Optimized palladium-based approaches to analogues of PK 11195

Article abstract of DOI:10.1002/jhet.5570450520

(Chemical Equation Presented) The peripheral-type benzodiazepine receptor ligands such as PK 11195 and Ro 5-4864 were found more than twenty years ago in the course of research on neurobiology. These ligands were instrumental in pointing out an involvement of the peripheral-type benzodiazepine receptor (PBR) in apoptosis processes. With in mind an improvement of the solubility of PK 11195 in biological media, we report here improved reaction conditions for the palladium-based arylation reaction of alkyl 1-bromoisoquinoline-3-carboxylates and its ethyl 4-bromoquinoline-2-carboxylate isomer. The use of [1,1′-bis(diphenylphosphino) ferrocene] dichloropalladium as a precatalyst enabled a much improved preparation of an array of the 1-arylisoquinoline-3- carboxylates as well as 4-arylquinoline-3-carboxylates. This work should pave the way for the design of chemical probes aiming at the elucidation of the PBR biological role(s).

Full text of DOI:10.1002/jhet.5570450520

Sep-Oct 2008
1377
Optimized Palladium-based Approaches to Analogues of PK 11195
Sandrine Guillou, Yves L. Janin*
RA 2128 CNRS-Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
yljanin@pasteur.fr
Received January 23, 2008
O
O
O
ArB(OH)2
O
N
N
Pd(dppf)
Br
Ar
The peripheral-type benzodiazepine receptor ligands such as PK 11195 and Ro 5-4864 were found more
than twenty years ago in the course of research on neurobiology. These ligands were instrumental in
pointing out an involvement of the peripheral-type benzodiazepine receptor (PBR) in apoptosis processes.
With in mind an improvement of the solubility of PK 11195 in biological media, we report here improved
reaction conditions for the palladium-based arylation reaction of alkyl 1-bromoisoquinoline-3-carboxylates
and its ethyl 4-bromoquinoline-2-carboxylate isomer. The use of [1,1'-bis(diphenylphosphino) ferrocene]
dichloropalladium as a precatalyst enabled
a much improved preparation of an array of the
1-arylisoquinoline-3-carboxylates as well as 4-arylquinoline-3-carboxylates. This work should pave the
way for the design of chemical probes aiming at the elucidation of the PBR biological role(s).
J. Heterocyclic Chem., 45, 1377 (2008).
The peripheral benzodiazepine receptors (PBR), also
named the mitochondrial diazepam binding inhibitor
receptor as well as mitochondrial benzodiazepine receptor
or the ꢀ3 receptor [1], or more recently the translocator
protein (18 kDa) [2], have been the subject of researches
for more than 25 years. The many biological studies
undertaken in this field have been very well reviewed
[3-10]. Its discovery stemmed from central nervous
system research programs that led to the preparation of
PK 11195 (1) [11,12] and Ro 5-4864 (2), which turned
out to bind PBR [13]. One the most remarkable aspect of
this field of research is the fact that the anxiolytic drug
diazepam (3) has a strong affinity for the PBR. This was
the source of some concern in oncology, and led to a
statistical survey in the 80's. This study showed that there
was no promotion or acceleration of breast cancer
progression in the case of diazepam use. On the contrary,
a positive effect, especially for long-term consumers, was
noted although an ascertainment bias could be involved
[14]. More recently, the anxiolytic drug alpidem (4),
another PBR ligand [15], was withdrawn from the human
pharmacopea as several cases of very severe hepatitis
occurred in patients also receiving hepatotoxic drugs
[16-18]. On the other hand, the closely related zolpidem
(5), does not bind PBR [19] and is still a successful
sedative and hypnotic. The fact remains that a clear-cut
picture, explaining the role(s) of PBR and the many-sided
biological effects of PBR ligands is still lacking [3-10].
The limitation of the catalytic system used in the course
of our preparation of 1-arylisoquinoline-3-carboxylates
[20] leads us to report here much improved reaction
O
O
N
N
N
N
Cl
Cl
2: R = Cl
3: R = H
1
R
Cl
O
N
O
N
N
N
N
N
5
4
Cl
Figure 1
conditions. Moreover, we used the optimized conditions
in the construction of the isomeric 3-carboxyl-4-aryl-
quinoline system.
As depicted in scheme 1, from 1-bromoisoquinoline 6,
the reaction conditions previously used [20,21] led to the
3-carboxyl-1-aryl-isoquinolines 7a-e which were readily
hydrolysed to the corresponding acids 8a-e. However, as
described in the experimental part, the coupling reaction
remained very slow and its completion much dependant
on the boronate considered. For instance, a low 36 %
yield was obtained from 4-chloroboronic acid and from
4-pyridylboronic acid very little of the corresponding
coupling product 7f could be detected by LC/MS.

1378
S. Guillou, Y.L. Janin
Vol 45
Scheme 1
out the occurrence of a reductive debromination of
compound 9 (peak with a m/z = 202) as well as the
reductive dimerization product 13 (peak with m/z = 401)
which was isolated in a 4 % yield. Further work led to an
assay using di-tert-butylmethylphosphine as the palladium
ligand and toluene for solvent which led to a much
improved 39 % of compound 12 along with reduced
material (m/z = 202) and as seen by LC/MS, traces of a
biarylether (peak with a m/z = 417).
O
O
OMe
R
i
N
N
6
Br
Ar
Ar
7a-e: R = OMe
8a-e: R = OH
% 7
% 8
65%
74%
75%
ii
C6H5
77%
a
b
c
2-ClC6H4
3-ClC6H4
4-ClC6H4
90%
75%
Scheme 3
O
O
d
e
36%
77%
74%
66%
OEt
OEt
3-pyridyl
4-pyridyl
N
N
f
+
traces
i or ii
9
O
N+
N
i: ArB(OH)2, Pd(PPh3)4, K3PO4, DMF 80°C, 2 days. ii: KOH, H2O /
EtOH reflux.
OEt
O
12
13
Trials from the ethyl ester 9 using [1,1'-bis(diphen-
ylphosphino)ferrocene] dichloro palladium (PdCl2, dppf)
for catalyst, as previously reported [22], turned out to be
rewarding. Indeed, a 72 % yield of the 4-chlorophenyl
ester 10a was obtained. Moreover, the reaction time
turned out to be drastically shorter (one hour instead of
days) and contrary to our previous trials the 4-pyridyl-
bearing product 10b could be prepared in a 58 % yield.
i: pyridine-N-oxide, Pd(OAc)2, P(tBu)3, K2CO3, dioxane, 150 °C μꢀ
heating 1 hour. ii: pyridine-N-oxide, Pd(OAc)2, PMe(tBu)2, K2CO3,
toluene, 170 °C μꢀ heating 45 mn.
By improving a reported procedure using 2-amino-
acetophenone (14) and dimethyloxalate [26] the isomeric
4-hydroxyquinoline 15 was obtained in a 41% yield.
Treatment of this compound with phosphorus oxybromide
gave the 4-bromoquinoline ester 16 in a 73 % yield.
Scheme 2
Scheme 4
O
O
O
OEt
OR
i
NH2
N
N
N
i
O
15 : R = OH
9
Br
Ar
ii
14
16 : R = Br
O
R
Ar
10a-b: R = Et
11b: R = H
% 10
% 11
-
ii
a
b
4-ClC6H4
4-pyridyl
72%
58%
i: (COOMe)2, MeONa, MeOH reflux. ii: POBr3, K2CO3, MeCN reflux.
80%
As shown in scheme 5, we focused on the preparation
of quinoline-bearing analogues 17a-f which are
structurally related to a family of strong PBR ligands [25].
The use of the optimized palladium-catalysed coupling
method described above led to the quinolines 17a-f in a
60-80% yield range. These esters were then readily
hydrolized into acids 18a-f. To prepare 2-pyridyl
derivatives such as compound 19, we investigated the
reaction between the recently reported [27] 2-pyridine-
boronic acid N-phenyldiethanolamine ester and compound
16. The LC/MS monitoring of few trials pointed out the
necessity of adding copper iodide in the reaction mixture
to obtain any coupling reaction. However, side reactions,
such as extensive transesterifications of the carboxyl
moiety, were observed and rendered the purification of
the reaction products quite difficult.
i: ArB(OH)2, PdCl2dppf, Cs2CO3, dioxane / H2O 85°C, 1 hour. ii: KOH,
H2O / EtOH reflux.
To further extend this study, we sought to prepare the 2-
pyridyl derivatives and focused on the recently reported
preparation of 2-pyridyl-N-oxide aryl derivatives from
pyridinine-N-oxide using palladium acetate and tri-tert-
butylphosphine as a catalyst [23,24]. From compound 9,
using dioxane as a solvent, a modest yield of the
corresponding 2-pyridyl-N-oxide 12 was obtained only if
quite strong reaction conditions were used. A microwave-
based heating turned out to be very useful as it enabled to
obtain pure compound 12 in 4.6 % yield using a one hour-
long irradiation time at 150 °C. The LC/MS monitoring of
the reaction explained this rather low yield as it pointed

Sep-Oct 2008
Optimized palladium-based approaches to analogues of PK 11195
1379
Scheme 5
depression [44], as well as the treatment of peripheral
neuropathy or neurodegenerative diseases [45]. Moreover,
some ligands were mentioned for their cosmetic
enhancing effects [46,47] or their potential in anticancer
chemotherapy [48-52]. Concerning the underlying
biological mechanism(s) at work for these effects, recent
investigations may herald a more complete unravelling of
this challenging puzzle [53-57]. The inhibition of the
mitochondrial F1F0-ATPase by PK 11195 (1) is
noteworthy [58]. We thus hope that this synthetic work
will be useful in the preparation of chemical tools
designed for the elucidation of the many-faceted effects of
PBR ligands.
O
O
N
N
OR
O
ii
Br
Ar
16
17a-f: R = Me
18a-f: R = H
iii
ii
O
N
O
Ar
% 17 % 18
C6H5
a
81%
64%
85%
78%
82%
77%
81%
72%
63%
O
N+
2-ClC6H4
3-ClC6H4
b
c
d
e
f
EXPERIMENTAL
19
72%
76%*
61%
4-ClC6H4
3-pyridyl
4-pyridyl
General Methods. A Biotage initiator 2 microwave oven was
1
used for of the reactions requiring microwaves irradiations. H
NMR and 13C NMR spectra were recorded on a Bruker Avance-
300 or 400 spectrometers at 300 or 400 MHz and 75 or 100
MHz, respectively. Unless otherwise noted, CDCl3 was the
solvent used. Shifts (ꢁ) are given in ppm with respect to the
TMS signal and coupling constants (J) are given in Hertz.
Column chromatography were performed over Merck silica gel
60 (0.035 - 0.070 mm), using a solvent pump operating at
pressure between 2 and 7 bar (25-50 mL/mn) and an automated
collecting system driven by a UV detector set to 254 nm unless
stated otherwise (i.e. if ethylacetate was used then it would be
set to 280 nm). Some of the low and high resolution mass
spectra (HRMS) were obtained by Mrs Nicole Morin (ENS, 24
rue Lhomond, F-75231 Paris) on a MS 700 Jeol. Others were
obtained on an Agilent 1100 serie LC/MSD system using an
atmospheric electrospray ionisation system and the high
resolution mass spectroscopy spectra (HRMS) were obtained
using a water Micromass Q-Tof with an electrospray ion source.
General preparation of methyl 4-arylisoquinoline-3-
carboxylates 7a-e. Under an inert atmosphere, a mixture of
compound 6 (5.63 mmol), the arylboronic derivative considered
(7.33 mmol), potassium phosphate (7.33 mmol) and tetrakis-
(triphenylphosphine) palladium (0.17 mmol) in dry DMF (50
mL, dried over 4 Å molecular sieves) was heated at 80 °C for 14
hours. As an 1H NMR monitoring of the reaction showed that the
reaction had stopped, another portion of 2-chlorophenylboronic
acid (2.23 mmol) and potassium phosphate (2.23 mmol) were
added and the heating resumed for another 12 hours. Again, as
*: using pyridine-3-boronic acid 1,3-propanediol ester
i: ArB(OH)2, PdCl2dppf, Cs2CO3, dioxane/H2O 85°C. ii: KOH,
H2O/EtOH reflux. iii: pyridine N-oxide, Pd(OAc)2, PMe(tBu)2, K2CO3,
toluene, 170 °C μꢀ heating 45 mn.
Accordingly, we studied the palladium-catalysed
coupling of compound 16 with pyridine-N-oxide. Using
the microwave–based heating approach described above,
the N-oxide derivative 19 was obtained in a 29 % yield.
The LC/MS monitoring of this trial pointed out the
occurrence of reduced material (peak with a m/z = 188),
the presence of some starting material and many other
substance including traces of an eventual dimerized
material (m/z = 373) homologous to compound 13.
In conclusion, from the isoquinoline or quinoline
bromide derivatives 6, 9 or 16, this work allowed the
preparation of a diverse array of biaryl compounds
featuring a core structure related to PK 11195 (1). The use
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
as a precatalyst instead of the tetrakis(triphenylphosphine)
palladium we and others initially used [20,28] was
rewarding in many instances. The few metal-catalysed
coupling trials with pyridine-N-oxide pointed out some
side reactions and the interest of using microwave
heating. A future challenge would be to find better
catalysts to further improve this reaction.
On the applications point of view, PBR ligands were
described for their potential use in imagery techniques
such as positron emission tomography [29,30]. Further
results have actually been reported more recently [31-39].
On the biology point of view, PBR and their many known
ligands [40,41] are the subject of a vast array of
investigations. Some compounds are studied for their
neuroprotective capacity [42], the treatment of
neuropathic pain [43], the treatment of anxiety and
1
an H NMR monitoring of the reaction showed that the reaction
had stopped, another portion of 2-chlorophenylboronic acid
(0.56 mmol) and potassium phosphate (0.56 mmol) were added
and the heating resumed for another 2 hours. The suspension
was then concentrated to dryness and the residue purified by
chromatography over silica gel as described below. Note: in the
case of compound 7c or 7d, despite repeated addition of
potassium phosphate and the corresponding arylboronic acid, the
1H NMR monitoring of the reaction showed that we could not
bring it to completion and thus work up was undertaken after 2
days.
Methyl 1-phenylisoquinoline-3-carboxylate (7a). This
compound was obtained in a 77% yield, via a chromatography
over silica gel eluting with dichloromethane. Mp = 155 °C

1380
S. Guillou, Y.L. Janin
Vol 45
(cyclohexane). 1H (CDCl3): ꢀ = 4.05 (s, 3H), 7.54 (m, 3H), 7.70
(m, 4H), 8.03 (d, 1H, J = 8.1), 8.14 (d, 1H, J = 8.4), 8.59 (s, 1H).
13C (CDCl3): ꢀ = 52.8, 123.3, 127.8, 128.2, 128.4, 128.9, 129.4,
130.1, 130.7, 135.5, 138.9, 140.8, 161.2, 166.5. Anal.
(C17H13NO2): Calc: C: 77.55, H: 4.98, N: 5.32, found: C: 77.11,
H: 4.98, N: 5.32.
Methyl 1-(2-chlorophenyl)isoquinoline-3-carboxylate (7b).
Obtained in a 90% yield as described previously [20].
Methyl 1-(3-chlorophenyl)isoquinoline-3-carboxylate (7c).
resulting 27 g of syrup containing the diethyl acetylamino-2-(3-
oxo-1,3-dihydroisobenzofuran- 1-yl)-malonic acid was heated to
reflux in acetic acid (300 mL) containing concentrated sulfuric
acid (0.5 mL) for 30 hours. This was concentrated to dryness,
the residue was dissolved in dichloromethane and the organic
phase was washed with water, dried over magnesium sulfate
before concentrating it to dryness. The residue was partially
purified by chromatography over silica gel (dichloromethane/
ethanol 98.5 – 1.5) to yield 12 g of a crude fraction containing
the ethyl 1-hydroxyisoquinoline-3-carboxylate. This crude
fraction was dissolved in acetonitrile (300 mL, dried over 4 Å
molecular sieves) potassium carbonate was added (15.29 g, 0.11
mol) followed by phosphorus oxobromide (31 g, 0.11 mol.).
This was heated to reflux for 90 minutes and the resulting
suspension was concentrated to dryness. The residue was
cautiously dispersed in cold water and extracted with
dichloromethane. The organic phase was washed with water,
dried over magnesium sulfate and concentrated to dryness. This
This compound was obtained in
chromatography over silica gel eluting with dichloromethane.
a 75% yield, via a
1
Mp = 138 °C (heptane). H (CDCl3): ꢀ = 4.04 (s, 3H), 7.46 (m,
2H), 7.55 (m, 1H), 7.71 (m, 2H), 7.79 (m, 1H), 8.03 (d, 1H, J =
8.1), 8.07 (d, 1H, J = 8.1), 8.6 (s, 1H). 13C (CDCl3): ꢀ = 52.9,
123.7, 127.3, 128.0, 128.3, 128.5, 129.0, 129.6, 129.7, 130.1,
130.9, 134.5, 136.5, 140.5, 140.8, 159.6, 166.3. Anal.
(C17H12NO2Cl) : Calc: C: 68.58, H: 4.06, N: 4.7, Cl: 11.91,
found: C: 68.35, H: 4.15, N: 4.70, Cl: 11.60.
was purified by
a chromatography over silica gel
Methyl 1-(4-chlorophenyl)isoquinoline-3-carboxylate (7d).
This compound was obtained in a 36% yield, via a chromatog-
raphy over silica gel eluting with dichloromethane. Mp = 188 °C
(dichloromethane/cyclohexane 80-20). The corresponding
fraction was concentrated to dryness, the resulting solid was
dispersed in cold cyclohexane and filtered to yield pure
compound 9 (6.94 g, 16 % from the starting phtalide). Mp =
1
(heptane-dichloromethane). H (CDCl3): ꢀ = 4.03 (s, 3H), 7.50
(d, 2H, J = 7), 7.67 (m, 3H), 7.78 (m, 1H), 8.05 (m, 2H), 8.58 (s,
1H). 13C (CDCl3): ꢀ = 52.9, 123.5, 127.4, 128.1, 128.6, 128.7,
129.6, 130.8, 135.2, 136.6, 137.3, 140.9, 159.9, 166.4. Anal.
(C17H12NClO2, 1/5 H2O) : Calc: C: 67.76, H: 4.15, N: 4.65, Cl:
11.68, found: C: 67.78, H: 3.95, N: 4.71, Cl: 11.94.
1
117°C. H (CDCl3): ꢀ = 1.49 (t, 3H, J = 7.1), 4.54 (q, 2H, J =
7.1), 7.86 (m, 2H), 7.99 (m, 1H), 8.42 (m, 1H); 8.54 (s, 1H). 13
C
(CDCl3): ꢀ = 14.4, 62.1, 124.3, 128.6, 129.1, 130.4, 131.0,
131.9, 136.8, 141.3, 145.5, 164.5.
Improved synthetic procedure for the preparation of
compounds 10a-b and 17a-f. In a 60 mL round-bottomed thick
glass tube fitted with a PTFE-faced screw-cap, a mixture of
compound 9 or 16 (1 mmol), the desired boronic acid (2.14
mmol), cesium carbonate (2.14 mmol) in dioxane (2 mL) and
water (1 mL) was degassed with a slow stream of argon for ten
minutes. Following this, [1,1'-bis(diphenylphosphino)ferrocene]
dichloro palladium complexed with dichloromethane (0.053
mmol) was added, the tube was closed tightly and heated at 85
°C for 1 hour. After cooling to room temperature, the reaction
mixture was diluted in water and extracted with ethyl acetate.
The organic phase was dried over sodium sulfate and
concentrated to dryness. The residue was purified by chromatog-
raphy on silica gel as described below.
Methyl 1-(3-pyridyl)isoquinoline-3-carboxylate (7e). This
compound was obtained in a 77% yield, via a chromatography
over silica gel (dichloromethane-methanol 98/2). Mp = 162 °C
1
(toluene-cyclohexane). H (CDCl3): ꢀ = 4.04 (s, 3H), 7.49 (dd,
1H, J = 5.2 and 8.1), 7.70 (m, 1H), 7.81 (m, 1H), 8.03 (m, 3H),
8.63 (s, 1H), 8.75 (d, 1H, J = 3.3), 8.96 (d, 1H, J = 1.5). 13C
(CDCl3): ꢀ = 52.9, 123.4, 123.9, 127.0, 128.2, 128.7, 130.0,
131.1, 134.7, 136.6, 137.5, 141.0, 150.0, 150.6, 158.0, 166.2.
Anal. (C16H12N2O2) : Calc: C: 72.72, H: 4.58, N: 10.6, found: C:
72.55, H: 4.57, N: 10.56.
Ethyl 1-bromoisoquinoline-3-carboxylate (9). This
compound was prepared using our previously reported strategy
[21] although from phthalide and diethyl acetamidomalonate as
described below. Phthalide (20 g, 0.149 mol) was dispersed in
carbon tetrachloride (500 mL). To this was added N-bromo-
succinimide (29.2 g, 0.16 mol) and benzoyl peroxide (0.36 g, 1.5
mmol). This was heated to reflux for 75 minutes and
concentrated to dryness. The residue was dissolved in
chloroform, filtered and concentrated to dryness again. The
resulting syrup containing the bromophthalide and much less
succinimide was then dissolved in DMF (250 mL, dried over 4
Å molecular sieves) and protected from air. In another flask
protected from moisture by a calcium guard, dry diethyl
acetamidomalonate (35.6 g, 0.164 mol) was dissolved in dry
DMF (400 mL; dried over 4 Å molecular sieves) and cooled to
0°C using an ice bath. To this solution was added 60% sodium
hydride (suspension in mineral oil) (6.56 g, 0.164 mol). The
suspension was stirred until the end of the gas evolution (30-45
minutes) and then the bromophthalide solution described above
was added. The resulting solution was stirred overnight at room
temperature and then concentrated to dryness. The residue was
dissolved in diethylether (800 mL), the organic phase was
washed with a 1 N solution of sodium hydroxide (five times 70
mL), with water (five times 70 mL) and dried over magnesium
sulfate before concentrating it to dryness. In the next step, the
Ethyl 1-(4-chlorophenyl)isoquinoline-3-carboxylate (10a).
This compound was obtained in a 72 % yield, via a chromatog-
raphy over silica gel (dichloromethane-ethanol 98/2). Mp = 119
1
°C. H (CDCl3): ꢀ = 1.47 (t, 3H, J = 7.2), 4.53 (q, 2H, J = 7.2),
7.50 (m, 4H,), 7.66 (m, 1H), 7.77 (m, 1H), 8.02 (d, 1H, J = 8.1),
8.09 (d, 1H, J = 8.3), 8.56 (s, 1H). 13C (CDCl3): ꢀ = 14.4, 61.8,
123.3, 127.3, 127.8, 128.5, 129.3, 129.6, 130.8, 131.5, 135.0,
136.5, 137.2, 141.0, 159.7, 165.7. HRMS m/z Calcd for
C18H14ClNO2 (M+H)+ 312.0791. Found: 312.0823.
Ethyl 1-(4-pyridyl)isoquinoline-3-carboxylate (10b). This
compound was obtained in a 58 % yield, via a chromatography
over silica gel (dichloromethane-ethanol 98/2). Mp = 169 °C. 1H
(CDCl3): ꢀ = 1.48 (t, 3H, J = 7.2), 4.54 (q, 2H, J = 7.2), 7.49 (m,
2H), 7.64 (m, 1H), 7.82 (m, 1H), 8.14 (s, 1H), 8.40 (m, 1H),
8.82 (m, 2H). 13C (CDCl3): ꢀ = 14.4, 61.9, 124.0, 124.8, 126.8,
127.7, 128.7, 129.9, 131.1, 136.6, 141.4, 146.4, 150.0, 158.3,
165.6. HRMS m/z Calcd for C17H14N2O2 (M+H)+ 279.1133.
Found: 279.1146.
Methyl 4-phenylquinoline-2-carboxylate (17a). This
compound was obtained in a 81 % yield, via a chromatography
over silica gel (cyclohexane-ethyl acetate 4/1). Mp = 103 °C lit.

Sep-Oct 2008
Optimized palladium-based approaches to analogues of PK 11195
1381
1
[59] 101-102 °C. H (CDCl3): ꢀ = 4.08 (s, 3H), 7.52-7.58 (m,
5H), 7.60 (m, 1H,), 7.76 (m, 1H), 7.97 (d, 1H), 8.15 (s, 1H),
8.38 (d, 1H). 13C (CDCl3): ꢀ = 53.2, 121.2, 125.7, 127.8, 128.6,
128.7, 129.5, 130.1, 131.1, 137.4, 147.4, 148.1, 149.9, 166.0.
HRMS m/z Calcd for C17H13NO2 (M+H)+ 264.1024. Found:
264.1026.
The residue was purified by chromatography on silica gel
(dichloromethane / ethanol 99-1 to 9-1) to yield compound 12
and 13 in 4.6 and 4% yield respectively.
2-(3-(Ethoxycarbonyl)isoquinolin-1-yl)pyridine 1-oxide
(12). This compound was contained in the least migrating
fraction of the chromatography and had to be further purified by
a recrystallisation in cyclohexane to yield 4.6 % of compound
12. Mp = 219 °C. 1H (CDCl3): ꢀ = 1.39 (t, 3H, J = 7.1), 4.46 (q,
2H, J = 7.1), 7.39 (m, 2H), 7.64 (m, 4H), 7.97 (d, 1H, J = 8.1),
8.29 (m, 1H), 8.62 (s, 1H). 13C (CDCl3): ꢀ = 14.4, 61.9, 125.5,
125.6, 126.4, 126.8, 128.4, 128.5, 128.9, 130.1, 131.2, 135.9,
139.9, 141.5, 148.0, 153.2, 165.4. HRMS m/z Calcd for
C17H15N2O3 (M+H)+ 295.1083. Found: 295.1092.
Diethyl 1,1'-biisoquinoline-3,3'-dicarboxylate (13). This
compound was contained in the most migrating fraction of the
chromatography and had to be further purified by a washing it in
boiling cyclohexane to yield 4 % of compound 13. Mp = 263 °C.
1H (CDCl3): ꢀ = 1.47 (t, 3H, J = 7.1), 4.54 (q, 2H, J = 7.1), 7.62
(m, 1H), 7.81 (m, 2H), 8.10 (d, 1H, J = 8.2), 8.75 (s, 1H). 13C
(CDCl3): ꢀ = 14.4, 61.8, 124.6, 127.5, 128.4, 129.4, 129.8,
131.2, 136.7, 140.9, 157.6, 165.7. HRMS m/z Calcd for
C24H21N2O4 (M+H)+ 401.1501. Found: 401.1488.
Palladium-catalysed coupling of pyridine-N-oxide to
compound 9 or 16. In a 0.5 – 2 mL model tube fitting the
Biotage microwave oven described above, a mixture of
compound 9 or 16 (0.8 mmol), pyridine-N-oxide (3.3 mmol),
potassium carbonate (1.7 mmol) and toluene (1 mL) was
degassed by a slow stream of argon for ten minutes. Following
this, palladium acetate (0.042 mmol) and di-tert-butylmethyl-
phosphine tetrafluoroborate (0.12 mmol) were added, the tube
was quickly sealed and heated at 170 °C for 45 minutes in the
microwave oven. After cooling to room temperature, the
reaction mixture was concentrated to dryness. From compound 9
using this procedure followed by the purification protocol
described above compound 12 was obtained in a 39 % yield.
From compound 16 a chromatography over silica gel of the
resulting residues (dichloromethane-ethanol 95/5) led to
compound 19 in 29 % yield.
Methyl 4-(2-chlorophenyl)quinoline-2-carboxylate (17b).
Obtained after a chromatography over silica gel eluting with a
mixture of cyclohexane-ethyl acetate 4/1 in a 72 % yield. Mp =
1
153 °C (heptane). H (CDCl3): ꢀ = 4.08 (s, 3H), 7.32-7.54 (m,
6H), 7.80 (m, 1H), 8.11 (s, 1H), 8.36 (d, 1H, J = 8.4), 13C
(CDCl3): ꢀ = 53.2, 121.7, 125.6, 126.8, 127.9, 128.8, 129.8,
130.1, 130.2, 131.0, 131.2, 133.1, 136.1, 147.2, 147.3, 147.7,
165.8. Anal. (C17H12NClO2, 1/4 H2O): Calc: C: 67.56, H: 4.17,
N: 4.63, Cl: 11.73, found: C: 67.81, H: 3.99, N: 4.70, Cl: 11.75.
Methyl 4-(3-chlorophenyl)quinoline-2-carboxylate (17c).
Obtained after a chromatography over silica gel eluting with
dichloromethane in a 63 % yield. Mp = 163 °C. 1H (CDCl3): ꢀ =
4.09 (s, 3H), 7.39-7.41 (m, 1H), 7.45-7.52 (m, 3H), 7.62 (m,
1H), 7.80 (m, 1H), 7.91 (m, 1H), 8.13 (s, 1H), 8.38 (d, 1H, J =
8.5) 13C (CDCl3): ꢀ = 53.3, 121.2, 125.3, 127.5, 127.7, 128.9,
129.0, 129.5, 130.2, 130.3, 131.1, 134.6, 139.1, 147.4, 148.0,
148.3, 165.8. HRMS m/z Calcd for C17H13ClNO2 (M+H)+
298.0635. Found: 298.0661.
Methyl 4-(4-chlorophenyl)quinoline-2-carboxylate (17d).
Obtained after a chromatography over silica gel eluting with a
mixture of cyclohexane-dichloromethane 70/30 in a 72 % yield.
1
Mp = 127 °C. H (CDCl3): ꢀ = 4.12 (s, 3H), 7.49 (m, 2H),7.52
(m, 2H), 7.61 (m, 1H), 7.83 (m, 1H), 7.95 (d, 1H, J = 8.5), 8.10
(s, 1H), 8.36 (d, 1H, J = 8.4). 13C (CDCl3): ꢀ = 53.3, 121.2,
125.4, 127.6, 128.9, 129.0, 130.3, 130.8, 131.2, 135.1, 135.8,
147.5, 148.1, 148.5, 165.9. HRMS m/z Calcd for C17H13ClNO2
(M+H)+ 298.0635. Found: 298.0648.
Methyl 4-(3-pyridyl)quinoline-2-carboxylate (17e).
Obtained after a chromatography over silica gel eluting with a
mixture of dichloromethane-ethanol 99/1 in a 76 % yield. Note:
in this case, the less expensive pyridine-3-boronic acid 1,3-
propanediol ester was used. Mp = 159 °C. 1H (CDCl3): ꢀ = 4.10
(s, 3H), 7.52 (m, 1H), 7.64 (m, 1H), 7.82 (m, 1H), 7.88 (m, 2H),
8.16 (s, 1H), 8.40 (d, 1H, J = 8.4), 8.80 (m, 2H). 13C (CDCl3): ꢀ
= 53.2, 121.5, 123.5, 124.9, 127.5, 129.2, 130.4, 131.3, 133.4,
136.9, 146.0, 147.5, 148.1, 149.7, 149.8, 165.7. HRMS m/z
Calcd for C16H13N2O2 (M+H)+ 265.0977. Found: 265.1014.
Methyl 4-(4-pyridyl)quinoline-2-carboxylate (17f).
Obtained after a chromatography over silica gel eluting with
a mixture of dichloromethane-ethanol 99/1 in a 61 % yield.
2-(2-(Methoxycarbonyl)quinolin-4-yl)pyridine 1-oxide
1
(19). Mp = 206 °C. H (CDCl3): ꢀ = 4.11 (s, 3H), 7.46-7.49 (m,
3H), 7.64 (m, 2H), 7.82 (m, 1H), 8.26 (s, 1H), 8.40 (m, 1H),
8.45 (m, 1H). 13C (CDCl3): ꢀ = 53.3, 122.0, 125.3, 125.5, 126.4,
126.9, 128.4, 129.4, 130.6, 131.4, 140.5, 140.8, 146.7, 147.7,
165.5. HRMS m/z Calcd for C16H13N2O3 (M+H)+ 281.0926.
Found: 281.0958.
General preparation of the corresponding acids 8a-e, 11b
and 18a-f. The ester (3.96 mmol) and potassium hydroxide (1 g,
15.8 mmol) were refluxed in 60% aqueous ethanol (80 mL) for
90 minutes. The ethanol was removed under a reduced pressure
and the residue made acid with diluted hydrochloric acid. This
was sometime extracted with dichloromethane; the organic layer
was washed with water and dried over magnesium sulfate as
described below.
1-(Phenyl)isoquinoline-3-carboxylic acid (8a). This
compound was obtained in a 65% yield via an extraction after
acidification of the aqueous phase. Mp = 220 °C (ethanol-
water). 1H (CDCl3 + DMSO-d6): ꢀ = 7.45 (m, 3H), 7.61 (m, 3H),
7.72 (m, 1H), 8.01 (d, 1H, J = 8.1), 8.07 (d, 1H, J = 8.4), 8.51 (s,
1H). 13C (CDCl3 + DMSO-d6): ꢀ = 122.0, 127.1, 127.5, 127.7,
127.9, 128.3, 129.0, 129.4, 130.3, 136.1, 137.9, 139.7, 159.9,
166.0. Anal. (C16H11NO2): Calc: C: 77.1, H: 4.45, N: 5.62,
found: C: 77.1, H: 4.44, N: 5.63.
1
Mp = 159 °C. H (CDCl3): ꢀ = 4.10 (s, 3H), 7.48 (m, 2H),
7.63 (m, 1H), 7.82 (m, 2H), 8.14 (s, 1H), 8.40 (d, 1H, J =
8.4), 8.82 (m, 2H). 13C (CDCl3): ꢀ = 53.3, 121.0, 124.3,
124.8, 126.8, 129.3, 130.5, 131.3, 145.4, 146.7, 147.5, 148.0,
149.9, 165.6. HRMS m/z Calcd for C16H13N2O2 (M+H)+
265.0977. Found: 265.0987.
Palladium-catalysed coupling of pyridine-N-oxide to
compound 9. In a 0.5 – 2 mL model tube fitting the Biotage
microwave oven described above, a mixture of compound 9 (0.8
mmol), pyridine-N-oxide (3.3 mmol), potassium carbonate (1.7
mmol) and dioxane (1 mL) was degassed by a slow stream of
argon for ten minutes. Following this, palladium acetate (0.042
mmol) and tri-tert-butylphosphine tetrafluoroborate (0.12 mmol)
were added, the tube was quickly sealed and heated at 150 °C
for 1 hour in the microwave oven. After cooling to room
temperature, the reaction mixture was concentrated to dryness.

1382
S. Guillou, Y.L. Janin
Vol 45
1-(2-Chlorophenyl)isoquinoline-3-carboxylic acid (8b).
Obtained in a 73 % yield as previously described [20].
3H). 13C (CDCl3): ꢀ = 119.3, 125.8, 127.7, 128.1, 129.2, 129.5,
130.0, 130.1, 131.0, 134.8, 139.4, 143.3, 145.4, 146.4, 149.9,
166.3. HRMS m/z Calcd for C16H11ClNO2 (M+H)+ 284.0478.
Found: 284.0479.
4-(4-Chlorophenyl)quinoline-2-carboxylic acid (18d). This
compound was obtained in a 78% yield via the filtration of the
precipitate obtained after acidification and was recristallized in
aqueous ethanol. Mp = 149 °C lit. [62] 148-150 °C. 1H (DMSO-
d6): ꢀ = 7.62-7.68 (m, 4H), 7.74 (m, 1H), 7.92 (m, 2H), 7.99 (s,
1H), 8.26 (m, 1H). 13C (DMSO-d6): ꢀ = 120.6, 125.2, 126.6,
128.8, 129.1, 130.2, 130.5, 131.3, 133.8, 135.6, 147.2, 147.8,
148.2, 166.0. HRMS m/z Calcd for C16H11ClNO2 (M+H)+
284.0478. Found: 284.0513.
1-(3-Chlorophenyl)isoquinoline-3-carboxylic acid (8c).
This compound was obtained in a 75% yield via the filtration of
the precipitate obtained after acidification. Mp = 238 °C
1
(toluene-heptane). H (DMSO-d6): ꢀ = 7.66 (m, 3H), 7.76 (m,
1H), 7.82 (m, 1H), 7.92 (m, 1H), 8.04 (d, 1H, J = 8.4), 8.30 (d,
13
1H, J = 8.0), 8.68 (s, 1H), 13.20 (s (br), 1H). C: ꢀ = 123.2,
126.5, 127.0, 128.6, 128.8 (two signals ?), 129.5, 130.2 (two
signals ?), 131.1, 133.2, 136.3, 140.5, 141.0, 158.3, 166.4. Anal.
(C16H10NO2Cl): Calc: C: 67.74, H: 3.55, N: 4.97, Cl: 12.5,
found: C: 67.49, H: 3.68, N: 4.93, Cl: 12.29.
1-(4-Chlorophenyl)isoquinoline-3-carboxylic acid (8d).
This compound was obtained in a 74% yield via the filtration of
the precipitate obtained after acidification. Mp = 242 °C (acetic
4-(3-Pyridyl)quinoline-2-carboxylic acid (18e). This
compound was obtained in a 82% yield via the filtration of the
precipitate obtained after acidification and was recristallized in
1
acid-water). H (DMSO-d6): ꢀ = 7.70 (m, 4H), 7.81 (m, 1H),
1
7.92 (m, 1H), 8.05 (m, 1H), 8.29 (d, 1H, J = 7.7), 8.58 (s, 1H),
13.15 (s, 1H). 13C (DMSO-d6): ꢀ = 123.0, 126.7, 127.0, 128.4,
128.8, 130.2, 131.1, 131.8, 133.8, 136.3, 137.3, 141.1, 158.7,
166.5. Anal. (C16H10NClO2): Calc: C: 67.74, H: 3.55, N: 4.97,
Cl: 12.5, found: C: 67.36, H: 3.53, N: 4.97, Cl: 12.24.
aqueous ethanol. Mp = 209 °C lit. [63] 203 °C. H (DMSO-d6):
ꢀ = 7.64 (m, 1H), 7.76 (m, 1H), 7.87-7.95 (m, 2H), 8.04-8.09
(m, 2H), 8.27 (d, 1H), 8.80 (m, 2H). 13C (DMSO-d6): ꢀ = 121.6,
124.2, 125.5, 127.2, 129.8, 130.9, 131.1, 133.2, 137.6, 146.0,
147.8, 148.8, 149.9, 150.4, 166.6. HRMS m/z Calcd for
C15H11N2O2 (M+H)+ 215.0820. Found: 251.0859.
1-(3-Pyridyl)isoquinoline-3-carboxylic acid (8e). This
compound was obtained in a 66% yield, via the filtration of the
precipitate obtained after acidification and a subsequent washing
4-(4-Pyridyl)quinoline-2-carboxylic acid (18f). This
compound was obtained in a 77% yield via the filtration of the
precipitate obtained after acidification and was recristallized in
1
with hot ethylacetate. Mp = 269 °C. H (DMSO-d6): ꢀ = 7.65
1
(dd, 1H, J = 5.0 and 8), 7.83 (m, 1H), 7.93 (m, 1H), 8.05 (d, 1H,
J = 8), 8.15 (m, 1H), 8. 31 (d, 1H, J = 8.1), 8.70 (s, 1H), 8.78
(dd, 1H, J = 2.5 and 4.8), 8.90 (d, 1H, J = 2.5), 13.2 (s(br), 1H).
13C (DMSO-d6): ꢀ = 123.2, 123.4, 126.5, 127.3, 128.9, 130.3,
131.2, 134.2, 136.2, 137.4, 141.2, 149.8, 150.1, 157.2, 166.4.
Anal. (C15H10N2O2): Calc: C: 71.99, H: 4.03, N: 11.19, found: C:
71.84, H: 4.02, N: 10.98.
aqueous ethanol. Mp = 215 °C lit. [63] 225 °C. H (DMSO-d6):
ꢀ = 7.77-7.81 (m, 1H), 7.88 (m, 2H), 7.89 (m, 1H), 7.94-7.98
(m, 1H), 8.08 (s, 1H), 8.30 (d, 1H), 8.92 (m, 2H). 13C (DMSO-
d6): ꢀ = 121.1, 125.3, 125.9, 126.2, 130.1, 131.0, 131.3, 145.9,
147.7, 148.0, 148.8, 166.5. HRMS m/z Calcd for C15H11N2O2
(M+H)+ 215.0820. Found: 251.0863.
Methyl 4-oxo-1,4-dihydroquinoline-2-carboxylate (15).
Under an inert atmosphere, a mixture of 2-aminoacetophenone
(14) (8 g, 0.059 mol), dimethyloxalate (28.0 g, 0.236 mol) and
sodium methoxide (13.4 g, 0.236 mol) was dispersed in dry
methanol (500 mL, dried over 3 Å molecular sieves). This was
stirred at 25 °C for one hour and then refluxed for 40 hours.
Most of the methanol was removed under reduced pressure and
the residue dispersed in water (600 mL). This was extracted with
dichloromethane six times and the organic layer was dried over
magnesium sulfate. After concentration to dryness, the residue
was purified by a chromatography over silica gel (ethyl acetate)
to yield compound 15 (5 g, 41%). Mp = 227 °C. 1H (DMSO-d6):
ꢀ = 3.97 (s, 3H), 6.62 (d, 1H, J = 1.8), 7.37 (m, 1H), 7.71 (m,
1H), 7.94 (d, 1H, J = 8.4), 8.07 (d, 1H, J = 8.1), 12.1 (s(br), 1H).
13C (DMSO-d6): ꢀ = 53.5, 110.2, 119.6, 124.0, 124.7, 125.9,
132.6, 137.7, 140.0, 162.7, 177.6. Anal. (C11H9NO3, 1/6 H2O):
Calc: C: 64.07, H: 4.56, N: 6.79, O: 24.57, found: C: 64.36, H:
4.48, N: 6.90, O: 24.56.
Methyl 4-bromoquinoline-2-carboxylate (16). A mixture of
compound 15 (5 g, 0.024 mol), phosphorus oxybromide (20 g,
0.073 mol) and potassium carbonate (10.5 g, 0.073 mol) was
dispersed in dry acetonitrile (dried over 4 Å molecular sieves).
The suspension was refluxed for 3 hours under a calcium
chloride-protected atmosphere. After cooling, water (200 mL)
was cautiously added and most of the acetonitrile removed under
reduced pressure. This residue was extracted with
dichloromethane and the organic layer was washed with water
and dried over magnesium sulfate. After concentration to
dryness, the residue was recristallized from heptane to give
compound 16 (4.84 g, 73%). An analytical sample was further
purified (from traces of the corresponding acid) by chromato-
1-(4-Pyridyl)isoquinoline-3-carboxylic acid (11b). This
compound was obtained in a 80% yield, via the filtration of the
precipitate obtained after acidification. Mp = 267 °C. 1H
(DMSO-d6): ꢀ = 7.71 (m, 2H), 7.82 (m, 1H), 7.93 (m, 1H), 8.03
(m, 1H), 8.32 (m, 1H), 8.71 (s, 1H), 8.81 (m, 2H). 13C (DMSO-
d6): ꢀ = 123.6, 124.5, 126.3, 126.8, 128.8, 130.3, 131.2, 136.2,
141.2, 145.8, 149.8, 157.5, 166.2. HRMS m/z Calcd for
C15H11N2O2 (M+H)+ 251.0820. Found: 251.0860.
4-Phenylquinoline-2-carboxylic acid (18a). This compound
was obtained in 81% yield via the filtration of the precipitate
obtained after acidification and was recristallized in aqueous
1
ethanol. Mp = 171 °C lit. [61] 170-173 °C. H (DMSO-d6): ꢀ =
7.58-7.63 (m, 5H), 7.73 (m, 1H), 7.91 (m, 1H), 7.94 (s, 1H),
8.25 (m, 2H). 13C (DMSO-d6): ꢀ = 120.6, 125.3, 126.7, 128.8,
129.4, 130.3, 136.9, 147.4, 148.6, 148.8, 166.3. HRMS m/z
Calcd for C16H12NO2 (M+H)+ 250.0868. Found: 250.0894.
4-(2-Chlorophenyl)quinoline-2-carboxylic acid (18b). The
residue obtained, after concentration to dryness, was
recristallized in toluene to yield compound 18a (0.74 g, 64 %).
1
Mp = 201 °C. H (CDCl3): ꢀ = 7.33 (dd, 1H, J = 2.2 and 7.6),
7.45 (m, 2H), 7.61 (m, 3H), 7.84 (m, 1H), 8.19 (s, 1H), 8.22 (d,
1H, J = 8.3). 13C (CDCl3): ꢀ = 120.0, 126.1, 127.0, 128.6, 129.3,
129.8, 130.0, 130.4, 131.0, 131.1, 133.0, 135.7, 145.4, 146.0,
146.0, 164.2. Anal. (C16H10NClO2): Calc: C: 67.74, H: 3.55, N:
4.94, Cl: 12.5, found: C: 67.33, H: 3.53, N: 4.93, Cl: 12.16.
4-(3-Chlorophenyl)quinoline-2-carboxylic acid (18c). This
compound was obtained in a 81% yield via the filtration of the
precipitate obtained after acidification and was recristallized in
1
aqueous ethanol. Mp = 100 °C. H (CDCl3): ꢀ = 7.45 (m, 1H),
7.55 (m, 2H), 7.72 (m, 1H), 7.90 (m, 1H), 8.01 (m, 1H), 8.26 (m,

Sep-Oct 2008
Optimized palladium-based approaches to analogues of PK 11195
1383
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Acknowledgement. Part of this work was supported by the
Medicen initiative (Chemical Library Project; grant of the
Région Ile de France n° I 06-222/R, as well as a fellowship for
S.G.). We thank Sanofi-Aventis as well as Pfizer for donations
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