N-arylation of 3-alkoxypyrazoles, the case of the pyridines

Full text of DOI:10.1016/j.tet.2010.02.032

Tetrahedron 66 (2010) 2654–2663
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-arylation of 3-alkoxypyrazoles, the case of the pyridines
*
´ ´
Sandrine Guillou, Frederic J. Bonhomme, Di Betina Chahine, Olivier Nesme, Yves L. Janin
Institut Pasteur, URA 2128 CNRS-Institut Pasteur, 28 rue du Dr. Roux, F 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:
In the course of a research program focused on the preparation of libraries of new chemical entities
derived from 3-alkoxypyrazoles, we studied their N-pyridylation using 2, 3 or 4-bromopyridines. This
was achieved using Cristau and Taillefer copper-catalyzed arylation method and mostly led to the 3-
alkoxy-1H-pyrazol-1-yl pyridine isomer along with lesser amount of the alternative 5-alkoxy-1H-pyr-
azol-1-yl pyridine. The structures of these isomers were often established via their chemical trans-
formations and sometimes recourse to unambiguous synthetic routes for comparison purposes. The
alternative use of 2-fluoropyridine-based arylation was also investigated and lifted some of the limita-
tions encountered in the course of this study.
Received 16 December 2009
Received in revised form 30 January 2010
Accepted 4 February 2010
Available online 10 February 2010
Keywords:
3-Alkoxypyrazole
Copper-catalyzed N-arylation
Microwave-assisted synthesis
Ó 2010 Elsevier Ltd. All rights reserved.
In the course of our preparation of new chemical entities,1–3 we
recently described2 the regioselectivity of the N-arylations of
readily available 3-alkoxypyrazoles1 using Lam and Chan
arylboronic-based reaction catalyzed by copper acetate.4–8 We wish
to report here investigations aiming at the introduction of a 2, 3
or 4 pyridyl moiety on various 3-alkoxypyrazoles. As only 3-
-pyridylboronates have been successfully used with the Lam and
Chan approach, we focused here on the use of various halogenated
pyridines under the optimized Ullmann-based N-arylation
method9–18 reported by Cristau and Taillefer.19,20 Scheme 1 depicts
such pyridylation from 3-isopropyloxypyrazole 1 and the three
possible bromopyridines 2a–c. The preparation of the isomeric
pairs of N-pyridyl derivatives 3a–c and 4a–c was initially possible
only if extensive heating was used, we thus resorted to the use of
a microwave oven in an attempt to shorten this. Few control
experiments with either 2- or 4-halogeno pyridines pointed out the
need for copper in these reaction as of only traces amount of
N-pyridyl derivatives were detected by LC/MS. In our experience
with such reactions,21 we suggest that deprotonation of the
substrate is required. This is probably less easy for alkoxypyrazoles
than for other pyrazole derivatives.22–24 In the course of optimi-
zation trials, 2-pyridinyloxybenzonitriles occurrence was observed
when using salicylaldoxime 5 as the copper ligand.19,20 On the
other hand, the use of the more elaborated [N,N0-bis-((20-pyridine)-
methylene)]-1,2-diaminocyclohexane (6)25 avoided this bisaryl-
ether occurrence and led to better yield of compounds 3a–c and
4a–c. Amongst the salient fact of this optimization work, we found
N
H
N
N
N
N
O
i or ii
N
N
N
+
+
N
Br
O
3a-c 4a-c
1
2a-c
O
OH
N
t (h)
2
2a-c
% 3 % 4
a
2-BrC5H4N
3-BrC5H4N
53 25
OH
b
b
c
c
5
2
13
30
8
5
2
N
N
N
6
"
26
2
4-BrC5H4N
N
6
17 10
"
6
Scheme 1. (i) or (ii): Cu2O, Cs2CO3, ligand 6, 4 Å molecular sieves, MeCN, MW 180 ꢀC, 2
(or 6) hours.
that addition of small amount of 4 Å molecular sieves was essential
for these reactions to proceed in dry acetonitrile. Aside from this,
a most crucial feature in this reaction is a proper dissolution of the
copper I oxide added. Upon the addition of this reagent, an
insoluble pink foam is usually formed. It is only when this foam is
dissolved that reproducible yield of N-pyridylation is obtained. This
was routinely achieved by a very short (30 s) heating of the sealed
vessel at 100 ꢀC in a microwave reactor followed by a thorough
shaking before heating at 180 ꢀC for 2 h. The LC/MS monitoring of
* Corresponding author.
E-mail address: yves.janin@pasteur.fr (Y.L. Janin).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.032

S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
2655
reaction trials using lower temperature or shorter reaction time
proved that such parameters were necessary, in the case of
2-bromopyridine (2a). The use of acetonitrile was found to be the
best as dimethylformamide led to the occurrence of small amount
of dimethylaminopyridines. Interestingly, if the reaction could be
brought to completion with 2-bromopyridine in 2 h at 180 ꢀC, this
was not the case when using 3 or 4-bromopyridine as much
starting material could be recovered. An increase of the reaction
duration led to the disappearance of the starting material 1 and
lesser amount of isomers 4b, and 4c, which are probably not too
stable under the reaction conditions. In effect this led to an ap-
parent inversion of the N-arylation ratio. An improvement (up to
49% for 3c along with 18% of compound 4c) was obtained for the
preparation of compounds 3c/4c when using the readily available
4-iodopyridine26 instead of 4-bromopyridine 2c.
insights in copper-catalyzed N-arylation mechanisms. From the
labile 5-iodinated compound 11k a similar reduction was seen
although along with extensive decomposition and only traces of the
reduced material 3a were detected. Interestingly, extensive
decomposition was the sole result seen when trying to arylate the
trifluoromethyl derivative 10b. From the ethoxy pyrazole 10c, the
proportion of the pyridyl isomers 11c and 12c obtained (55 and 26%)
was fairly identical with the one obtained from the isopropyloxy
derivative 1. From the 4-fluoro derivative 10d, no fluorine reduction
was observed and isomers 11d and 12d were isolated in 67% and 9%
yield, respectively. From the 5-phenyl derivative 10e, a close to 1/1
ratio of the isomers 11e and 12e was observed. Such ratio from 10e
was unexpected. We previously observed that the N-arylation of 10e
using 4-chlorophenylboronic acid at room temperature leads to 2%
of the isomer 13 as well as 83% of compound 14.2 On the other hand,
As depicted in Scheme 2, the structural assignments of the
isomeric pairs 3a–c and 4a–c were made after an acidic cleavage of
their isopropyloxy group to give compounds 7a–c and 8a–c. This
was achieved in 60 mL sealed tubes with a small amount of 33%
hydrogen bromide in acetic acid (1–2 mL) at 140 ꢀC. It was quickly
found that the exclusion of air was important to obtain the pyrazol-
5-ones 8b and 8c. For the preparation of the isomer 8a, as well as
for 8c, the reaction duration had to be shortened and its temper-
ature had to be lowered to 100 ꢀC. Indeed, isomer 8a is fairly
unstable and refluxing a sample in 2 N hydrochloric acid for 1 h
led to an unreported pyrazole ring opening, followed by
a decarboxylation, and thus to 55% of hydrazone 9. The NMR study
(in CDCl3) of compounds 8b and 8c displayed 1H NMR and 13C NMR
spectra featuring a methylene signal only compatible with the
1H-pyrazol-5(4H)-ones tautomers depicted in Scheme 1. From this,
we could then determine the structure of the parent compounds
3b–c and 4b–c. In the case of 8a, because of an internal hydrogen
bond, the 1H NMR and 13C NMR spectra do not feature a methylene
signal in any solvent tried.27 A structural assignment could still be
made as compound 8a has been prepared in the past, from the
condensation of 2-hydrazinopyridine and ethyl acetoacetate.28
More thorough studies of the tautomeric forms of some pyrazol-
3-ones adopted in solution have also been reported.29,30
as depicted, a control reaction between compound 10e and
4-chloroiodobenzene under the present conditions led to a change
in this ratio as compound 13 and its isomers 14 were isolated in 15%
and 49% yield, respectively. Since one of the biggest difference in
these reactions lies in the temperature (25 ꢀC vs 180 ꢀC), this
suggests an increase of the freedom of rotation of the 5-phenyl bond.
N
H
N
N
N
R1O
R3
R3
R2
i, 2a
N
N
N
N
+
R2
R2
R3
R1O
R1O
10a-l
11a-l
12a-l
N
ii
N
O
I
3a
N
11a (98%)
Cl
Cl
iii
10e
N N
N N
+
OEt
EtO
13 (15%)
14 (49%)
a: 2-pyridyl
R1
iPr
Et
Et
Et
Et
Et
Et
R2
I
H
H
F
H
H
Ph
R3
Me
CF3
Me
Me
Ph
CH2Ph
Me
Me
H
%11* %12*
reduction of 10a
decomposition
N
H
i
i
N
b: 3-pyridyl
c: 4-pyridyl
a
b
c
d
e
f
g
h
i
N
3a-c
O
7a-c
55
67
36
41
79
66
72
70
26
9
41
25
5
N
ii
(from 8a)
N
N
N
4a-c
N N
H
O
9 (55 %)
Et CH2Ph
7
8a-c
Scheme 2. (i): HBr–AcOH 140 ꢀC (or 100 ꢀC). (ii): 2 N HCl, reflux.
Et
Et
Et
Et
CO2Et
traces
traces
j
k
l
H
H
H
H
I
decomposition
7**
As depicted in Scheme 3, further reactions were studied from
2-bromopyridine (2a) and the 3-ethoxypyrazoles 10a–k, previously
reported1,2,31 or prepared as described in the Experimental part. Few
remarkable facts were noticed in this study. Reaction with the
4-iododerivative 10a led to the isolation of 45% of the reduced
N-pyridyl compound 3a. However, this difficulty was circumvented
as 4-iodo isomer 11a was obtained in an excellent 98% yield by
iodination of 2a using N-iodosuccinimide in cyclohexane in
a microwave oven. Interestingly, this kind of reduction has been
reported recently in the course of a copper-catalyzed arylation of
pyrazole using 1,2-diiodobenzene.32 Such phenomenon, along with
a room temperature reduction we recently observed,31 do provide
CH2CO2Et
*: isolated yields. **: 17 % of 11c were also isolated
Scheme 3. (i): Cu2O, Cs2CO3, ligand 6, 4 Å molecular sieves, MeCN, MW 180 ꢀC, 2 h.
(ii): NIS, cyclohexane, MW 140 ꢀC, 45 min. (iii): conditions i, using 4-ClC6H4I.
This would lessen eventual hindrance and/or electronic effect,
provided by conjugation, which could be precluding the arylation on
the neighboring nitrogen at room temperature to give the isomer 13.
From the less hindered 5-benzyl pyrazole 10f, a lesser amount of
the pyridyl isomer 12f was obtained. Moreover, from the 4-phenyl,

2656
S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
the 4-benzyl or the 4-ethoxycarbonyl derivatives 10g–i, the
N-pyridylation ratio is similar to the ones observed using arylboronic
acids.2,31
As depicted in Scheme 4, when sufficient amount of the
N-pyridyl derivatives was obtained, their ethyl ether cleavage was
undertaken to give compounds 15c–j or 16e–g. In these instances,
out the occurrence of compound 11cdand none of 12cdalong with
unidentified material, thus establishing the structure of 11l.
Aside for the previously described compound 15j33, which gave,
directly or indirectly, the basis for the structures assignments of
compounds 11i, 11j as well as 17 and 18, the lack of precedent in the
literature or easily obtained NMR NOE effects, led us to attempt
unambiguous chemical synthesis. Accordingly as depicted in
Scheme 5, we undertook the condensation of 2-hydrazinopyridine
N
H
N
(19) and various
b-ketoesters (20d–h) to obtain the 1-(pyridin-2-
i or ii
i or ii
O
yl)-1H-pyrazol-5-ol isomers 16d–h. From the
b
-ketoesters 20e, 20g
N
11a-l
12a-l
or 20h, the 1H-pyrazol-5-ols 16e, 16g or 16h were prepared with
little trouble although in the case of compound 16e, the reaction
15d-j
16e-f
R3
R2
N
R3
R2
N
N
HO
O
O
H
N
N
N
N
NH2
EtO
R3
i
N
N
+
O
N
iii
N
HO
R2
N
N
R2
O
N
i
HO
19
20d-h
R3
17
11i
O
11j
R2
R3
Me
Ph
Me
Me
% 16
0%, see text
ii
16d-h
H
N
N
O
F
H
d
N
e
g
h
HO
90
69
70
O
18
Ph
CH2Ph
R2
R3
%15
%16
H
F
H
H
Ph
CH2Ph
CO2Et
H
Me
Me
Ph
CH2Ph
Me
Me
H
45 (7a)*
72
c
d
e
f
g
h
i
Scheme 5. (i): AcOH, MW 100 ꢀC or 25 ꢀC (see text).
64
55
69
88
see text
84
29**
39
-
-
-
had to be made at room temperature to avoid an extensive de-
composition. However, from ethyl 2-fluoroacetoacetate 20d, many
attempts only led to decomposition. The LC/MS monitoring of a trial
at room temperature in ethanol pointed out the possible occur-
rence of uncyclized material (m/z¼240) but, again, extensive
decomposition was observed when further purification or heating
was attempted in either neutral, basic or acidic conditions.
Related difficulties have actually been reported in the past in other
cases.34–36 Moreover, attempts to fluorinate compound 11c were
surprisingly devoid of success. Further NMR studies pointed out the
unexpectedly large values of the hydrogen’s T1 (i.e., between 2 and
3 s for compound 11c) for this type compounds and only led to
useful NOESY spectra only at the frequency of 600 MHz. However,
in recording the spectrum at 400 MHz, we found that the use of 1D
measurement with degassed samples (by bubbling argon through
the solution) led to good NOE effects. Thus, for isomers 11c as for
11d, the similar NOE seen between their methyl moieties and the
2-pyridyl protons H6 and H3 established the structure of 11d.
Since the trifluoromethyl-bearing derivative 10b, or the iodine-
bearing compounds 10k, could not be successfully subjected to the
2-pyridylation conditions described above, we look for alternatives.
Scheme 6 depicts our trials using the reported use of 2-fluoropyr-
idine under basic condition and heating.37,38 Initial optimization
trials led us to heat compound 10c, 2-fluoropyridine, and cesium
carbonate without any solvent at 180 ꢀC for 2 h and gave 56% of
isomer 11c along with only traces of isomer 12c, which also appears
to be unstable under these reaction conditions. From compound
10k, 2 h of reaction turned out to lead to only small amount of the
isomers 11k and 12k along with extensive decomposition. How-
ever, shortening the reaction time down to 15 min and lowering the
reaction temperature to 160 ꢀC improved the matter and isomers
11k and 12k were obtained in 24 and 24% yield, respectively. From
the trifluoromethyl derivative 10b, 180 ꢀC for 15 min led to traces
H
-
j
*: 7 days of reaction; 45 % of 11c were recovered.
**: 32 % of 12e were recovered.
Scheme 4. (i): HBr–AcOH, 140 ꢀC. (ii): BBr3, CH2Cl2, 25 ꢀC, 48 h. (iii): Cu2O, phenan-
throline, Cs2CO3, DMF, MW, 200 ꢀC 2 h.
1 M boron tribromide in dichloromethane at room temperature
was used in an attempt to alleviate the decomposition trend
observed when using hydrobromic acid in acetic acid at 140 ꢀC. As
seen from the yield of compounds 16e–g, this met a limited success
and we also observed the occurrence of strongly colored but
intractable material. In few cases, 48 h at room temperature was
not enough for a complete hydrolysis. Increasing the reaction time
to 7 days, in the case of 11c, only led to 45% of the hydrolysis
product 7a along with 45% of starting material. For this reason, we
resorted to hydrogen bromide in acetic acid at 140 ꢀC in the case of
11g. Treatment of compound 11i with hydrogen bromide in acetic
acid at 140 ꢀC only gave the 3-ethoxy acid 17, which, as described in
the experimental part, can also be obtained by saponification of 11i.
The use of boron tribromide on 11i, allowed the isolation of the
corresponding pyrazole-3-one 18 in 34% yield. The decarboxylation
of acid 17 actually required rather harsh condition (200 ꢀC) and led
to compound 11j in a 71% yield, this result establishing the struc-
ture of 11i. Finally, upon saponification of ester 11l, the corre-
sponding acid was obtained. The 1H NMR monitoring of a sample of
this acid heated in a Kugelrohr at 240 ꢀC for up to 15 min pointed

S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
2657
amount of isomer 11b along with 38% of the isomer 12b. Its
structural assignment was achieved by the observation of 1D NOE
effects between its terminal methyl group (not from the ethylene)
and the H2 and H6 of the 2-pyridyl moiety. To illustrate the
salts were actually reported recently.40,41 In our case, this hydro-
genation gives rise to an unstable aminal, which undergoes an
immediate hydrolysis to give compound 26. On the NMR point of
view, the methylenes 1H NMR signals of compound 25 are a bit
spread out because of the ring flexibility. On the other hand, this is
far worse in the case of 26 as its ‘visible’ 1H NMR as well as 13C NMR
signals can be summed up to one ethoxy signal. It is only the
high-resolution mass spectrum of 26, which provided a proof of
structure in this case. This unexpected cleavage is currently leading
us to redesign our strategy to prepare compounds featuring a pyr-
azolopyridine core structure.
N
N
R
H
N
N
N
R
i
N
N
R
+
N
O
O
10b, c, k
11b, c, k
12b, c, k
O
In conclusion, this work provides some insights on the regio-
selectivity of copper-catalyzed N-arylation, hopefully useful
beyond the alkoxypyrazoles. Our studies of the reaction condi-
tions provided by the work of Cristau and Taillefer pointed out the
importance of proper dissolution of the catalyst, the possible
importance (in our cases) of adding small amount of molecular
sieves as well as the interest of using a microwave oven to shorten
the reaction duration. Further investigations on the alternative
use of 2-fluoropyridine as a 2-pyridyl source provided a fairly
simple alternative access to 2-pyridyl derivatives. As mentioned in
a recent work,32 this classic approach remains very useful, espe-
cially in the case of copper-sensitive substrates, such as iodinated
substrates. Interestingly, one set of the pyridyl isomers obtained
was usually found to be rather unstable either toward heat or acid
treatment. In one instance, a previously unreported pyrazole ring
acidic cleavage was observed. Moreover, our results also pointed
out that a 2-pyridyl group can eventually be considered as
a (rather expensive) protecting group of the nitrogen of the
3-alkoxypyrazoles.
% 11 % 12
R
38
traces
24
traces
56
24
b
CF3
CH3
I
c
k
N
N
ii
iii
11k
N
N
N
N
O
O
11e
11f
R
N
H
N
O
O
HN
N
iv
O
O
O
+
N
N
N
23
21
22: R = H
24: R = 2-pyridyl
i or v
1. Experimental part
N
H
N
N
N
N
vi
A Biotage initiator 2 microwave oven was used for the reactions
requiring microwaves irradiations. 1H NMR and 13C NMR spectra
were recorded on a Bruker Avance 400 spectrometers at 400 MHz
+
O
O
N
N
H
H
25
26
and 100 MHz, respectively. Shifts (d) are given in parts per million
(ppm) with respect to the TMS signal and coupling constants (J) are
given in Hertz. Column chromatography were performed either
Merck silica gel 60 (0.035–0.070 mm) or neutral alumina contain-
ing a suitable proportion of water, using a solvent pump operating
at pressure between 2 and 7 bar (25–50 mL/min) and an automated
collecting system driven by a UV detector set to 254 nm unless
required otherwise (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 followed 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)
was obtained using a Waters Micromass Q-Tof with an electrospray
ion source.
Scheme 6. (i): 2-Fluoropyridine, Cs2CO3, MW, 180 ꢀC, 15 min to 3 h (see text). (ii):
PheB(OH)2, Cs2CO3, n-PrOH–H2O, MW 130 ꢀC. (iii): PhCH2ZnBr, THF, MW 110 ꢀC. (iv):
NH2NH2, HCl$EtOH, reflux. (v): 2a, Cu2O, Cs2CO3, ligand 6, 4 Å molecular sieves, MeCN,
MW 180 ꢀC, 3 h. (vi): H2, 25 bar, 10% Pd–C, AcOH, 65 ꢀC, 3 h.
‘diversity’ potential of compound 11k, a Suzuki reaction with
phenylboronic acid gave to the 5-phenyl isomer 11e along with the
reduced material 11j in 39 and 20%, respectively. Moreover,
a Negishi reaction with benzylzincbromide gave the 5-benzyl
isomer 11f as well as the reduced compound 11j, in 43 and 32%,
respectively. These two transformations actually confirmed the
structure assignment of compounds 11k as well as 11f. Finally, as an
illustration of the quirk we encountered in this work, we also
undertook the synthesis of N-pyridyl derivative 24 obtained via the
pyrazolopyridine 22; very simply prepared in one step from 21. The
reaction of compound 22 with 2-bromopyridine gave 42% of isomer
24 as seen by 1D NOE effects between the methylene on carbon 7 of
the pyrazolopyridine ring and the H2 and H6 of the 2-pyridyl
moiety. A trial with 2-fluoropyridine (at 180 ꢀC for 3 h) gave an
improved 55% yield along with traces amount of the other isomer
(not depicted). However, the next step of our work called for the
hydrogenolysis of the benzyl group to give compound 25. This
required rather strong conditions and gave 16% of 25 although
along with substantial disappearance of the pyridine ring to give
the pyrazolopyridine 26 in a 13% yield. A literature search pointed
out that such chelation-assisted palladium-based hydrogenation of
an aryl had been reported for another N-phenylpyrazole, which
led to the corresponding N-cyclohexyl pyrazole.39 Other interesting
chelation-assisted reactions with N-arylpyrazoles and ruthenium
1.1. General method for the copper-catalyzed arylation of
alkoxypyrazoles with bromopyridines
In a 20 mL Biotage tube the 3-alkoxypyrazole (10 mmol), the
bromopyridines 2a–c (10.5 mmol), cesium carbonate (10.5 mmol,
3.42 g), 4 Å molecular sieves (0.5 g, 3.2 mm pellets) [N,N0-bis-((20-
pyridine)-methylene)]-1,2-diaminocyclohexane (6)25 (0.1 mmol,
0.29 g) were dispersed in acetonitrile (14 mL, dried over 4 Å mo-
lecular sieves). The suspension was degassed using a slow stream of
argon bubbling in the suspension. Copper oxide (0.05 mmol,
0.072 g) was then added and the tube was sealed. The tube was
then 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

2658
S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
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. An
LC/MS monitoring of a sample usually points out the quasi disap-
pearance of the starting alkoxypyrazole. As described in the text,
further heating brought the reaction to an apparent completion in
the case of 3- or 4-bromopyridines. The resulting suspension was
dispersed in ethyl acetate, directly adsorbed over a small amount of
the relevant solid phase and purified by a chromatography over
that phase as described below.
mentioned in Scheme 1 after two chromatography (silica gel;
dichloromethane–ethanol 98/2 and then neutral aluminaþ1.5%
H2O; cyclohexane–dichloromethane 1/2). 1H NMR (CDCl3): 1.46
(d, 6H, J¼6.1); 2.27 (s, 3H); 4.50 (sept, 1H, J¼6.1); 5.48 (s, 1H);
7.79 (m, 2H); 8.58 (s (br), 2H); nota: the 7.79 signal is de-
pendent on the acidity of the solvent; and is sometimes seen at
7.93. 13C NMR (CDCl3): 11.6; 21.9; 76.3; 87.2; 113.8; 145.5; 150.5;
150.6; 155.3. HRMS: calcd for C12H15N3OþH: 218.1293; exp:
218.1200.
1.1.1. 2-(3-Isopropoxy-5-methyl-1H-pyrazol-1-yl)pyridine
(3a). Obtained as an oil after a chromatography over silica gel
(dichloromethane–ethanol 99/1) in a 53% yield. 1H NMR (CDCl3):
1.40 (d, 6H, J¼6.1); 2.67 (s, 3H); 4.83 (sept, 1H, J¼6.1); 5.66 (s, 1H);
7.07 (m, 1H); 7.73 (m, 1H); 7.82 (m, 1H); 8.37 (m, 1H). 13C NMR
(CDCl3): 15.1; 22.1; 71.4; 96.1; 114.8; 119.7; 137.9; 142.5; 147.1;
153.8; 162.6. HRMS: calcd for C12H15N3OþH: 218.1293; exp:
218.1246.
1.2. Deprotection using hydrobromic acid in acetic acid
The alkoxypyrazole (1 mmol) was placed in a 60 mL round-
bottomed thick glass tube fitted with a PTFE-faced screw-cap. The
tube 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 3 h. The resulting suspension was cooled,
dissolved in ethanol, concentrated to dryness made basic with
ethanolic ammonia and concentrated to dryness again. The resi-
dues were further purified as described below.
1.1.2. 2-(5-Isopropoxy-3-methyl-1H-pyrazol-1-yl)pyridine
(4a). Obtained as an oil in a 2% yield following a second chroma-
tography of this fraction over neutral alumina containing 1.5% H2O
(cyclohexane–dichloromethane 3/1 to 1/4). 1H NMR (CDCl3): 1.42
(d, 6H, J¼6.1); 2.30 (s, 3H); 4.48 (sept, 1H, J¼6.1); 5.49 (s, 1H); 7.15
(m, 1H); 7.66 (m, 1H); 7.73 (m, 1H); 8.54 (m, 1H). 13C NMR (CDCl3):
14.6; 21.8; 71.4; 87.8; 115.8; 120.8; 137.6; 148.8; 150.0; 150.8; 154.5.
HRMS: calcd for C12H15N3OþH: 218.1293; exp: 218.1328.
Isomers 3b and 4b: these isomers were obtained after two
chromatography (neutral aluminaþ1.5% H2O; cyclohexane–
dichloromethane 3/2 and then silica gel; dichloromethane–ethanol
99/1 to 98/2).
1.2.1. 5-Methyl-1-(pyridin-2-yl)-1H-pyrazol-3(2H)-one
(7a). Obtained as a solid in a 46% yield after a chromatography over
silica gel (dichloromethane–ethanol 9/1). Mp¼185 ꢀC. 1H NMR
(CDCl3): 2.62 (s, 3H); 5.70 (s,1H); 7.17 (m,1H); 7.61 (m,1H); 7.84 (m,
1H); 8.43 (m, 1H). 13C NMR (CDCl3): 14.7; 95.9; 115.3; 120.6; 138.6;
143.4; 147.6; 152.5; 162.8. HRMS: calcd for C9H9N3OþH: 176.0824;
exp: 176.0864.
1.2.2. 3-Methyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (8a)28. This com-
pound was obtained in a better 53% yield as a solid if the heating was
shortened to 1 h and the temperature kept to 100 ꢀC. Obtained as
a solid after a chromatography over silica gel (dichloromethane–
ethanol 9/1). Mp¼111 ꢀC. 1H NMR (CDCl3): 2.27 (s, 3H); 5.44 (s, 1H);
7.12–7.18 (m, 1H); 7.80–7.86 (m, 1H); 7.89–7.97 (m, 1H); 8.20–8.30
(m, 1H). 13C NMR (CDCl3): 14.5; 88.7; 111.9; 119.5,139.8; 145.1; 151.5;
154.1; 157.3. HRMS: calcd for C9H9N3OþH: 176.0824; exp: 176.0790.
1.1.3. 3-(3-Isopropoxy-5-methyl-1H-pyrazol-1-yl)pyridine
(3b). Obtained as an oil in the yields mentioned in Scheme 1. 1H
NMR (CDCl3): 1.38 (d, 6H, J¼6.1); 2.35 (s, 3H); 4.83 (sept, 1H, J¼6.1);
5.70 (s, 1H); 7.39 (m, 1H); 7.83 (m, 1H); 8.55 (m, 1H); 8.76 (m, 1H).
13C NMR (CDCl3): 13.0; 22.1; 71.5; 95.0; 123.6; 131.2; 136.7; 140.5;
144.7; 147.2; 163.3. HRMS: calcd for C12H15N3OþH: 218.1293; exp:
218.1215.
1.2.3. 5-Methyl-1-(pyridin-3-yl)-1H-pyrazol-3(2H)-one
(7b). Obtained in a 65% yield as a solid after a chromatography over
silica gel (dichloromethane–ethanol 95/5). Mp¼190 ꢀC. 1H NMR
(CDCl3): 2.35 (s, 3H); 5.70 (s, 2H); 7.47 (m, 1H); 7.82 (m, 1H); 8.60
(m, 1H); 8.93 (s, 1H). 13C NMR (CDCl3): 12.7; 94.8; 123.8; 131.0;
135.8; 141.2; 145.3; 147.4; 163.3. HRMS calcd for C9H9N3OþH:
176.0824; exp: 176.0764.
1.1.4. 3-(5-Isopropoxy-3-methyl-1H-pyrazol-1-yl)pyridine
(4b). Obtained as an oil in the yields mentioned in Scheme 1. 1H
NMR (CDCl3): 1.42 (d, 6H, J¼6.1); 2.28 (s, 3H); 4.48 (sept, 1H, J¼6.1);
5.49 (s, 1H); 7.36 (m, 1H); 8.08 (m, 1H); 8.47 (m, 1H); 9.07 (m, 1H).
13C NMR (CDCl3): 14.6; 21.9; 76.1; 87.1; 123.5; 128.6; 135.8; 142.5;
146.1; 150.1; 154.4. HRMS: calcd for C12H15N3OþH: 218.1293; exp:
218.1212.
1.2.4. 3-Methyl-1-(pyridin-3-yl)-1H-pyrazol-5(4H)-one
(8b). Obtained in a 69% yield as a solid after a chromatography over
silica gel (dichloromethane–ethanol 95/5). Mp¼129 ꢀC. 1H NMR
(CDCl3): 2.23 (s, 3H); 3.46 (s, 2H); 7.34 (m, 1H); 8.29 (m, 1H); 8.45
(m, 1H); 9.20 (s, 1H). 13C NMR (CDCl3): 17.1; 42.7; 123.7; 125.6;
134.9; 139.9; 145.3; 157.3; 170.8. HRMS: calcd for C9H9N3OþH:
176.0824; exp: 176.0788.
1.1.5. 4-(3-Isopropoxy-5-methyl-1H-pyrazol-1-yl)pyridine (3c). The
reaction was undertaken from 4-bromopyridine hydrochloride.
This forced the use of twice the amount of cesium carbonate. For
this reason, the reaction was usually run on a smaller scale (i.e.,
5 mmol). Compound 3c was obtained as an oil in the yield men-
tioned in Scheme
1 after two chromatography (silica gel;
dichloromethane–ethanol 98/2 and then neutral aluminaþ1.5%
H2O; cyclohexane–dichloromethane 1/2). 1H NMR (CDCl3): 1.40 (d,
6H, J¼6.1); 2.48 (s, 3H); 4.85 (sept, 1H, J¼6.1); 5.73 (s, 1H); 7.49 (m,
2H); 8.63 (s (br), 2H). 13C NMR (CDCl3): 14.1; 28.1; 71.6; 97.1; 115.9;
140.9; 146.7; 150.6; 163.2. HRMS: calcd for C12H15N3OþH:
218.1293; exp: 218.1230.
1.2.5. 5-Methyl-1-(pyridin-4-yl)-1H-pyrazol-3(2H)-one
(7c). Obtained in a 82% yield as a solid after a chromatography over
silica gel (dichloromethane–ethanol 94/6). Mp¼204 ꢀC. 1H NMR
(CDCl3): 2.48 (s, 3H); 5.78 (s, 1H); 7.43 (m, 2H); 8.71 (m, 2H). 1H NMR
(DMSO-d6): 2.44 (s, 3H); 5.73 (s, 1H); 7.54 (m, 2H); 8.58 (m (br), 2H);
10.28 (s, 1H). 13C NMR (DMSO-d6): 13.5; 96.9; 115.5 (br); 141.2; 146.1;
150.5; 162.2. HRMS: calcd for C9H9N3OþH: 176.0824; exp: 176.0866.
1.1.6. 4-(5-Isopropoxy-3-methyl-1H-pyrazol-1-yl)pyridine (4c). The
reaction was undertaken from 4-bromopyridine hydrochloride.
This forced the use of twice the amount of cesium carbonate.
For this reason, the reaction was usually run on a smaller scale
(i.e., 5 mmol). Compound 4c was obtained as an oil in the yield
1.2.6. 3-Methyl-1-(pyridin-4-yl)-1H-pyrazol-5(4H)-one
(8c). Obtained in a 52% yield as a yellow solid after a chromatog-
raphy over silica gel (dichloromethane–ethanol 96/4) if, as for
compound 8a, the heating was shortened to 1 h and the

S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
2659
temperature kept to 100 ꢀC. Mp¼206 ꢀC. 1H NMR (CDCl3): 2.23 (s,
3H); 3.47 (s, 2H); 7.88 (m, 2H); 8.57 (m, 2H). 1H NMR (DMSO-d6):
2.13 (s, 3H); 5.36 (s (br), 1H); 7.81 (m, 2H); 8.53 (m, 2H). 13C NMR
(DMSO-d6): much dispersed signals 14.0; 89.5; 112.4; 145.0; 150.0;
151.1; 157.4. HRMS: calcd for C9H9N3OþH: 176.0824; exp: 176.0771.
cyclohexane (4 mL). The tube was heated in a microwave oven at
140 ꢀC for 45 min. The resulting purple solution was dissolved in
ethyl acetate and water, the mixture was decolorized with sodium
sulfite, the organic layer was washed with water, brine, dried over
magnesium sulfate, and concentrated to dryness under high vac-
uum to yield pure compound 11a as an oil (0.28 g, 98%). 1H NMR
(CDCl3): 1.44 (d, 3H, J¼6.1); 2.72 (s, 3H); 5.03 (sept, 1H, J¼6.1); 7.13
(m, 1H); 7.78 (m, 2H); 8.40 (m, 1H). 13C NMR (CDCl3): 15.6; 22.1;
54.9; 117.4; 120.3; 138.3; 143.3; 147.2; 153.4; 162.0. HRMS: calcd for
C12H14IN3OþH: 344.0260; exp: 344.0269.
1.2.7. 2-(2-(Propan-2-ylidene)hydrazinyl)pyridine (9). Compound
4a (0.17 g, 0.97 mmol) was boiled in 2 N hydrochloric acid (15 mL)
for 1 h. The resulting suspension was made basic with sodium
hydrogencarbonate, and extracted with ethyl acetate. The organic
phase was washed with brine dried over magnesium sulfate and
concentrated to dryness to yield compound 9 (0.08 g, 55%) as an
off-white solid. Mp¼73 ꢀC (lit.42¼69–70 ꢀC). 1H NMR (CDCl3): 1.92
(s, 3H); 2.07 (s, 3H); 6.73 (m, 1H); 7.24 (m, 1H); 7.57 (m, 1H); 7.80
(s (br), 1H); 8.09 (m, 1H). 13C NMR (CDCl3): 15.9; 25.2; 107.4; 115.1;
138.3; 146.0; 146.9; 157.2. HRMS: calcd for C8H11N3þH: 150.1031;
exp: 150.1050.
By using the copper-based N-arylation protocol described
above, the following compounds were also obtained.
1.3.5. 2-(3-Ethoxy-5-methyl-1H-pyrazol-1-yl)pyridine
(11c). Obtained as an oil that slowly crystallized after a chroma-
tography over silica gel (cyclohexane–ethyl acetate 95/5 to 1/1) in
a 55% yield. Mp<50 ꢀC. 1H NMR (CDCl3): 1.43 (t, 3H, J¼7.1); 2.66
(s, 3H); 4.28 (q, 2H, J¼7.1); 5.68 (s, 1H); 7.08 (m, 1H); 7.73 (m, 1H);
7.82 (m, 1H); 8.38 (m, 1H). 13C NMR (CDCl3): 14.8; 15.1; 64.5; 95.6;
114.9; 119.8; 138.1; 142.7; 147.1; 153.7; 163.3. HRMS: calcd for
C11H13N3OþH: 204.1137; exp: 204.1083.
1.3. Preparation of 3-ethoxypyrazoles 10g, 10i, 22, and 23
As previously described,1 the relevant ethyl
b-ketoesters
(0.01 mmol) and hydrazine hydrochloride (0.89 g, 0.0103 mmol)
were refluxed in ethanol (20 mL) for 8 h. The solvent was removed
under reduced pressure, the residue was dispersed in dichloro-
methane and an excess of a saturated solution of sodium hydro-
gencarbonate. The organic phase was washed three times with
sodium hydrogencarbonate, dried over magnesium sulfate, and
concentrated to dryness to yield compounds 10g, 10i, 22, and 23as
described below.
1.3.6. 2-(5-Ethoxy-3-methyl-1H-pyrazol-1-yl)pyridine
(12c). This
compound was obtained as an oil in a 26% yield after a second
chromatography over neutral alumina containing 1.5% H2O
(cyclohexane–ethyl acetate 7/3). 1H NMR (CDCl3): 1.44 (t, 3H,
J¼7.0); 2.28 (s, 3H); 4.16 (q, 2H, J¼7.0); 5.48 (s, 1H); 7.13 (m, 1H);
7.67 (m,1H); 7.74 (m, 1H); 8.52 (m,1H). 13C NMR (CDCl3): 14.5; 14.6;
68.1; 87.0; 115.8; 120.9; 137.8; 148.7; 150.0; 150.9; 155.5. HRMS:
calcd for C11H13N3OþH: 204.1137; exp: 204.1113.
1.3.1. 3-Ethoxy-5-methyl-4-phenyl-1H-pyrazole (10g). Obtained as
a solid in a 39% yield after a chromatography over silica gel
(dichloromethane–ethanol 99/1). Mp¼141 ꢀC. 1H NMR (CDCl3):
1.43 (t, 3H, J¼7.1); 2.38 (s, 3H); 4.34 (q, J¼7.1 Hz, 2H); 7.23 (m, 1H);
7.39 (m, 2H); 7.50 (m, 2H); 7.70 (s (br), 1H). 13C NMR (CDCl3): 11.6;
14.9; 64.6; 104.8; 125.8; 128.2; 128.3; 132.3; 137.6; 161.0. HRMS:
calcd for C12H14N2OþH: 203.1184; exp: 203.1149.
1.3.7. 2-(3-Ethoxy-4-fluoro-5-methyl-1H-pyrazol-1-yl)pyridine
(11d). This compound was obtained as an oil that slowly solidified in
a 67% yield after a chromatography over silica gel (dichloromethane
and then dichloromethane–ethanol 99/1). Mp<50 ꢀC. 1H NMR
(CDCl3): 1.47 (t, 3H, J¼7.2); 2.65 (s, 3H); 4.40 (q, 2H, J¼7.2); 7.08
(m,1H); 7.75 (m, 2H); 8.36 (m,1H). 13C NMR (CDCl3): 11.5; 14.7; 65.0;
113.9; 119.8; 127.4 (J¼24 Hz); 136.2 (J¼243 Hz); 138.2; 147.1; 150.9;
153.9. HRMS: calcd for C11H12N3OFþH: 222.1043; exp: 222.0974.
1.3.2. Ethyl 2-(3-ethoxy-1H-pyrazol-5-yl)acetate (10i). Obtained as
an oil in a 43% yield. 1H NMR (CDCl3): 1.30 (t, 3H, J¼7.0); 1.40 (t, 3H,
J¼7.0); 3.69 (s, 2H); 4.21 (m, 4H); 5.62 (s, 1H); 9.00 (s (br), 1H). 13C
NMR (CDCl3): 14.1; 14.8; 32.1; 61.5; 64.9; 90.2; 137.3; 163.1; 169.6.
HRMS: calcd for C9H14N2O3þH: 199.1083; exp: 199.1039.
1.3.8. 2-(5-Ethoxy-4-fluoro-3-methyl-1H-pyrazol-1-yl)pyridine
(12d). This compound was obtained as an oil in a 9% yield after
a second chromatography over neutral alumina containing 1.5%
H2O (cyclohexane–ethyl acetate 9/1). 1H NMR (CDCl3): 1.42 (t, 3H,
J¼7.1); 2.29 (s, 3H); 4.41 (m, 2H); 7.19 (m, 1H); 7.66 (m, 1H); 7.77
(m, 1H); 8.55 (m, 1H). 13C NMR (CDCl3): 10.9; 15.3; 69.6; 115.6;
121.4; 134.2 (J¼240 Hz); 138.0 (J¼10 Hz); 138.1; 139.2 (J¼20 Hz);
148.7; 150.9. HRMS: calcd for C11H12N3OFþH: 222.1043; exp:
222.0979.
1.3.3. 5-Benzyl-3-ethoxy-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyri-
dine (22) and 5-benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyr-
idin-3(2H)-one (23). Compound 22 was obtained as a glass in a 38%
yield, from the commercially available hydrochloride salt of 21,
after an extraction as described above, using ethyl acetate. Whereas
the hydrochloride salt of 23 was filtered off from the initial etha-
nolic solution (isolated as a white powder in a 52% yield).
1.3.9. 2-(3-Ethoxy-5-phenyl-1H-pyrazol-1-yl)pyridine
(11e). This
Compound 22: mp¼105 ꢀC. 1H NMR (CDCl3): 1.37 (t, 3H, J¼7.0);
2.65 (q, 2H); 2.76 (q, 2H); 3.42 (s, 2H); 3.73 (d, 2H); 4.23 (q, 2H,
J¼7.0); 7.2–7.4 (m, 5H); 8.9 (s, 1H). 13C NMR (CDCl3): 14.9; 22.3;
47.8; 62.0; 64.1; 99.9; 127.1; 128.3; 129.0; 138.4; 139.0; 159.6.
HRMS: calcd for C15H19N3OþNa: 280.1426; exp: m/z, 280.1442.
Hydrochloride salt of 23: mp>240 ꢀC (dec). 1H NMR (DMSO-d6):
2.99 (s (br), 1H); 3.15 (s (br), 1H); 3.37 (s (br), 1H); 3.64 (s (br), 1H);
4.01 (s (br), 2H); 4.45 (m, 2H); 7.50 (m, 3H); 7.71 (m, 2H); 11.87
(s (br), 1H); 13.46 (s (br), 3H). 13C NMR (DMSO-d6): 18.8; 45.2; 47.9;
57.7; 92.8; 128.7; 129.4; 129.8; 131.4; 139.8; 153.7. HRMS: calcd for
C13H15N3OþH: 230.1293; exp: m/z, 230.1229.
compound was obtained as a wax in a 36% yield after a chroma-
tography over neutral alumina containing 1.5% H2O (cyclohexane–
ethyl acetate 95/5 to 9/1). 1H NMR (CDCl3): 1.45 (t, 3H, J¼7.1); 4.38
(q, 2H, J¼7.1); 5.99 (s, 1H); 7.13 (m, 1H); 7.31 (m, 5H); 7.42 (m, 1H);
7.69 (m, 1H); 8.31 (m, 1H). 13C NMR (CDCl3): 14.8; 64.7; 95.9; 118.0;
121.4; 128.1; 128.2; 128.7; 131.3; 138.0; 145.1; 148.2; 152.4; 163.9.
HRMS: calcd for C16H15N3OþH: 266.1293; exp: 266.1242.
1.3.10. 2-(5-Ethoxy-3-phenyl-1H-pyrazol-1-yl)pyridine (12e). This
compound was obtained as an oil in a 41% yield after a chroma-
tography over neutral alumina containing 1.5% H2O (cyclohexane–
ethyl acetate 95/5 to 9/1). 1H NMR (CDCl3): 1.51 (t, 3H, J¼7.1); 4.30
(q, 2H, J¼7.1); 6.04 (s, 1H); 7.22 (m, 1H); 7.35 (m, 1H); 7.44 (m, 2H);
7.80 (m, 1H); 7.82 (m, 1H); 7.91 (m, 2H); 8.62 (m, 1H). 13C NMR
(CDCl3): 14.6; 68.5; 84.6; 116.8; 121.4; 125.8; 128.3; 128.4; 133.1;
1.3.4. 2-(4-Iodo-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)pyridine
(11a). In a Biotage vial, compound 2a (0.18 g, 0.83 mmol) and
N-iodosuccinimide (0.22 g, 0.91 mmol) were dispersed in

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S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
138.2; 148.6; 151.2; 151.7; 156.0. HRMS: calcd for C16H15N3OþH:
Mp¼60 ꢀC. 1H NMR (CDCl3): 1.36 (t, 3H, J¼7.1); 1.52 (t, 3H, J¼7.1);
4.32 (q, 2H, J¼7.1); 4.47 (q, 2H, J¼7.1); 7.20 (m, 1H); 7.83 (m, 1H);
7.86 (m, 1H); 8.41 (m, 1H); 8.89 (s, 1H). 13C NMR (CDCl3): 14.3; 14.6;
60.0; 65.4; 103.0; 112.1; 121.4; 131.6; 138.7; 148.1; 150.1; 162.3;
163.0. HRMS: calcd for C13H15N3O3þH: 262.1192; exp: 262.1114.
266.1293; exp: 266.1216.
1.3.11. 2-(5-Benzyl-3-ethoxy-1H-pyrazol-1-yl)pyridine
(11f). This
compound was obtained as an oil in a 41% yield after a chromatog-
raphy over silica gel (dichloromethane and then dichloromethane–
ethanol 99/1). 1H NMR (CDCl3): 1.42 (t, 3H, J¼7.1); 4.27 (q, 2H, J¼7.1);
4.55 (s, 2H); 5.51 (s,1H); 7.08 (m,1H); 7.28 (m, 5H); 7.74 (m,1H); 7.81
(m, 1H); 8.36 (m, 1H). 13C NMR (CDCl3): 14.8; 34.9; 64.5; 96.2; 115.0;
120.0; 126.3; 128.3; 129.1; 138.1; 138.8; 146.1; 147.1; 153.6; 163.3.
HRMS: calcd for C17H17N3OþH: 280.1450; exp: 280.1378.
1.3.18. 2-(3-Ethoxy-1H-pyrazol-1-yl)pyridine (11j). This compound
was obtained as an oil in a 70% yield after a chromatography over
silica gel (cyclohexane–ethyl acetate 95/5). 1H NMR (CDCl3): 1.44 (t,
3H, J¼7.0); 4.33 (q, 2H, J¼7.0); 5.92 (d, 1H, J¼2.7); 7.09 (m, 1H); 7.75
(m, 1H); 7.82 (m, 1H); 8.34 (m, 1H); 8.38 (d, 1H, J¼2.7). 13C NMR
(CDCl3): 14.8; 64.9; 94.8; 115.5; 120.1; 128.2; 138.5; 147.7; 151.5;
165.0. HRMS: calcd for C10H11N3OþH: 190.0980; exp: 190.0919.
1.3.12. 2-(3-Benzyl-5-ethoxy-1H-pyrazol-1-yl)pyridine (12f). This
compound was obtained as an oil that slowly solidified in a 25%
yield after a second chromatography over neutral alumina con-
taining 1.5% H2O (cyclohexane–ethyl acetate 9/1). Mp<50 ꢀC. 1H
NMR (CDCl3; solution becomes bright red over time): 1.43 (t, 3H,
J¼7.1); 4.02 (s, 2H); 4.13 (q, 2H, J¼7.1); 5.40 (s,1H); 7.19 (m,1H); 7.24
(m, 1H); 7.32 (m, 4H); 7.72 (m, 1H); 7.79 (m, 1H); 8.61 (m, 1H). 13C
NMR (CDCl3): 14.5; 35.8; 68.2; 86.4; 116.0; 121.1; 126.3; 128.5;
128.9; 138.2; 139.4; 148.7; 150.7; 153.4; 155.6. HRMS: calcd for
C17H17N3OþH: 280.1450; exp: 280.1405.
1.3.19. Ethyl 2-(3-ethoxy-1-(pyridin-2-yl)-1H-pyrazol-5-yl)acetate
(11l). Obtained as an oil after a chromatography over silica gel
(cyclohexane–ethyl acetate 95/5 then 9/1). This chromatography
first gave 17% of compound 11c followed by 5% of compound 11l. 1H
NMR (CDCl3): 1.17 (t, 3H, J¼7.0); 1.44 (t, 3H, J¼7.0); 4.12 (q, 2H,
J¼7.0); 4.31 (q, 2H, J¼7.0); 5.84 (s, 1H); 7.06 (m, 1H); 7.75 (m, 1H);
7.87 (m, 1H); 8.28 (m, 1H). 13C NMR (CDCl3): 14.1; 14.8; 35.2; 60.7;
64.6; 97.4; 113.8; 119.8; 138.3; 138.4; 146.6; 153.2; 163.2; 169.7.
HRMS: calcd for C14H17N3O3þH: 276.1348; exp: 276.1265.
1.3.13. 2-(3-Ethoxy-5-methyl-4-phenyl-1H-pyrazol-1-yl)pyridine
(11g). Obtained as an oil that slowly crystallized in a 79% yield after
a chromatography over silica gel (cyclohexane–ethyl acetate 95/5 to
1/1). Mp¼78 ꢀC. 1H NMR (CDCl3): 1.34 (t, 3H, J¼7.1); 2.62 (s, 3H); 4.31
(q, 2H, J¼7.1); 7.13 (m,1H); 7.31 (m,1H); 7.42 (m, 2H); 7.50 (m, 2H); 7.79
(m, 1H); 7.85 (m, 1H); 8.44 (m, 1H). 13C NMR (CDCl3): 14.0; 14.8; 64.5;
109.9; 115.6; 120.1; 126.3; 128.3; 129.3; 131.7; 138.2; 138.9; 147.3;
153.7; 161.2. HRMS: calcd for C17H17N3OþH: 280.1450; exp: 280.1370.
1.3.20. Preparation of 1-(4-chlorophenyl)-3-ethoxy-5-phenyl-1H-
pyrazole (13) and 1-(4-chlorophenyl)-5-ethoxy-3-phenyl-1H-pyrazole
(14). As mentioned in the text, this pair of isomers were obtained in
15 and 49% yield, respectively using the protocol described above
from compound 10e and 4-chloroiodobenzene after a initial chro-
matography over silica gel (cyclohexane–ethyl acetate 97/3) fol-
lowed by second chromatography over silica gel (cyclohexane–
dichloromethane 4/1). Their analytical data were identical to the
previously reported one.2
1.3.14. 2-(5-Ethoxy-3-methyl-4-phenyl-1H-pyrazol-1-yl)pyridine
(12g). Obtained as an oil in a 5% yield after a second chromatography
over alumina containing 1.5% of water (cyclohexane–ethyl acetate
5/1). 1H NMR (CDCl3): 1.18 (t, 3H, J¼7.0); 2.38 (s, 3H); 3.96 (q, 2H,
J¼7.0); 7.22 (m, 1H); 7.32 (m, 1H); 7.44 (m, 2H); 7.51 (m, 2H); 7.76 (m,
1H); 7.80 (m, 1H); 8.59 (m, 1H). 13C NMR (CDCl3): 10.0; 15.1; 70.7;
108.5; 116.3; 121.4; 126.6; 128.4; 128.9; 132.1; 138.1; 148.5; 148.7;
151.0; 151.2. HRMS: calcd for C17H17N3OþH: 280.1450; exp: 280.1404.
1.3.21. Deprotection using boron tribromide in dichloromethane. The
alkoxypyrazole (1 mmol) was placed in a 60 mL round-bottomed
thick glass tube fitted with a PTFE-faced screw-cap. A 1 N solu-
tion of boron tribromide in dichloromethane (1.5 mL) was then
added. The tube was tightly closed and stirred at 25 ꢀC for 48 h. The
tube was then cooled to 0 ꢀC, opened, and cautiously quenched
with 90% ethanol. The resulting solution was concentrated to
dryness, made basic with ethanolic ammonia, and concentrated to
dryness again. The residues were further purified as described
below.
1.3.15. 2-(4-Benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)pyridine
(11h). This compound was obtained as an oil in a 66% yield after
a chromatography over silica gel (dichloromethane and then
dichloromethane–ethanol 99/1). 1H NMR (CDCl3): 1.42 (t, 3H,
J¼7.2); 2.59 (s, 3H); 3.76 (s, 2H); 4.36 (q, 2H, J¼7.2); 7.07 (m, 1H);
7.19 (m, 1H); 7.29 (m, 4H); 7.74 (m, 1H); 7.79 (m, 1H); 8.38 (m, 1H).
13C NMR (CDCl3): 13.2; 14.8; 27.7; 64.2; 107.1; 115.0; 119.5; 125.7;
128.2; 128.3; 138.2; 139.5; 140.8; 147.1; 153.8; 162.4. HRMS: calcd
for C18H20N3OþH: 294.1606; exp: 294.1579.
1.3.22. 4-Fluoro-5-methyl-1-(pyridin-2-yl)-1H-pyrazol-3(2H)-one
(15d). This compound was obtained in a 72% yield as a white
powder after a chromatography over silica gel (dichloromethane–
ethanol 99/1 to 95/5). Mp¼216 ꢀC (toluene). 1H NMR (DMSO-d6):
2.55 (d, 3H, J¼2.0); 7.22 (m, 1H); 7.66 (m, 1H); 7.89 (m, 1H); 8.37
(m, 1H); 10.98 (s (br), 1H). 13C NMR (DMSO-d6): 11.9; 113.7; 120.7;
126.7 (d, J¼24); 136.2 (d, J¼241); 139.3; 147.9; 149.8; (d, J¼9.5);
153.7. HRMS: calcd for C9H8N3OFþH: 194.0730; exp: 194.0676.
1.3.16. 2-(4-Benzyl-5-ethoxy-3-methyl-1H-pyrazol-1-yl)pyridine
(12h). This compound was obtained as an oil in a 7% yield after
a second chromatography over neutral alumina containing 1.5%
H2O (cyclohexane–ethyl acetate 9/1). 1H NMR (CDCl3): 1.29 (t, 3H,
J¼7.1); 2.17 (s, 3H); 3.81 (s, 2H); 4.05 (q, 2H, J¼7.1); 7.19 (m, 1H);
7.23 (m, 3H); 7.29 (m, 2H); 7.75 (m, 1H); 7.80 (m, 1H); 8.56 (m, 1H).
13C NMR (CDCl3): 13.2; 15.2; 28.3; 71.3; 106.1; 115.7; 121.1; 126.0;
128.1; 128.4; 138.2; 140.1; 148.5; 149.8; 151.3; 152.0. HRMS: calcd
for C18H19N3OþH: 294.1606; exp: 294.1602.
1.3.23. 5-Phenyl-1-(pyridin-2-yl)-1H-pyrazol-3(2H)-one (15e). This
compound was obtained in a 64% yield as a white powder after
a chromatography over silica gel (dichloromethane–ethanol 100/
0 to 97/3). Mp¼186 ꢀC. 1H NMR (DMSO-d6): 6.17 (s, 1H); 7.22 (m,
3H); 7.31 (m, 3H); 7.56 (m, 1H); 7.92 (m, 1H); 8.16 (m, 1H); 10.32 (s,
1H). 13C NMR (DMSO-d6): 96.5; 118.0; 122.2; 128.3; 128.4; 128.7;
131.7; 139.2; 144.6; 148.0; 152.7; 162.4. HRMS: calcd for
C14H11N3OþH: 238.0980; exp: 238.0937.
1.3.17. Ethyl 3-ethoxy-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate
(11i). This compound was obtained as a solid in a 67% yield after
a chromatography over silica gel (dichloromethane and then
dichloromethane–ethanol 99/1) followed by drying it under high
vacuum to remove traces of the decarboxylated material.
1.3.24. 3-Phenyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (16e). This com-
pound was obtained in a 29% yield as a white powder after
a chromatography over silica gel (dichloromethane). Nota: the

S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
2661
more polar (!) starting material 12e was also recovered in the
course of this chromatography in a 32% yield. Alternatively, this
compound was prepared by stirring overnight ethyl 3-oxo-3-phe-
nylpropanoate (0.17 g, 0.91 mmol) and 2-pyridylhydrazine (19)
(0.1 g, 0.91 mmol) in acetic (1 mL) at room temperature. The solu-
tion was concentrated to dryness in a high vacuum. The residue was
dissolved in ethyl acetate, washed with saturated sodium
bicarbonate, brine, and dried over magnesium sulfate. The slowly
crystallizing solid obtained after concentration (0.19 g, 90%)
featured spectral characteristics identical with the one described
below. Mp¼118 ꢀC. 1H NMR (DMSO-d6): 6.17 (s, 1H); 7.38 (m, 2H);
7.46 (m, 2H); 7.91 (m, 3H); 8.08 (m, 1H); 8.48 (m, 1H); 12.5 (s, 1H).
13C NMR (DMSO-d6): 86.0; 113.2; 121.4; 126.0; 129.1 (two signals);
133.2; 140.9; 147.0; 151.7; 153.4; 156.6. HRMS: calcd for
C14H11N3OþH: 238.0980; exp: 238.0893.
122.6; 131.8; 140.1; 148.9; 150.2; 162.7; 163.0. HRMS: calcd for
11H11N3O3þH: 234.0879; exp: 234.0828.
C
1.3.30. 3-Oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrazole-4-carbox-
ylic acid (18). Compound 11i, was treated with boron tribromide in
dichloromethane as described above, the corresponding acid 18
was obtained in a 34% yield as a white powder after a chromatog-
raphy over silica gel (dichloromethane–ethanol–acetic acid 90/9/1)
followed by dispersion of the corresponding fraction in boiling
toluene. Mp>250 ꢀC (dec). 1H NMR (DMSO-d6): 7.34 (m, 1H); 7.70
(m, 1H); 7.98 (m, 1H); 8.46 (m, 1H); 8.67 (s, 1H). 13C NMR (DMSO-
d6): 102.7; 111.5; 121.9; 130.4; 139.6; 148.4; 149.8; 162.1; 163.3.
HRMS: calcd for C9H7N3O3ꢁH: 204.0409; exp: 204.0381.
1.3.31. 1-(Pyridin-2-yl)-1H-pyrazol-3(2H)-one (15j). This compound
was obtained from 11j by treatment with boron tribromide in a 84%
yield as described above as a white powder after a chromatography
over silica gel (dichloromethane–ethanol 100/0 to 97/3). Mp¼157 ꢀC.
1H NMR (CDCl3): 5.98 (d, 1H, J¼2.8); 7.15 (m, 1H); 7.63 (m, 1H); 7.85
(m, 1H); 8.40 (m, 2H); identical with the reported33 data. 1H NMR
(DMSO-d6): 5.88 (d, J¼2.7); 7.22 (m, 1H); 7.66 (m, 1H); 7.90 (m, 1H);
8.38 (m, 2H); 10.45 (s, 1H). 13C NMR (DMSO-d6): 96.1; 111.1; 120.8;
128.3; 139.7; 148.5; 151.2; 163.8. HRMS: calcd for C8H7N3OþH:
162.0667; exp: 162.0663.
1.3.25. 5-Benzyl-1-(pyridin-2-yl)-1H-pyrazol-3(2H)-one (15f). This
compound was obtained in a 55% yield as a white powder after
a chromatography over silica gel (dichloromethane–ethanol 100/0
to 99/1). Mp¼152 ꢀC. 1H NMR (DMSO-d6): 4.47 (s, 2H); 5.47 (s, 1H);
7.24 (m, 6H); 7.63 (m, 1H); 7.86 (m, 1H); 8.38 (m, 1H); 10.18 (s, 1H).
13C NMR (DMSO-d6): 34.3; 97.2; 114.7; 120.7; 126.6; 128.7; 129.2;
139.2; 139.3; 145.5; 147.8; 153.5; 162.0. HRMS: calcd for
C15H13N3OþH: 252.1137; exp: 252.1082.
1.3.26. 3-Benzyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (16f). This com-
pound was obtained in a 39% yield as an oil after a chromatography
over silica gel (dichloromethane). 1H NMR (CDCl3): 3.96 (s, 2H);
5.39 (s, 1H); 7.12 (m, 1H); 7.25 (m, 1H); 7.33 (m, 4H); 7.86 (m, 1H);
7.96 (m, 1H); 8.26 (m,1H). 13C NMR (CDCl3): 35.6; 88.2; 112.1; 119.7;
126.4; 128.5; 128.8; 138.9; 139.9; 145.1; 154.2; 154.5; 157.2. HRMS:
calcd for C15H13N3OþH: 252.1137; exp: 252.1077.
1.4. Compounds only obtained from 2-pyridylhydrazine (19),
general protocol
The appropriate
b-ketoester (0.91 mmol) and 2-pyridylhy-
drazine (0.1 g, 0.91 mmol) were heated at 130 ꢀC in acetic acid
(1 mL) for 5 min using a microwave oven. The solution was con-
centrated to dryness under high vacuum and the residue further
purified as described below.
1.3.27. 5-Methyl-4-phenyl-1-(pyridin-2-yl)-1H-pyrazol-3(2H)-one
(15g). This compound was obtained in a 69% yield when using the
hydrobromic acid in acetic acid deprotection method described
above, as a white powder after a chromatography over silica gel
(dichloromethane the dichloromethane–ethanol 94/6). Mp¼216 ꢀC.
1H NMR (DMSO-d6): 2.64 (s, 3H); 7.25 (m, 2H); 7.43 (m, 4H); 7.71 (d,
1H, J¼8.3); 7.93 (m,1H); 8.44 (m,1H); 10.61 (s,1H).13C NMR (DMSO-
d6): 14.4; 109.6; 115.4; 120.9; 126.6; 128.7; 129.4; 132.2; 138.3;
139.3; 147.9; 153.5; 160.1. HRMS: calcd for C15H13N3OþH: 252.1137;
exp: 252.1146.
1.4.1. 3-Methyl-4-phenyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (16g). A
recrystallisation in cyclohexane led to compound 16g (0.16 g, 69%).
Mp¼118 ꢀC. 1H NMR (DMSO-d6): 2.38 (s, 3H); 7.23 (m, 2H); 7.40 (m,
2H); 7.60 (m, 2H); 7.97 (m, 1H); 8.41 (s (br), 1H); 8.46 (m, 1H). 13C
NMR (DMSO-d6): spectra features broad peaks 12.8 (br); 104.3(br);
112.0 (br); 120.7; 125.9; 127.8; 128.6; 132.7; 139.4 (br); 146.2 (br);
147.8 (br); 148.8 (br); 161.2 (br). HRMS: calcd for C15H13N3OþH:
252.1137; exp: 252.1111.
1.4.2. 4-Benzyl-3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (16h). A
chromatography over silica gel (dichloromethane–ethanol 100/0 to
98/2) led to compound 16h as an oil (0.17 g, 70%). 1H NMR (DMSO-
d6): 2.12 (s, 3H); 3.54 (s, 2H); 7.14 (m, 1H); 7.24 (m, 5H); 7.89 (m,
1H); 8.40 (m, 2H). 1H NMR (CDCl3): 2.17 (s, 3H); 3.74 (s, 2H); 7.09
(m, 1H); 7.20 (m, 1H); 7.29 (m, 4H); 7.83 (m, 1H); 7.96 (m, 1H); 8.25
(m, 1H). 13C NMR (CDCl3): 12.9; 27.6; 99.0; 111.8; 119.4; 125.9;
128.2; 128.3; 139.8; 140.7; 145.2; 150.8; 153.8; 155.8. HRMS: calcd
for C16H15N3OþH: 266.1293; exp: 266.1247.
1.3.28. 4-Benzyl-5-methyl-1-(pyridin-2-yl)-1H-pyrazol-3(2H)-one
(16h). This compound was obtained in a 88% yield as a white
powder after a chromatography over silica gel (dichloromethane–
ethanol 100/0 to 97/3). Mp¼163 ꢀC. 1H NMR (DMSO-d6): 2.53
(s, 3H); 3.66 (s, 2H); 7.22 (m, 6H); 7.65 (d, 1H, J¼8.1); 7.87 (m, 1H);
8.37 (m, 1H); 10.36 (s, 1H). 13C NMR (DMSO-d6): 13.2; 27.1; 106.7;
114.1; 119.8; 125.7; 127.9; 128.2; 138.4; 138.6; 140.9; 147.3; 153.3;
160.8. HRMS: calcd for C16H15N3OþH: 266.1293; exp: 266.1241.
1.3.29. 3-Ethoxy-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic
acid
1.5. General preparation of 2-pyridyl derivatives using 2-
fluoropyridine
(17). By treating 11i with hydrogen bromide in acetic acid at 140 ꢀC
as described above, compound 17 was obtained in a 63% yield as
a white powder after a chromatography over silica gel (dichloro-
methane–ethanol 100/0 to 96/4). Alternatively, this compound was
obtained by heating in a microwave oven compound 11i (0.25 g;
0.95 mmol) and sodium hydroxide (0.86 g, 21.5 mmol) in a 3/1
water–ethanol mixture (2 mL) for 15 min at 140 ꢀC. Upon acidifi-
cation of the diluted reaction mixture and extraction with ethyl
acetate, compound 17 was also obtained (0.19 g, 85%). Mp¼190 ꢀC.
1H NMR (DMSO-d6): 1.38 (t, 3H, J¼7.1); 4.36 (q, 2H, J¼7.0); 7.36 (m,
1H); 7.78 (d, 1H, J¼8.2); 7.99 (m, 1H); 8.45 (m, 1H); 8.73 (s, 1H);
12.43 (s (br), 1H). 13C NMR (DMSO-d6): 15.0; 65.2; 103.5; 112.1;
In a 0.5–2 mL Biotage tube, the alkoxypyrazoles (3.9 mmol),
cesium carbonate (1.42 g, 4.3 mmol) were dispersed 2-fluoropyr-
idine (1.1 mL). The suspension was heated as described in the text,
and diluted in ethyl acetate. The organic layer was washed with
water, with brine, dried over magnesium sulfate, and concentrated
to dryness. The residue was purified as described below.
1.5.1. 2-(5-Ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine
(12b). A chromatography over silica gel (dichloromethane–cyclo-
hexane 1/1 to 3/1) led to compound 12b as an oil in a 38% yield. 1H

2662
S. Guillou et al. / Tetrahedron 66 (2010) 2654–2663
NMR (CDCl3): 1.48 (t, 3H, J¼7.1); 4.26 (q, 2H, J¼7.1); 5.94 (s, 1H);
7.30 (m, 1H); 7.70 (m, 1H); 7.84 (m, 1H); 8.60 (m, 1H). 13C NMR
(CDCl3): 14.4; 69.0; 85.1; 117.5; 120.8 (q, J¼268); 122.7; 138.3; 142.8
(q, J¼38); 148.9; 150.4; 155.5. HRMS: calcd for C11H10F3N3OþH:
258.0854; exp: 258.0826.
Mp¼93 ꢀC. 1H NMR (CDCl3): 1.41 (t, 3H, J¼7.0); 2.81 (m, 2H); 3.31 (s,
2H); 3.46 (s, 2H); 3.77 (s, 2H); 4.34 (q, 2H, J¼7.0); 7.00 (m, 1H);
7.28–7.43 (m, 5H); 7.70 (m, 1H); 7.78 (m, 1H); 8.31 (m, 1H). 13C NMR
(CDCl3): 14.8; 26.7; 47.8; 50.0; 62.0; 64.3; 104.5; 112.9; 119.1; 127.2;
128.3; 129.0; 138.0; 138.4; 140.1; 147.4; 153.6; 160.2. HRMS: calcd
for C20H22N4OþH: 335.1872; exp.: 335.1870.
1.5.2. 2-(3-Ethoxy-5-iodo-1H-pyrazol-1-yl)pyridine (11k). A chro-
matography over alumina containing 1.5% of water (dichloro-
methane–cyclohexane 1/2) led to compound 11k as a solid.
Mp¼76 ꢀC. 1H NMR (CDCl3): 1.43 (t, 3H, J¼7.1); 4.29 (q, 2H, J¼7.1);
6.17 (s,1H); 7.25 (m,1H); 7.74 (m,1H); 7.82 (m,1H); 8.50 (m,1H). 13C
NMR (CDCl3): 14.8; 64.8; 106.3; 116.9; 120.0; 121.9; 138.3; 147.4;
152.3; 165.6. HRMS: calcd for C10H10IN3OþH: 315.9947; exp:
315.9933.
1.8. Reduction of compound 24, isolation of 25 and 26
In a 22 mL steel reactor, compound 24 (0,29 g 0,87 mmol) and
10% palladium over charcoal (0.09 g, 0.087 mmol) were dispersed
in acetic acid (10 mL). Hydrogen was charged into the reactor
(25 bar) and then heated at 65 ꢀC for 3 h. The reactor was cooled,
hydrogen was removed under vacuum, and the resulting solution
filtrated and concentrated to dryness. The residue was dissolved in
dichloromethane; this solution was washed with a saturated
solution of sodium hydrogencarbonate, with brine, dried over
magnesium sulfate, and concentrated to dryness. The residue was
purified by a chromatography over silica gel (dichloromethane–
ethanol 9/1) to yield compounds 25 and 26 as described below.
1.5.3. 2-(5-Ethoxy-3-iodo-1H-pyrazol-1-yl)pyridine (12k). A second
chromatography of the corresponding fraction over silica gel (ethyl
acetate–cyclohexane 1/4).led to compound 12k as
a solid.
Mp¼71 ꢀC. 1H NMR (CDCl3): 1.46 (t, 3H, J¼7.0); 4.21 (q, 2H, J¼7.0);
5.86 (s, 1H); 7.24 (m, 1H); 7.76 (m, 1H); 7.80 (m, 1H); 8.56 (m, 1H).
13C NMR (CDCl3): 14.5; 68.7; 95.8; 98.3; 116.5; 122.0; 138.2; 148.8;
150.2; 155.5. HRMS: calcd for C10H10IN3OþH: 315.9947; exp:
316.0002.
1.8.1. 3-Ethoxy-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
c]pyridine (25). This compound was obtained as a solid in a 16%
yield. Mp¼99 ꢀC. 1H NMR (DMSO-d6): 1.35 (t, 3H, J¼7.0); 2.92 (s
(br), 2H); 3.05 (s (br), 2H); 3.58 (s (br), 2H); 4.28 (q, 2H, J¼7.0); 7.18
(m, 1H); 7.69 (m, 1H); 7.88 (m, 1H); 8.36 (m, 1H). 13C NMR (DMSO-
d6): 14.7; 26.9; 30.7; 42.3; 63.8; 104.4; 112.6; 119.7; 138.8; 140.1;
147.5; 152.8; 159.6. HRMS: calcd for C18 H16N4OþH: calcd 245.1333;
exp: 245.1402.
1.6. Suzuki reaction between 11k and phenylboronic acid,
alternative preparation of 11e
In a 10 mL Biotage tube, compound 11k (0.24 g, 0.76 mmol),
phenylboronic acid (0.11 g, 0.91 mmol), cesium carbonate (0.62 g,
1.9 mmol) were dispersed in a 1/1 mixture of propanol and water
(4 mL). The suspension was degassed by a slow stream of argon and
[1,10-bis(diphenylphosphino)ferrocene] dichloropalladium com-
plexed with dichloromethane (0.03 g, 0.038 mmol) was added. The
tube was sealed and heated in a microwave oven for 90 min at
130 ꢀC. The resulting mixture was diluted in ethyl acetate, washed
with brine, dried over magnesium sulfate, and concentrated to
dryness. The residue was purified by a chromatography over silica
gel (cyclohexane–ethyl acetate 98/2 to 9/1) to yield compound 11j
(0.03 g, 20%) and then compound 11e (0.08 g, 39%) as described
above.
1.8.2. 3-Ethoxy-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine
(26). This compound was obtained as a solid in a 13% yield.
Mp¼78 ꢀC (dec). 1H NMR (CDCl3): 1.36 (m, 3H); 2.64 (s (br), 2H);
2.00–5.00 (large ‘bump’, 4H); 4.35 (m, 2H). 13C NMR (CDCl3): 14.9;
64.2; with our reverse 13C NMR probe no other carbon signals could
be seen. HRMS: calcd for C8H13N3OþH: calcd 168.1137; exp:
168.1115.
Acknowledgements
This work was supported by the Medicen initiative (Chemical
1.7. Negishi reaction between 11k and benzylzincbromide,
alternative preparation of 11f
´
Library Project; grants of the Region Ile de France no I 06-222/R and
I 09-1739/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.
In a 10 mL Biotage tube, under an argon atmosphere, compound
11k (0.21 g, 0.66 mmol) and [1,10-bis(diphenylphosphino)ferro-
cene] dichloropalladium complexed with dichloromethane
(0.027 g, 0.033 mmol) were dissolved in a 0.5 M solution of ben-
zylzincbromide in THF (4 mL, 2 mmol). The tube was sealed and
heated in a microwave oven for 30 min at 110 ꢀC. The solution was
diluted in ethyl acetate, washed with brine, dried over magnesium
sulfate, and concentrated to dryness. The resulting residue was
purified by a chromatography over alumina containing 1.5% of
water (cyclohexane–ethyl acetate 98/2) to yield, as seen by 1H NMR,
a ‘pure’ 1/2.8 mixture of compound 11j and 11f (0.12 g) from which
the more volatile compound 11j (0.04 g, 32%) could be completely
removed under high vacuum in a few days to give clean compound
11f (0.08 g, 43%) as described above.
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