3-Methoxypyrazoles from 1,1-dimethoxyethene, few original results

Article abstract of DOI:10.1016/j.tet.2012.02.057

From the condensation between 1,1-dimethoxyethene and anhydrides, synthetically useful β,β-dimethoxy-α,β-unsaturated ketones were prepared. Upon addition of hydrazine, followed by iodination, 4-iodinated 3-methoxypyrazoles were obtained. The occurrence of a side compound also provided insights in the scope of this synthesis. In a second part, 1-(4-chlorophenyl)-3,3-dimethoxyprop-2-en-1-one was obtained from 1,1-dimethoxyethene and 4-chlorobenzoylchloride. The subsequent addition of hydrazine or phenylhydrazine led to 5-(4-chlorophenyl)-3-methoxy-1H-pyrazole or 1-phenyl-5-(4-chlorophenyl)-3-methoxypyrazole in unprecedented 64 or 54% overall yield. Unexpectedly, addition of 2-pyridylhydrazine led to the 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(4-chlorophenyl) ethanone. This led us to design original conditions, which led to the target 1-(2-pyridyl)-5-(4- chlorophenyl)-3-methoxypyrazole in a 39% overall yield. Additional examples are provided, starting from various carboxychlorides.

Full text of DOI:10.1016/j.tet.2012.02.057

Tetrahedron 68 (2012) 3165e3171
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
3-Methoxypyrazoles from 1,1-dimethoxyethene, few original results
,
,
,
b
a
,
,b,
*
Elise Salanouve a b, Sandrine Guillou a b, Marine Bizouarne a , Frederic J. Bonhomme b, Yves L. Janin a
ꢀ ꢀ
a Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
b CNRS, UMR 3523, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 January 2012
Received in revised form 16 February 2012
Accepted 23 February 2012
Available online 1 March 2012
From the condensation between 1,1-dimethoxyethene and anhydrides, synthetically useful
edimethoxye -unsaturated ketones were prepared. Upon addition of hydrazine, followed by io-
b
,b
a,b
dination, 4-iodinated 3-methoxypyrazoles were obtained. The occurrence of a side compound also
provided insights in the scope of this synthesis. In a second part, 1-(4-chlorophenyl)-3,3-dimethoxyprop-
2-en-1-one was obtained from 1,1-dimethoxyethene and 4-chlorobenzoylchloride. The subsequent ad-
dition of hydrazine or phenylhydrazine led to 5-(4-chlorophenyl)-3-methoxy-1H-pyrazole or 1-phenyl-
5-(4-chlorophenyl)-3-methoxypyrazole in unprecedented 64 or 54% overall yield. Unexpectedly, addition
of 2-pyridylhydrazine led to the 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(4-chlorophenyl) ethanone. This
led us to design original conditions, which led to the target 1-(2-pyridyl)-5-(4-chlorophenyl)-3-
methoxypyrazole in a 39% overall yield. Additional examples are provided, starting from various
carboxychlorides.
Keywords:
Heterocycle
1,1-Dimethoxyethene
Pyrazole
Cross-coupling
N-Arylation
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
R
O
R
Cl
O
O
O
O
O
+
R
R
R'
Cl
Following our work on the design of fast accesses to new
chemical entities featuring a pyrazole ring,1e7 biological screenings
in the domain of infectious diseases led to the identification of few
series of potential interest. In order to explore the structure-activity
relationships of these compounds, alternative approaches to 3-
alkoxypyrazoles were sought. We wish to describe here a syn-
thetic path stemming from various reports describing condensa-
R'
1
2
3
R
O
O
O
+
+
RCl
R
OR
R'
O
4
5
6
R
R'
tions between
related substrates and hydrazine8e11 or substituted hydrazines.12e16
As depicted in Scheme 1, amongst few approaches,17e22
-un-
saturated ketones (4) have been prepared via condensations be-
tween an excess of 1,1-dialkoxyethenes (2) and carboxychlorides
(1).23e25 This reaction leads to the ketones 4 as well as the corre-
sponding ester 5 and alkyl chloride 6. The condensation between
b,b-dialkoxy-a,b-unsaturated ketones as well as
H
O
O
N N
N N R'
R'NHNH2
R
H
R'
O
R
O
R'
a,b
7
8
Scheme 1. 3-Alkoxypyrazoles from carboxychlorides and 1,1-dialkoxyethenes.
Accordingly, the opposite selectivity of condensation was ob-
served with methylhydrazine.11 A patent is also describing such
opposite selectivity when using 2-pyrimidylhydrazines. However,
since in this case methanol and acetic acid were used as solvents,13
it is likely that a different reaction intermediate occurred, thus re-
versing the condensation regioselectivity back to the usual orien-
tation of the Knorr pyrazolones synthesis.26,27
these reactive b,b-dialkoxy-a,b-unsaturated ketones with hydrazine
does provide a quite efficient access to alkoxypyrazoles (8). More
importantly, from arylhydrazines, a regioselective condensation,
leading to 3-aryl-1-alkoxypyrazoles (8) was noted.10,12,14,16 The or-
igin of this regioselectivity lies in the occurrence of the intermediate
7 prior to its cyclization. It is thus the respective nucleophilic power
of the two nitrogens of substituted hydrazines, which governs the
addition on the most electrophilic center of compound 4.
2. Results/discussion
As depicted in Table 1, in an attempt to avoid the generation of
chloromethane inherent to the use of carboxychlorides in this syn-
thetic path,23,24 we investigated the use of anhydrides thus leading
* Corresponding author. Tel.: þ33 0 1 45 68 82 97; fax: þ33 0 1 45 68 84 04;
e-mail address: yves.janin@pasteur.fr (Y.L. Janin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.057

3166
E. Salanouve et al. / Tetrahedron 68 (2012) 3165e3171
Table 1
a control reaction using with methylacetoacetate (21) and 1,1-
One pot preparation of 4-iodopyrazoles 13aed
dimethoxyethene (10) under the same conditions, followed by
the addition of hydrazine, did gave the related pyrazole ester 22 in
an unoptimized 23% yield. Thus, amongst the factors governing the
ratio of occurrence of these rearrangements, the steric bulk of the
anhydride used appears to favor a path leading to compound 14.
O
O
O
O
O
110-130 °C
neat
+
O
R
O
9a-e
R
R
O
10
11a-e
HN N
I2, NaI
K2CO3
NH2NH2, H2O
HN N
O
R
H
O
R
N N
O
O
I
13a-d
i, ii, iii
13d +
12a-d
O
R
% of 13a
Remarks
11a is volatile
O
9d
O
a
b
c
d
e
Me
Et
50
37
31
29
0
14 (19 %)
nBu
iPr
O
O
O
O
O
O
O
O
C6H5
11e was not detected
O
O
a
Isolated overall yield from 9aee.
H
15
16
to the generation of much less harmful methyl esters. Contrary to the
carboxychlorides, which usually reacted at room temperature with
1,1-dimethoxyethene (10), the 1H NMR monitoring of our trials
pointed out that the reaction with acetic anhydride (9a) required to
raise the temperature to at least 110 ꢀC. Slightly more than 2 equiv of
1,1-dimethoxyethene (10) were found necessary to bring the re-
action to completion. The use of solvents lowered the reaction rate in
all cases (cyclohexane, ethyl acetate, tetrahydrofuran or dichloro-
methane), and if acetonitrile had a similar drawback, the 1H NMR
spectra pointed out a somehow cleaner reaction. Moreover, 1H NMR
monitoring of this first stage also pointed out that if heating at 110 ꢀC
for 30 min was sufficient to bring the reaction to completion in the
case of acetic anhydride (9a), increasingly higher temperature (upto
130 ꢀC) as well as longer heating time (upto 60 min) were found
necessary in the cases of the bulkier anhydrides 9bed. The addition
of hydrazine hydrate on the crude reaction products 11aed gave the
corresponding pyrazoles 12aed along with few side compounds
discussed below. The use of anhydrous hydrazine did not improve
the yield of this second stage. Finally, in order to simplify the puri-
fication procedure of these quite TLC-invisible compounds, a 4-
- iPrCO2H (17)
- iPrCO2Me (18)
O
O
O
O
O
O
O
i
O
O
O
11d
19
20
H
N N
O
O
i, ii
O
O
O
21
22 (23 %)
Scheme 2. i: 10, 130 ꢀC. ii: NH2NH2, H2O, iii: NaI, I2, K2CO3.
The unexpected complete lack of reaction between benzoic
anhydride (9e) and 1,1-dimethoxyethene (10) led us to resort to the
use of aroylchloride. As depicted in Scheme 3, the reaction between
the model 4-chlorobenzoylchloride (23) and 1,1-dimethoxyethene
(10) was investigated. Contrary to the use of anhydrides 9aed,
this reaction turned out to take place at room temperature and to
be exothermic. The 1H NMR monitoring of reaction trials pointed
out the need of 3 equiv of 1,1-dimethoxyethene (10) for its com-
pletion. Moreover, it was again best conducted without recourse to
a solvent. Upon addition of hydrazine to the crude mixture con-
taining 24, an exothermic process took place to give the 3-
iodination
followed
and
the
pure
5-alkyl-4-iodo-3-
methoxypyrazoles 13aed were obtained in unprecedented
29e50% overall yield. Unexpectedly, despite few trials, as seen by 1H
NMR monitoring, benzoic anhydride (9e) failed to react with 1,1-
dimethoxyethene (10).
In order to clarify the overall yield decrease, apparently de-
pendant on the steric bulk of the anhydride used, an extensive
analysis of the reaction product was made in the case of the re-
actions sequence with isobutyric anhydride (9d). As shown in
Scheme 2, aside from unidentified water-soluble products and
volatiles, the 3-methoxypyrazole 13d as well as the quite un-
expected pyrazole methyl ester 14 were isolated. We suggest, two
different rearrangements of the reaction intermediate depicted by
the conformers 15 and 16. This adduct would result from a [2þ4]
concerted process between anhydride 9d and 1,1-dimethoxyethene
(10). From conformation 15, a 6-centered elimination of isobutyric
acid (17) would lead to compound 11d, which upon addition of
hydrazine, would provide the 3-methoxypyrazole 12d. To account
for compound 14, a less favored evolution of conformer 16 would
involve a 6-centered methyl migration from its orthoacetal to the
carboxyl group of its isobutyryl moiety. This would lead to a direct
elimination of isobutyric methyl ester (18) and the generation of
methoxypyrazole 25 in
chlorobenzoylchloride (23). Addition of phenylhydrazine on the
a remarkable 64% yield from 4-
O
O
O
i
O
+
Cl
O
O
Cl
Cl
23
10
24
R
N
H
N
ii or iii
iv
N
O
N
O
Cl
the b-ketoester 19. Alternatively, a methanol elimination followed
Cl
25: R = H (64 %)
26: R = Ph (54 %)
by methanolysis of the isobutyric ester can be considered. Sub-
sequent reaction of 19 with 1,1-dimethoxyethene (10) would pro-
vide compound 20 and thus give the 4-carboxypyrazole 14 upon
addition of hydrazine. Concerning the last part of this mechanism,
27 (84 %)
Scheme 3. i: 20 ꢀC, neat; ii: NH2NH2, H2O, 0 to 20 ꢀC; iii: PhNHNH2, 110 ꢀC; iv: HBr/
AcOH, 140 ꢀC.

E. Salanouve et al. / Tetrahedron 68 (2012) 3165e3171
3167
crude compound 24 followed by heating to achieve the pyrazole
ring closure gave the 3-methoxypyrazole 26 in a 54% yield. It is
important to point out that the use of more than 3 equiv of 1,1-
dimethoxyethene in the first step of this preparation is very
much detrimental to the yield of compound 26 (very likely because
of a side reaction related to the transformation 19 to 20). Hydrolysis
of 26, using hydrogen bromide in acetic acid, gave the 1,3-
diphenylpyrazol-3-one (27). This compound, contrary to its iso-
mer, cannot display a 1H NMR methylene signal by pyrazole ring
tautomerism2 thus establishing the structure of 26.
The reaction of the crude mixture containing compound 24 with
2-pyridylhydrazine (28) turned out to be far less straightforward.
Indeed, as depicted in Scheme 4, upon heating to transform what,
as seen by 1H NMR of a reaction sample, could be the (unstable)
intermediate 29, we isolated compound 31 in an unoptimized 17%
yield. Mechanism-wise, we suggest a methanol elimination, from
29, which would lead to compound 30. This would be followed by
an internal 1e4 addition of the pyridine nitrogen on the conjugated
double bound to give 31. A fair number of trials were conducted to
avoid this cyclization. To make a long story short it is only pure
(beginners) luck, which led us to adsorb the unheated reaction
mixture containing intermediate 29 over silica and only then apply
heat. With this protocol, the side reactions were diminished and we
could isolate some target compound 32. Further study pointed out
that alumina of the acid type was the solid support of choice
and an unprecedented overall 39% of compound 32 from 4-
chlorobenzoylchloride (23) was obtained. We suggest an attenua-
tion of the nucleophilic strength of the pyridyl moiety by the solid
support, which allows the alternative cyclization into pyrazole 32
to occur. A trial with the more acidic borontrifluoride etherate was
not successful. To firmly establish the structure of compound 32, as
extensive NMR experiments were not useful, the hydrolysis of the
methoxy group was made with hydrogen bromide in acetic acid to
give pyrazol-3-one 33. Moreover, an identical sample of 33 was also
obtained via the unambiguous route based on a SuzukieMiyaura
coupling between 4-chlorophenylboronic acid and the 5-iodo-3-
ethoxypyrazole 34,4,7 followed by the acidic hydrolysis of the
resulting 3-ethoxypyrazole 35. This control preparation also illus-
trates the fact that synthesis of 33 from 1,1-dimethoxyethene (10) is
actually faster and more efficient than via the SuzukieMiyaura
reaction using the building block 34, which requires four synthetic
steps to be prepared.7
The scope of this synthetic method is illustrated in Table 2.
Starting from a variety of carboxychlorides 36ael, the corre-
sponding 3-methoxypyrazoles 37aek were obtained in yield be-
tween 11 and 52%. Unexpectedly, from the 2-trifluromethylbenzoyl
chloride (36i) or from 4-dimethylaminobenzoylchloride (36l) the
sequence of reactions only led in the first instance to traces of the
expected product 37i, along with extensive decomposition and
none in the second case. The 1H NMR monitoring of the reaction
steps pointed out that in the first case the reaction stalled before the
elimination leading to the dimethoxy-a,b-unsaturated ketone re-
lated to compound 24 depicted in Scheme 3. The addition of hy-
drazine on this intermediate actually led to 5-(2-trifluorophenyl)-
3-methoxy-1H-pyrazole, thus establishing the occurrence of an
initial addition process between 1,1-dimethoxyethene and com-
pound 36i. A trifluoromethyl-based stabilization of an enol form of
the ketone could explain the lack of hydrogen chloride elimination.
This putative ketone would react with hydrazine to give the cor-
responding pyrazole. However, upon reaction of this ketone with
2-pyridylhydrazine, we have previously observed that the resulting
intermediate hydrazone can be very reluctant to cyclize into
what would have been the isomer of compound 37f. We often
observed extensive decomposition very reminiscent to the
one seen here.5 Related to the eventual enol stabilization effect
it is important to mention that, as seen by 1H NMR, the
preparation of compound 37d required heating the mixture 1,1-
dimethoxyethene (10) and 2-methoxybenzoylchloride (36d) at
60 ꢀC for 1 h to achieve the elimination reaction leading to the
O
O
O
H2N
HN
N
i
HN
24
NH
+
Cl
N
28
29
O
O
H
N
ii
N
N
H
Cl
corresponding dimethoxy-a,b-unsaturated ketone. In the case of 4-
30
dimethylaminobenzoylchloride (36l), aside from decomposition, so
far no reaction took place between the 1,1-dimethoxyethene and
compound 36l despite the various conditions tried.
N
N
O
N
Cl
31 (17 %)
Table 2
Scope of the preparation of 3-methoxy pyrazoles
N
1) 10, neat
2) 28, neat
N
N
O
H
N
iii
iv
N N
N
R
Cl
36a-l
N
N
29
O
O
3) Al203, 110°C
R
OMe
37
Cl
Cl
R
% 37
32 (39 % from 23)
33 (79 %)
a
b
c
d
e
f
g
h
i
C6H5
35
27
11
24
30
20
15
21
traces
26
52
0
C6H5CH2ꢁ
C6H5CH2CH2ꢁ
2-MeOC6H4ꢁ
2-ClC6H4ꢁ
2-FC6H4ꢁ
iv
N
N
N
N
N
N
v
O
3-FC6H4ꢁ
O
4-FC6H4ꢁ
I
2-CF3C6H4ꢁ
3-CF3C6H4ꢁ
4-CF3C6H4ꢁ
4-Me2NC6H4ꢁ
34
35 (38 %)
Cl
j
k
l
Scheme 4. i: neat; ii: 110 ꢀC; iii: adsorption on Al2O3 (Hþ form), toluene reflux; iv:
HBr/AcOH 140 ꢀC; v: 4-ClC6H4B(OH)2, Pd(OAc)2, 2XPhos, Cs2CO3, DMF, 140 ꢀC.

3168
E. Salanouve et al. / Tetrahedron 68 (2012) 3165e3171
3. Conclusion
set to 254 nm unless required otherwise. Sample deposition was
carried out by absorption of the mixture to be purified on a small
amount of the solid phase followed by its deposition of the top of the
column. The low resolution mass spectra were obtained on an Agi-
lent 1100 series LC/MSD system using an atmospheric electrospray
ionization system and the high resolution mass spectra (HRMS)
were obtained using a Waters Micromass Q-Tof with an electrospray
ion source. 1,1-dimethoxyethene or 1,1-diethoxyethene used to be
commercially available (Aldrich) and a number of preparation
methods have been reported,32e38 including a recent one, which
avoids some difficulties.39
In conclusion, this work first secured a more efficient synthetic
access to 4-iodinated building blocks such as 13aed. It also offers an
alternative, regioselective and more efficient route to 1,3-
bisarylated pyrazoles such as compound 32 and 33 or 37aek,
contrary to the unselective N-arylation methodology we previously
investigated.2,4 Concerning this aspect, as depicted in Scheme 5, one
more unexpected result arose from the TaillefereCristau copper-
catalyzed arylation of compound 25 with 2-bromopyridine using
[N,N0-bis-((20-pyridine)-methylene)]-1,2-diaminocyclohexane as
the copper ligand.28e30 This reaction led to the expected low 14.8%
yield of the N-pyridyl derivative 32 and an unexpected smaller 12%
of the corresponding isomer 38. Instead, out of a complex mixture of
products, the 3-methoxy-1-methyl-5-phenylpyrazole (39) and 5-
methoxy-1-methyl-3-phenylpyrazole (40) were isolated in 3.6
and 8.6% yield, respectively. We suggest the occurrence of the pyr-
azolium 41, resulting from a second arylation of the isomer 38,
which could then serve as a methylating agent for the unreacted
compound 25. A related precedent was reported in a patent.31 Such
mechanism would explain why ethylation was never observed in
the course of the many N-pyridylations we conducted with ethox-
ypyrazoles derivatives.2,4,7 In these cases the corresponding N-ethyl
pyrazolium would, under the reaction conditions, immediately
eliminate ethylene instead of providing an ethylation source. In any
case, all these studies are providing few additional insights in
alkoxypyrazole chemistry as well as simple and original synthetic
accesses from which optimal preparations can be chosen. These
routes are currently used for the synthesis of many compounds of
biological interest and we hope that we will be able to report all this
in the future.
4.2. General procedure for the preparation of compounds
13aed
In a Biotage tube, 1,1-dimethoxyethene (10) (0.91 g, 10.33 mmol)
was added to the considered anhydride (4.91 mmol). This was
heated in a microwave oven at 110 ꢀC for 30 min in the case of
anhydride 9a, 120 ꢀC for 60 min in the case of anhydride 9b or at
130 ꢀC for 45 min in the case of anhydride 9c and 9d. The 1H NMR
sample of the crude mixtures, in DMSO-d6, pointed out the occur-
rence of a singlet between 4.58 and 4.66 ppm corresponding to
compounds 11aed. The tube was cooled to 0 ꢀC, hydrazine hydrate
(0.26 mL, 5.41 mmol) was added and after 10 min at 0 ꢀC, the so-
lution was stirred at room temperature for 30 min. The reddish
solution was concentrated to dryness, the resulting residue was
dissolved in a 1/1 mixture of ethanol and water (50 mL), potassium
carbonate (2.2 g, 14.68 mmol), sodium iodide (0.68 g, 4.91 mmol)
and iodine (1.86 g, 7.32 mmol) were then added in that order. This
was stirred at room temperature for 2 h before pouring it in water
(100 mL). The excess of iodine was removed by the addition of
sodium sulfite and the aqueous phase was extracted with ethyl
acetate (3ꢂ50 mL). The organic layer was washed with water
(3ꢂ50 mL), brine (30 mL) and dried over magnesium sulfate before
concentrating it to dryness. The resulting residue was purified by
a chromatography as described below.
N
N
O
HN
N
i
N
O
32 (14.8 %)
+
4.2.1. 4-Iodo-3-methoxy-5-methyl-1H-pyrazole (13a). Obtained as
a yellow powder in a 50% yield from the corresponding anhydride
after a chromatography over silica gel (dichloromethane/ethanol
25
Cl
Cl
98/2). Mp 132 ꢀC 1H NMR (400 MHz, CDCl3):
d
¼2.22 (s, 3H); 3.94 (s,
38 (12 %)
3H); 10.15 (s(br), 1H). 13C NMR (100 MHz, CDCl3):
d
¼12.1; 45.8;
56.4; 142.9; 163.7. HRMS-ES: m/z [MþH]þ calcd for C5H8IN2O:
N
N
O
O
N
N
238.9681; found: 238.9626.
N
+N
N
N
+
+
O
4.2.2. 4-Iodo-3-methoxy-5-ethyl-1H-pyrazole (13b). Obtained as
a yellow powder in a 37% yield from the corresponding anhydride
after a chromatography over silica gel (dichloromethane/ethanol
Cl
Cl
40 (8.6 %)
98.5/1.5). Mp 129 ꢀC 1H NMR (400 MHz, CDCl3):
d
¼1.25 (t, J¼7.1 Hz,
39 (3.4 %)
41
ꢁ
3H); 2.63 (q, J¼7.1 Hz 2H); 3.95 (s, 3H); 9.85 (s(br), 1H). 13C NMR
Scheme 5. i: 2-bromopyridine, Cu2O, Cs2CO3, ligand, 4 A molecular sieves, MeCN, MW
180 ꢀC, 2h.
(100 MHz, CDCl3):
d¼12.3; 20.1; 44.6; 56.4; 147.7; 163.8. HRMS-ES:
m/z [MþH]þ calcd for C6H10IN2O: 252.9838; found: 252.9855.
4. Experimental section
4.1. General
4.2.3. 4-Iodo-3-methoxy-5-butyl-1H-pyrazole (13c). Obtained as
a yellow powder in a 31% yield from the corresponding anhydride
after a chromatography over silica gel (dichloromethane/ethanol
A Biotage initiator 2 microwave oven was used for reactions
mentioning such heating method (infrared temperature monitor-
ing; the irradiation time stated are the actual reaction time at the
temperature mentioned). 1H NMR and 13C NMR spectra were
recorded on a Bruker Avance 400 spectrometer at 400 MHz and
99/1). Mp 55 ꢀC 1H NMR (400 MHz, CDCl3):
d
¼0.94 (t, J¼7.3 Hz, 3H);
1.38 (m, 2H); 1.58 (m, 2H); 2.57 (t, J¼7.5 Hz, 2H); 3.95 (s, 3H); 8.30
(s(br), 1H). 13C NMR (100 MHz, CDCl3):
d
¼13.7; 22.2; 26.3; 30.2;
45.2; 56.4; 146.8; 163.6. HRMS-ES: m/z [MþH]þ calcd for
C8H14IN2O: 281.0151; found: 281.0121.
100 MHz, respectively. Shifts (d) are given in parts per million with
respect to the TMS signal and coupling constants (J) are given in
Hertz. Column chromatography were performed either on Merck
silica gel 60 (0.035e0.070 mm) or neutral alumina using a solvent
pump and an automated collecting system driven by a UV detector
4.2.4. 4-Iodo-3-methoxy-5-isopropyl-1H-pyrazole (13d). Obtained
as a yellow powder in a 29% yield from the corresponding anhy-
dride after a chromatography over silica gel (dichloromethane/
ethanol 99/1). Mp 110 ꢀC 1H NMR (400 MHz, CDCl3):
d
¼1.31 (d,

E. Salanouve et al. / Tetrahedron 68 (2012) 3165e3171
3169
35
J¼7.2 Hz, 6H); 3.07 (sept, J¼7.2 Hz,1H); 3.96 (s, 3H); 9.75 (s(br),1H).
HRMS-ES: m/z [MþH]þ calcd for C16
H
14
ClN2O: 285.0682; found:
13C NMR (100 MHz, CDCl3):
d
¼20.8; 26.9; 43.7; 56.3; 150.9; 163.7.
285.0735.
HRMS-ES: m/z [MþH]þ calcd for C7H12IN2O: 266.9994; found:
266.9942.
4.2.9. 5-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3(2H)-one
(27). The methoxypyrazole 26 (0.1 g, 0.35 mmol) was placed in
a 60 mL round-bottomed thick glass tube fitted with a PTFE-faced
screw cap. This was degassed with argon and then 33% hydrogen
bromide in acetic acid (1.5 mL) was added. The tube was tightly
closed and was heated at 140 ꢀC for 4 h. The suspension was then
cooled, diluted in ethanol (30 mL), concentrated to dryness, made
basic with 2M ethanolic ammonia and concentrated to dryness
again. The resulting solid was purified by a chromatography over
silica gel (dichloromethane/ethanol 99/1 to 97/3) to yield com-
pound 27 (0.08 g, 84%) as a white powder. Mp gt; 260 ꢀC 1H NMR
4.2.5. Methyl 5-isopropyl-3-methyl-1H-pyrazole-4-carboxylate
(14). Further elution following the collection of compound 13d
with dichloromethane/ethanol 96/4 led to the isolation of com-
pound 14 in a 19% yield as a yellow powder. Mp 55 ꢀC 1H NMR
(400 MHz, CDCl3):
d
¼1.29 (d, J¼7.0 Hz, 6H); 2.46 (s, 3H); 3.61 (sept,
1H, J¼7.0); 3.83 (s, 3H); 7.90 (s(br), 1H). 13C NMR (100 MHz, CDCl3):
d
¼13.4; 21.6; 26.3; 50.9; 107.5; 148.9; 157.4; 164.9. HRMS-ES: m/z
[MþH]þ calcd for C9H15N2O2: 183.1134; found: 183.1098.
4.2.6. Methyl
3,5-dimethyl-1H-pyrazole-4-carboxylate
(22). In
(400 MHz, DMSO-d6):
d
¼5.97 (s, 1H); 7.17 (m, 2H); 7.22 (m, 1H);
a biotage tube, methylacetoacetate (0.81 g, 6.97 mmol) and 1,1-
dimethoxyethene (10) (0.67 g, 7.67 mmol) were stirred. After an
exothermic reaction, the tube was sealed and heated in a micro-
wave oven at 110 ꢀC for 30 min. Hydrazine hydrate (0.37 mL,
7.67 mmol) was cautiously added (exothermic reaction) and this
was stirred for 20 min. The resulting solid was dispersed in water
(50 mL), filtered and dried in open air (sublimation occurs under
vacuum at 50 ꢀC) to yield compound 22 (0.25 g, 23%) as a yellow
7.28 (m, 1H); 7.36 (m, 2H). 7.41 (m, 2H); 10.24 (s, 1H). 13C NMR
(100 MHz, DMSO-d6):
d
¼95.0; 125.1; 127.2; 129.1; 129.4; 129.6;
130.5; 133.5; 140.1; 142.3; 162.2. HRMS-ES: m/z [MþH]þ calcd for
35
C15
H ClN2O: 271.0638; found: 271.0573.
12
4.2.10. Isolation of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(4-
chlorophenyl)ethanone (31). In a 60 mL tube fitted with a Teflon-
covered screw cap, 1,1-dimethoxyethene (10) (0.78 g, 8.85 mmol)
powder. Mp 124 ꢀC 1H NMR (400 MHz, CDCl3):
d¼2.50 (s, 6H); 3.85
was added cautiously to 4-chlorobenzoylchloride (0.52
g
(s, 3H); 10.20 (s(br), 1H). 13C NMR (100 MHz, CDCl3):
d¼13.1; 50.9;
2.97 mmol). An exothermic reaction took place, the tube was closed
and this was stirred at room temperature for 1 h. The 2-
pyridylhydrazine (0.65 g, 5.95 mmol) was added, the tube was
closed again and the mixture was heated in an oil bath at 110 ꢀC for
20 min. The resulting mixture was purified by a chromatography
over silica gel (dichloromethane/ethanol 100/0 to 95/5) to yield
a fraction, which was further purified by a recrystallization in tol-
uene (40 mL) to give, with losses, compound 31 (0.14 g; 17%). Mp
109.1; 148.5; 164.9. HRMS-ES: m/z [MþH]þ calcd for C7H11N2O2:
155.0821; found: 155.0797.
4.2.7. 5-(4-Chlorophenyl)-3-methoxy-1H-pyrazole (25). In a 60 mL
tube fitted with a Teflon-covered screw cap, 1,1-dimethoxyethene
(10) (0.91 g, 10.32 mmol) was added cautiously to 4-
chlorobenzoylchloride (0.55 g 3.14 mmol). An exothermic re-
action took place, the tube was closed and this was stirred at room
temperature for 1 h. The 1H NMR spectra of a sample in DMSO-d6,
pointed out the occurrence of a singlet at 5.46 ppm along with the
disappearance of the signals corresponding to the chlorobenzoyl-
chloride (or the acid if water is present in the DMSO-d6). Hydrazine
hydrate (0.32 mL, 6.60 mmol) was added to the resulting pre-
cipitate, again an exothermic reaction was noted and this was
stirred for 15 min. The resulting solid was dispersed in water
(100 mL), filtered and dried in open air before dispersing it in
boiling cyclohexane (50 mL) upon cooling, this was filtered and
dried to yield compound 25 (0.42 g, 64%) as a white solid, an ad-
ditional less clean fraction was obtained upon concentration of the
246 ꢀC 1H NMR (400 MHz, DMSO-d6): ketone form:
6.94 (m, 1H); 7.38 (m, 1H); 7.68 (m, 2H); 7.77 (d, J¼9.3 Hz, 1H); 8.12
d
¼5.16 (s, 2H);
(m, 2H); 8.39 (d, J¼6.9 Hz, 1H); enol form: ¼7.10 (m, 2H); 7.45 (m,
d
1H); 7.58 (m, 2H); 7.83 (m, 1H); 7.99 (m, 2H); 8.84 (d, J¼7.0 Hz, 1H);
12.20 (s(l), 1H). 13C NMR (100 MHz, DMSO-d6), ketone form:
d
¼40.6; 118.3; 120.4; 129.7; 132.7; 134.1; 135.7; 139.6; 144.0; 147.2;
154.8; 198.8; enol form:
d¼87.5; 119.2; 120.8; 129.4; 132.2; 133.9;
138.2; 139.5; 152.2; 152.8; 162.7; one signal missing probably be-
cause of an insufficient overall solubility. Nota: 1H NMR experiment
at different temperature pointed out a variation of the ratio the
signals corresponding to the keto and enol form of compound 31.
35
HRMS-ES: m/z [MþH]þ calcd for C14
H
ClN3OþH: 272.0591; found:
11
filtrate (0.13 g). Mp 182 ꢀC 1H NMR (400 MHz, DMSO-d6):
d
¼3.83 (s,
272.0508.
3H); 6.20 (s, 1H); 7.52 (m, 2H); 7.75 (m, 2H); 12.43 (s, 1H). 13C NMR
(100 MHz, DMSO-d6):
d
¼56.3; 87.8; 117.6; 127.1; 128.9; 129.4;
4.2.11. 2-(5-(4-Chlorophenyl)-3-methoxy-1H-pyrazol-1-yl)pyridine
(32). In a 60 mL tube fitted with a Teflon-covered screw cap, 1,1-
dimethoxyethene (0.78 g, 8.85 mmol) was added cautiously to 4-
chlorobenzoylchloride (0.52 g 2.97 mmol). An exothermic re-
action took place, the tube was closed and this was stirred at room
temperature for 1 h. The 2-pyridylhydrazine (0.65 g, 5.95 mmol)
was added, the tube was closed again and the suspension was
stirred for 15 min. The resulting oil was diluted in dichloromethane
(40 mL), acidic alumina, from Merck, ref 1.01078, containing 1.5%
water (6 g) was added and the suspension was concentrated to
dryness. The resulting powder was boiled in toluene (50 mL) for
15 min, this was concentrated to dryness and the residue was
subjected to a chromatography over silica gel (dichloromethane/
ethanol 100/0 to 98/2) to yield a fraction, which was further puri-
fied by a chromatography over neutral alumina containing 1.5%
water (cyclohexane/ethyl acetate 96/4) to yield compound 32
(0.33 g, 39%) as an oil that slowly solidified. Mp 60 ꢀC 1H NMR
35
133.1; 142.2; 164.7. HRMS-ES: m/z [MþH]þ calcd for C10
H ClN2O:
10
209.0482; found: 209.0430.
4.2.8. 5-(4-Chlorophenyl)-3-methoxy-1-phenyl-1H-pyrazole (26). In
60 mL tube fitted with Teflon-covered screw cap, 1,1-
a
a
dimethoxyethene (10) (0.75 g, 8.57 mmol) was added cautiously
to 4-chlorobenzoylchloride (0.50 g 2.85 mmol). An exothermic re-
action took place, the tube was closed and this was stirred at room
temperature for 1 h. Phenylhydrazine (0.46 mL, 4.28 mmol) was
added and this was heated at 110 ꢀC for 45 min. The resulting oil
was purified by two consecutive chromatography, the first one over
silica gel (cyclohexane/ethyl acetate 95/5 to 9/1), the second one
over neutral alumina containing 1.5% water (cyclohexane/
dichloromethane from 95/5 to 75/25) to yield compound 26 as pale
yellow solid (0.44 g, 54%), an additional colored and less clean
fraction was also recovered (0.12 g). Mp 123 ꢀC 1H NMR (400 MHz,
CDCl3):
(m, 4H); 7.33 (m, 2H). 13C NMR (100 MHz, CDCl3):
125.0; 127.0; 128.7; 129.0; 129.1; 129.9; 134.5; 139.9; 143.1; 164.2.
d
¼4.00 (s, 3H); 5.97 (s, 1H); 7.17 (m, 2H); 7.25 (m, 1H); 7.27
(400 MHz, CDCl3):
2H); 7.29 (m, 2H); 7.50 (m, 1H); 7.74 (m, 1H); 8.28 (m, 1H). 13C NMR
(100 MHz, CDCl3):
¼56.3; 95.9; 117.7; 121.5; 128.3; 129.9; 130.0;
d
¼4.03 (s, 3H); 5.98 (s, 1H); 7.13 (m, 1H); 7.16 (m,
d
¼56.3; 93.6;
d

3170
E. Salanouve et al. / Tetrahedron 68 (2012) 3165e3171
134.3; 138.1; 144.1; 148.1; 152.4; 164.4. HRMS-ES: m/z [MþH]þ
138.9; 147.6; 152.8; 159.6 (J¼250 Hz); 164.2. HRMS: Calcd for
15H12FN3OþH: 270.1043; found: 270.0976.
35
calcd for C15
H
ClN3O: 286.0747; found: 286.0650.
C
13
Using the same protocol, the following 3-methoxypyrazoles
were obtained.
4.2.18. 2-(3-Methoxy-5-(3-fluorophenyl)-1H-pyrazol-1-yl)pyridine
(37g). This compound was obtained as an oil in 15% yield after
a chromatography over silica gel (dichloromethane/ethanol 99/1)
followed by a chromatography over alumina containing 1.5% water
(cyclohexane/ethyl acetate 95/5). 1H NMR (CDCl3): 4.02 (s, 3H);
6.00 (s, 1H); 7.05 (m, 3H); 7.15 (m, 1H); 7.27 (m, 1H); 7.51 (m, 1H);
7.73 (m, 1H); 8.28 (m, 1H). 13C NMR (CDCl3): 56.3; 96.1; 115.1
(J¼21 Hz); 115.7 (J¼23 Hz); 117.7; 121.6; 124.4; 129.6; 133.3; 138.1;
143.9; 148.1; 152.3; 162.4 (J¼245 Hz); 164.3. HRMS: Calcd for
C15H12FN3OþH: 270.1043; found: 270.0981.
4.2.12. 2-(3-Methoxy-5-phenyl-1H-pyrazol-1-yl)pyridine
(37a). This compound was obtained as an oil in 35% yield after
a chromatography over silica gel (dichloromethane/ethanol 99/1)
followed by a chromatography over alumina containing 1.5% water
(cyclohexane/ethyl acetate 95/5). 1H NMR (CDCl3): 4.04 (s, 3H);
6.00 (s, 1H); 7.13 (m, 1H); 7.32 (m, 5H); 7.38 (m, 1H); 7.69 (m, 1H);
8.33 (m, 1H). 13C NMR (CDCl3): 56.3; 95.6; 118.2; 121.5; 128.2;
128.3; 128.7; 131.2; 138.0; 145.3; 148.3; 152.4; 164.4. HRMS: Calcd
for C15H13N3OþH: 252.1137; found: 252.1063.
4.2.19. 2-(3-Methoxy-5-(4-fluorophenyl)-1H-pyrazol-1-yl)pyridine
(37h). This compound was obtained as a yellow solid in 21% yield
after a chromatography over silica gel (dichloromethane/ethanol
97/3) followed by a chromatography over alumina containing 1.5%
water (cyclohexane/ethyl acetate 95/5). Mp¼75 ꢀC 1H NMR (CDCl3):
4.03 (s, 3H); 5.97 (s, 1H); 7.02 (m, 2H); 7.13 (m, 1H); 7.27 (m, 2H);
7.46 (m, 1H); 7.72 (m, 1H); 8.31 (m, 1H). 13C NMR (CDCl3): 56.2;
95.8; 115.1 (J¼22 Hz); 117.8; 121.5; 127.5; 130.5; 138.1; 144.3; 148.1;
152.4; 162.7 (J¼248 Hz); 164.3. Calcd for C15H12FN3OþH: 270.1043;
found: 270.0993.
4.2.13. 2-(5-Benzyl-3-methoxy-1H-pyrazol-1-yl)pyridine (37b). This
compound was obtained as an oil in 27% yield after a chromatog-
raphy over silica gel (dichloromethane/ethanol 99/1) followed by
a chromatography over alumina containing 1.5% water (cyclohex-
ane/ethyl acetate 96/4). 1H NMR (CDCl3): 3.94 (s, 3H); 4.54 (s, 2H);
5.51 (s, 1H); 7.09 (m, 1H); 7.28 (m, 5H); 7.73 (m, 1H); 7.81 (m, 1H);
8.37 (m, 1H). 13C NMR (CDCl3): 34.9; 56.0; 95.9; 115.0; 120.1; 126.3;
128.3; 129.1; 138.2; 138.7; 146.3; 147.2; 153.6; 163.8. HRMS: Calcd
for C16H15N3OþH: 266.1293; found: 266.1208.
4.2.14. 2-(3-Methoxy-5-phenethyl-1H-pyrazol-1-yl)pyridine
(37c). This compound was obtained as an oil in 11% yield after
a chromatography over silica gel (dichloromethane/ethanol 99/1)
followed by a chromatography over alumina containing 1.5% water
(cyclohexane/ethyl acetate 9/1). 1H NMR (CDCl3): 3.04 (m, 1H); 3.48
(m, 2H); 3.99 (s, 3H); 5.75 (s, 1H); 7.12 (m, 1H); 7.29 (m, 5H); 7.77
(m, 1H); 7.86 (m, 1H); 8.42 (m, 1H). 13C NMR (CDCl3): 30.5; 35.3;
56.0; 94.7; 115.1; 120.1; 126.0; 128.4; 128.5; 138.2; 141.6; 146.9;
147.3; 153.7; 163.9. HRMS: Calcd for C17H17N3OþH: 280.1450;
found: 280.1450.
4.2.20. 2-(3-Methoxy-5-(3-(trifluoromethyl)phenyl)-1H-pyrazol-1-
yl)pyridine (37j). This compound was obtained as a wax in 26%
yield after a chromatography over silica gel (dichloromethane/
ethanol 99/1) followed by a chromatography over alumina con-
taining 1.5% water (cyclohexane/ethyl acetate 95/5). 1H NMR
(CDCl3): 4.03 (s, 3H); 6.04 (s, 1H); 7.13 (m, 1H); 7.58 (m, 2H); 7.61
(m, 3H); 7.75 (m, 1H); 8.21 (m, 1H). 13C NMR (CDCl3): 56.3; 96.4;
117.2; 121.6; 124.0 (J¼276 Hz); 124.7; 125.7; 128.4; 130.4 (J¼35 Hz);
132.0; 132.3; 138.3; 143.7; 147.8; 152.3; 164.3. HRMS: Calcd for
C16H12F3N3OþH: 320.1011; found: 320.1029.
4.2.15. 2-(3-Methoxy-5-(2-methoxyphenyl)-1H-pyrazol-1-yl)pyri-
dine (37d). This compound was obtained, following 1 h at 60 ꢀC to
achieve the completion of the first step described above, as an oil in
24% yield after a chromatography over silica gel (dichloromethane/
ethanol 99/1) followed by a chromatography over alumina con-
taining 1.5% water (cyclohexane/ethyl acetate 95/5). 1H NMR
(CDCl3): 3.36 (s, 3H); 4.03 (s, 3H); 5.95 (s,1H); 6.79 (m,1H); 6.99 (m,
1H); 7.03 (m, 1H); 7.34 (m, 2H); 7.45 (m, 1H); 7.66 (m, 1H); 8.20 (m,
1H). 13C NMR (CDCl3): 54.8; 56.2; 96.1; 110.7; 116.1; 120.6; 120.7;
121.2; 130.1; 130.4; 137.6; 141.8; 147.7; 153.3; 156.4; 164.3. HRMS:
Calcd for C16H15N3O2þH: 282.1243; found: 282.1173.
4.2.21. 2-(3-Methoxy-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-1-
yl)pyridine (37k). This compound was obtained as a solid in 52%
yield after a chromatography over silica gel (dichloromethane/
ethanol 99/1) followed by a chromatography over alumina con-
taining 1.5% water (cyclohexane/ethyl acetate 95/5). Mp¼71 ꢀC 1H
NMR (CDCl3): 4.04 (s, 3H); 6.04 (s, 1H); 7.13 (m, 1H); 7.42 (d, 2H,
J¼8.0 Hz); 7.61 (m, 3H); 7.75 (m,1H); 8.21 (m, 1H). 13C NMR (CDCl3):
56.3; 96.5; 117.4; 121.6; 124.0 (J¼273 Hz); 125.0; 129.0; 130.1
(J¼33 Hz); 135.1; 138.3; 143.7; 148.0; 152.3; 164.3. HRMS: Calcd for
C16H12F3N3OþH: 320.1011; found: 320.0954.
4.2.22. 2-(5-(4-Chlorophenyl)-3-ethoxy-1H-pyrazol-1-yl)pyridine
(35). In a Biotage tube, compound 344 (0.33 g, 1.04 mmol), cesium
carbonate (1.36 g, 4.19 mmol) and 4-chlorophenylboronic acid
(0.36 g, 2.30 mmol) were dispersed in dimethylformamide (16 mL,
4.2.16. 2-(3-Methoxy-5-(2-chlorophenyl)-1H-pyrazol-1-yl)pyridine
(37e). This compound was obtained as an oil in 30% yield after
a chromatography over silica gel (dichloromethane/ethanol 92/8)
followed by a chromatography over alumina containing 1.5% water
(cyclohexane/dichloromethane 2/1). 1H NMR (CDCl3): 4.05 (s, 3H);
5.97 (s, 1H); 7.02 (m, 1H); 7.30 (m, 2H); 7.38 (m, 2H); 7.67 (m, 2H);
8.06 (m, 1H). 13C NMR (CDCl3): 56.3; 97.0; 115.3; 120.7; 126.4;
129.3; 129.6; 131.2; 132.0; 133.7; 137.9; 141.7; 147.6; 152.6; 164.0.
HRMS: Calcd for C15H12ClN3OþH: 286.0747; found: 286.0682.
ꢁ
dried over 4 A molecular sieve). The suspension was degassed with
a slow stream of argon and a pre-milled 1:2 mixture of palladiu-
m(II) acetate and XPhos (0.06 g, 0.05 mmol) was added. This was
sealed and heated using a microwave oven for 140 ꢀC for 3 h. The
resulting suspension was diluted in ethyl acetate (80 mL), the or-
ganic layer was washed with water (4ꢂ40 mL) and brine (20 mL),
dried over magnesium sulfate and concentrated under vacuum. The
resulting residue was then purified a chromatography over silica
gel (cyclohexane/ethyl acetate 95:5 to 9/1) to give compound 35
(0.12 g, 38%) as an oil. Nota: a fair amount of unreacted iodopyrazole
34 (0.11 g, 33%) and the corresponding reduced compound4 (0.02 g,
9.6%) were also recovered in the course of this chromatography. 1H
4.2.17. 2-(3-Methoxy-5-(2-fluorophenyl)-1H-pyrazol-1-yl)pyridine
(37f). This compound was obtained as a wax in 20% yield after
a chromatography over silica gel (dichloromethane/ethanol 99/1)
followed by a chromatography over alumina containing 1.5% water
(cyclohexane/ethyl acetate 95/5). 1H NMR (CDCl3): 4.04 (s, 3H);
6.02 (s, 1H); 7.02 (m, 1H); 7.07 (m, 1H); 7.17 (m, 1H); 7.36 (m, 2H);
7.66 (m, 1H); 7.73 (m, 1H); 8.15 (m, 1H). 13C NMR (CDCl3): 56.3; 97.0;
115.4 (J¼22 Hz); 115.9; 120.4; 121.0; 123.8; 130.2; 130.6; 138.0;
NMR (400 MHz, CDCl3):
2H); 5.96 (s, 1H); 7.12 (m, 1H); 7.22 (m, 2H); 7.31 (m, 2H); 7.52 (m,
1H); 7.73 (m, 1H); 8.25 (m, 1H). 13C NMR (100 MHz, CDCl3):
¼14.8;
d¼1.42 (t, J¼7.1 Hz, 3H); 4.34 (d, J¼7.1 Hz,
d

E. Salanouve et al. / Tetrahedron 68 (2012) 3165e3171
3171
64.8; 96.2; 117.6; 121.4; 128.3; 130.0 (two signals); 134.2; 138.1;
3.95 (s, 3H); 5.81 (s, 1H); 7.36 (m, 2H); 7.70 (m, 2H). 13C NMR
143.9; 148.0; 152.4; 163.8. HRMS-ES: m/z [MþH]þ calcd for
(100 MHz, CDCl3):
d
¼33.7; 58.6; 81.5; 126.4; 128.6; 132.4; 133.2;
35
35
C16H
ClN3O: 300.0904; found: 300.0872.
148.1; 156.2. HRMS-ES: m/z [MþH]þ calcd for C11
H ClN2O:
12
15
223.0638; found: 223.0595.
4.2.23. 5-(4-Chlorophenyl)-1-(pyridin-2-yl)-1H-pyrazol-3(2H)-one
(33). By using exactly the same protocol described above for the
synthesis of 27, either from the 3-methoxypyrazole 32 or from the
3-ethoxypyrazole 35 (0.1 g, 0.33 mmol), compound 33 was ob-
tained as a white powder (0.06 g, 79%). Mp 261 ꢀC 1H NMR
Acknowledgements
This work was supported by the Medicen initiative (Chemical
Library Project; grant of the Region Ile de France n I 06-222/R and I
09-1739/R, which included a fellowship for S.G.) and a grant from
the DARRI (Institut Pasteur). Dr. Daniel Larzul as well as Dr. Emile
Bisagni are also acknowledged for their interest and support.
ꢀ
(400 MHz, DMSO-d6):
7.61 (d, J¼8.2 Hz, 1H); 7.92 (m, 1H); 8.16 (m, 1H); 10.39 (s(br), 1H).
13C NMR (100 MHz, DMSO-d6):
¼97.1; 117.6; 122.2; 128.5; 130.5;
d¼5.99 (s, 1H); 7.24 (m, 3H); 7.39 (m, 2H);
d
130.7; 133.1; 139.3; 143.4; 147.9; 152.5; 162.4. HRMS-ES: m/z
35
[MþH]þ calcd for C14
H ClN3O: 272.0591; found: 272.0542.
11
References and notes
4.3. Arylation of methoxypyrazole 25 using Taillefer and
Cristau method
1. Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Synthesis 2008, 3504e3508.
2. Guillou, S.; Nesme, O.; Ermolenko, M. S.; Janin, Y. L. Tetrahedron 2009, 65,
3529e3535.
3. Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Tetrahedron 2009, 65, 2660e2668.
4. Guillou, S.; Janin, Y. L. Chem. Eur. J. 2010, 16, 4669e4677.
5. Guillou, S.; Bonhomme, F. J.; Chahine, D.; Nesme, O.; Janin, Y. L. Tetrahedron
2010, 66, 2654e2663.
6. Salanouve, E.; Retailleau, P.; Janin, Y. L. Tetrahedron 2012, 68, 2135e2140.
7. Guillou, S.; Bonhomme, F. J.; Ermolenko, M. S.; Janin, Y. L. Tetrahedron 2011, 67,
8451e8457.
In a 20 mL Biotage tube compound 25 (0.54 g, 2.58 mmol), 2-
bromopyridine (0.27 mL, 2.84 mmol), cesium carbonate (0.93 g,
0
ꢁ
2.84.5 mmol), 4 A molecular sieves (0.4 g, 3.2 mm pellets), [N,N -
bis-((20-pyridine)-methylene)]-1,2-diaminocyclohexane28 (0.075 g,
ꢁ
0.24 mmol) were dispersed in acetonitrile (10 mL, dried over 4 A
molecular sieves). This was degassed using a slow stream of argon
bubbling in the suspension. Copper oxide (0.018 g, 0.12 mmol) was
then added and the tube was sealed. This was shaken thoroughly,
heated for 30 s in the microwave oven at 100 ꢀC and shaken again.
At this stage the pink copper oxide is well dissolved in the reaction
mixture; if not, another 30 s heating at 100 ꢀC is required. The
heating is then resumed at 180 ꢀC for 2 h. The crude reaction
mixture was concentrated to dryness and directly purified by a first
chromatography over alumina containing 1.5% of water (cyclo-
hexane/ethyl acetate from 99/1 to 9/1). This led, in order of elution,
to a fraction containing compound 39, 40, and 31 and a second one
containing pure compound 38 (0.09 g, 12). The first fraction was
subjected to a second chromatography over silica gel (cyclohexane/
dichloromethane from 1/2 to 0/1) to yield, in order of elution,
compound 40 (0.05 g, 8.6%), compound 39 (0.02 g, 3.4%) and
compound 31 (0.12 g, 14.8%) as described above.
8. Middleton, W. J.; Engelhardt, V. A. J. Am. Chem. Soc. 1958, 80, 2829e2832.
9. Chauhan, S. M. S.; Junjappa, H. Synthesis 1975, 798e801.
10. Martins, M. A. P.; Pereira, C. M. P.; Zimmermann, N. E. K.; Cunico, W.; Moura, S.;
Beck, P.; Zanatta, N.; Bonacorso, H. G. J. Fluorine Chem. 2003, 123, 261e265.
11. Neidlen, R.; Kikelj, D.; Kramer, W. J. Heterocycl. Chem. 1989, 26, 1335e1340.
12. Stachel, H.-D.; Papenberg, G. Arch. Pharmacol. 1981, 314, 65e71.
13. Porter, H.D.; Weissberger, A.; Gregory, W.A. U.S. Patent 2,439,098.
14. Tang, F. Patent CN 2006-10012859.
15. Morita, Y.; Samejima, Y.; Shimada, S. Patent JP 7372176.
16. Martins, M. A. P.; Cunico, W.; Brondani, S.; Peres, R. L.; Zimmermann, N.; Rosa,
F. A.; Fiss, G. F.; Zanatta, N.; Bonacorso, H. G. Synthesis 2006, 1485e1493.
17. Hojo, M.; Masuda, R.; Okada, E. Synthesis 1986, 1013e1014.
18. Guenther, K.; Mau, G. U.S. Patent 4,825,008.
19. Guenther, K. U.S. Patent 4967012.
20. Nesmeyanov, A. N.; Reutov, O. A.; Gudkova, A. S. Izv. Akad. Nauk. SSSR, Ser. Khim
1961, 260e264.
21. Pochat, F.; Levas, E. Bull. Soc. Chim. Fr. 1972, 8, 3151e3156.
22. Banville, J.; Brassard, P. J. Chem. Soc., Perkin Trans. I 1976, 1852e1856.
23. McElvain, S. M.; Kundiger, D. J. Am. Chem. Soc. 1942, 64, 254e259.
24. McElvain, S. M.; McKay, G. R. J. Am. Chem. Soc. 1956, 78, 6086e6091.
25. Opitz, G.; Zimmermann, F. Chem. Ber. 1964, 97, 1266e1274.
26. Varvounis, G.; Fiamegos, Y.; Pilidis, G. Pyrazol-3-ones, part 1: synthesis and
applications In; Katritzky, A. R., Ed. . Adv. Heterocyclic Chem.; Academic: 2001;
vol. 80, pp 74e144.
4.3.1. 2-(3-(4-Chlorophenyl)-5-methoxy-1H-pyrazol-1-yl)pyridine
(38). Obtained as a solid. Mp 76 ꢀC 1H NMR (400 MHz, CDCl3):
d
¼4.08 (s, 3H); 6.04 (s, 1H); 7.25 (m, 1H); 7.42 (m, 2H); 7.82 (m, 4H);
27. Stanovik, E.; Svete, J. Product class 1: pyrazoles In; Neier, R., Ed. . Science of
Synthesis; Thieme: 2002; vol. 12, pp 15e225.
28. Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.; Taillefer, M. Org. Lett. 2004,
6, 913e916.
29. Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chem.dEur. J. 2004, 10,
5607e5622.
8.61 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
¼59.4; 84.1; 116.7; 121.5;
127.0; 128.7; 131.6; 134.1; 138.2; 148.6; 150.4; 151.5; 157.2. HRMS-
35
ES: m/z [MþH]þ calcd for C15
H ClN3O: 286.0747; found: 286.0698.
13
30. Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Eur. J. Org. Chem. 2004,
695e709.
31. Jasserand, D.; Christen, M.-O.; Biard, D.; Yavordios, D. U.S. Patent 4672063.
32. McElvain, S. M.; Anthes, H. I.; Shapiro, S. H. J. Am. Chem. Soc. 1942, 64,
2525e2531.
33. McElvain, S. M.; McShane, H. F. J. Am. Chem. Soc. 1952, 74, 2662e2667.
34. McElvain, S. M.; Kundiger, D. Org. Synth. Coll. Vol. III; 1955, 506e508.
35. Taskinen, E.; Pentikainen, M. L. Tetrahedron 1978, 34, 2365e2370.
36. Dehmlow, E. V.; Veretenov, A. L. Synthesis 1992, 939e940.
37. Argade, A. B.; Joglekar, B. R. Synth. Commun. 1993, 23, 1979e1984.
38. Zheng, Q.-H.; Su, J. Synth. Commun. 1999, 29, 3467e3476.
39. Kesteleyn, B.; De Kimpe, N. J. Org. Chem. 2000, 65, 635e639.
4.3.2. 5-(4-Chlorophenyl)-3-methoxy-1-methyl-1H-pyrazole
(39). Obtained as a solid. Mp 51 ꢀC 1H NMR (400 MHz, CDCl3):
d
¼3.71 (s, 3H); 3.91 (s, 3H); 5.72 (s, 1H); 7.34 (m, 2H); 7.42 (m, 2H).
13C NMR (100 MHz, CDCl3):
d
¼36.9; 56.2; 90.5; 128.9; 129.1; 130.0;
35
134.7; 144.0; 163.0. HRMS-ES: m/z [MþH]þ calcd for C11
H ClN2O:
12
223.0638; found: 223.0583.
4.3.3. 3-(4-Chlorophenyl)-5-methoxy-1-methyl-1H-pyrazole
(40). Obtained as an oil. 1H NMR (400 MHz, CDCl3):
¼3.69 (s, 3H);
d