Few unexpected results from a Suzuki-Miyaura reaction

Article abstract of DOI:10.1016/j.tet.2012.01.019

In the course of the synthesis of original anti-infectious compounds we focused on the palladium-catalyzed Suzuki-Miyaura aryl-aryl coupling reaction between 2-(3-ethoxy-5-iodo-1H-pyrazol-1-yl)pyridine and phenylboronic acid. A study of the reaction products obtained under different conditions (various ligands and solvents), not only provided us with insights to optimize this reaction but also with few side compounds, resulting from CH activation, along with the unexpected bis(3-ethoxy-1-(pyridin-2-yl)-1H-pyrazol-5-yl)palladium. Stochiometric experiments with this remarkably stable biscyclopalladated reagent and phenylhalides pointed out the occurrence of aryl-aryl coupling, possibly via palladium IV intermediates.

Full text of DOI:10.1016/j.tet.2012.01.019

Tetrahedron 68 (2012) 2135e2140
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Few unexpected results from a SuzukieMiyaura reaction
,
,
a,b,
Elise Salanouve a b, Pascal Retailleau c , Yves L. Janin
*
*
a Institut Pasteur, 28 rue du Dr. Roux, F-75724 Paris cedex 15, France
b CNRS UMR 3523, 28 rue du Dr. Roux, F-75724 Paris cedex 15, France
c Service de Cristallochimie, Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette cedex, 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 the synthesis of original anti-infectious compounds we focused on the palladium-
catalyzed SuzukieMiyaura arylearyl coupling reaction between 2-(3-ethoxy-5-iodo-1H-pyrazol-1-yl)
pyridine and phenylboronic acid. A study of the reaction products obtained under different conditions
(various ligands and solvents), not only provided us with insights to optimize this reaction but also with
few side compounds, resulting from CH activation, along with the unexpected bis(3-ethoxy-1-(pyridin-2-
yl)-1H-pyrazol-5-yl)palladium. Stochiometric experiments with this remarkably stable biscyclopalla-
dated reagent and phenylhalides pointed out the occurrence of arylearyl coupling, possibly via palla-
dium IV intermediates.
Received 4 November 2011
Received in revised form 3 January 2012
Accepted 11 January 2012
Available online 16 January 2012
Keywords:
Palladacycle
Palladium(IV)
CH activation
CeC coupling
Cross-coupling
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
H
i
N
N
ii
N
N
N
RO
RO
Following our work on the preparation of libraries of new
chemical entities in the pyrazole series,1e6 screening campaigns
resulted in the identification of few derivatives of potential bi-
ological interest. This led to renewed effort to design simple
preparations of analogues of these compounds and, in the
present instance, to focus on the model preparation of 2-(3-
ethoxy-5-phenyl-1H-pyrazol-1-yl)pyridine (6). The synthesis of
6 was planned via a SuzukieMiyaura arylearyl coupling7e9 of
the 5-iodinated pyrazole building block 4 and phenylboronic
acid (5).
1a: R = Et
1b: R = Me
3a (95 %)
3b (80 %)
B(OH)2
N
N
N
N
N
N
EtO
EtO
+
I
4 (73 %)
6
5
Scheme 1. i: 2-FC5H4N (2),Cs2CO3, MeCN, 140 ꢀC ii: (a) BuLi, THF, ꢁ78 ꢀC, (b) I2, THF.
Table 1 summarizes up few SuzukieMiyaura coupling trials
between compound 4 and phenylboronic acid (5). Entry 1 de-
scribes our previously reported results for comparison purposes.5
A change of solvent for a dioxane/water mixture with the same
catalyst was not successful. The use of the combination of pal-
ladium acetate and XPhos depicted in entries 2 and 3 were more
successful. Most unexpectedly, from the 5% of palladium used in
the assay described in entry 2, we could isolate 4% of the bis(1-
(pyridin-2-yl)-1H-pyrazol-5-yl)palladium II complex (7a) along
with 51% of the target compound 6 and 40% of the reduced
material 3a. The 1H NMR and LC/MS analysis of reaction samples
also pointed out the occurrence of the dimeric compound 8 al-
though we could not properly separate it from phosphine oxide
derivatives in this trial. Finally, in a series of trials in DMF (entries
3e5) we could point out that a high temperature was detrimental
2. Results and discussion
As shown in Scheme 1, to avoid a low 11% overall yield we en-
countered in our previous preparation of compound 4,5 we un-
dertook the pyridylation of 3-alkoxypyrazole 1a,b with 2-
fluoropyridine (2). Selective N-arylations of 1a,b were achieved at
140 ꢀC in 80e95 % yield using 2-fluoropyridine, caesium carbonate
in acetonitrile. Treatment of the resulting 1-pyridyl-3-
ethoxypyrazole 3a with butyllithium followed by the addition of
iodine then gave the 5-iodinated building block 4 in a much im-
proved 60% overall yield.
* Corresponding authors. Tel.: þ33 (0) 145688297; fax: þ33 (0) 1456888404;
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.2012.01.019

2136
E. Salanouve et al. / Tetrahedron 68 (2012) 2135e2140
Table 1
Coupling trials of compounds 4 and 5a
Pd, ligands
4 + 5
PdOAc
i
6 + 3a +
N
Cs2CO3, Solvent,
t (h) and T (°C)
10
ref 10
N
N
N
N
N
N
N
ii
EtO
+
N
N
Pd
OEt
N
N
9
N
ref 12
N
N
N
OEt
EtO
7a
8
11 (86 %)
Catalyst
PdCl2, dppf
Pd(OAc)2, 2XPhos Dioxane/H2O 3:1 100/12
Solvent
T/tb
130/1.5 39
%6 %3a %7a %8
N
N
AcO
1
2
3
4
5
n-PrOH/H2O 1:1
20
40
7
d
d
Pd
12 (98 %)
51
52
62
80
4
<5
<5
<5
d
N
AcO
Pd(OAc)2, 2XPhos DMF
Pd(OAc)2, 2XPhos DMF
Pd(OAc)2, 2XPhos DMF
160/3
140/3
120/40
n.i.
n.i.
n.i.
i
6
9
EtO
a
Isolated yield.
In ꢀC and hours.
N
b
N
N
N
EtO
N
N
N
N
N
EtO
+
iii/iv
N
to the reaction yield as the coupling reaction stalled and the
corresponding starting material recovered. However, at 120 ꢀC,
the target 5-phenyl derivative 6 was obtained in 80% yield. We
N
OEt
N
N
N
N
EtO
RO
3a: R = Et
3b: R = Me
suggest that
a temperature-dependant catalyst deactivation,
13 (16 % via iii)
14 (4.5 % via iii)
leading to compound 7a, is the source of this effect. A 120 ꢀC
temperature is appearing to be optimal in balancing this de-
activation and the coupling reaction. At 100 ꢀC, the latter turned
out to be exceedingly slow (50% conversion in 3 days).
N
N
N
N
N
EtO
v
+
Beyond this optimization, the isolation of the uncommonly
stable palladium derivative 7a was of interest in itself. A litera-
ture search pointed out another case of a stable pyrazole-bearing
palladacycle10 and the remarkable chemistry of 2-phenylpyridine
PdII derivatives involving reaction intermediates related to
compound 7a.11e16 Indeed, the preparation of the cyclo-
N
N
N
Pd
N
OEt
N
N
N
OR
RO
7a (7 %, via iii; 75 % via iv)
7b (50 % via iv)
8 (34 %)
Scheme 2. i: Pd(OAc)2, MeOH, 25 ꢀC, 12 h. ii: 5% Pd(OAc)2, oxone, i-PrOH, 25 ꢀC. iii:
1 equiv Pd(OAc)2, Cs2CO3, DMF, MW, 160 ꢀC. iv: (a) BuLi, THF, ꢁ78 ꢀC, (b) Pd(OAc)2, THF.
v: NCS, DMF 20 ꢀC reflux.
palladated complex 10 (existing mostly as a bimetallic species17
)
was easily achieved by CH activation of 2-phenylpyridine 9 using
palladium acetate at room temperature.11 Moreover, still at room
temperature and under catalytic conditions, the addition of
oxone to this reaction gave 86% of compound 11, resulting from
the palladium-catalyzed oxidative dimerization of compound 9.13
Interestingly, the chemical behaviour of compound 3a markedly
differed from 2-phenylpyridine 9. In our case, the reaction of 3a
with palladium acetate only gave the unmistakable liganded
palladium salt 12 in a 98% yield. We also tried to achieve the
oxidative dimerization of compound 3a with oxone in the pres-
ence of catalytic amount of palladium acetate in isopropanol.13
No reaction occurred at room temperature andddespite the in-
herent explosion risk of heating an oxidizer in an organic sol-
ventdraising the reaction temperature to 110 ꢀC in a microwave
oven had little effect. We suggest that, in the case of 3a, a strong
chelation by the pyridine as well as the pyrazole nitrogens
remove any carbonehydrogen bond from the reach of the pal-
ladium atom. This could also explain why, although carbon 4 or 5
pyrazole CH arylation reactions have been reported,18e24 our
attempts to achieve a catalytic C-5 arylation of compound 3a
have so far met limited success. For instance, heating a stoichio-
metric mixture of 3a and palladium acetate, in DMF at 160 ꢀC in
the presence of caesium carbonate gave the two other possible
dimers 13 and 14 in 16% and 4.5% yield, respectively, along with
7% of palladium complex 7a as well as 43% of unreacted material
3a. The cyclopalladated derivatives 7a,b were also obtained in
much improved 75% and 50% yield via the deprotonation of 3a,b,
followed by the addition of a palladium acetate solution (con-
ditions iv in Scheme 2).25
Few attempts to achieve a simple PdII to Pd0 reductive elimina-
tion with compound 7a, to prepare the dimer 8 failed. On the other
hand, as previously reported for 2-phenylpyridine-based cyclo-
palladated derivatives,14 the oxidation of compound 7a with N-
chlorosuccinimide followed by heating at 130 ꢀC led to an adequate
amount of 8. Interestingly, none of the other two possible dimers 13
and 14 were detected in this experiment. Finally, if compound 7a
failed to provide monocrystals suitable for X-ray diffraction, the
methoxy analogue 7b secured the solid state structure depicted in
Fig. 1. This bispalladacycle thus adopts a symmetrical planar con-
ꢀ
formation, with an average carbonepalladium bond length of 1.97 A
ꢀ
and a nitrogenepalladium bond length of 2.15 A.
Few experiments were conducted in order to investigate the
reactivity of compound 7a and attempt to explain the occurrence of
the side compounds described in Table 1. Heating at up to 190 ꢀC
equal amount of complex 7a, the 5-iodinated derivative 4 and
caesium carbonate in DMF gave the reduced compound 3a in 48%
yield along with traces amount of the dimer 8. Far more in-
terestingly, 86% of the cyclopalladated compound 7a were re-
covered from this trial. This experimental fact led us to suspect
a palladium II-based catalytic process leading to the reduction of
compound 4. Accordingly, as depicted in Table 2 few reactions were
conducted with compound 7a. Heating at 160 ꢀC a mixture of 7a,
3 equiv of the less hindered iodobenzene and caesium carbonate in
DMF (entry 1) gave compound 6 in a 22% yield along with 33% of
unreacted 7a, less than 6% of the reduced material 3a as well as 20%
of the volatile biphenyl (15). A trial with 1.5 equiv of phenylboronic

E. Salanouve et al. / Tetrahedron 68 (2012) 2135e2140
2137
also providing insights in the behaviour of the biscyclopalladated
compound 7a, which markedly differs from other N-pyridylpyr-
azole palladium complexes previously suggested26,27 or character-
ized.10,28 Indeed, we are reporting here an instance of arylearyl
coupling between bromo or iodobenzene and a cyclopalladated
substance. What remains to be fully demonstrated is whether
products 6 and 8 are occurring via an oxidative addition of iodo-
benzene on a palladium II entities to give a palladium IV in-
termediate, or by other more conventional mechanisms.29e31
Reviews are actually describing cases where such oxidative in-
sertions were suggested.32e36 For that matter, recent work have
reported palladium III reaction intermediates for, arguably, related
CH oxidation reactions16,37 and bis(2-pyridylphenyl)palladium IV
sulfinate was demonstrated to undergo a reductive elimination.38
The fact that phenyl bromide reacts more efficiently than phenyl-
iodide with the biscyclopalladated compound 7a to give compound
6 (Table 2 entry 1 and 4) is reminiscent of another case where
a palladium IV intermediate is suspected.39 Concerning the occur-
rence of biphenyl 15, such palladium-catalyzed Ullmann reaction is
far more documented.40e42 In conclusion, we hope that all theses
results are providing an original direction for the design of new
(and remarkably stable) metallic entities potentially useful as tool
for mechanistic studies.31
Fig. 1. X-ray derived ORTEP diagram of the biscyclopalladated compound 7b.
Table 2
Reactivity of 7a with PhX or PhB(OH)2
a
4. Experimental section
4.1. General
N
N
reagents
N
N
Pd
N
N
Cs2CO3, DMF
160 °C, 3h
A Biotage initiator 2 microwave oven was used for reactions
mentioning such heating method. 1H NMR and 13C NMR spectra
were recorded on a Bruker Avance 400 spectrometer at 400 MHz
OEt
EtO
7a
and 100 MHz, respectively. Shifts (d) are given in parts per million
N
N
N
N
N
N
+
+
EtO
with respect to the TMS signal and coupling constants (J) are given
in hertz. Column chromatographies 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 set to 254 nm unless required otherwise. Sample de-
position 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 ob-
tained on an Agilent 1100 series LC/MSD system using an atmo-
spheric electrospray ionization system and the high resolution
mass spectra (HRMS) were obtained using a Waters Micromass Q-
Tof with an electrospray ion source.
EtO
6
3a
15
%15
Reagents
PhIb
%6
%3a
%7a
1
2
3
4
5
21
17
<5
46
d
<6
12
<5
<5
<3
20
50
d
24
d
33
28
>90
6
PhIcþPhB(OH)2
c
b
PhB(OH)2
PhBrb
PhClb
84
a
b
c
Isolated yield.
3 equiv.
1.5 equiv.
4.1.1. 3-Methoxy-1H-pyrazole (1b). This compound was prepared
in the two following steps. Step 1: dimethylmethox-
ymethylenemalonate (54.40 g, 0.31 mol) and hydrazine mono-
hydrochloride (22.04 g, 0.32 mol) were refluxed in ethanol
(600 mL) for 16 h. The solvents were removed under reduced
pressure and the residue was dispersed in water (500 mL). The
precipitate was filtered, washed with 1N hydrochloric acid. The
filtrate was cautiously made basic with solid potassium carbonate,
this was extracted with ethyl acetate and the organic layer was
washed with a saturated solution of sodium hydrogencarbonate,
brine, dried over sodium sulfate and concentrated to dryness. The
resulting residue was recrystallized in toluene (130 mL) to yield
methyl 3-methoxy-1H-pyrazole-4-carboxylate (8.51 g, 17%).
Mp¼125 ꢀC. 1H (CDCl3): 3.83 (s, 3H); 4.02 (s, 3H); 7.92 (s, 1H); 10.25
(br s, 1H). 13C (CDCl3): 51.3; 56.6; 99.3; 134.3; 162.8; 163.3. HRMS:
calcd for C6H8N2O3þH: 157.0613. Found: m/z, 157.0620. Step 2: the
intermediate ester (3.3 g, 0.021 mmol) was dispersed in 6N
hydrochloric acid (40 mL). This was heated to reflux until the end of
the carbon dioxide evolution (1 h in the present case). The aqueous
phase was diluted in water, slowly made basic by the addition of
sodium hydrogencarbonate, saturated with sodium chloride and
acid and 1.5 equiv of iodobenzene (entry 2) resulted in 34% of 6, 28%
of unreacted 7a, 12% of 3a and an increased 50% of biphenyl (15).
Slightly more unexpectedly, a trial with only phenylboronic acid
under the same conditions (entry 3) actually led to detectable
amount of compounds 6 and 3a, although 90% of the cyclo-
palladated complex 7a was recovered and the occurrence of phenol
was noted. Remarkably, the arylation reaction with bromobenzene
(entry 4) was far more efficient as a 46% yield of compound 6 was
isolated (close to a theoretical maximum of 50% ?) along with traces
of the reduced 3a, 20% of biphenyl 15 and 6% of the starting ma-
terial 7a. In this somewhat cleaner reaction, we could also detect
traces of the dimer 13. Finally, no arylation with chlorobenzene was
detected (entry 5) and the occurrence of less than 3% of 3a was
observed. All our attempts to isolate the water-soluble components
of these reaction trials have, so far, only pointed out their instability.
3. Conclusion
This report is describing few side reactions involving nitrogen-
bearing chelating substrates, such as 3a or 4 and palladium. It is

2138
E. Salanouve et al. / Tetrahedron 68 (2012) 2135e2140
extracted with ethyl acetate four times. The organic phase was
washed with a 1N solution of sodium hydrogencarbonate once,
with brine once, dried over sodium sulfate and concentrated to
dryness to yield compound 1b as a volatile oil (1.25 g, 60%). 1H
(CDCl3): 3.92 (s, 3H); 5.73 (d, 1H, J¼2.5 Hz); 7.37 (d, 1H, J¼2.5 Hz).
13C (CDCl3): 56.6; 89.6; 130.4; 164.4.
compound 6 (0.21 g, 80%) featuring spectroscopic data identical
with the previously reported one.5
4.2.5. Compound 3a, complexed with palladium acetate (12). A
suspension of compound 3a (0.41 g, 0.0021 mol) and palla-
dium acetate (0.38 g, 0.0017 mol) were stirred overnight in
methanol (5 mL). The resulting solution was dispersed in
diethyl ether, the precipitate formed was filtered washed with
diethyl ether and dried under vacuum to yield complex 12
(0.69 g, 98%). 1H (CDCl3): 1.42 (t, 3H, J¼7.1 Hz); 2.05 (s, 3H);
2.14 (s, 3H); 3.98 (q, 2H, J¼7.1 Hz); 5.99 (d, 1H, J¼3.4 Hz); 7.05
(m, 1H); 7.78 (m, 1H); 8.10 (m, 1H); 8.55 (m, 1H); 9.37 (d, 1H,
J¼3.4 Hz). Note: this substance is not soluble enough
in chloroform to obtain complete 13C spectra and it partially
decomplexes in DMSO.
4.2. General method for the preparation of 3a,b
In
a 450 mL pressure steel reactor the considered 3-
alkoxypyrazole (0.044 mol), caesium carbonate (20.2 g,
0.062 mol), 2-fluoropyridine (6.02 g, 0.062 mol) and acetonitrile
ꢀ
ꢀ
(145 mL, dried over 4 A molecular sieve) were heated at 140 C for
72 h. After cooling, the suspension was diluted in water and
extracted with ethyl acetate. The organic layer was washed with
water, brine and concentrated to dryness to yield pure compounds
3a,b as oils in the yield mentioned in the text.
4.3. General method for the preparation of 7a,b
4.2.1. 2-(3-Ethoxy-1H-pyrazol-1-yl)pyridine
(3a). Spectroscopic
Under an argon atmosphere, the considered alkoxypyrazole
data identical with the reported one.5
3a or 3b (3.70 mmol) was dissolved in dry tetrahydrofuran
ꢀ
(37 mL, dried over 4 A molecular sieve). This was cooled to
4.2.2. 2-(3-Methoxy-1H-pyrazol-1-yl)pyridine (3b). 1H (CDCl3):
4.01 (s, 3H); 5.93 (d, 1H, J¼2.7 Hz); 7.10 (m, 1H); 7.76 (m, 1H); 7.83
(m, 1H); 8.35 (m, 1H); 8.38 (d, 1H, J¼2.7 Hz). 13C (CDCl3): 56.3; 94.6;
111.4; 120.2; 128.3; 138.5; 147.9; 151.4; 165.5. HRMS: calcd for
C9H9N3OþH: 176.0824; found: 176.0804.
ꢁ78 ꢀC and 2 M n-butyllithium solution in cyclohexane (1.8 mL,
3.70 mmol) was then slowly added with a syringe. The resulting
yellow mixture was stirred at ꢁ78 ꢀC for 30 min before adding
a solution of palladium (II) acetate (0.33 g, 1.48 mmol) dissolved
ꢀ
in dry tetrahydrofuran (20 mL, dried over 4 A molecular sieve).
This was stirred at ꢁ78 ꢀC for 30 min and then allowed to warm
to room temperature. The resulting solution was diluted in ethyl
acetate, washed successively with water and brine. The organic
phase was dried over magnesium sulfate and the solvent re-
moved under vacuum. The resulting residue was dispersed in
boiling cyclohexane and the cold suspension filtered to yield
compounds 7a or 7b as yellow powders in the yield mentioned in
the text.
4.2.3. 2-(3-Ethoxy-5-iodo-1H-pyrazol-1-yl)pyridine (4). Under an
argon atmosphere, a stirred solution of compound 6a (3.5 g,
18.5 mmol) in dry tetrahydrofuran (35 mL, dried over 4 A molec-
ꢀ
ular sieve) was cooled to ꢁ78 ꢀC. A 2 M n-butyllithium solution in
cyclohexane (11.1 mL, 22.2 mmol) was slowly added with a syringe.
The yellow mixture was then stirred at ꢁ78 ꢀC for 40 min. The
resulting reddish solution was quenched with a solution of iodine
(7.04 g, 27.7 mmol) dissolved in dry tetrahydrofuran (25 mL, dried
ꢀ
over 4 A molecular sieve) and then allowed to warm to room
4.3.1. Bis(3-ethoxy-1-(pyridin-2-yl)-1H-pyrazol-5-yl)palladium
(7a). Mp>260 ꢀC. 1H (CDCl3): 1.47 (t, 3H, J¼7.1 Hz); 4.28 (q, 2H,
J¼7.1 Hz); 5.87 (s, 1H); 6.94 (m, 1H); 7.47 (m, 1H); 7.74 (m, 1H); 8.14
(m, 1H) 13C (CDCl3): 26.9; 64.7; 100.7; 110.6; 117.5; 140.1; 145.9;
154.0; 154.7; 166.7. HRMS: calcd for C20H20N6O2PdþH: 483.0761;
found: 483.0775. Micro-analysis: calcd for C20H20N6O2Pdþ1/11th
toluene C: 50.46%; H: 4.25%; N: 17.11%; found: C: 50.37%; H: 4.50%;
N: 17.49%.
temperature. This was treated with a sodium disulfite solution and
extracted with ethyl acetate. The organic phase was washed with
water, brine, dried over magnesium sulfate and the solvent was
removed under vacuum to give a yellow oil. This was purified by
a chromatography over silica gel (cyclohexane/ethyl acetate 6:1) to
yield compound 4 (4.62 g, 79%) as a light yellow powder. Its
spectroscopic data were identical with the reported one,5 although
one 13C signal had slipped our attention; here is the corrected
spectra: 13C (CDCl3): 14.7; 64.8; 77.7; 106.4; 116.8; 121.7; 138.2;
147.3; 152.3; 165.6. Another chromatography fraction yielded 2-(3-
ethoxy-5-iodo-1H-pyrazol-1-yl)-3-iodopyridine (0.92 g, 11%) as
a white powder. Mp¼146 ꢀC. 1H (CDCl3): 1.49 (t, 3H); 4.29 (q, 2H);
6.11 (s, 1H); 7.15 (m, 1H); 8.32 (m, 1H); 8.61 (m, 1H); 7.86 (m, 1H).
13C (CDCl3): 14.7; 64.8; 82.4; 93.8; 103.4; 125.6; 148.4; 148.9;
153.6; 165.2. HRMS: calcd for C10H9N3I2OþNa: 463.8733; found:
463.8723.
4.3.2. Bis(3-methoxy-1-(pyridin-2-yl)-1H-pyrazol-5-yl)palladium
(7b). Mp>260 ꢀC. 1H (CDCl3): 4.00 (s, 3H); 5.90 (s, 1H); 6.98 (m,
1H); 7.52 (m, 1H); 7.78 (m, 1H); 8.20 (m, 1H). 13C (CDCl3): 56.2;
100.7; 110.6; 117.6; 140.6; 146.0; 154.1; 154.8; 167.5. HRMS: calcd
for C18H17N6O2PdþH: 455.0448; found: 455.0487. A sample of 3b
was dissolved in an excess of boiling toluene and left in an open
flask to crystallize inside a large dessiccator over a month to yield
monocrystals, containing some toluene but suitable for X-ray
analysis.
4.2.4. 2-(3-Ethoxy-5-phenyl-1H-pyrazol-1-yl)pyridine (6) by the
SuzukieMiyaura reaction. In a Biotage tube, compound 4 (0.31 g,
0.98 mmol), caesium carbonate (1.28 g, 3.92 mmol) and phenyl-
boronic acid (0.26 g, 2.13 mol) were dispersed in dime-
4.3.3. 5,50-Diethoxy-2,20-di(pyridin-2-yl)-2H,20H-3,30-bipyrazole
(8). Compound 7a (0.15 g, 0.31 mmol) was dissolved in dry DMF
ꢀ
(20 mL, dried over 4 A molecular sieve). N-chlorosuccinimide
ꢀ
thylformamide (16 mL, dried over 4 A molecular sieve). The
(0.039 g, 0.29 mmol) was added and the solution was stirred at
room temperature for 30 min before heating it to reflux for 15 min.
The resulting dark solution was diluted in ethyl acetate, washed five
times with water, brine, dried over magnesium sulfate and con-
centrated to dryness. The residue was further purified by a chro-
matography over silica gel (cyclohexane/ethyl acetate 5:1) to yield
compound 8 as white powder (0.04 g, 34%). Mp¼218 ꢀC. 1H (CDCl3):
1.46 (t, 3H, J¼7.1 Hz); 4.36 (q, 2H, J¼7.1 Hz); 6.07 (s, 1H); 6.83 (m,
1H); 7.50 (m, 2H); 7.93 (m, 1H). 13C (CDCl3): 14.9; 64.9; 97.3; 114.6;
suspension was degassed with a slow stream of argon and a pre-
milled 1:2 mixture of palladium(II) acetate and XPhos (0.058 g,
0.049 mmol) was added. This was sealed and heated in an oil bath
at 120 ꢀC for 40 h. The resulting suspension was diluted in ethyl
acetate, the organic layer was washed with water and brine, dried
over magnesium sulfate and concentrated under vacuum. The
resulting residue was then purified by a chromatography over
first over silica (cyclohexane/ethyl acetate 95e5 to 9/1) to give

E. Salanouve et al. / Tetrahedron 68 (2012) 2135e2140
2139
120.1; 134.4; 137.6; 147.5; 152.3; 163.3 HRMS: calcd for
C20H20N6O2þH: 377.1726; found: 377.1741.
squares methods (SHELXL-97).45 All non-hydrogen atoms were
refined anisotropically whereas all H atoms were located in dif-
ference maps and then treated as riding atoms in geometrically
idealized positions. Despite efforts to model the toluene molecule
disordered over a centre of inversion satisfactorily, decision was
taken to resort to the squeeze procedure as implemented in the
PLATON46 suite was used to treat the solvent disorder. Its contri-
bution to the diffraction pattern was removed and modified Fo2
written to a new HKL file. The number of electrons thus located, 54
per unit cell, was approximately assigned to one molecule of tol-
4.4. Preparation of compounds 13 and 14
In a Biotage tube, compound 3a (0.44 g, 0.0023 mol), palladium
acetate (0.52 g, 0.0023 mol) and caesium carbonate (1.6 g,
0.0046 mol) were dispersed in dimethylformamide (12 mL, dried
ꢀ
over 4 A molecular sieve). This was sealed and heated in a micro-
wave oven at 160 ꢀC for 4 h. The resulting suspension was dispersed
in ethyl acetate and water, the organic layer was washed with water
five times, with brine, dried over magnesium sulfate and concen-
trated to dryness. The residue was purified by a chromatography
over silica gel (cyclohexane/ethyl acetate from 95:5 to 1:2) to yield,
in order of elution, compound 3a (0.19 g, 43%), compound 13 as
a white powder (0.07 g, 16%), compound 14 as an oil (0.02 g, 4.5%)
and compound 7a as a yellow powder (0.04 g, 7%).
ꢀ
uene solvent per unit cell corresponding to a void of 154 A. This was
taken into account in the formula, formula weight, calculated
density, and F(000).
Results for compound 7b: C18H16N6O2 Pd, 0.5(C7H8) Mr¼500.83,
ꢀ
0.30ꢂ0.25ꢂ0.05 mm, triclinic, space group Pꢁ1, a¼8.269(2) A,
ꢀ
ꢀ
b¼10.966(2)ꢀ A, c¼11.960(4) A,
a
¼68.326(4)ꢀ,
b
¼79.224(6)ꢀ,
3
ꢀ
g
¼89.443(7) , V¼988.0(4) A , Z¼2, rcalcd¼1.684 g cmꢁ3, F(000)¼
max¼59.54ꢀ (dmin¼0.83 A), ꢁ8ꢃhꢃ8,
ꢀ
ꢀ
506,
l
(PX-3¼0.8266 A, 2
q
4.4.1. 3,30-Diethoxy-1,10-di(pyridin-2-yl)-1H,10H-4,40-bipyrazole
(13). Mp¼214 ꢀC. 1H (CDCl3): 1.57 (t, 3H, J¼7.1 Hz); 4.53 (q, 2H,
J¼7.1 Hz); 7.08 (m,1H); 7.75 (m,1H); 7.81 (m,1H); 8.39 (m,1H); 8.73
(s, 1H) 13C (CDCl3): 14.9; 65.0; 101.6; 111.3; 119.7; 124.6; 138.3;
147.9; 151.6; 161.8. HRMS: calcd for C20H20N6O2þH: 377.1726;
found: 377.1717.
ꢁ11ꢃkꢃ12, ꢁ13ꢃlꢃ13, 5068 measured reflections, 2546 in-
dependent, R(int)¼0.0759, 246 parameters were refined against all
reflections, R1¼0.0568, wR2¼0.1395 (using all data) based on ob-
served F values, R1¼0.0557, wR2¼0.1382 (2438 reflections with
ꢀꢁ3
I>2
based on F2.
The file CCDC-847343 contains the supplementary crystallo-
s
(I)), Drmin and Drmax¼ꢁ1.146 and 1.612 e A , GOF¼1.038
4.4.2. 30,5-Diethoxy-10,2-di(pyridin-2-yl)-10H,2H-3,40-bipyrazole
(14). 1H (CDCl3): 1.16 (t, 3H, J¼7.1 Hz); 1.46 (t, 3H, J¼7.1 Hz); 4.20 (q,
2H, J¼7.1 Hz); 4.35 (q, 2H, J¼7.1 Hz); 6.13 (s, 1H); 7.11 (m, 1H); 7.19
(m, 1H); 7.66 (m, 1H); 7.78 (m, 3H); 8.35 (m, 1H); 8.40 (m, 1H); 8.53
(s, 1H). 13C (CDCl3): 14.4; 14.9; 64.7 (two signals); 95.5; 101.8; 111.4;
117.6; 120.3; 121.3; 127.1; 135.0; 138.1; 138.4; 147.7; 147.9; 151.2;
153.3; 161.4; 163.9. HRMS: calcd for C20H20N6O2þH: 377.1726;
found: 377.1717.
graphic data for compound 7b. These data can be obtained free of
charge on application to the Director, CCDC 12 Union Road, Cam-
bridge CB2 1EZ, UK (fax (þ44) 1223 336033; or e-mail depos-
it@ccdc.cam.uk) or via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
The initial project, leading to this work, was supported by the
ꢁ
Medicen initiative (Chemical Library Project; grants of the Region
4.5. Typical procedure used for the trials described in Table 2
Ile de France no I 06-222/R and I 09-1739/R). We also acknowledge
Synchrotron SLS (Villigen, Switzerland) for the provision of syn-
chrotron radiation facilities, and we would like to thank Martin
Fuchs for assistance with the use of the beamline X06DA.
In a Biotage vial, compound 7a (0.245 g, 0. 50 mmol), (0.24 g,
1.52 mmol) and caesium carbonate (0.51 g, 1.57 mmol) in DMF
ꢀ
(3 mL, dried over 4 A molecular sieve) were heated with micro
waves at 160 ꢀC for 3 h. The resulting suspension, containing in-
soluble black material, was dispersed in a mixture of water and
ethyl acetate. The organic layer was washed five times with water,
once with brine, dried over magnesium sulfate and concentrated to
dryness. The resulting residue was purified by a chromatography
over silica gel (cyclohexane/ethyl acetate, from 95:5 to 1:2) to yield,
in order of elution, compound 15 (0.03 g, 24%), compound 3a along
with detectable amount of compound 13 (0.009 g, less than 5%)
compound 5 (0.125 g, 46%) and the starting material 7a (0.012 g,
6%). Biphenyl (15) displayed 1H and 13C NMR spectra identical with
a commercially available sample.
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