Synthesis of quinolinyl and isoquinolinyl phenyl ketones as novel agonists for the cannabinoid CB2 receptor

Article abstract of DOI:10.1016/j.bmc.2009.05.013

A series of quinolinyl and isoquinolinyl phenyl ketones was synthesized and their CB₂ receptor-dependent G-protein activities were determined using the [³⁵S]GTPγS binding assay. Both quinoline and isoquinoline derivatives exhibited similar CB₂ receptor agonist activity, the most potent ligands being the 2-(Me₂N)-phenyl substituted derivatives, which were also full agonists at the CB₂-receptor.

Full text of DOI:10.1016/j.bmc.2009.05.013

Bioorganic & Medicinal Chemistry 17 (2009) 4441–4447
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of quinolinyl and isoquinolinyl phenyl ketones as novel agonists
for the cannabinoid CB2 receptor
Bastien Reux a, Tapio Nevalainen b, Katri H. Raitio b, Ari M. P. Koskinen a,
*
a Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland
b Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of quinolinyl and isoquinolinyl phenyl ketones was synthesized and their CB2 receptor-depen-
dent G-protein activities were determined using the [35S]GTP
cS binding assay. Both quinoline and iso-
Received 7 March 2009
Revised 4 May 2009
Accepted 7 May 2009
Available online 12 May 2009
quinoline derivatives exhibited similar CB2 receptor agonist activity, the most potent ligands being the
2-(Me2N)-phenyl substituted derivatives, which were also full agonists at the CB2-receptor.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cannabinoid receptor
CB2
Quinoline
Isoquinoline
1. Introduction
molecules that act as agonists, inverse agonists, antagonists or sim-
ply new drugs for clinical use.14–17
The CB2 receptor is a seven-transmembrane-domain G-protein-
coupled receptor.1 It is part of the endocannabinoid system which
consists of another cannabinoid receptor (CB1), endogenous ago-
nist ligands derived from arachidonic acid (endocannabinoids)
and a mechanism of deactivation involving enzymes and mem-
brane transport system.2 The gene encoding the human cannabi-
noid CB2 receptor was cloned in 1993.3 The CB1 receptor is
largely present in the central nervous system (CNS) with high den-
sity in the brain causing the well known psychotropic side-effects
associated with the use of cannabis derivatives which are agonists
to the receptor.4 It has been thought for some time that the CB2
receptor is absent from the CNS and it is abundant in the immune
system.5 More recent studies have suggested that CB2 is also ex-
pressed in certain subpopulations of the CNS.6
Recently, Salo et al.18 have used a comparative model of CB2
receptor constructed using the bovine rhodopsin X-ray structure
to identify new hit compounds. After virtual screening of chemical
databases for hit molecules, the results of [35]GTP
cS G-protein acti-
vations assays showed that one of them acted as a selective CB2
agonist (NRB-04079, 2). This rather small isoquinolinyl phenyl ke-
tone was suitable for pharmacomodulation together with its quin-
oline analogue NRB-04080 (1) which also showed CB2 agonist
properties and no sign of CB1 activity (Fig. 1). We report here the
synthesis and the biological evaluation of such derivatives.
2. Results
2.1. Chemistry
Together with this discovery and the understanding of the
mechanism involved, the potential of therapeutic uses for CB2
has increased. It has been shown that the expression of CB2 recep-
tors increases with the degree of malignancy in glial7 and breast8
tumors and that activation of the receptor could stop the tumor
progression7,9 or induce apoptosis of the cancerous cells.5 Cannab-
inoid receptor activation has also been suggested in therapeutic
approaches in the treatment of pain,10 inflammation,11 osteoporo-
sis12 or sclerosis.13 These observations have spurred wide spread
interest in synthetic CB2-selective cannabinoid receptor specific
In this study we investigated the modifications on the benzene
ring of the phenyl quinolinyl ketones, which can be synthesized by
F3C
N
F3C
N
O
O
1
(NRB-04080)
2 (NRB-04079)
* Corresponding author. Tel.: +358 9 451 2526; fax: +358 9 451 2538.
E-mail address: ari.koskinen@tkk.fi (A.M.P. Koskinen).
Figure 1. The structures of the hit compounds.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.013

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B. Reux et al. / Bioorg. Med. Chem. 17 (2009) 4441–4447
logue [35]GTP
cS. The relative efficacy responses of the molecules
are expressed as percentage of the full (both CB1 and CB2) potent
cannabinoid agonist HU-210. All the compounds were first evalu-
ated at 10 lM concentration. For the compounds that showed over
R
R
+
Br
N
N
CN
3
O
50% relative activity, the dose response curves were generated and
the EC50 and Emax values were calculated by nonlinear regression
analysis with the equation for a sigmoidal concentration–response
curve (GRAPHPAD PRISM 4). The possible CB1 receptor agonist and
Scheme 1. Synthetic plan.
antagonism of all the compounds were screened at 10 lM concen-
tration in rat cerebellar membranes as previously described21 to
estimate the CB2 selectivity of the compounds.
a
b
N
N
CN
N
O
3
3. Discussion
quinoline
Scheme 2. Reagents and conditions: (a) m-CPBA, CH2Cl2, 2 h; (b) benzoyl chloride,
KCN, MeOH, CH3CN, overnight, 82% overall.
We have synthesized two series of compounds that are listed
together with their yields and their efficacy results in Table 1
(quinolines) and Table 2 (isoquinolines).
3.1. Quinolines
a
b
N
N
N
Both electron donating and electron withdrawing substituents
were evaluated. Of the 4-substituted molecules, the best com-
pound (5k, Àlog EC50 = 5.4, Emax = 62) possesses an electron donat-
ing NMe2 group. An electron-withdrawing 4-chloro substituent
(5m) and electron-donating 4-methoxy substituent (5e) also main-
tain considerable relative activity, whereas electron-withdrawing
4-CF3 (5b) and 4-F substituents (5o) showed weaker activity.
Moving the CF3 group from the 4-position to the 3-position (2)
led to slight improvement in CB2 activity whereas introducing CF3
O
4
isoquinoline
CN
Scheme 3. Reagents and conditions: (a) m-CPBA, CH2Cl2, 2 h; (b) benzoyl chloride,
KCN, MeOH, CH3CN, overnight, 68% overall.
a Grignard coupling of an appropriate arylmagnesium halide and
quinoline-2-carbonitrile 3 (Scheme 1).
The carbonitrile 3 was obtained from quinoline through N-oxi-
dation followed by in situ conversion to an N-benzoate and addi-
tion of cyanide (Scheme 2). The oxidation of quinoline was more
efficient with m-CPBA (after 30 min no more starting material
was detected by TLC, 74% yield) than with hydrogen peroxide
(3 days, 60% yield). The N-oxide was used without purification
and 3 was obtained in high yield. Similarly, the isoquinolinyl car-
bonitrile 4 was obtained by oxidation of isoquinoline with m-CPBA
and treatment with potassium cyanide and benzoyl chloride
(Scheme 3).
The coupling reaction to give the isoquinolinyl aryl ketones in-
volved the formation of a Grignard reagent from adequately substi-
tuted bromobenzenes (Scheme 4). Addition to the carbonitrile (3 or
4) led to the corresponding imine which gave the desired ketone
upon hydrolysis with 1 M HCl. The reaction was conducted in a
mixture of THF/toluene 1:2 in order to enhance the reactivity of
the nucleophile toward the nitrile.19
to the 2-position (5c) gives
a potent high efficacy ligand
(Àlog EC50 = 5.7, Emax = 87). That pattern is also apparent with
electron-donating substituents. Moving a methoxy group from
the 4-position (5e) to the 3-position (5f) and then to the 2-position
(5g) leads to improved activity. The gain in CB2 efficacy and
potency is even better when 4-NMe2 substituent is moved to 2-po-
sition (5l, Àlog EC50 = 6.1, Emax = 91). Moving 4-chloro (5m) to 2-
position (data not shown) or 4-fluoride (5j) to 3-position (5i) does
not noticeably improve the CB2 activity.
Elongation of the alkoxy group at the 4-position (5h, 5i and 5j)
leads to loss of CB2 activity. Those observations suggest that the
binding area of the CB2 receptor is not sensitive to the electronic
nature of the compounds but more likely to the size and shape
and is intolerant to steric bulk. This assertion is supported by the
bis-functionalized molecules 5d (3,5-CF3) and 5n (3,4-Cl) which
lose almost all activity.
3.2. Isoquinolines
2.2. Pharmacology
The 4-CF3 analogue 6b (Àlog EC50 = 5.5, Emax = 57) seems to be
equipotent with the 3-CF3 hit 2 (Àlog EC50 = 5.3, Emax = 53) but like
in the quinoline series, the 2-CF3 analogue 6c has higher CB2 po-
tency and efficacy (Àlog EC50 = 6.3, Emax = 72). A further 3-CF3 is
still responsible for a dramatically drop of the activity (6d). Overall,
the isoquinoline compounds show approximately the same effi-
cacy and potency as the quinoline analogues with the exception
The new quinolinyl and isoquinolinyl phenyl ketones have been
tested for their capacity of G-protein activation of the human CB2
receptor (hCB2) via a [35]GTP
cS binding assay according to the pro-
cedure described by Savinainen et al.20 The receptors used were
hCB2 stably expressed in Chinese hamster ovary (CHO) cells. In this
assay, the effects of the tested cannabinoid agonists are obtained
from agonist-induced binding of the nonhydrolyzable GTP ana-
R
4
3
R
R
3
2
2
a
b
c
4
BrMg
Br
R
or
N
N
O
O
5
6
Scheme 4. Reagents and conditions: (a) Mg, THF; (b) 3 or 4, toluene, 0 °C then rt; (c) 1 M HCl, Et2O.

B. Reux et al. / Bioorg. Med. Chem. 17 (2009) 4441–4447
4443
Table 1
CB2 receptor activity data of the quinolinyl phenyl ketonesa
R
4
3
2
N
O
5
M ligand concdb
CB2 agonism at 10
l
M ligand concdc
CB2 Relative Emax
CB2 Àlog EC50
5.1 0.2
c
Compound
R=
H
Yield (%)
97
CB1 agonism at 10
l
5a, BTB14404
103
1
29
1
52
5
5b
4-CF3
3-CF3
80
—
105
102
5
1
20
42
1
3
n.d.
42
n.d.
5.3 0.2
1, NRB-04080d
3
3
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
2-CF3
3,5-CF3
4-OMe
3-OMe
2-OMe
4-OEt
4-OPr
4-OiPr
4-NMe2
2-NMe2
4-Cl
46
76
98
90
96
67
87
64
94
81
81
64
93
98
102
108
108
102
106
100
108
102
101
101
101
100
99
1
3
7
4
5
2
3
5
6
3
3
3
80
11
45
6
1
2
87
5.7 0.1
n.d.
n.d.
5.7 0.2
5.6 0.1
n.d.
n.d.
n.d.
5.2 0.1
6.1 0.1
5.4 0.1
n.d.
n.d.
n.d.
54
52 12
4
3
46
19
7
10
45
85
47
18
34
34
7
4
1
2
6
8
2
2
2
5
53
n.d.
n.d.
n.d.
62
91
63
n.d.
n.d.
n.d.
2
2
2
5m
5n
5o
5p
3,4-Cl
4-F
3-F
2
n.d.
n.d.
106
2
a
Values are mean SEM of at least three experiments performed in duplicate.
The data are presented as % basal.
Relative responses as percentage of the 10 nM HU-210 agonist response.
Ordered from Maybridge. n.d. = not determined.
b
c
d
of the 4-methoxy analogue 6e which has very weak potency. The
same observations can be made regarding the non-influence of
the electronic nature of the substituents (6b and 6g have the same
relative agonist activity) and the large impact of its position on the
benzene ring as can be seen by comparing the compounds 6h and
6g. We finally observe that the 2-NMe2 analogue 6h has higher po-
tency and efficacy (Àlog EC50 = 6.2, Emax = 95) than the 4-NMe2
analogue 6g (Àlog EC50 = 5.6, Emax = 68) as was the case in quino-
line series.
tilled from CaH2. All other solvents and reagents were used as ob-
tained from the supplier. Analytical TLC was performed on Merck
silica gel F254 (230–400 mesh) plates and visualized under UV
light. Flash chromatography was performed on Merck Silica Gel
60 (230–400 mesh) and p.a. grade solvents. Infrared spectra were
measured on a Perkin Elmer Spectrum One FT-IR spectrometer
using KBr disc. The 1H and 13C NMR spectra were recorded in a
CDCl3 solution on a Bruker Avance 400 (1H 399.98 MHz; 13C
100.59 MHz) spectrometer. Chemical shifts are reported in ppm
relative to tetramethylsilane (d 0) for 1H NMR. For the 13C NMR
spectra, the signal for CDCl3 (d 77.16) was used as the internal
standard. High-resolution mass spectrometric data were obtained
on Waters LCT Premier—spectrometer. Melting points were ob-
tained on Gallenkamp and Stuart SMP3 melting point apparatuses.
The elemental analyses were performed at the Analytical Services
of the Department of Chemical Technology, Laboratory of Organic
Chemistry.
4. Conclusions
The pharmacomodulation of the hit compounds 1 and 2 was
achieved to give better agonist capacity (Emax >42, Àlog EC50 >5.3
for the quinoline series; Emax >53, Àlog EC50 >5.3 for the isoquino-
line series). However, only compounds 5l, 6h and 5c are full CB2
agonists (respectively Emax = 91, 95 and 87). None of these com-
pounds showed any significant CB1 receptor activation.
In conclusion, the quinolinyl and isoquinolinyl phenyl ketones
represent a new class of CB2-selective receptor ligands, which re-
vealed full or partial CB2 cannabinoid receptor agonistic properties
5.1.1. Quinoline-2-carbonitrile (3)
To a solution of quinoline (1.50 g, 11.6 mmol, 100 mol %) in
15 mL of CH2Cl2 was added m-CPBA (70% with water, 2.87 g,
11.6 mmol, 100 mol %) portionwise. After 2 h, the solution was
dried with Na2SO4, filtered and evaporated. The solid obtained
was dissolved in acetonitrile (51 mL) and added to a solution of
KCN (1.51 g, 23.2 mmol, 200 mol %) in methanol (39 mL). Benzoyl
chloride (2.70 mL, 23.2 mmol, 200 mol %) was added dropwise
and the reaction was stirred overnight. After evaporation of the
solvent, the residue was taken up in CH2Cl2 and washed twice with
a solution of saturated NaHCO3. The organic layer was dried over
Na2SO4, filtered, and evaporated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc, 9:1) affording com-
pound 3 (1.47 g, 82%) as a white solid. 1H NMR (CDCl3) d 8.32 (d,
1H, J = 8.4 Hz), 8.17 (br d, 1H, J = 8.6 Hz), 7.91 (br d, 1H,
J = 8.2 Hz), 7.85 (ddd, 1H, J = 6.9 Hz, J = 1.4 Hz), 7.72 (m, 2H).
in the [35]-GTP
cS binding assay. Both isoquinoline and quinoline
derivatives showed more or less same efficacy and potency. The
most potent ligands were the 2-NMe2 substituted compounds (5l
and 6h).
5. Experimental
5.1. General methods
All reactions were carried out under an atmosphere of argon in
flame-dried glassware. Non-aqueous reagents were transferred un-
der argon via syringe or cannula and dried prior to use. THF was
distilled from Na/benzophenone ketyl. CH2Cl2 and MeOH were dis-

4444
B. Reux et al. / Bioorg. Med. Chem. 17 (2009) 4441–4447
Table 2
129.23, 128.97, 127.82, 125.14 (q, 2C, J = 3.6 Hz), 123.92 (q,
CB2 receptor activity of the isoquinolinyl phenyl ketonesa
J = 271.0 Hz), 120.73. Anal. (C17H10F3NOÁ0.2H2O) C, H, N. HRMS
(ESI+) calcd for C17H11F3NO (M+H), 302.0793; found, 302.0782.
3
2
4
R
5.2.2. Quinolin-2-yl-(2-trifluoromethylphenyl)-methanone (5c)
This was prepared from quinoline-2-carbonitrile and 2-bromo-
N
benzotrifluoride in 46%. White solid mp; 87 °C (hexane); IR (KBr)
m
O
1678, 1315, 1161, 1126, 927, 771 cmÀ1 1H NMR (CDCl3) d 8.34 (d,
;
6
1H, J = 8.6 Hz), 8.29 (d, 1H), 8.01 (br d, 1H, J = 8.5 Hz), 7.88 (dd, 1H,
J = 1.1 Hz, J = 8.0 Hz), 7.78 (m, 1H), 7.71 (ddd, 1H, J = 1.5 Hz,
J = 6.9 Hz), 7.64 (m, 3H), 7.56 (m, 1H); 13C NMR (CDCl3) d 196.20,
153.09, 147.24, 138.16 (d, J = 2.2 Hz), 137.18, 131.16, 130.95,
130.14, 129.95, 129.51, 129.25, 129.09, 128.75 (q, 1C, J = 32.1 Hz),
127.71, 126.52 (q, 1C, J = 4.3 Hz), 123.96 (q, 1C, J = 272.0 Hz),
119.31. Anal. (C17H10F3NOÁ0.1H2O) C, H, N. HRMS (ESI+) calcd for
C17H11F3NO (M+H), 302.0793; found, 302.0790.
Compound
R=
Yield CB1
CB2
agonism
at 10
CB2
CB2
(%)
agonism
at 10
relative Àlog EC50
c
l
M
l
M
Emax
ligand
ligand
concdb
concdc
6a
H
94
89
—
102
95
106
7
7
3
24 15
46
—
n.d.
57
n.d.
6b
4-CF3
3-CF3
3
1
5.5 0.1
2, NRB-
04079d
6c
53 4e
5.3 0.2e
2-CF3
3,5-
CF3
44
55
112
101
6
1
63
16
3
4
72
n.d.
2
6.3 0.1
n.d.
5.2.3. (3,5-Bis-trifluoromethylphenyl)-quinolin-2-yl-
methanone (5d)
6d
6e
6f
6g
4-OMe 93
3-OMe 90
85
112
99
1
3
17
41
56
3
4
5
n.d.
n.d.
68
n.d.
n.d.
5.6 0.2
This was prepared from quinoline-2-carbonitrile and 3,5-
bis(trifluoromethyl) bromobenzene in 76% yield. Pale yellow crys-
4
4-
54
5
2
tals; mp 86 °C (hexane); IR (KBr)
m 1668, 1285, 1148, 1127,
NMe2
2-
775 cmÀ1 1H NMR (CDCl3) d 8.87 (s, 2H), 8.39 (d, 1H, J = 8.5 Hz),
;
6h
96
116
5
2
2
3
9
90
5
95
6.2 0.1
8.26 (d, 1H), 8.16 (br d, 1H, J = 8.4 Hz), 8.12 (br s, 1H), 7.93 (br d,
1H), 7.82 (ddd, 1H, J = 1.2 Hz, J = 7.0 Hz), 7.70 (ddd, 1H); 13C NMR
(CDCl3) d 190.21, 152.85, 146.83, 138.04, 137.74, 1321.83 (br s,
2C), 131.65 (q, 2C, J = 33.7 Hz), 130.72 (2C), 129.41, 127.84,
125.90 (sept., 1C, J = 3.6 Hz), 123.29 (q, 2C, J = 271.1 Hz), 120.62.
Anal. (C18H9F6NO) C, H, N. HRMS (ESI+) calcd for C18H10F6NO
(M+H), 370.0667; found, 370.0650.
NMe2
4-F
3-F
4-Cl
3,4-Cl
6i
6j
6k
6l
86
92
98
83
104
99
101
111
20
17
40
45
5
2
4
4
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
a–d
See the corresponding footnotes in Table 1.
Ref. 18.
e
5.2.4. (4-Methoxyphenyl)-quinolin-2-yl-methanone (5e)
This was prepared from quinoline-2-carbonitrile and 4-bromo-
anisole in 98% yield. White solid; mp 87 °C (hexane/EtOAc); IR
5.1.2. Isoquinoline-1-carbonitrile (4)
This was prepared from isoquinoline (1.50 g, 11.6 mmol) fol-
lowing the same procedure as for quinoline-2-carbonitrile 3 to give
isoquinoline-1-carbonitrile 4 (1.23 g, 68%) as a white solid. 1H NMR
(CDCl3) d 8.64 (d, 1H, J = 5.7 Hz), 8.30 (br d, 1H, J = 8.2 Hz), 7.95 (br
d, 1H, J = 7.8 Hz), 7.91 (d, 1H), 7.81 (m, 2H).
(KBr)
m ;
1659, 1605, 1328, 1257, 1164, 925, 773 cmÀ1 1H NMR
(CDCl3) d 8.34 (d, 1H, J = 8.5 Hz), 8.29 (d, 2H, J = 9.0 Hz), 8.21 (br
d, 1H, J = 8.4 Hz), 8.06 (d, 1H), 7.91 (br d, 1H), 7.79 (ddd, 1H,
J = 1.4 Hz, J = 6.9 Hz), 7.66 (ddd, 1H), 7.00 (d, 2H), 3.90 (s, 3H);
13C (CDCl3) d 192.31, 163.83, 155.48, 146.74, 137.12, 134.01 (2C),
130.51, 130.12, 129.03, 128.86, 128.29, 127.74, 120.98, 113.63
5.2. General procedure for the quinolinyl and isoquinolinyl
phenyl ketones
.
(2C), 55.59. Anal. (C17H13NO2 0.1H2O) C, H, N. HRMS (ESI+) calcd
for C17H14NO2 (M+H), 264.1025; found, 264.1018.
A
solution of the appropriate bromophenyl derivative
(1.43 mmol, 200 mol %) in 1.5 mL of THF was treated with magne-
sium (1.71 mmol, 240 mol %). After the formation of the Grignard
reagent, the solution was added to a solution of the appropriate
carbonitrile (0.713 mmol, 100 mol %) in toluene (3 mL) at 0 °C.
When TLC showed no more starting material, the reaction was
quenched by addition of a solution of satd NH4Cl. The organic layer
was separated and extracted twice with CH2Cl2. After evaporation,
the organic layer was redissolved in Et2O (10 mL) and 1 M HCl
(4 mL) was added. After 20 min, the organic layer was separated;
the aqueous layer basified with saturated NaHCO3 and then ex-
tracted three times with CH2Cl2. The combined organic layers were
dried over Na2SO4 and evaporated in vacuo. The residue was puri-
fied by column chromatography (hexane/EtOAc) and crystallized.
5.2.5. (3-Methoxyphenyl)-quinolin-2-yl-methanone (5f)
This was prepared from quinoline-2-carbonitrile and 3-bromo-
anisole in 90% yield. White solid; mp 77 °C (hexane/EtOAc); IR
(KBr)
m ;
1662, 1598, 1462, 1318, 1143, 760 cmÀ1 1H NMR (CDCl3)
d 8.34 (d, 1H, J = 8.5 Hz), 8.20 (br d, 1H, J = 8.5 Hz), 8.09 (d, 1H),
7.91 (br d, 1H, J = 8.2 Hz), 7.80 (m, 3H), 7.66 (m, 1H), 7.41 (t, 1H,
J = 8.3 Hz), 7.18 (m, 1H); 13C NMR (CDCl3) d 193.50, 159.43,
154.76, 146.72, 137.37, 137.08, 130.52, 130.12, 129.14, 128.87,
128.42, 127.66, 124.44, 120.80, 119.78, 115.43, 55.45. Anal.
(C17H13NO2) C, H, N. HRMS (ESI+) calcd for C17H14NO2 (M+H),
264.1025; found, 264.1015.
5.2.6. (2-Methoxyphenyl)-quinolin-2-yl-methanone (5g)
This was prepared from quinoline-2-carbonitrile and 2-bromo-
anisole in 96% yield. White solid; mp 93 °C (diisopropyl ether); IR
5.2.1. Quinolin-2-yl-(4-trifluoromethylphenyl)-methanone
(5b)
(KBr)
m ;
1682, 1599, 1315, 1251, 921 cmÀ1 1H NMR (CDCl3) d
This was prepared from quinoline-2-carbonitrile and 4-bromo-
8.28 (d, 1H, J = 8.4 Hz), 8.09 (br d, 1H, J = 8.5 Hz), 8.05 (d, 1H),
7.86 (dd, 1H, J = 8.1 Hz, J = 1.0 Hz), 7.70 (ddd, 1H, J = 6.9 Hz), 7.65
(dd, 1H, J = 7.5 Hz, J = 1.7 Hz), 7.60 (ddd, 1H, J = 1.2 Hz), 7.52 (ddd,
1H, J = 8.3 Hz, J = 7.5 Hz), 7.09 (td, 1H, J = 0.9 Hz), 7.00 (d, 1H),
3.59 (s, 3H); 13C NMR (CDCl3) d 196.35, 158.96, 155.28, 147.27,
136.78, 133.05, 131.09, 130.71, 129.85, 129.15, 128.24, 128.18,
127.67, 120.63, 119.82, 112.03, 55.91. Anal. (C17H13NO2) C, H, N.
benzotrifluoride in 80% yield. White needles; mp 99 °C (hexane); IR
(KBr)
m ;
1671, 1338, 1318, 1103, 777 cmÀ1 1H NMR (CDCl3) d 8.37
(m, 3H), 8.19 (d, 1H, J = 8.5 Hz), 8.18 (d, 2H, J = 8.2 Hz), 7.92 (br d,
1H, J = 8.2 Hz), 7.79 (m, 3H), 7.69 (ddd, 1H, J = 1.1 Hz, J = 7.0,
J = 8.1 Hz); 13C NMR (CDCl3) d 192.70, 153.77, 146.85, 139.36,
137.46, 134.12 (q, J = 32.3 Hz), 131.82 (2C), 130.69, 130.43,

B. Reux et al. / Bioorg. Med. Chem. 17 (2009) 4441–4447
4445
HRMS (ESI+) calcd for C17H14NO2 (M+H), 264.1025; found,
264.1024.
(td, 1H, J = 1.0 Hz), 2.69 (s, 6H); 13C NMR (CDCl3) d 196.90,
155.44, 152.85, 147.37, 136.55, 132.29, 132.01, 130.80, 129.86,
129.02, 128.42, 128.16, 127.57, 120.65, 118.89, 116.87, 43.79. Anal.
(C18H16N2O) C, H, N. HRMS (ESI+) calcd for C18H17N2O (M+H),
277.1341; found, 277.1348.
5.2.7. (4-Ethoxyphenyl)-quinolin-2-yl-methanone (5h)
This was prepared from quinoline-2-carbonitrile and 1-bromo-
4-ethoxybenzene in 67% yield. White solid; mp 68 °C (diisopropyl
ether); IR (KBr)
m
2983, 2943, 1657, 1605, 1275, 1257, 1163,
5.2.12. (4-Chlorophenyl)-quinolin-2-yl-methanone (5m)
This was prepared from quinoline-2-carbonitrile and 4-bromo-
chlorobenzene in 81%. White needles; mp 133 °C (hexane/EtOAc);
7.62 cmÀ1 1H NMR (CDCl3) d 8.28 (m, 3H), 8.20 (br d, 1H,
;
J = 8.5 Hz), 8.04 (d, 1H, J = 8.5 Hz), 7.88 (br d, 1H, J = 8.1 Hz), 7.76
(ddd, 1H, J = 6.9 Hz, J = 1.4 Hz), 7.63 (ddd, 1H, J = 1.2 Hz), 6.97 (d,
2H, J = 9.0 Hz), 4.12 (q, 2H, J = 7.0 Hz), 1.44 (t, 3H); 13C NMR (CDCl3)
d 192.29, 163.26, 155.54, 146.72, 137.09, 134.00 (2C), 130.49,
130.09, 128.82, 128.80, 128.25, 127.73, 120.98, 114.06 (2C),
63.84, 14.78. Anal. (C18H15NO2) C, H, N. HRMS (ESI+) calcd for
C18H16NO2 (M+H), 278.1181; found, 278.1179.
IR (KBr)
m
1665, 1591, 1318, 1091, 924, 772 cmÀ1; 1H NMR (CDCl3)
d 8.35 (d, 1H, J = 8.4 Hz), 8.24 (d, 2H, J = 8.6 Hz), 8.19 (br d, 1H,
J = 8.5 Hz), 8.13 (d, 1H), 7.91 (br d, 1H, J = 8.1 Hz), 7.80 (ddd, 1H,
J = 1.3 Hz, J = 6.9 Hz), 7.67 (ddd, 1H), 7.49 (d, 2H); 13C NMR (CDCl3)
d 192.41, 154.30, 146.75, 139.63, 137.32, 134.61, 133.02 (2C),
130.61, 130.30, 129.07, 128.71, 128.54, 127.77, 120.81. Anal.
(C16H10ClNO.0.1 H2O) C, H, N. HRMS (ESI+) calcd for C16H11ClNO
(M+H), 268.0529; found, 268.0520.
5.2.8. (4-Propoxyphenyl)-quinolin-2-yl-methanone (5i)
This was prepared from quinoline-2-carbonitrile and 1-bromo-
4-propoxybenzene in 87% yield. Beige crystals; mp 89 °C (hexane/
5.2.13. (3,4-Dichlorophenyl)-quinolin-2-yl-methanone (5n)
This was prepared from quinoline-2-carbonitrile and 4-bromo-
1,2-dichlorobenzene in 64% yield. White solid; mp 146 °C (hexane/
EtOAc); IR (KBr)
m 2962, 2874, 1650, 1599, 1316, 1257, 1158,
780 cmÀ1 1H NMR (CDCl3) d 8.33 (d, 1H, J = 8.5 Hz), 8.27 (d, 2H,
;
J = 9.0 Hz), 8.21 (br d, 1H, J = 8.4 Hz), 8.05 (d, 1H), 7.90 (dd, 1H,
J = 8.2 Hz, J = 1.2 Hz), 7.78 (ddd, 1H, J = 6.9 Hz, J = 1.5 Hz), 7.65
(ddd, 1H, J = 1.2 Hz), 6.98 (d, 2H), 4.02 (t, 2H, J = 6.6 Hz), 1.85 (sext,
2H), 1.06 (t, 3H, J = 7.4 Hz); 13C (CDCl3) d 192.33, 163.49, 155.57,
146.75, 137.09, 134.01 (2C), 130.52, 130.10, 128.85, 128.77,
128.25, 127.74, 121.01, 114.10 (2C), 69.83, 22.55, 10.57. Anal.
(C19H17NO2) C, H, N. HRMS (ESI+) calcd for C19H18NO2 (M+H),
292.1338; found, 292.1333.
EtOAc); IR (KBr) m ;
1670, 1584, 1313, 1295, 1166, 764 cmÀ1 1H
NMR (CDCl3) d 8.45 (d, 1H, J = 2.0 Hz), 8.37 (d, 1H, J = 8.4 Hz),
8.20 (br d, 1H, J = 8.4 Hz), 8.15 (m, 2H), 7.92 (dd, 1H, J = 8.2 Hz,
J = 1.1 Hz), 7.82 (ddd, 1H, J = 6.9 Hz), 7.69 (ddd, 1H, J = 1.2 Hz),
7.60 (d, 1H, J = 8.4 Hz); 13C NMR (CDCl3)
d 191.12, 153.74,
146.77, 137.63, 137.48, 135.94, 133.53, 132.73, 130.70 (2C),
130.45, 130.30, 129.20, 128.97, 127.80, 120.74. Anal. (C16H9Cl2NO)
C, H, N. HRMS (ESI+) calcd for C16H10Cl2NO (M+H), 302.0139;
found, 302.0150.
5.2.9. (4-Isopropoxyphenyl)-quinolin-2-yl-methanone (5j)
This was prepared from quinoline-2-carbonitrile and 1-bromo-
4-isopropoxybenzene in 64%. Pale yellow crystals; mp 66 °C (diiso-
5.2.14. (4-Fluorophenyl)-quinolin-2-yl-methanone (5o)
This was prepared from quinoline-2-carbonitrile and 4-bromo-
fluorobenzene in 93% yield. White needles; mp 131 °C (hexane/
propyl ether); IR (KBr)
m 2983, 2967, 1647, 1597, 1322, 1256, 1156,
774 cmÀ1 1H NMR (CDCl3) d 8.31 (d, 1H, J = 8.4 Hz), 8.26 (d, 2H,
;
EtOAc); IR (KBr) m ;
1664, 1598, 1506, 1322, 1236, 766 cmÀ1 1H
J = 9.0 Hz), 8.20 (br d, 1H, J = 8.2 Hz), 8.04 (d, 1H), 7.88 (dd, 1H,
J = 8.1 Hz, J = 1.2 Hz), 7.77 (ddd, 1H, J = 6.9 Hz), 7.63 (ddd, 1H,
J = 1.2 Hz), 6.96 (d, 2H), 4.68 (sept, 1H, J = 6.1 Hz), 1.38 (d, 6H);
13C NMR (CDCl3) d 192.24, 162.38, 155.57, 146.72, 137.08, 134.03
(2C), 130.49, 130.07, 128.82, 128.51, 128.22, 127.72, 120.98,
114.97 (2C), 70.15, 22.02 (2C). Anal. (C19H17NO2) C, H, N. HRMS
(ESI+) calcd for C19H17NO2Na (M+Na), 314.1157; found, 314.1167.
NMR (CDCl3) d 8.34 (m, 3H), 8.20 (br d, 1H, J = 8.5 Hz), 8.12 (d,
1H, J = 8.5 Hz), 7.92 (dd, 1H, J = 1.1 Hz), 7.80 (ddd, 1H, J = 6.9 Hz),
7.67 (ddd, 1H), 7.19 (t, 2H, J = 8.6 Hz); 13C NMR (CDCl3) d 192.10,
165.96 (d, 1C, J = 253.7 Hz), 154.59, 146.75, 137.33, 134.36 (d, 2C,
J = 9.3 Hz), 132.58 (d, 1C, J = 2.9 Hz), 130.59, 130.30, 129.04,
128.65, 127.79, 120.90, 115.41 (d, 2C, J = 21.6 Hz). Anal.
(C16H10FNOÁ0.1H2O) C, H, N. HRMS (ESI+) calcd for C16H11FNO
(M+H), 252.0825; found, 252.0821.
5.2.10. (4-Dimethylaminophenyl)-quinolin-2-yl-methanone
(5k)
This was prepared from quinoline-2-carbonitrile and 4-bromo-
N,N-dimethylaniline in 94% yield. Yellow needles; mp 120 °C (hex-
5.2.15. (3-Fluorophenyl)-quinolin-2-yl-methanone (5p)
This was prepared from quinoline-2-carbonitrile and 3-bromo-
fluorobenzene in 98%. Pale yellow needles; mp 116 °C (hexane/
ane/EtOAc); IR (KBr)
m
2909, 2821, 1632, 1590, 1371, 1330, 1157,
EtOAc); IR (KBr) m ;
1666, 1586, 1438, 1316, 768 cmÀ1 1H NMR
776 cmÀ1 1H NMR (CDCl3) d 8.30 (d, 1H, J = 8.2 Hz), 8.21 (m, 3H),
;
(CDCl3) d 8.36 (d, 1H, J = 8.4 Hz), 8.21 (br d, 1H, J = 8.3 Hz), 8.14 (d,
1H), 8.06 (td, 1H, J = 1.2 Hz, J = 7.9 Hz), 8.01 (ddd, 1H, J = 2.6 Hz,
J = 9.7 Hz), 7.92 (dd, 1 h, J = 1.0 Hz, J = 8.2 Hz), 7.80 (ddd, 1H,
J = 1.5 Hz, J = 6.9 Hz), 7.67 (ddd, 1H), 7.49 (td, 1H, J = 5.6 Hz), 7.34
(tdd, 1H); 13C NMR (CDCl3) d 192.28, 162.46 (d, 1C, J = 245.1 Hz),
154.17, 146.79, 138.25 (d, 1C, J = 6.7 Hz), 137.36, 130.68, 130.33,
129.81 (d, 1C, J = 7.7 Hz), 129.11, 128.77, 127.77, 127.37 (d, 1C,
J = 2.9 Hz), 120.80, 120.07 (d, 1C, J = 21.2 Hz), 118.35 (d, 1C,
J = 22.8 Hz). Anal. (C16H11FNOÁ0.1H2O) C, H, N. HRMS (ESI+) calcd
for C16H11FNO (M), 252.0825; found, 252.0823.
7.99 (d, 1H), 7.89 (dd, 1H, J = 8.2 Hz, J = 1.1 Hz), 7.77 (ddd, 1H,
J = 8.5 Hz, J = 6.9 Hz), 7.63 (ddd, 1H, J = 1.2 Hz), 6.71 (d, 2H,
J = 9.2 Hz), 3.09 (s, 6H); 13C NMR (CDCl3) d 191.73, 156.66,
153.74, 146.75, 136.84, 133.88 (2C), 130.40, 129.88, 128.61,
127.83, 127.69, 123.70, 121.09, 110.67 (2C), 40.09 (2C). Anal.
(C18H16N2O) C, H, N. HRMS (ESI+) calcd for C18H17N2O (M+H),
277.1341; found, 277.1348.
5.2.11. (2-Dimethylaminophenyl)-quinolin-2-yl-methanone
(5l)
This was prepared from quinoline-2-carbonitrile and 2-bromo-
5.2.16. Isoquinolin-1-yl-phenyl-methanone (6a)
N,N-dimethylaniline in 81% yield. Orange solid; 84 °C (diisopropyl
ether); IR (KBr)
(CDCl3) d 8.24 (d, 1H, J = 8.5 Hz), 8.16 (br d, 1H, J = 8.4 Hz), 7.95
(d, 1H), 7.85 (dd, 1H, J = 8.1 Hz, J = 1.0 Hz), 7.71 (ddd, 1H,
J = 6.9 Hz), 7.60 (ddd, 1H, J = 1.2 Hz), 7.52 (dd, 1H, J = 7.7 Hz,
J = 1.6 Hz), 7.43 (ddd, 1H, J = 8.4 Hz, J = 7.2 Hz), 7.03 (d, 1H), 6.91
This was prepared from isoquinoline-1-carbonitrile and phenyl
magnesium bromide in 94% yield. White solid; mp 81 °C (hexane/
EtOAc); IR (KBr)
m ;
1655, 1596, 1558, 1501, 917 cmÀ1 1H NMR
m ;
1665, 1450, 1252, 924, 711 cmÀ1 1H NMR
(CDCl3) 8.60 (d, 1H, J = 5.6 Hz), 8.22 (dd, 1H, J = 8.5 Hz,
d
J = 0.9 Hz), 7.96 (m, 2H), 7.91 (br d, 1H, J = 8.3 Hz), 7.80 (d, 1H),
7.73 (ddd, 1H, J = 6.9 Hz), 7.60 (m, 2H), 7.47 (m, 2H); 13C NMR

4446
B. Reux et al. / Bioorg. Med. Chem. 17 (2009) 4441–4447
(CDCl3) d 194.79, 156.47, 141.21, 136.72, 136.67, 133.71, 130.79
(2C), 130.76, 128.51 (2C), 128.36, 127.15, 126.44, 126.17, 122.64.
Anal. (C16H11NOÁ0.1H2O) C, H, N. HRMS (ESI+) calcd for C16H11NO-
Na (M+Na), 256.0738; found, 256.0732.
J = 1.5 Hz), 7.41 (td, 1H, J = 7.6 Hz), 7.35 (t, 1H), 7.16 (ddd, 1H), 3.86
(s, 3H); 13C NMR (CDCl3) d 194.73, 159.85, 156.64, 141.32, 138.06,
136.79, 130.84, 129.58, 128.43, 127.22, 126.49, 126.26, 124.10,
122.68, 120.57, 114.41, 55.61. Anal. (C17H13NO2) C, H, N. HRMS
(ESI+) calcd for C17H14NO2 (M+H), 264.1025; found, 264.1012.
5.2.17. Isoquinolin-1-yl-(4-trifluoromethylphenyl)-methanone
(6b)
5.2.22. Isoquinolin-1-yl-(4-dimethylaminophenyl)-methanone
(6g)
This was prepared from isoquinoline-1-carbonitrile and 4-bro-
mobenzotrifluoride in 89% yield. White needles; mp 96 °C (hex-
ane/EtOAc); IR (KBr)
This was prepared from isoquinoline-1-carbonitrile and 4-bro-
mo-N,N-dimethylaniline in 54% yield. Pale green needles; mp
m ;
1670, 1332, 1120, 1068, 926, 830 cmÀ1 1H
NMR (CDCl3) d 8.61 (d, 1H, J = 5.6 Hz), 8.35 (dd, 1H, J = 8.5 Hz,
J = 0.6 Hz), 8.08 (d, 2H, J = 8.1 Hz), 7.94 (br d, 1H, J = 8.3 Hz), 7.85
(d, 1H), 7.75 (m, 3H), 7.67 (ddd, 1H, J = 7.00 Hz, J = 1.2 Hz); 13C
NMR (CDCl3) d 193.58, 154.96, 141.17, 139.84, 136.98, 134.61 (q,
J = 32.6 Hz), 131.16 (2C), 130.99, 128.87, 127.32, 126.73, 126.10,
125.48 (q, 2C, J = 13.8 Hz), 123.74 (q, J = 271.1 Hz), 123.51. Anal.
(C17H10F3NO) C, H, N. HRMS (ESI+) calcd for Cg17H10F3NONa
(M+Na), 324.0612; found, 324.0624.
102 °C (Et2O); IR (KBr)
m 3053, 2913, 1638, 1587, 1386, 1286,
1181, 925 cmÀ1 1H NMR (CDCl3) d 8.58 (d, 1H, J = 5.7 Hz), 8.12
;
(dd, 1H, J = 8.5 Hz, J = 0.8 Hz), 7.87 (br d, 1H, J = 8.3 Hz), 7.83 (d,
2H, J = 9.1 Hz), 7.73 (d, 1H), 7.69 (ddd, 1H, J = 6.9 Hz, J = 1.1 Hz),
7.55 (ddd, 1H), 6.63 (d, 2H), 3.04 (s, 3H); 13C NMR (CDCl3) d
192.97, 158.48, 154.01, 141.42, 136.60, 133.09 (2C), 130.55,
127.86, 126.99, 126.66, 126.35, 124.36, 121.66, 110.75 (2C),
40.09 (2C). Anal. (C18H16N2O) C, H, N. HRMS (ESI+) calcd for
C18H17N2O (M+H), 277.1341; found, 277.1346.
5.2.18. Isoquinolin-1-yl-(2-trifluoromethylphenyl)-methanone
(6c)
5.2.23. Isoquinolin-1-yl-(2-dimethylaminophenyl)-methanone
(6h)
This was prepared from isoquinoline-1-carbonitrile and 2-bro-
mobenzotrifluoride in 44% yield. Pale green crystals; mp 109 °C
This was prepared from isoquinoline-1-carbonitrile and 2-bro-
mo-N,N-dimethylaniline in 96% yield. Orange solid; mp 73 °C
(hexane/EtOAc); IR (KBr)
m ;
1674, 1318, 1242, 1114, 924 cmÀ1 1H
NMR (CDCl3) d 9.01 (m, 1H), 8.51 (d, 1H, J = 5.5 Hz), 7.90 (m, 1H),
7.81 (d, 1H), 7.74 (m, 3H), 7.62 (m, 2H), 7.55 (m, 1H); 13C NMR
(CDCl3) d 197.05, 152.92, 141.21, 139.94, 137.05, 131.48, 130.75,
130.22, 129.58, 129.53, 128.12 (q, 1C, J = 32.1 Hz), 127.22, 126.96,
126.61 (q, 1C, J = 272.3 Hz), 126.57, 126.55 (q, 1C, J = 4.5 Hz),
124.83. Anal. (C17H10F3NO) C, H, N. HRMS (ESI+) calcd for
C17H11F3NO (M+H), 302.0793; found, 302.0785.
(diisopropyl ether); IR (KBr) m ;
1661, 1593, 1489, 1284, 920 cmÀ1
1H NMR (CDCl3) d 8.50 (d, 1H, J = 5.6 Hz), 8.42 (dd, 1H, J = 8.5 Hz,
J = 0.7 Hz), 7.89 (br d, 1H, J = 8.3 Hz), 7.70 (m, 2H), 7.61 (ddd, 1H,
J = 7.0 Hz, J = 1.2 Hz), 7.41 (m, 2H), 7.04 (d, 1H, J = 8.2 Hz), 6.86
(td, 1H, J = 7.9 Hz, J = 0.9 Hz), 2.74 (s, 6H); 13C NMR (CDCl3) d
196.42, 157.72, 153.15, 141.27, 136.76, 133.12, 132.57, 130.49,
129.25, 128.27, 127.07, 126.64, 126.47, 122.60, 119.12, 117.33,
44.05. Anal. (C18H16N2O) C, H, N. HRMS (ESI+) calcd for
C18H17N2O (M+H), 277.1341; found, 277.1353.
5.2.19. (3,5-Bis-trifluoromethylphenyl)-isoquinolin-1-yl-
methanone (6d)
This was prepared from isoquinoline-1-carbonitrile and 3,5-
bis(trifluoromethyl) bromobenzene in 55% yield. White solid; mp
118 °C (hexane); IR (KBr)
5.2.24. Isoquinolin-1-yl-(4-fluorophenyl)-methanone (6i)
This was prepared from isoquinoline-1-carbonitrile and 4-bro-
mofluorobenzene in 86% yield. Beige crystals; mp 92 °C (hexane/
m ;
1678, 1278, 1190, 1126, 681 cmÀ1 1H
EtOAc); IR (KBr)
m ;
1664, 1596, 1247, 1151, 925 cmÀ1 1H NMR
NMR (CDCl3) d 8.63 (d, 1H, J = 5.6 Hz), 8.49 (dd, 1H, J = 8.6 Hz,
J = 0.8 Hz), 8.47 (br s, 2H), 8.10 (br s, 1H), 7.98 (br d, 1H, J = 8.2 Hz),
7.91 (d, 1H), 7.81 (ddd, 1H, J = 6.9 Hz), 7.73 (ddd, 1H, J = 1.2 Hz);
13C NMR (CDCl3) d 191.52, 153.34, 141.14, 138.91, 137.27, 132.05
(q, 2C, J = 33.6 Hz), 131.21, 131.02 (q, 2C, J = 3.4 Hz), 129.36,
127.51, 127.07, 126.40 (sept, J = 3.6 Hz), 126.07, 124.43, 123.13 (q,
2C, J = 271.3 Hz). Anal. (C18H9F6NO) C, H, N. HRMS (ESI+) calcd for
C18H10F6NO (M+H), 370.0667; found, 370.0669.
(CDCl3) d 8.60 (d, 1H, J = 5.6 Hz), 8.23 (dd, 1H, J = 8.5 Hz, J = 0.9 Hz),
8.01 (dd, 2H, J = 9.0 Hz, J = 5.5 Hz), 7.93 (br d, 1H, J = 8.3 Hz), 7.82
(d, 1H), 7.76 (ddd, 1H, J = 6.9 Hz, J = 1.1 Hz), 7.64 (ddd, 1H,
J = 1.2 Hz), 7.15 (t, 2H); 13C NMR (CDCl3) d 193.14, 166.21 (d,
J = 254.3 Hz), 156.07, 141.19, 136.86, 133.63 (d, 2C, J = 9.3 Hz),
133.13 (d, J = 2.8 Hz), 130.89, 128.54, 127.24, 126.52, 126.19,
122.90, 115.75 (d, 2C, J = 21.8 Hz). Anal. Calcd for C16H10FNO: C,
76.49; H, 4.01; N, 5.57. Found: C, 76.85; H, 3.85; N, 5.55. HRMS
(ESI+) calcd for C16H11FNO (M+H), 252.0825; found, 252.0835.
5.2.20. Isoquinolin-1-yl-(4-methoxyphenyl)-methanone (6e)
This was prepared from isoquinoline-1-carbonitrile and 4-
bromoanisole in 93% yield. Pale yellow solid; mp 74 °C (Et2O); IR
5.2.25. Isoquinolin-1-yl-(3-fluorophenyl)-methanone (6j)
This was prepared from isoquinoline-1-carbonitrile and 3-bro-
mofluorobenzene in 92% yield. White crystals; mp 99 °C (hexane/
(KBr)
m ;
1651, 1601, 1249, 1155, 1023, 925 cmÀ1 1H NMR (CDCl3)
d 8.58 (d, 1H, J = 5.6 Hz), 8.16 (br d, 1H, J = 8.5 Hz), 7.94 (d, 2H,
J = 8.9 Hz), 7.89 (br d, 1H, J = 8.3 Hz), 7.77 (d, 1H), 7.71 (br t, 1H,
J = 7.1 Hz), 7.58 (br t, 1H), 6.94 (d, 2H), 3.85 (s, 3H); 13C NMR
(CDCl3) d 193.46, 164.19, 157.16, 141.26, 136.70, 133.22 (2C),
130.72, 129.60, 128.19, 127.11, 126.38, 126.33, 122.31, 113.87
(2C), 55.61. Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32.
Found: C, 76.94; H, 4.86; N, 5.18. HRMS (ESI+) calcd for
C17H14NO2 (M+H), 264.1025; found, 264.1023.
EtOAc); IR (KBr)
m ;
1666, 1586, 1441, 1256, 1136, 871 cmÀ1 1H
NMR (CDCl3) d 8.61 (d, 1H, J = 5.6 Hz), 8.26 (dd, 1H, J = 8.5 Hz,
J = 0.9 Hz), 7.93 (br d, 1H, J = 8.3 Hz), 7.83 (d, 1H), 7.75 (m, 2H),
7.69 (ddd, 1H, J = 9.4 Hz, J = 2.5 Hz, J = 1.5 Hz), 7.64 (ddd, 1H,
J = 6.9 Hz, J = 1.2 Hz), 7.45 (td, 1H, J = 8.1 Hz, J = 5.5 Hz), 7.31 (tdd,
1H); 13C NMR (CDCl3) d 193.37, 162.73 (d, 1C, J = 246.2 Hz),
155.60, 141.22, 138.88 (d, 1C, J = 6.5 Hz), 136.92, 130.95, 130.21
(d, 1C, J = 7.6 Hz), 128.69, 127.31, 126.82 (d, 1C, J = 3.1 Hz),
126.59, 126.15, 123.17, 120.74 (d, 1C, J = 21.6 Hz), 117.44 (d, 1C,
J = 22.5 Hz). Anal. (C16H10FNO) C, H, N. HRMS (ESI+) calcd for
C16H11FNO (M+H), 252.0825; found, 252.0837.
5.2.21. Isoquinolin-1-yl-(3-methoxyphenyl)-methanone (6f)
This was prepared from isoquinoline-1-carbonitrile and 3-
bromoanisole in 90% yield. Beige crystals; mp 59 °C (diisopropyl
ether); IR (KBr)
m
1674, 1595, 1463, 1279, 1263, 747 cmÀ1; 1H NMR
(CDCl3) 8.60 (d, 1H, J = 5.64 Hz), 8.20 (dd, 1H, J = 8.5 Hz,
J = 0.8 Hz), 7.92 (br d, 1H, J = 8.2 Hz), 7.80 (d, 1H), 7.75 (ddd, 1H,
J = 6.9 Hz), 7.62 (ddd, 1H, J = 1.2 Hz), 7.58 (dd, 1H, J = 2.5 Hz,
d
5.2.26. Isoquinolin-1-yl-(4-chlorophenyl)-methanone (6k)
This was prepared from isoquinoline-1-carbonitrile and 4-chlo-
rofluorobenzene in 98% yield. Pale yellow crystals; mp 103 °C (hex-

B. Reux et al. / Bioorg. Med. Chem. 17 (2009) 4441–4447
4447
ane/EtOAc); IR (KBr)
m ;
1664, 1585, 1245, 1092, 922 cmÀ1 1H NMR
References and notes
(CDCl3) d 8.59 (d, 1H, J = 5.6 Hz), 8.25 (br d, 1H, J = 8.5 Hz), 7.91 (m,
3H), 7.81 (d, 1H), 7.74 (ddd, 1H, J = 6.9 Hz, J = 0.9 Hz), 7.63 (ddd, 1H,
J = 1.0 Hz), 7.44 (d, 2H, J = 8.6 Hz); 13C NMR (CDCl3) d 193.44,
155.70, 141.16, 140.22, 136.85, 135.13, 132.25 (2C), 130.89,
128.85 (2C), 128.60, 127.24, 126.54, 126.14, 123.04. Anal.
(C16H10ClNO) C, H, N. HRMS (ESI+) calcd for C16H11ClNO (M+H),
268.0529; found, 268.0520.
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5.2.27. (3,4-Dichlorophenyl)-isoquinolin-1-yl-methanone (6l)
This was prepared from isoquinoline-1-carbonitrile and 4-bro-
mo-1,2-dichlorobenzene in 83% yield. White solid; mp 147 °C
(hexane/EtOAc); IR (KBr)
m ;
1666, 1557, 1248, 935, 756 cmÀ1 1H
NMR (CDCl3) d 8.61 (d, 1H, J = 5.6 Hz), 8.30 (br d, 1H, J = 8.6 Hz),
8.07 (d, 1H, J = 2.0 Hz), 7.94 (br d, 1H, J = 8.2 Hz), 7.86 (d, 1H),
7.82 (dd, 1H, J = 8.4 Hz), 7.77 (ddd, 1H, J = 6.9 Hz, J = 1.1 Hz), 7.67
(ddd, 1H, J = 1.2 Hz), 7.56 (d, 1H); 13C NMR (CDCl3) d 192.26,
154.80, 141.16, 138.22, 136.99, 136.54, 133.15, 132.74, 131.01,
130.62, 129.93, 128.86, 127.34, 126.66, 126.07, 123.51. Anal.
(C16H9Cl2NO) C, H, N. HRMS (ESI+) calcd for C16H9Cl2NONa
(M+Na), 323.9959; found, 323.9967.
Acknowledgments
This work was supported by the National Technology Agency of
Finland and the Academy of Finland (Grant 110277). We are grate-
ful to Mrs. Minna Glad for technical assistance.
Supplementary data
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Pharmacol. 2003, 140, 1451.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.05.013.