. Solid potassium car-
bonate (0.022 g) was added to the resulting dark solution, which
was concentrated to dryness to yield a dark oil containing the
mixture of product 19. Without further purification, the residue
was dispersed in propanol (5 mL) and transferred in a 10 mL Biot-
age tube. To this was added water (5 mL), potassium carbonate
(0.55 g, 3.98 mmol), and phenylboronic acid (0.21 g, 1.75 mmol).
The suspension was degassed by argon bubbling for 10 mn and
[1,10-bis(diphenylphosphino)ferrocene] dichloropalladium com-
plexed with dichloromethane (0.064, 0.079 mmol) was added. The
tube was sealed and heated at 120 ꢀC for 30 min in the microwave
oven. The resulting cooled mixture was treated with 12 N hydro-
chloric acid (0.70 mL), stirred for 45 min and then diluted in ethyl
acetate. The organic phase was washed with brine three times,
dried over sodium sulfate, and concentrated to dryness. The residue
was then purified as described above to yield compound 18
(0.25 g, 59%).
3.8. General method for the deprotection of 3-
alkoxypyrazoles using hydrogen bromide in acetic acid
In a 60 mL round-bottomed thick glass tube fitted with a PTFE-
faced screw-cap, a mixture of the considered 3-alkoxypyrazole
(1 mmol) was degassed with argon. Following this, 33% hydrogen
bromideinaceticacid(1.5 mL)wasadded;thetubewastightlyclosed
and was heated at 140 ꢀC for 2 h. The resulting solution was cooled,
diluted in water extracted with ethyl acetate. The organic layer was
washed with brine, dried over sodium sulfate, and concentrated to
dryness. The resulting residue was purified as described below.
3.8.1. 5-Methyl-1-phenyl-1H-pyrazol-3(2H)-one 26
This compound was obtained in a 74% yield from compound 242
as
a white powder after a chromatography over silica gel
(dichloromethane–ethanol 98/2). Mp¼165 ꢀC (lit.32¼164 ꢀC). 1H
(CDCl3): 2.27 (s, 3H), 5.61 (s, 1H), 7.40 (m, 3H), 7.48 (m, 2H). 13C
(CDCl3): 13.0, 93.8, 125.1, 127.3, 129.6, 139.2, 141.1, 163.2. HRMS:
Calcd for C10H10N2OþH: 175.0871. Found: m/z, 175.0894.
3.7.1. 2-(3-Isopropoxy-5-methyl-1-phenyl-1H-pyrazol-4-yl)-
pyridine 1-oxide 22
In a 5 mL Biotage vial, 4-bromo-3-isopropoxy-5-methyl-1-
phenyl-1H-pyrazole 212 (0.28 g, 0.95 mmol), pyridine N-oxide (20)
(0.35 g, 3.75 mmol), di-tert-butylmethyl phosphonium tetra-
fluoroborate (0.035 g, 0.14 mmol), potassium carbonate (0.26 g,
1.87 mmol), and palladium acetate (10.5 mg, 0.047 mmol) were
dispersed in toluene (5 mL). This was degassed by a slow stream of
argon for 10 min, sealed and heated in the microwave oven for
40 min at 170 ꢀC. The resulting mixture was adsorbed over a small
amount of silica and purified by a chromatography over silica gel
(dichloromethane–ethanol 98/2) to yield compound 22 (0.18 g,
61%) as a solid. Mp¼152 ꢀC. 1H (CDCl3): 1.34 (d, 6H, J¼6.1 Hz), 2.36
(s, 3H), 5.01 (sept, 1H, J¼6.1 Hz), 7.11–7.34 (m, 3H), 7.42–7.53 (m,
5H), 8.30 (m, 1H). 13C (CDCl3): 14.2, 22.2, 71.8, 99.8, 123.4, 124.8,
125.0, 127.3, 128.8, 128.9, 139.5, 139.9, 141.3, 142.9, 159.9. HRMS:
Calcd for C18H19N3OþH: 310.1555. Found: m/z, 310.1570.
3.8.2. 3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one 27
This compound was obtained in a 76% yield from 25 as a white
powder after a chromatography over silica gel (dichloromethane–
ethanol 98/2). Its analytical data are identical with a commercially
available sample. Note: a spectrum in deuterated chloroform
displays a unique methylene signal whereas a spectrum in deu-
terated dimethylsulfoxide features a mixture of the two possible
bonds distribution in the pyrazole ring. This observation and more
have actually been reported recently.29
3.8.3. 5-Methyl-4-phenyl-1H-pyrazol-3(2H)-one 29a
Obtained as a white solid in a 43% yield from 8a after the ex-
traction. Mp¼140 ꢀC (dec), (lit.4¼211 ꢀC). 1H (DMSO-d6): 2.27 (s, 3H,
CH3), 7.13 (m, 1H), 7.33 (m, 2H), 7.46 (m, 2H), 10.50 (br s, 2H). 13
C
3.7.2. 2-(3-Isopropoxy-5-methyl-1-phenyl-1H-pyrazol-4-yl)-
pyridine 23
(DMSO-d6): 11.5, 102.3, 124.7,127.3,128.1,133.5,136.5, 158.8. HRMS:
Calcd for C10H10N2O2þH: 191.0821. Found: m/z, 191.0841.
Compound 22 (0.15 g, 0.48 mmol), ammonium formate (0.3 g,
4.85 mmol), and 10% palladium over charcoal (5 mg, 0.05 mmol)
were heated to reflux in methanol (10 mL) for 20 h. The crude
residue obtained after concentration to dryness was purified by
a chromatography over silica gel (dichloromethane) to yield com-
pound 23 (0.1 g, 71%) as a solid. Mp¼71 ꢀC. 1H (CDCl3): 1.45 (d, 6H,
J¼6.1 Hz), 2.65 (s, 3H), 5.13 (sept, 1H, J¼6.1 Hz), 7.07 (m, 1H), 7.36
(m, 1H), 7.49 (m, 4H), 7.66 (m, 1H), 7.90 (m, 1H), 8.62 (m, 1H). 13C
(CDCl3): 13.2, 22.4, 71.6, 106.7, 119.9, 122.7, 125.3, 127.2, 129.0, 135.8,
139.7, 139.9, 148.8, 153.2, 160.5. HRMS: Calcd for C18H19N3þH:
294.1606. Found: m/z, 294.1624.
3.8.4. 4,5-Diphenyl-1H-pyrazol-3(2H)-one 29b
Obtained as a white solid in a 73% yield from 18 after a chro-
matography over silica gel (dichloromethane–ethanol 98/2).
Mp¼175 ꢀC (dec), (lit.¼111,33 23234 or 19435 ꢀC). 1H (DMSO-d6): 7.15
(m, 1H), 7.34 (m, 9H), 10.00 (br s, 1H), 11.95 (br s, 1H). 13C (DMSO-
d6): 102.6, 125.5, 127.4, 128.0 (two signals?), 128.6, 128.8, 130.6,
132.7, 139.6, 159.0. HRMS: Calcd for C15H12N2OþH: 191.0821.
Found: m/z, 191.0841.
3.8.5. 1,5-Dimethyl-4-phenyl-1H-pyrazol-3(2H)-one 30
Obtained as white solid in a 76% yield from 13a after the ex-
traction of the aqueous phase, which had been saturated with so-
dium chloride. Mp >260 ꢀC (lit.36¼250–252 ꢀC).1H (DMSO-d6): 2.25
(s, 3H, CH3), 3.58 (s, 3H), 7.17 (m, 1H), 7.34 (m, 4H), 9.71 (br s, 1H).
13C (DMSO-d6): 11.0, 35.8, 103.9, 125.4, 128.3, 128.6, 133.8, 136.5,
157.6. HRMS: Calcd for C11H12N2OþH: 189.1028. Found: m/z,
189.1054.
3.7.3. 2-(2-Methyl-5H-benzo[c]pyrazolo[1,5-e][1,5,2]oxazaborinin-
5-yloxy)propane-1,2,3-tricarboxylic acid 28
The N-phenyl derivative 25 (0.2 g, 0.925 mmol) was dissolved in
dichloromethane (20 mL). To this was added 1 M boron tribromide
in dichloromethane (1.85 mL, 1.85 mmol) and the mixture was
heated to reflux overnight. This was cautiously quenched with ice
and an excess of citric acid was added. The precipitate was dis-
persed in water and dichloromethane, filtered, and dried in open air
to yield compound 28 as a white powder (0.1 g, 28%). Mp >260 ꢀC.
1H (DMSO-d6): 2.29 (s, 3H), 2.62 (d, 1H, J¼14.1 Hz), 2.70 (d, 1H,
J¼14.1 Hz), 2.83 (d, 1H, J¼15.5 Hz), 2.95 (d, 1H, J¼15.5 Hz), 5.63 (s(l),
3.8.6. 5-Methyl-1,4-diphenyl-1H-pyrazol-3(2H)-one 31
Obtainedasawhitesolidina92%yieldfrom14a afterprecipitation
of the reaction mixture with an excess of water followed by a filtra-
tion. Mp¼237 ꢀC. 1H (DMSO-d6): 2.35 (s, 3H, CH3), 7.25 (m, 1H), 7.36

S. Guillou et al. / Tetrahedron 65 (2009) 3529–3535
3535
(m, 2H), 7.42 (m, 2H), 7.48 (m, 5H), 10.32 (br s, 1H). 13C (DMSO-d6):
13.0, 107.0, 124.4, 126.1, 127.0, 128.7, 128.8, 129.5, 132.9, 136.7, 139.9,
159.8. HRMS: Calcd for C16H14N2OþH: 251.1184. Found: m/z, 251.1199.
5. Offe, H. A.; Siefken, W.; Domagk, G. Z. Naturforsch. 1952, 7b, 446–462.
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Academic Press: London, 2001; Vol. 80, pp 74–144.
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3.8.7. 1-(3-Hydroxyphenyl)-5-methyl-1H-pyrazol-3(2H)-one 33
This compound was obtained in a 64% yield from 322 as a white
powder after a chromatography over silica gel (dichloromethane–
ethanol 98/2 to 95/5). Mp¼203 ꢀC. 1H (DMSO-d6): 2.25 (s, 3H, CH3),
5.55 (s, 1H), 6.70 (m, 1H), 6.86 (m, 2H), 7.22 (m, 1H), 9.68 (br s, 1H),
9.84 (br s, 1H). 13C (DMSO-d6): 12.8, 93.7, 110.4, 113.1, 113.7, 129.6,
139.4, 140.7, 157.7, 161.1. HRMS: Calcd for C10H10N2O2þH: 191.0821.
Found: m/z, 191.0841.
16. Elguero, J.; Jaramillo, C.; Pardo, C. Synthesis 1997, 563–566.
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3.8.8. 1-(3-Methoxyphenyl)-5-methyl-1H-pyrazol-3(2H)-one 34
Compound 322 (0.080 g, 0.4 mmol) was refluxed for 4 h in 37%
hydrochloric acid (10 mL). This was concentrated to dryness and
the residue was purified by a chromatography over silica gel (cyclo-
hexane–ethyl acetate 9/1) to yield compound 34 as a colorless solid
(0.035 g, 43%). Mp¼163 ꢀC. 1H (CDCl3): 2.30 (s, 3H, CH3), 3.88 (s,
3H), 5.61 (s, 1H), 6.90 (dd, 1H, J¼2.4 and 0.8 Hz), 6.98 (m, 2H), 7.36
(t,1H, J¼8.3 Hz). 13C (CDCl3): 13.1, 55.9, 93.9,110.6,113.7,117.0,130.1,
140.3, 141.2, 160.5, 163.2. HRMS: Calcd for C11H12N2O2þH:
205.0977. Found: m/z, 205.0999.
Acknowledgements
25. Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.; Newton, C. L.; Pellicore, J.
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This work was supported by the Medicen initiatiꢀve (Chemical
´
Library Project; grant of the Region Ile de France n I 06-222/R,
which included a fellowship for S.G.). Dr. Daniel Larzul as well as Dr.
Emile Bisagni are also acknowledged for their interest and support.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.01.109.
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