Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and quinazoline derivatives as CB2 receptor agonists

Article abstract of DOI:10.1016/j.bmc.2010.11.059

Quinoline, isoquinoline, quinoxaline, and quinazoline derivatives were synthesized using microwave-assisted synthesis and their CB1/CB2 receptor activities were determined using the [³⁵S]GTPγS binding assay. Most of the prepared quinoline, isoquinoline, and quinoxalinyl phenyl amines showed low-potency partial CB2 receptor agonists activity. The most potent CB2 ligand was the 4-morpholinylmethanone derivative (compound 40e) (-log EC ₅₀ = 7.8; E_max = 75%). The isoquinolin-1-yl(3- trifluoromethyl-phenyl)amine (compound 26c) was a high efficacy CB2 agonist (-log EC₅₀ = 5.8; E_max = 128%). No significant CB1 receptor activation or inactivation was shown in these studies, except 40e, which showed weak CB1 agonist activity (CB1 -log EC₅₀ = 5.0). These ligands serve as novel templates for the development of selective CB2 receptor agonist.

Full text of DOI:10.1016/j.bmc.2010.11.059

Bioorganic & Medicinal Chemistry 19 (2011) 939–950
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and
quinazoline derivatives as CB2 receptor agonists
⇑
Raimo Saari, Jonna-Carita Törmä, Tapio Nevalainen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 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:
Received 7 July 2010
Revised 23 November 2010
Accepted 24 November 2010
Available online 9 December 2010
Quinoline, isoquinoline, quinoxaline, and quinazoline derivatives were synthesized using microwave-
assisted synthesis and their CB1/CB2 receptor activities were determined using the [35S]GTP
cS binding
assay. Most of the prepared quinoline, isoquinoline, and quinoxalinyl phenyl amines showed low-potency
partial CB2 receptor agonists activity. The most potent CB2 ligand was the 4-morpholinylmethanone deriv-
ative (compound 40e) (ꢀlog EC50 = 7.8; Emax = 75%). The isoquinolin-1-yl(3-trifluoromethyl-phenyl)amine
(compound 26c) was a high efficacy CB2 agonist (ꢀlog EC50 = 5.8; Emax = 128%). No significant CB1 receptor
activation or inactivation was shown in these studies, except 40e, which showed weak CB1 agonist activity
(CB1 ꢀlog EC50 = 5.0). These ligands serve as novel templates for the development of selective CB2 receptor
agonist.
Keywords:
Receptors
Agonists
Cannabinoid receptor 2
Quinoline
Ó 2010 Elsevier Ltd. All rights reserved.
Isoquinoline
Quinoxaline
Quinazoline
Microwave irradiation
1. Introduction
compounds by Adolor Corporation, (7)12 and 3-amino-6-aryl-
pyridazines (8) by GlaxoSmithKline13 (Fig. 1).
Recent research evidence has demonstrated the therapeutic po-
tential for the selective CB2 receptor ligands. CB2 selective cannab-
inoids are expected to devoid of undesired CB1-mediated
psychotropic side effects and would have therapeutic value in
the pain relief, inflammation, osteoporosis, and in treating cancers.
In recent years, structurally diverse CB2 selective agonists exhibit-
ing analgesic activity in various pain models have been discovered
and recently reviewed.1–3 These CB2 selective agonists include tet-
rahydrocannabinol mimetics such as JWH-133 (1), which was
shown to inhibit inflammatory and neuropathic pain.4 AM1241
(2) is a widely studied CB2 agonist from the aminoalkylindole
family, which has also shown efficacy in inflammatory and
neuropathic pain models.5,6 NESS400 is a CB2 selective pyrazole-
carboxamide derivative,7 which inhibits neuropathic pain through
downregulation of microglial activation.8 Many other chemically
heterogeneous CB2 selective agonists have been developed re-
cently. Representative examples of novel chemotypes include pyr-
imidinecarboxamide based structure 4 (GW842166X)9 and 5-
azaindole 5 (GSK554418A)10 disclosed by GlaxoSmithKline. Other
examples of recently published CB2 selective agonists are A-
836339 (6) developed by Abbott Laboratories,11 pyridine-based
Our previously reported CB2 agonist NRB04079 (isoquinolin-
1-yl-[3-(trifluoromethyl)phenyl]-methanone, 9) (Fig. 2) served as
a lead structure in our search for more potent CB2 agonists.14
NRB04079 was found in a molecular database search study using
a CB2 receptor model and it act as a partial agonist at the human
CB2 receptor (ꢀlog EC50 = 5.3; Emax = 53%). Later we found that
N-phenyl-2-naphthylamine (10) ( Fig. 2) show full CB2 agonist
activity (ꢀlog EC50 = 5.2; Emax = 93%), which inspired us to synthe-
size diarylketone and -amine derivatives. In our previous paper, we
discussed structure–activity relationships of quinolinyl and iso-
quinolinyl phenyl ketones as novel agonists for the cannabinoid
CB2 receptor.15 Here, we present series of quinolinyl, isoquinolinyl,
quinoxalinyl, and quinazoline phenyl amines, phenylsulfanylquin-
olines and phenoxyquinolines, which were synthesized using
microwave irradiation and their CB2 receptor-dependent G-pro-
tein activities were determined using the [35S]GTP
assay.
cS binding
2. Results and discussion
2.1. Chemistry
In general, microwave-assisted synthesis was used in all cou-
pling reactions of aryl amines and aryl halides to reduce reaction
times and increase yields. The quinoline-, quinazoline- quinoxa-
⇑
Corresponding author.
E-mail address: tapio.nevalainen@uef.fi (T. Nevalainen).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.11.059

940
R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
X
N
X
Y
Y
NO2
150 °C, 15 min
Microwave
R
NH2
O
N
+
R
N
H
O
N
Cl
NH
12a-z
, X=CH, Y=CH
14a-b, X=N, Y=CH
16a-b, X=CH, Y=N
11,
13, X=N, Y=CH
X=CH, Y=CH
I
N
15
, X=CH, Y=N
N
Cl
X
Y
X
N
O
150 °C, 15 min
Microwave
Y
R
NH2
Cl
+
1 (JWH-133)
2 (AM1241)
3 (NESS400)
HN
R
Cl
17, X=N, Y=CH
19
18a-b, X=N, Y=CH
CF3
N
O
, X=CH, Y=N
21, X=N, Y=N
20a-d,
N
O
X=CH, Y=N
Cl
22a-b, X=N, Y=N
N
N
H
N
O
Scheme 1. Synthesis of quinoline-, quinazoline- quinoxaline, and isoquinoline-
N
H
O
Cl
N
H
N
amines.
Cl
4 (GW842166X)
5 (GSK554418A)
O
H
N
Cl
N
O
N
Cl
N
O
Zn, NH3 (aq)
POCl3 , (Et)2NH
N
N
S
NH
N
100 °C, 10 min
Microwave
N
150 °C, 15 min
Microwave
N
O
N
O
Cl
N
23
24
15
N
N
NH
O
Scheme 2. Synthesis of 2-chloroquinazoline (15).
6 (A-836339)
7
8
N
N
Figure 1. Structures of CB2 selective agonists.
NH2
CN
POCl3 , (Et)2NH
HCOOH,H2SO4
N
NH
100°C, 5min
Microwave
100 °C, 5min
Microwave
O
Cl
line-, and isoquinolineamines were prepared by reacting chlorides
(17, 13, 15, 17, 19, and 21) with 4–5 equiv of amine under micro-
wave irradiation without solvent (Scheme 1).
25
26
21
Scheme 3. Synthesis of 4-chloroquinazoline (21).
The 2-chloroquinazoline 15 was synthesized in two steps from
commercially available 1H,3H-quinazoline 2,4-dione 23 by a mod-
ification of the previously published procedure.16 The starting
material was reacted with POCl3 under microwave irradiation in
N,N-diethylamine to provide 2,4-dichloroquinazoline 24, which is
then selectively reduced by activated zinc to yield 2-chloroquinaz-
oline 1517 (Scheme 2).
The 4-chloroquinazoline 21 was prepared from 2-aminobenzo-
nitrile 25, which was first converted to quinazolin-4(3H)-one 26 by
acid-catalyzed cyclization with formic acid under microwave irra-
diation.18 Treatment of 26 under microwave irradiation with an
excess amount of POCl3 in N,N-diethylamine yielded the 4-chloro-
quinazoline 2119 (Scheme 3).
1-(Phenylamino)-isoquinoline-3-carboxylic acid derivatives (32
and 33a–c) were prepared from methyl 1-chloroisoquinoline-
3-carboxylate 31. 2-Formyl benzoic acid 27 was converted to its
methyl ester 28 using methyl iodide under microwave irradiation.
Oxazolone 29 was formed by condensation of hippuric acid with
the methyl 2-formylbenzoate 28 under microwave irradiation
applying the literature procedure.20 Cyclization with KOH in MeOH
again under microwave irradiation gave the methyl 1-oxo-1,2-
dihydroisoquinoline-3-carboxylate 30, which on treatment with
POCl3 is chlorinated and aromatized to the methyl 1-chloroiso-
quinoline-3-carboxylate 31.21 The substitution reaction of 30 with
3-trifluoromethylaniline produced methyl 1-(phenylamino)-iso-
quinoline-3-carboxylate 32, which was subjected to potassium
tert-butoxide-induced aminolysis under microwave irradiation to
yield the amides 33a–c (Scheme 4).
In case of 1-(3-trifluoromethylphenylamino)-isoquinoline-
4-carboxamides (40a–e) synthetic route starts from the commer-
cially available 4-bromoisoquinoline 34, which was first oxidized
to the corresponding N-oxide 35 with aqueous H2O2 in the pres-
ence of Na2WO4 and then treated with POCl3 in DMF to give the
4-bromo-1-chloroisoquinoline 36.22 Lithiation of the remaining
bromide 36 and subsequent quenching with dry ice delivers the
1-chloroisoquinoline-4-carboxylic acid 37. The acid was treated
with thionyl chloride to give substituted acid chloride 38, which
was further substituted with amines to yield 1-chloroisoquino-
line-4-carboxamides 39a–e which were treated with 3-trifluoro-
methylaniline to give the desired products 40a–e (Scheme 5).
Phenylsulfanylquinolines (41a and 41e), 1-phenylsulfanylquin-
oline 41e (Scheme 6), 3-phenoxyquinoline 41b, and 1-phenoxyiso-
quinoline 41d (Scheme 7) were synthesized by microwave
irradiation of haloquinoline with PhSNa or phenol at 150 °C for
15 min to give the desired products.23
2.2. Biological testing
The quinoline-, quinazoline- quinoxaline-, and isoquinolineam-
ines were tested for their capacity to induce G-protein activation of
N
the human recombinant CB2 receptor (hCB2) via a [35S]GTP
cS
CF3
O
binding assay according to the procedure described by Savinainen
et al.25 (Tables 1–4). The receptors used were hCB2 stably ex-
pressed in Chinese hamster ovary (CHO) cells.
N
H
9
(NRB04079)
10
All the synthesized compounds were also screened at 10
lM
Figure 2. The chemical structures of the CB2 agonist lead structures.
concentration for their CB1 agonist activity and for their ability

R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
941
O
N
H
CO2H
CO2Me
O
CO2H
CHO
CO2Me
CHO
MeI, K2CO3, DMF
O
150 °C, 10 min
Microwave
NaOAc, Ac2O
100 °C, 20 min
Microwave
N
27
28
29
CO2Me
CO2Me
POCl3
KOH, MeOH
N
NH
130 °C, 10 min
Microwave
100 °C, 25 min
Microwave
Cl
O
31
30
O
O
N
H2N
CF3
R
NH2
R
OCH3
CF3
H
N
(CH3)3COK
N
200 °C, 30 min
Microwave
150 °C, 15 min
Microwave
HN
HN
CF3
32
33a-c
Scheme 4. Synthesis of 1-[3-(trifluoromethyl)phenylamino]-isoquinoline-3-carboxylic acid derivatives (32 and 33a–c).
O
OH
N
Br
Br
Br
1. t-BuLi
H2O2,
Na2WO4
POCl3
DMF
2. CO2 (s)
+
O-
N
N
N
THF
AcOH
Cl
Cl
34
35
37
36
O
R
Cl
N
O
R
N
O
H2N
CF3
SOCl2
RH
N
120°, 20 min
toluene
microwaves
100°, 20 min
toluene
microwaves
150°, 15 min
toluene
microwaves
HN
CF3
Cl
Cl
38
39a-e
40a-e
Scheme 5. Synthesis of 1-[3-(trifluoromethyl)phenylamino]-isoquinoline-4-carboxamides (40a–e).
Br
O
Cl
Br
S
S
N
N
Phenol
N
N
11
41a
41c
Cu, KOH, DMSO
41b
42
°
150 C, 15 min
PhSNa, DMSO
N
Microwave
N
150 °C, 15 min
Microwave
N
N
O
42
Cl
19
41d
N
Scheme 7. Synthesis of 3-phenoxyquinoline 41b and 1-phenoxyisoquinoline 41d.24
N
S
Cl
19
All the compounds were first evaluated for CB2 at 10 lM con-
41e
centration. For the compounds that showed over 50% relative
activity, the dose–response curves were generated and the logEC50
and Emax values were calculated by nonlinear regression analysis
with the equation for a sigmoidal concentration–response curve
(GraphPad Prism 4).
Scheme 6. Synthesis of phenylthioquinolines (48a and 48c) and 1-(phenylthio)-
isoquinoline 48e.
to antagonize agonist (10 nM HU-210) response in rat cerebellar
membranes as previously described.26 No significant CB1 receptor
activation or inactivation was shown in these studies, except
compound 40e, which showed weak CB1 agonist activity (CB1
ꢀlog EC50 = 5.0).
2.3. Results
In general the CF3-, OMe-, and Cl-substituted phenyl quinoline
amines showed partial or full agonist activity at the human CB2

942
R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
Table 1
CB2 receptor activity data of the quinoline-2-amines (12a–z).
R
N
N
H
N
R
12a-x
12y 12z
,
b
Entry
R =
Yield
CB2 agonism at 10
l
Ma,b
Relative Emax
ꢀlog EC50
12a
12b
12c
12d
12e
12f
12g
12h
12i
Phenyl
Benzyl
49
42
61
42
75
25
69
85
33
85
67
58
57
87
93
44
86
33
97
47
68
65
79
62
53
39
20
63
64
48
69
50
49
56
58
75
64
25
20
8
5
3
4
4
1
4
3
4
2
3
5
2
2
2
—
—
103
65
—
102
61
51
91
70
80
69
—
—
—
2-CF3-Phenyl
3-CF3-Phenyl
4-CF3-Phenyl
2-OMe-Phenyl
3-OMe-Phenyl
4-OMe-Phenyl
2-Cl-Phenyl
3-Cl-Phenyl
4-Cl-Phenyl
3-Br-Phenyl
3-CN-Phenyl
4-(Me)2N-phenyl
4-OH-Phenyl
4-EtO2C-Phenyl
4-(HOCH2CH2)-Phenyl
2-(Benzyl)phenyl
2-MeO-4-CF3-Phenyl
Cyclohexyl
Cyclohexylmethyl
Cyclopentyl
n-Hexyl
Ppiperidinyl
Morpholinyl
3
3
2
4
3
2
4
3
5.2 0.1
5.9 0.1
—
3
5.3 0.1
5.6 0.1
5.7 0.2
5.2 0.1
5.6 0.1
5.7 0.1
5.7 0.1
—
—
—
—
—
12j
12k
12l
12m
12n
12o
12p
12q
12r
12s
12t
12u
12v
12x
12y
12z
—
—
—
—
1
2
3
20
18
33
57
44
22
10
10
7
2
4
3
3
1
2
2
2
88
—
—
2
5.2 0.1
—
—
—
—
—
1
—
a
CB2 agonism at 10 lM ligand concentration. Values are mean SEM of at least three experiments performed in duplicate.
Relative responses as percentage of the 10 nM HU-210 agonist response.
b
Table 2
CB2 receptor activity data of the quinoxalineamines (14a–b), quinazoline-2-amines (16a–b), quinoline-4-amines, (18a–b), isoquinoline-1-
amines (20a–d), and quinazoline-4-amines (22a–b).
N
N
N
H
N
N
N
R
N
R
R
R
N
N
H
N
HN
20a-d
HN
18a-b
HN
22a-b
R
14a-b
16a-b
b
Entry
R =
Yield
CB2 agonism
at 10
Ma,b
Relative Emax
ꢀlog EC50
l
14a
14b
16a
16b
18a
18b
20a
20b
20c
20d
22a
22b
Phenyl
3-CF3-Phenyl
Phenyl
3-CF3-Phenyl
Phenyl
3-CF3-Phenyl
Phenyl
2-CF3-Phenyl
3-CF3-Phenyl
4-CF3-Phenyl
Phenyl
95
95
75
91
96
98
14
42
93
53
61
46
30
52
38
53
9
50
7
43
1
3
3
2
1
3
1
2
2
—
69
—
67
—
58
—
—
124
—
—
79
—
2
2
3
5.4 0.1
—
5.5 0.1
—
5.5 0.1
—
—
5.8 0.1
—
—
102
25
10
4
3
2
6
3-CF3-Phenyl
68
4
5.6 0.1
a
CB2 agonism at 10 lM ligand concentration. Values are mean SEM of at least three experiments performed in duplicate.
Relative responses as percentage of the 10 nM HU-210 agonist response.
b
receptor. The ortho-substituted quinoline 2-amines (12c, 12f, 12i,
Table 1) had weak potency (ꢀlog EC50 = 5.2–5.3) but high efficacy
(Emax = 91–103%). The most potent compound in this series was
the meta CF3-substituted amine 12d with ꢀlog EC50 of 5.9.
at 10 lM concentration when compared to the unsubstituted
12a. Both electron withdrawing (CF3) and electron donating
(OMe) substituents had similar efficacy and potency. The data
clearly indicates that, derivatives with polar residues (e.g., 12n–
q) show very low or no activity.
Of the quinazoline- quinoxaline-, and isoquinoline-amines, the
CF3-substituted ones were more potent than their parent com-
pounds. The 3-CF3-substituted analogues (14b, 16b, 18b, and
22b) exhibited moderate partial agonist activity. Of the CF3-substi-
Non-aromatic cycloalkyl and heteroalkyl derivatives were only
weakly active or inactive, except cycloalkyl (12t), which showed
good efficacy Emax = 88%) but low potency (ꢀlog EC50 = 5.2). Phenyl
derivatives with large substituents (12p–s) had low efficacy. The
substituted phenyl derivatives (12c–l) showed increased activity

R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
943
Table 3
CB2 receptor activity data of 1-[(3-trifluoromethyl)-phenylamino]-isoquinoline-3-carboxylic acid derivatives (32, 33a–c) and -isoquin-
oline-4-carboxylic acid derivatives (40a–e).
H
O
N
O
R
N
O
O
R
R
N
H
R
N
N
N
HN
CF3
HN
CF3
CF3
HN
CF3
HN
32
33a-c
40a-d
CB2 agonism at 10
40e
b
Entry
R =
Yield
l
M)a,b
Relative Emax
ꢀlog EC50
32
MeO
Cyclohexylmethyl
Cyclohexyl
Benzyl
Benzyl
Cyclohexylmethyl
Cyclohexyl
2-MeO-Phenyl
73
47
95
55
4
1
—
—
—
—
—
67
73
—
—
—
—
—
33a
33b
33c
40a
40b
40c
40d
ꢀ2
13
0
21
58
54
1
2
2
2
53c
73d
24c
18c
4
3
4
—
2
4
5.8 0.1
5.7 0.1
—
1
41c
76
4
75
1
7.8 0.1
N
O
40e
a
b
c
CB2 agonism at 10 lM ligand concentration. Values are mean SEM of at least three experiments performed in duplicate.
Relative responses as percentage of the 10 nM HU-210 agonist response.
Yield for 3 steps from 37.
Yield from 39b.
d
duced [35S]GTP
cS binding assay at human CB2 and rat CB1 recep-
Table 4
Phenylsulfanyl-quinolines (41a, 41c, 41e) and phenoxyquinolines (41b, 41d).
tors. Most of the prepared quinoline, isoquinoline, quinaxolinyl,
and quinoxalinyl phenyl amines showed low-potency partial CB2
receptor agonists activity. The isoquinolin-1-yl(3-trifluoromethyl-
phenyl)amine 20c and 4-morpholinylmethanone derivative 40e
appear to be the most promising ligands. The amine 20c showed
to be a high efficacy CB2 agonist (ꢀlog EC50 =5.8; Emax = 128%) and
X
N
N
S
N
X
41a
41b
41c
41d
41e
(X=O), (X=S)
(X=O),
(X=S)
Ma,b
Relative Emax
ꢀlog EC50
5.4 0.1
—
—
—
—
b
Entry
Yield
CB2 agonism at 10
l
the derivative 40e show considerable potency at CB2 (ꢀlog EC50
=
41a
41b
41c
41d
41e
83
75
86
79
92
47
17
13
31
33
3
1
1
4
4
61
—
—
—
—
1
7.8; Emax = 75%). All the synthesized compounds were also screened
at 10 M concentration for their CB1 agonist activity and for their
ability to antagonize agonist (10 nM HU-210) response in rat cere-
bellar membranes as previously described.25 In this GTP
S binding
l
c
assay we used non-recombinant membrane fractions from CB1 rat
cerebellar membranes, which display 97% homology to correspond-
ing human CB1. No significant CB1 receptor activation or inactiva-
tion was shown in these studies, except the most potent CB2
agonist 40e, which also showed weak CB1 agonist activity (CB1
ꢀlog EC50 = 5.0), exhibiting 600-fold selectivity for the CB2 receptor.
These ligands serve as novel templates for the development of
selective CB2 receptor agonist.
a
CB2 agonism at 10 lM ligand concentration. Values are mean SEM of at least
three experiments performed in duplicate.
b
Relative responses as percentage of the 10 nM HU-210 agonist.
tuted isoquinolineamines, the meta CF3-substituted isoquinolinyl
amine 20c exhibited the highest efficacy with reasonable potency
(Emax = 128%; ꢀlog EC50 = 5.8, Table 2).
The 3-substituted carboxamide derivatives (33a–c) were inac-
tive, whereas 4-substituted cycloalkyl derivatives (40b, 40c, and
40e) were active (Table 3). However, the aromatic 2-MeO-
phenyl-substituted analogue 40d was inactive. The most potent
analogue was 4-morpholinylmethanone 40e, which showed
nanomolar potency (ꢀlog EC50 = 7.8) and fairly good affinity
(Emax = 75%). This is not surprising since the previously discovered
potent and selective CB2 agonist 5 (GSK554418A) has similar mor-
pholinylmethanone structure.
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded on a Bruker Avance
instrument operating at 500.1 and 25.8 MHz, respectively. Chemi-
cal shifts are reported as d values (ppm) relative to an internal
standard of tetramethylsilane (TMS) or to the solvent line of DMSO
(dH = 2.50 ppm quintuplet, dC = 39.43 ppm septuplet). Electro-
spray ionization mass spectra were determined on Finnigan MAT
LCQ quadrupole ion trap mass spectrometer. Elemental analyses
were performed on ThermoQuest CE instrument (EA 1110
CHNS-O). The Biotage Initiator 2.0 was used for microwave-as-
sisted synthesis. All chemicals and solvents were of commercial
quality and were used without further purification. Most interme-
diate and end products were purified by flash chromatography
The unsubstituted phenylsulfanyl-quinoline 41a exhibited
moderate partial agonist activity. The phenoxyquinoline 41b and
the phenylsulfanyl-quinoline 41c showed faint, and phenoxyiso-
quinoline 41d and phenylsulfanyl-quinoline 41b equipotent weak
activation of CB2 (Table 4).
3. Conclusion
The purpose of this study was to determine both the affinity and
agonist efficacy of novel heterocyclic diarylamines using ligand-in-
using 30–60 lm silica gel and an appropriate eluent.

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R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
4.1.1. Phenyl-quinolin-2-yl-amine (12a)
NMR): C, 76.78; H, 5.64; N, 11.19. Found: C, 76.88; H, 5.66; N,
11.11.
A mixture of 2-chloroquinoline 17 (200 mg, 1.22 mmol) and
aniline (455 mg, 4.89 mmol) was heated 15 min at 150 °C using
microwave synthesizer. The resulting reaction mixture was dis-
solved in ethyl acetate (50 ml) and washed with saturated Na2CO3
(2ꢁ 50 ml) and H2O (2ꢁ 50 ml). The organic phase was dried
(Na2SO4) and evaporated to leave a clear oil. This oil was purified
by flash chromatography (silica gel) eluting with dichloromethane
to give 12a as a light brown solid (133 mg, 49%). 1H NMR (DMSO-
d6): d 9.39 (s, 1H); 8.05–7.99 (m, 3H); 7.72–7.68 (m, 2H); 7.59–7.55
(m, 1H); 7.34–7.27 (m, 3H); 7.07 (d, 1H, J = 8.9 Hz); 6.97–6.94 (m,
1H). 13C NMR (DMSO-d6): d 154.6; 147.4; 141.9; 137.3; 129.8;
129.0 (2C); 127.9; 126.8; 124.0; 123.1; 121.4; 118.8 (2C); 114.6.
ESI-MS 221.2 (M+H). Anal. Calcd for C15H12N2ꢂ0.1H2O: C, 81.13;
H, 5.54; N, 12.61. Found: C, 81.26; H, 5.59; N, 12.69.
4.1.7. (3-Methoxy-phenyl)-quinolin-2-yl-amine (12g)
1H NMR (DMSO-d6): d 9.42 (s, 1H); 8.02 (d, 1H, J = 8.8 Hz); 7.95
(t, 1H, J = 2.2 Hz); 7.71 (m, 2H); 7.58 (t, 1H, J = 8.3 Hz); 7.45 (d, 1H,
J = 7.9 Hz); 7.28 (t, 1H, J = 7.9 Hz); 7.22 (t, 1H, J = 8.1 Hz); 7.09 (d,
1H, J = 8.8 Hz); 6.55 (ddd, 1H, J = 8.1, 2.4, 0.6 Hz); 3.82 (s, 3H). 13C
NMR (DMSO-d6): d 153.7; 148.2; 147.5; 137.1; 130.0; 129.5;
127.2; 126.9; 123.9; 122.9; 121.6; 120.9; 118.7; 113.1; 109.9:
55.5 (3C). ESI-MS 251.3 (M+H). Anal. Calcd for (C16H14N2Oꢂ0.1
toluene, based on 1H NMR): C, 77.29; H, 5.75; N, 10.79. Found: C,
77.11; H, 6.06; N, 10.98.
4.1.8. (4-Methoxy-phenyl)-quinolin-2-yl-amine (12h)
1H NMR (CDCl3): d 7.85 (d, 2H, J = 8.8 Hz); 7.72 (d, 1H,
J = 8.5 Hz); 7.61 (dd, 1H, J = 7.9, 1.0 Hz); 7.55 (m, 1H); 7.40 (m,
2H); 7.26 (m, 1H); 6.91(m, 2H); 6.85 (d, 1H, J = 8.8 Hz), 3.81 (s,
3H). 13C NMR (CDCl3): d 156.4; 155.3; 147.2; 137.9; 132.7;
129.8; 127.4; 126.0; 124.0 (2C); 123.8; 122.8; 114.5 (2C); 110.9;
55.5 (3C). ESI-MS 251.3 (M+H). Anal. Calcd for (C16H14N2Oꢂ0.03 tol-
uene, based on 1H NMR): C, 76.94; H, 5.67; N, 11.07. Found: C,
77.29; H, 5.67; N, 11.28.
The following analogues (12b–z) were prepared using the pro-
cedure outlined for 12a above.
4.1.2. Benzyl-quinolin-2-yl-amine (12b)
1H NMR (DMSO-d6): d 7.85 (d, 1H, J = 8.9 Hz); 7.61–7.59 (m,
1H); 7.50–7.39 (m, 5H); 7.33–7.30 (m, 2H); 7.24–7.21 (m, 1H);
7.15–7.12 (m, 1H); 6.84 (d, 1H, J = 8.9 Hz); 4.65–4.64 (m, 2H). 13C
NMR (DMSO-d6): d 157.2; 148.2; 140.8; 136.7; 129.4; 128.7 (2C);
128.0 (2C); 127.9; 126.1; 123.5: 121.6; 113.5; 44.3. ESI-MS 235.1
(M+H). Anal. Calcd for C16H14N2ꢂ0.1H2O: C, 81.40; H, 6.06; N,
11.86. Found: C, 81.24; H, 6.13; N, 11.59.
4.1.9. (2-Chloro-phenyl)-quinolin-2-yl-amine (12i)
1H NMR (DMSO-d6): d 8.69 (s, 1H); 8.49 (d, 1H, J = 8.1 Hz); 8.07
(d, 1H, J = 8.8 Hz); 7.74 (d, 1H, J = 8.8 Hz); 7.64 (m, 1H); 7.56 (t, 1H,
J = 8.0 Hz); 7.49 (dd, 1H, J = 7.9, 1.5 Hz); 7.36 (t, 1H, J = 8.0 Hz); 7.31
(d, 1H, J = 8.8 Hz); 7.30 (m, 1H); 7.07 (m, 1H). 13C NMR (DMSO-d6):
d 154.0; 146.5; 137.1; 137.0; 129.2 (2C); 127.3; 127.1; 126.2;
124.1; 123.8; 123.3 (2C); 122.7; 113.8. ESI-MS 255.2 (M+H). Anal.
Calcd for (C15H11ClN2): C, 70.73; H, 4.35; N, 11.00. Found: C, 70.36;
H, 4.29; N, 10.80.
4.1.3. Quinolin-2-yl-(2-trifluoromethyl-phenyl)-amine (12c)
1H NMR (DMSO-d6): d 8.63 (s, 1H); 8.07 (d, 1H, J = 8.5 Hz); 7.92
(m, 1H); 7.73 (m, 2H); 7.68 (t, 1H, J = 7.8 Hz); 7.55–7.46 (m, 2H);
7.36 (t, 1H, J = 7.5 Hz); 7.27 (t, 1H, J = 7.2 Hz); 7.16 (m, 1H). 13C
NMR (DMSO-d6): d 155.1; 146.8; 138.2; 137.3; 131.6; 129.3;
3
128.3; 127.4 (q, JCF = 5.2 Hz); 126.4; 126.1; 125.1; 124.5; 123.8;
122.9; 122.6; 120.5; 113.1. ESI-MS 289.1 (M+H). Anal. Calcd for
C
16H11F3N2ꢂ0.1H2Oꢂ0.05 hexane: C, 66.51; H, 4.07; N, 9.52. Found:
4.1.10. (3-Chloro-phenyl)-quinolin-2-yl-amine (12j)
C, 66.77; H, 4.23; N, 9.22.
1H NMR (DMSO-d6): d 9.65 (s, 1H); 8.39 (t, 1H, J = 2.0 Hz); 8.10
(d, 1H, J = 8.8 Hz); 7.83 (dd, 1H, J = 8.2, 1.2 Hz); 7.75 (t, 1H,
J = 8.1 Hz); 7.62 (m, 1H); 7.36 (d, 1H, J = 8.2 Hz); 7.33 (m, 1H);
7.10 (d, 1H, J = 8.8 Hz); 7.00 (dd, 1H, J = 7.9, 2.0 Hz). 13C NMR
(DMSO-d6): d 153.7; 146.5; 142.8; 137.0; 133.0; 130.0; 129.4;
127.4; 126.3; 123.6; 122.9; 120.2; 117.4; 116.5; 114.0. ESI-MS
255.2 (M+H). Anal. Calcd for C15H11ClN2: C, 70.73; H, 4.35; N,
11.00. Found: C, 70.57; H, 4.30; N, 10.79.
4.1.4. Quinolin-2-yl-(3-trifluoromethyl-phenyl)-amine (12d)
1H NMR (DMSO-d6): d 9.78 (s, 1H); 8.64 (s, 1H); 8.16 (d, 1H,
J = 8.2 Hz); 8.11 (d, 1H, J = 8.9 Hz); 7.77 (d, 1H, J = 7.9 Hz); 7.71
(d, 1H, J = 8.2 Hz); 7.63–7.61 (m, 1H); 7.57–7.53 (m, 1H); 7.35–
7.32 (m, 1H); 7.27 (d, 1H, J = 7.6 Hz); 7.09 (d, 1H, J = 8.9 Hz). 13C
NMR (DMSO-d6): d 153.8; 146.5; 142.1; 137.2; 129.5 (2C); 129.3
2
1
(q, JCF = 31.3 Hz); 127.5; 126.4; 124.3 (q, JCF = 270.0 Hz); 123.7;
3
3
123.1; 121.4; 116.8 (q, JCF = 3.7 Hz); 114.1(q, JCF = 4.0 Hz);
114.0. ESI-MS 289.1 (M+H). Anal. Calcd for C16H11F3N2ꢂ0.15 H2O:
C, 66.05; H, 3.91; N, 9.63. Found: C, 66.25; H, 4.17; N, 9.24.
4.1.11. (4-Chloro-phenyl)-quinolin-2-yl-amine (12k)
1H NMR (CDCl3): d 7.91 (d, 2H, J = 8.7 Hz); 7.79 (d, 1H,
J = 8.4 Hz); 7.64 (dd, 1H, J = 8.0, 1.2 Hz); 7.61–7.56 (m, 3H);
7.33–7.28 (m, 3H); 6.88 (d, 1H, J = 8.8 Hz). 13C NMR (CDCl3): d
153.7; 147.4; 138.8; 129.9; 129.1 (2C); 127.4; 126.8; 124.1;
123.4; 121.2 (2C); 111.9. ESI-MS 255.3 (M+H). Anal. Calcd for
4.1.5. Quinolin-2-yl-(4-trifluoromethyl-phenyl)-amine (12e)
1H NMR (DMSO-d6): d 9.83 (s, 1H); 8.22 (d, 2H, J = 8.6 Hz); 8.12
(d, 1H, J = 8.9 Hz); 7.77–7.76 (m, 2H); 7.66–7.60 (m, 3H); 7.36–7.32
C15H11ClN2: C, 70.73; H, 4.35; N, 11.00. Found: C, 71.00; H, 4.32;
(m, 1H); 7.12 (d, 1H, J = 8.9 Hz). 13C NMR (DMSO-d6): d 153.6;
N, 11.11.
3
146.5; 144.9; 137.2; 129.5; 127.5; 126.5; 125.7 (q, 2C, JCF
=
1
3.2 Hz); 124.6 (q, JCF = 270.7 Hz); 123.7; 123.1; 120.6 (q,
2JCF = 31.9 Hz); 117.7 (2C); 114.1. ESI-MS 289.2 (M+H). Anal. Calcd
for C16H11F3N2ꢂ0.1 H2O: C, 66.25; H, 3.89; N, 9.66. Found: C, 66.12;
H, 4.17; N, 9.29.
4.1.12. (3-Bromo-phenyl)-quinolin-2-yl-amine (12l)
1H NMR (CDCl3): d 7.91 (m, 2H); 7.81 (d, 1H, J = 8.4 Hz); 7.64
(dd, 1H, J = 8.0, 1.2 Hz); 7.59 (t, 1H, J = 8.4 Hz); 7.50–7.46 (m,
1H); 7.31 (t, 1H, J = 8.0 Hz); 7.33 (m, 1H); 7.18–7.15 (m, 2H);
6.89 (d, 1H, J = 8.8 Hz). 13C NMR (CDCl3): d 153.5; 147.3; 141.7;
137.9; 130.3; 129.9; 127.4; 126.9; 125.5; 124.2; 123.6; 122.8;
122.5; 118.2; 112.1. ESI-MS 299.2 (M). Anal. Calcd for
4.1.6. (2-Methoxy-phenyl)-quinolin-2-yl-amine (12f)
1H NMR (CDCl3): d 8.72 (dd, 1H, J = 7.9, 1.5 Hz); 7.82 (m, 2H);
7.59–7.53 (m, 2H); 7.31–7.22 (m, 2H); 7.02 (td, 1H, J = 7.7,
1.5 Hz); 6.96 (td, 1H, J = 7.7, 1.5 Hz); 7.32 (dd, 1H, J = 8.0, 1.3 Hz);
6.85 (d, 1H, J = 8.8 Hz); 3.83 (s, 3H). 13C NMR (CDCl3): d 153.7;
148.2; 147.5; 137.1; 130.0; 129.5; 127.2; 126.9; 123.9; 122.9;
121.6; 120.9; 119.9; 118.7; 113.1; 55.5 (3C). ESI-MS 251.2
(M+H). Anal. Calcd for (C16H14N2Oꢂ0.02 toluene, based on 1H
C
15H11BrN2ꢂ0.02toluene: C, 60.41; H, 3.74; N, 9.31. Found: C,
60.73; H, 3.75; N, 9.25.
4.1.13. 3-(Quinolin-2-ylamino)-benzonitrile (12m)
1H NMR (DMSO-d6): d 9.77 (s, 1H); 8.70 (t, 1H, J = 1.8 Hz); 8.16
(ddd, 1H, J = 8.4, 2.2, 1.0 Hz); 8.09 (dd, 1H, J = 8.8 Hz); 7.77 (t, 1H,

R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
945
2
3
J = 8.5 Hz); 7.62 (t, 1H, J = 8.4 Hz); 7.52 (t, 1H, J = 7.9 Hz);
7.38–7.30 (m, 2H); 7.10 (d, 1H, J = 8.9 Hz). 13C NMR (DMSO-d6): d
153.5; 146.4; 142.1; 137.1; 129.6; 129.3; 127.3; 126.4; 123.8;
123.6; 123.6; 123.0; 122.4; 120.4; 119.0; 113.9; 111.4. ESI-MS
246.3 (M+H). Anal. Calcd for C16H11N3: C, 78.35; H, 4.52; N,
17.13. Found: C, 78.60; H, 4.59; N, 16.98.
120.9 (q, JCF = 31.7 Hz); 118.1 (q, JCF = 4.4 Hz); 115.2 (q,
3JCF = 3.9 Hz); 114.7; 110.2; 55.9. ESI-MS 319.2 (M+H). Anal. Calcd
for C17H13F3N2O: C, 64.15; H, 4.12; N, 8.80. Found: C, 63.99; H,
4.46; N, 8.59.
4.1.20. Cyclohexyl-quinolin-2-yl-amine (12t)
1H NMR (DMSO-d6): d 7.78 (d, 1H, J = 8.9 Hz); 7.56 (dd, 1H,
J = 7.8, 0.9 Hz); 7.46 (d, 1H, J = 8.1 Hz); 7.42 (t, 1H, J = 8.1 Hz);
7.10 (t, 1H, J = 7.9 Hz); 6.82 (bd, 1H, J = 7.6 Hz); 6.74 (d, 1H,
J = 8.9 Hz); 3.95 (m, 1H); 2.01–1.94 (m, 2H); 1.78–1.70 (m, 2H);
1.65–1.58 (m, 1H); 1.43–1.31 (m, 2H); 1.29–1.17 (m, 3H).
13C,NMR (DMSO-d6): d 156.2; 147.9; 135.9; 128.7; 127.2; 125.4;
122.6; 120.7; 113.2; 48.2; 32.5 (2C); 25.5 (2C); 24.6. ESI-MS
227.2 (M+H). Anal. Calcd for C15H18N2ꢂ0.1H2O: C, 78.98; H, 8.04;
N, 12.28. Found: C, 79.36; H, 8.28; N, 11.93.
4.1.14. N,N-Dimethyl-N0-quinolin-2-yl-benzene-1,4-diamine
(12n)
1H NMR (DMSO-d6): d 9.04 (s, 1H); 7.92 (d, 1H, J = 8.9 Hz); 7.77
(d, 2H, J = 9.0 Hz); 7.64 (dd, 1H, J = 7.9, 1.2 Hz); 7.61 (d, 1H,
J = 8.4 Hz); 7.51 (t, 1H, J = 8.3 Hz); 7.20 (t, 1H, J = 8.0 Hz); 6.97 (d,
1H, J = 8.9 Hz); 6.76 (d, 2H, J = 9.0 Hz); 2.85 (s, 6H). 13C NMR
(DMSO-d6): d 154.5; 147.3; 145.8; 131.4; 129.0; 127.2; 125.8;
123.1; 121.7; 120.3 (2C); 113.6; 113.0 (2C); 40.6 (6C). ESI-MS
264.2 (M+H). Anal. Calcd for C17H17N3: C, 77.54; H, 6.51; N,
15.96. Found: C, 77.21; H, 6.47; N, 15.81.
4.1.21. Cyclohexylmethyl-quinolin-2-yl-amine (12u)
1H NMR (DMSO-d6): d 7.78 (d, 1H, J = 8.9 Hz); 7.56 (dd, 1H,
J = 7.8, 0.9 Hz); 7.47 (d, 1H, J = 8.2 Hz); 7.42 (t, 1H, J = 8.2 Hz);
7.10 (t, 1H, J = 7.9 Hz); 6.92 (bt, 1H, J = 5.5 Hz); 6.78 (d, 1H,
J = 8.9 Hz); 3.25 (t, 2H, J = 6.1 Hz); 1.85–1.75 (m, 2H); 1.75–1.55
(m, 4H); 1.30–1.10 (m, 3H); 1.05–0.90 (m, 2H). 13C,NMR (DMSO-
d6): d 157.1; 147.9; 135.8; 128.7; 127.3; 125.4: 122.7; 120.7;
113.1; 46.8; 37.2; 30.7 (2C); 26.1; 25.5 (2C). ESI-MS 241.2 (M+H).
Anal. Calcd for C16H20N2ꢂ0.12 H2O: C, 79.24; H, 8.41; N, 11.55.
Found: C, 79.47; H, 8.61; N, 11.16.
4.1.15. 4-(Quinolin-2-ylamino)-phenol (12o)
1H NMR (DMSO-d6): d 8.63 (s, 1H); 8.07 (d, 1H, J = 8.7 Hz); 7.92
(m, 1H); 7.80–7.60 (m, 3H); 7.55–7.45 (m, 2H); 7.36 (t, 1H,
J = 7.6 Hz); 7.27 (t, 1H, J = 7.0 Hz); 7.16 (m, 1H). 13C NMR (DMSO-
d6): d 155.1; 146.7; 138.1; 137.3; 132.8; 129.3; 127.4; 126.3;
126.1; 124.5; 123.8; 122.0 (2C); 113.1 (2C). ESI-MS 237.2 (M+H).
Anal. Calcd for C15H12N2Oꢂ0.1 H2Oꢂ0.02 EtOAc: C, 74.92; H, 5.31;
N, 11.35. Found: C, 74.88; H, 5.47; N, 10.99.
4.1.16. 4-(Quinolin-2-ylamino)-benzoic acid ethyl ester (12p)
1H NMR (CDCl3): d 8.05 (d, 2H, J = 8.7 Hz); 7.97 (d, 1H,
J = 8.8 Hz); 7.85 (d, 1H, J = 8.4 Hz); 7.76 (d, 2H, J = 8.6 Hz); 7.67
(d, 1H, J = 8.0 Hz); 7.62 (t, 1H, J = 7.7 Hz); 7.35 (t, 1H, J = 7.5 Hz);
7.06 (bs, 1H); 6.96 (d, 1H, J = 8.8 Hz); 4.37 (q, 2H, J = 7.1 Hz); 1.39
(q, 3H, J = 7.1 Hz). 13C,NMR (CDCl3): d 166.4 (C@O); 153.0; 147.3;
144.7; 137.9; 131.0 (2C); 129.9; 127.4; 127.2; 124.4; 123.8;
123.7; 117.8 (2C); 112.7; 60.6; 14.4. ESI-MS 293.2 (M+H). Anal.
Calcd for C18H16N2O2: C, 73.96; H, 5.52; N, 9.58. Found: C, 73.86;
H, 5.50; N, 9.69,
4.1.22. Cyclopentyl-quinolin-2-yl-amine (12v)
1H NMR (DMSO-d6): d 7.86 (d, 1H, J = 8.9 Hz); 7.62 (d, 1H,
J = 7.9 Hz); 7.58 (d, 1H, J = 8.3 Hz); 7.42 (bs, 1H); 7.48 (t, 1H,
J = 8.0 Hz); 7.17 (t, 1H, J = 7.3 Hz); 6.81 (d, 1H, J = 8.9 Hz); 4.38
(m, 1H); 2.00 (m, 2H); 1.71 (m, 2H); 1.65–1.45 (m, 4H). ESI-MS
213.2 (M+H). Anal. Calcd for (C14H16N2ꢂ0.3H2Oꢂ0.1 EtOAc: C,
76.36; H, 7.74; N, 12.37. Found: C, 76.39; H, 7.67; N, 12.24.
4.1.23. Hexyl-quinolin-2-yl-amine (12x)
1H NMR (DMSO-d6): d 7.78 (d, 1H, J = 8.9 Hz); 7.57 (d, 1H,
J = 7.9 Hz); 7.48 (d, 1H, J = 8.0 Hz); 7.43 (t, 1H, J = 8.0 Hz); 7.11 (t,
1H, J = 8.0 Hz); 6.91 (bt, 1H, J = 5.1 Hz); 6.74 (d, 1H, J = 8.9 Hz);
3.38 (q, 2H, J = 7.1, 5.5 Hz); 1.59 (p, 2H, J = 7.2 Hz); 1.42–1.24 (m,
6H); 0.88 (t, 6H, J = 7.1 Hz). 13C,NMR (DMSO-d6): d 156.9; 147.8;
135.7; 128.6; 127.2; 125.4; 122.6; 120.7; 112.9; 40.3; 31.0; 28.8;
26.2; 22.0; 13.8. ESI-MS 229.2 (M+H). Anal. Calcd for C15H20N2ꢂ
0.147H2O: C, 78.00; H, 8.86; N, 12.13. Found: C, 78.40; H, 9.09; N,
11.73.
4.1.17. 2-[4-(Quinolin-2-ylamino)-phenyl]-ethanol (12q)
1H NMR (CDCl3): d 7.87 (d, 2H, J = 8.9 Hz); 7.75 (d, 1H, J = 8.3 Hz);
7.62 (d, 1H, J = 8.0 Hz); 7.57 (t, 1H, J = 8.4 Hz); 7.44 (d, 2H, J = 8.3 Hz);
7.28 (t, 1H, J = 7.9 Hz); 7.20 (d, 2H, J = 8.3 Hz); 6.93 (d, 1H, J = 8.9 Hz);
3.86 (t, 2H, J = 6.5 Hz); 2.85 (t, 2H, J = 6.5 Hz). 13C,NMR (CDCl3): d
154.5; 147.3; 138.3; 137.8; 133.6; 129.9; 129.8 (2C); 127.4; 126.2;
124.0; 123.1; 121.2 (2C); 111.5; 63.5: 38.6. ESI-MS 265.2 (M+H).
Anal. Calcd for C17H16N2Oꢂ0.1H2Oꢂ0.4EtOAc: C, 74.13; H, 6.49; N,
9.30. Found: C, 73.74; H, 6.25; N, 9.55.
4.1.24. 2-Piperidin-1-yl-quinoline (12y)
1H NMR (DMSO-d6): d 7.97 (d, 1H, J = 9.1 Hz); 7.65 (d, 1H,
J = 7.9 Hz); 7.54 (d, 1H, J = 7.8 Hz); 7.49 (t, 1H, J = 8.3 Hz); 7.21–
7.15 (m, 2H); 3.70 (m, 4H); 1.70–1.50 (m, 6H). 13C,NMR (DMSO-
d6): d 156.8; 147.3; 137.0; 129.0; 127.1; 125.7; 122.3; 121.4;
109.9; 45.4 (2C); 25.1 (2C); 24.3. ESI-MS 213.3 (M+H). Anal. Calcd
for C14H16N2ꢂ0.1 H2O: C, 78.54; H, 7.63; N, 13.08. Found: C, 78.80;
H, 7.75; N, 12.75.
4.1.18. (2-Benzyl-phenyl)-quinolin-2-yl-amine (12r)
1H NMR (DMSO-d6): d 8.66 (s, 1H); 7.98 (d, 1H, J = 8.8 Hz); 7.87
(dd, 1H, J = 8.0, 1.0 Hz); 7.68 (dd, 1H, J = 8.0, 1.0 Hz); 7.58 (d, 1H,
J = 8.4 Hz); 7.51 (t, 1H, J = 8.4 Hz); 7.28–7.18 (m, 4H); 7.18–7.03
(m, 4H); 4.10 (m, 2H). 13C,NMR (DMSO-d6): d 155.2; 147.1;
140.3; 138.3; 136.8; 134.6; 130.0; 129.1; 128.7 (2C); 128.1 (2C);
127.3; 126.4; 125.9; 125.7; 124.3; 123.8; 123.5; 122.0; 112.9;
36.7. ESI-MS 311.3 (M+H). Anal. Calcd for C22H18N2ꢂ0.07H2O: C,
84.79; H, 5.87; N, 8.99. Found: C, 84.70; H, 5.85; N, 8.80.
4.1.25. 2-Morpholin-4-yl-quinoline (12z)
1H NMR (DMSO-d6): d 8.04 (d, 1H, J = 9.1 Hz); 7.70 (d, 1H,
J = 8.0 Hz); 7.59 (d, 1H, J = 7.9 Hz); 7.53 (t, 1H, J = 8.3 Hz);
7.25–7.19 (m, 2H); 3.74 (m, 4H); 3.65 (m, 4H). 13C,NMR (DMSO-
d6): d 157.0; 147.0; 137.2; 129.2; 127.2; 126.0; 122.8; 122.0;
109.7; 65.9 (2C); 44.9 (2C). ESI-MS 215.2 (M+H). Anal. Calcd for
4.1.19. (2-Methoxy-5-trifluoromethyl-phenyl)-quinolin-2-yl-
amine (12s)
1H NMR (DMSO-d6): d 9.49 (d, 1H, J = 2.2 Hz); 8.81 (s, 1H); 8.09
(d, 1H, J = 8.9 Hz); 7.76 (dd, 1H, J = 8.0, 1.0 Hz); 7.68 (d, 1H,
J = 8.6 Hz); 7.62 (t, 1H, J = 8.3 Hz); 7.45 (d, 1H, J = 8.9 Hz);
7.36–7.30 (m, 2H); 7.20 (d, 1H, J = 8.4 Hz); 4.00 (s, 3H). 13C,NMR
C
13H14N2Oꢂ0.05H2Oꢂ0.01EtOAc: C, 72.49; H, 6.62; N, 12.37. Found:
C, 72.82; H, 6.84; N, 12.57.
5
The following analogues (18a–b) were prepared using the pro-
cedure outlined for 12a above (23 as starting material)
(DMSO-d6): d 153.8; 150.6 (q, JCF = 1.4 Hz); 146.6; 136.8; 130.4;
2
129.4; 127.3; 126.2; 124.7 (q, JCF = 271.1 Hz); 123.7; 123.0;

946
R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
4.1.26. Phenyl-quinolin-4-yl-amine (18a)
tion mixture and then extracted with CH2Cl2 (3ꢁ 50 ml) and EtOAc
3
1H NMR (DMSO-d6): d 8.97 (br, 1H); 8.45 (d, 1H, JHH = 5.2 Hz);
(3ꢁ 50 ml). The organic phase was dried (Na2SO4) and evaporated
to dryness. The crude product was purified by flash chromatogra-
phy (silica gel) eluting with EtOAc/PE 1:2 to give 26 (235 mg,
64%). 1H NMR (DMSO-d6): d 12.26 (bs, 1H); 8.16 (dd, 1H, J = 7.9,
1.2 Hz); 8.12 (s, 1H); 7.82 (t, 1H, J = 7.6 Hz); 7.69 (d, 1H,
J = 7.8 Hz); 7.54 (t, 1H, J = 7.5 Hz). 13C NMR (DMSO-d6): d 161.2;
149.2; 145.8; 134.6; 127.6; 127.1; 126.3; 123.1.
3
8.40–8.39 (m, 1H); 7.88 (d, 1H, JHH = 8.3 Hz); 7.71–7.68 (m, 1H);
7.54–7.51 (m, 1H); 7.44–7.37 (m, 4H); 7.16–7.13 (m, 1H); 6.94
3
(d, 1H, JHH = 5.2 Hz). 13C,NMR (DMSO-d6): d 150.5; 148.8; 147.7;
140.5; 129.2 (2C); 129.1; 129.0; 124.5; 123.6; 122.3; 122.0;
119.7; 101.4. ESI-MS 221.2 (M+H). Anal. Calcd for C16H11F3N2ꢂ0.1
H2O: C, 81.13; H, 5.54; N, 12.61. Found: C, 81.15; H, 5.47; N, 12.37.
4.1.27. Quinolin-4-yl-(3-trifluoromethyl-phenyl)-amine (18b)
4.1.33. 4-Chloro-quinazoline (21)
3
1H NMR (DMSO-d6): d 9.20 (s, 1H); 8.55 (d, 1H, JHH = 4.3 Hz);
26 (230 mg, 1.57 mmol) was heated with POCl3 (362 mg,
2.36 mmol) and N,N-diethylamine (1.0 ml) 10 min at 100 °C using
Biotage Initiator microwave synthesizer. The resulting reaction
mixture was dissolved in ethyl acetate (50 ml) and washed with
HCl (1 M) (3ꢁ 50 ml). The organic phase was dried (Na2SO4) and
evaporated to dryness. The crude product was purified by flash
chromatography (silica gel) eluting with EtOAc/PE 1:10 to give
21 (187 mg, 72%). 1H NMR (DMSO-d6): d 8.46 (s, 1H); 8.18 (dd,
1H, J = 7.9, 0.9 Hz); 7.87 (t, 1H, J = 7.6 Hz); 7.77 (d, 1H, J = 8.1 Hz);
7.59 (t, 1H, J = 7.6 Hz). 13C NMR (DMSO-d6): d 160.0; 146.5;
145.6; 134.6; 127.2; 126.0; 125.0; 122.0.
3
8.37–8.35 (m, 1H); 7.93 (d, 1H, JHH = 8.3 Hz); 7.74–7.55 (m, 5H);
3
7.41 (d, 1H, JHH = 7.7 Hz); 7.10–9.09 (m, 1H). 13C NMR (DMSO-
2
d6): d 156.4; 151.1; 140.2; 134.7; 131.3 (q, JCF = 32.1 Hz); 129.4
1
(2C); 127.5; 126.4; 125.4; 124.4; 124.2 (q, JCF = 272.3 Hz); 121.8
5
3
(q, JCF = 1.3 Hz); 121.1; 118.9 (q, JCF = 3.8 Hz); 115.6 (q,
3JCF = 4.0 Hz). ESI-MS 289.2 (M+H). Anal. Calcd for C16H11F3N2ꢂ
0.1H2O: C, 66.25; H, 3.89; N, 9.66. Found: C, 66.57; H, 4.02; N, 9.32.
The following analogues (20a–d) were prepared using the pro-
cedure outlined for 12a above (19 as starting material).
4.1.28. Isoquinolin-1-yl-phenyl-amine (20a)
The following analogues (22a–b) were prepared using the pro-
cedure outlined for 12a above (21 as starting material).
3
1H NMR (DMSO-d6): d 9.13 (s, 1H); 8.54 (d, 1H, JHH = 8.4 Hz);
3
7.99–7.98 (m, 1H); 7.91–7.88 (m, 2H); 7.81 (d, 1H, JHH = 8.1 Hz);
7.72–7.69 (m, 1H); 7.63–7.60 (m, 1H); 7.33–7.30 (m, 2H); 7.17
4.1.34. Phenyl-quinazolin-4-yl-amine (22a)
3
(d, 1H, JHH = 5.8 Hz); 7.00–6.97 (m, 1H). 13C NMR (DMSO-d6): d
1H NMR (DMSO-d6): d 9.81 (s, 1H); 8.64 (s, 1H); 8.60 (d, 1H,
3
152.6; 141.2; 140.5; 136.9; 129.9; 128.1 (2C); 126.7; 126.1;
123.2; 121.2; 120.3; 120.2; 118.5; 112.4. ESI-MS 221.2 (M+H).
Anal. Calcd for C15H12N2ꢂ0.1 H2O: C, 81.13; H, 5.54; N, 12.61.
Found: C, 81.18; H, 5.77; N, 12.28.
3JHH = 7.9 Hz); 7.92 (d, 2H, JHH = 7.7 Hz); 7.87–7.80 (m, 2H); 7.63
3
3
(t, 2H, JHH = 8.2 Hz); 7.41 (m, 2H); 7.15 (t, 1H, JHH = 7.4 Hz);
3
7.17 (d, 1H, JHH = 5.8 Hz). 13C NMR (DMSO-d6): d 158.3; 154.9;
150.2: 139.7; 133.3; 128.8 (2C); 128.2; 126.5; 124.1; 123.4:
122.9 (2C); 115.706. ESI-MS 222.3 (M+H). Anal. Calcd for
4.1.29. Isoquinolin-1-yl-(2-trifluoromethyl-phenyl)-amine (20b)
C14H11N3: C, 76.00; H, 5.01; N, 18.99. Found: C, 75.85; H, 5.16; N,
18.66.
1H NMR (CDCl3): d 8.43 (d,1H, 3JHH = 7.9 Hz); 8.10 (bd, 1H, 3JHH
=
3
3
4.6 Hz); 7.87 (d, 1H, JHH = 8.3 Hz); 7.77 (d, 1H, JHH = 8.1 Hz);
7.70–7.63 (m, 2H); 7.61–7.51 (m, 2H); 7.20 (d, 1H, JHH = 5.5 Hz);
7.13 (t, 1H, JHH = 7.6 Hz). ESI-MS 289.1 (M+H). Anal. Calcd for
3
4.1.35. Quinazolin-4-yl-(3-trifluoromethylphenyl)-amine (22b)
3
1H NMR (DMSO-d6): d 10.01 (s, 1H); 8.72 (s, 1H); 8.61 (d, 1H,
3
C
16H11F3N2ꢂ0.1H2Oꢂ0.13 hexane: C, 66.90; H, 4.36; N, 9.30. Found:
3JHH = 8.2 Hz); 8.40 (s, 1H); 8.31 (d, 1H, JHH = 8.0 Hz); 7.92–7.82
3
3
C, 67.12; H, 4.73; N, 8.94.
(m, 2H); 7.68 (t, 2H, JHH = 8.2 Hz); 7.63 (t, 1H, JHH = 794 Hz);
7.45 (d, 1H, JHH = 7.7 Hz). 13C NMR (DMSO-d6): d 157.4; 154.0;
149.6; 140.1; 132.9; 129.3; 129.2 (q, JCF = 31.5 Hz); 127.8; 126.2;
125.2; 124.1 (q, JCF = 272.4 Hz); 122.8; 119.3 (q, JCF = 4.2 Hz);
117.8 (q, JCF = 4.2 Hz); 115.0. ESI-MS 290.2 (M+H). Anal. Calcd
3
2
4.1.30. Isoquinolin-1-yl-(3-trifluoromethyl-phenyl)-amine (20c)
3
1
3
1H NMR (DMSO-d6): d 9.46 (s, 1H); 8.56 (d, 1H, JHH = 8.6 Hz);
3
3
8.38–8.37 (m, 1H); 8.27–8.25 (m, 1H); 8.06 (d, 1H, JHH = 5.8 Hz);
3
7.86 (d, 1H, JHH = 8.0 Hz); 7.76–7.73 (m, 1H); 7.67–7.64 (m, 1H);
for C15H10F3N2: C, 62.29; H, 3.48; N, 14.53. Found: C, 62.58; H,
3.52; N, 14.26.
7.56–7.52 (m, 1H); 7.29–7.25 (m, 2H). 13C NMR (DMSO-d6): d
2
152.1; 142.0; 140.2; 136.9; 130.1; 129.2; 129.1 (q, JCF = 31.3 Hz);
1
126.8; 126.3; 124.3 (q, JCF = 272.2 Hz); 123.2; 123.1; 118.5 (2C);
4.1.36. 2,4-Dichloro-quinazoline (24)
3
3
117.3 (q, JCF = 3.8 Hz); 115.7 (q, JCF = 4.3 Hz); 113.4. ESI-MS
289.2 (M+H). Anal. Calcd for C16H11F3N2ꢂ0.1 H2O: C, 66.25; H,
3.89; N, 9.66. Found: C, 66.62; H, 4.29; N, 9.33.
A
mixture of 1H,3H-quinazoline 2,4-dione 23 (1.00 g,
6.15 mmol), POCl3 (2.83 g, 18.5 mmol) and N,N-diethylamine
(3.0 ml) was heated 15 min at 150 °C using Biotage Initiator micro-
wave synthesizer. The resulting reaction mixture was dissolved in
ethyl acetate (100 ml) and washed with H2O (2ꢁ 100 ml) and sat-
urated Na2CO3 (2ꢁ 100 ml). The organic phase was dried (Na2SO4)
and evaporated to dryness. The crude product was purified by flash
chromatography (silica gel) eluting with EtOAc/PE 1:20 to give 24
(754 mg, 62%). 1H NMR (CDCl3): d 8.27 (d, 1H, J = 8.4 Hz); 8.02–8.00
(m, 2H); 7.75 (m, 1H).
4.1.31. Isoquinolin-1-yl-(4-trifluoromethyl-phenyl)-amine (20d)
1H NMR (DMSO-d6):
d 9.51 (br, 1H, 9.51); 8.56 (d, 1H,
3
3JHH = 8.5 Hz); 8.15 (m, 2H); 8.07 (d, 1H, JHH = 5.7 Hz); 7.86 (d,
3
3
1H, JHH = 8.0 Hz); 7.74 (t, 1H, JHH = 7.5 Hz); 7.70–7.60 (m, 3H);
3
7.29 (d, 1H, JHH = 5.7 Hz). 13C NMR (DMSO-d6): d 151.9; 145.0;
3
140.2; 137.0; 130.2; 126.8; 126.4; 125.4 (q, 2C, JCF = 3.9 Hz);
1
2
124.6 (q, JCF = 270.7 Hz); 123.3; 121.0 (q, JCF = 31.3 Hz); 119.2
(2C); 118.8; 113.7. ESI-MS 289.2 (M+H). Anal. Calcd for C16H11F3N2ꢂ
0.15H2O: C, 66.05; H, 3.91; N, 9.63. Found: C, 66.40; H, 4.29; N,
9.37.
4.1.37. 2-Chloro-quinazoline (15)
A mixture of 24 (900 mg, 0.502 mmol), Zn-powder (900 mg,
1.53 mmol), saturated NaCl with 9% NH3 (2 ml) and CH2Cl2 (2 ml)
was heated 15 min at 100 °C using microwave synthesizer. The
resulting reaction mixture was dissolved in ethyl acetate
(100 ml) and washed with HCl (1 M) (2ꢁ 100 ml) and H2O (2ꢁ
100 ml). The organic phase was dried (Na2SO4) and evaporated to
dryness. The crude product was purified by flash chromatography
(silica gel) eluting with EtOAc/PE 1:10 to give 15 (82 mg, 13%). 1H
4.1.32. 3H-Quinazolin-4-one (26)
A mixture of 2-cyanoaniline 25 (300 mg, 2.53 mmol), formic
acid (175 mg, 3.80 mmol) and sulfuric acid (373 mg, 3.80 mmol)
was heated 5 min at 100 °C using Biotage Initiator microwave syn-
thesizer. Saturated Na2CO3 (50 ml) was added to the resulting reac-

R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
947
NMR (CDCl3): d 9.31 (s, 1H); 8.02–7.95 (m, 3H); 7.70 (t, 1H,
J = 7.4 Hz); 7.77 (d, 1H, J = 8.1 Hz); 7.59 (t, 1H, J = 7.6 Hz). 13C
NMR (CDCl3): d 163.0; 157.6; 151.9; 135.5; 128.3; 127.6; 127.3;
123.4.
The following analogues (16a–b) were prepared using the pro-
cedure outlined for 12a above.
reaction mixture was dissolved in ethyl acetate (100 ml) and
washed with saturated Na2CO3 (2ꢁ 100 ml) and H2O (2ꢁ 100 ml).
The organic phase was dried (Na2SO4) and evaporated to dryness.
The crude (Z)-methyl 2-[(5-oxo-2-phenyloxazol-4(5H)-ylidene)-
methyl]-benzoate 29 was used in the next step without purification.
A mixture of the crude 29 (3.05 g, 9.92 mmol) from the previous
step, KOH (1.11 g, 19.8 mmol) and MeOH (10 ml) was heated
25 min at 100 °C using Biotage Initiator microwave synthesizer.
The resulting reaction mixture was dissolved in ethyl acetate
(100 ml) and washed with saturated Na2CO3 (2ꢁ 100 ml) and H2O
(2ꢁ 100 ml). The organic phase was dried (Na2SO4) and evaporated
to dryness. The crude product was purified by flash chromatography
(silica gel) eluting with EtOAc/PE 1:5 to 1:1 to give 30 (1.53 g, 76%
calculated from 28). 1H NMR (DMSO-d6): d 10.70 (s, 1H); 8.25 (d,
4.1.38. Phenyl-quinazolin-2-yl-amine (16a)
1H NMR (CDCl3): d 9.08 (s, 1H); 7.82 (m, 2H); 7.76–7.70 (m, 3H);
7.57 (bs, 1H); 7.38 (m, 2H); 7.33 (m, 1H); 7.07 (t, 1H, 3JHH = 7.4 Hz).
13C NMR (CDCl3): d 161.9; 156.8; 151.4; 139.6; 134.4; 128.9 (2C);
127.4; 126.3; 123.8; 122.6; 120.8; 119.1 (2C). ESI-MS 222.3
(M+H). Anal. Calcd for C14H11N3: C, 76.00; H, 5.01; N, 18.99. Found:
C, 76.17; H, 5.11; N, 18.83.
3
3
1H, JHH = 8.0 Hz); 7.80–7.68 (m, 2H), 7.54 (t, 1H, JHH = 8.1 Hz);
6.82 (s, 1H), 3.20 (s, 3H). 13C NMR (DMSO-d6): d 162.5; 136.8;
135.3; 132.94; 127.5; 127.4; 127.1; 126.5; 112.4; 105.7; 49.9.
4.1.39. Quinazolin-2-yl-(3-trifluoromethylphenyl)-amine (16b)
1H NMR (CDCl3): d 9.12 (s, 1H); 8.29 (s, 1H); 7.93 (d, 1H,
3JHH = 8.0 Hz); 7.81–7.74 (m, 3H); 7.72 (bs, 1H); 7.46 (t, 1H,
3
3JHH = 7.9 Hz); 7.38 (m, 1H); 7.30 (d, 1H, JHH = 7.7 Hz). 13C NMR
4.1.44. Methyl 1-chloroisoquinoline-3-carboxylate (31)
2
(CDCl3): d 162.1; 156.4; 151.1; 140.2; 134.7; 131.3 (q, JCF
=
A mixture of 30 (594 mg, 2.92 mmol) and POCl3 (3 ml,
1
31.5 Hz); 129.4; 127.5; 126.4; 124.4; 124.2 (q, JCF = 272.4 Hz);
32.8 mmol) was heated 10 min at 130 °C using Biotage Initiator
microwave synthesizer. The resulting reaction mixture was dis-
solved in ethyl acetate (100 ml) and washed with HCl (1 M, 3ꢁ
100 ml). The organic phase was dried (Na2SO4) and evaporated to
dryness. The crude product was purified by flash chromatography
(silica gel) eluting with EtOAc/PE 1:3 to give 31 (585 mg, 90%). 1H
NMR (DMSO-d6): d 8.59 (s, 1H); 8.27 (d, 1H, 3JHH = 8.1 Hz); 8.23 (d,
1H, 3JHH = 7.3 Hz); 7.94 (m, 2H); 3.99 (s, 3H). 13C NMR (DMSO-d6): d
163.9; 150.1; 139.3; 136.6; 132.0; 131.2; 128.7; 127.1; 125.4;
124.0; 52.2.
5
3
121.8 (q, JCF = 1.4 Hz); 121.1; 118.9 (q, JCF = 3.7 Hz); 115.6 (q,
3JCF = 4.2 Hz). ESI-MS 290.2 (M+H). Anal. Calcd for C15H10F3N3: C,
62.29; H, 3.48; N, 14.53. Found: C, 62.40; H, 3.70; N, 14.43.
The following analogues (14a–b) were prepared using the pro-
cedure outlined for 12a above (13 as starting material).
4.1.40. N-Phenylquinoxalin-2-amine (14a)
1H NMR (DMSO-d6): d 9.94 (s, 1H); 8.58 (s, 1H); 8.01 (m, 2H);
3
3
7.86 (dd, 1H, JHH = 8.1, 1.1 Hz); 7.74 (d, 1H, JHH = 8.3 Hz); 7.65
3
3
(t, 1H, JHH = 8.3 Hz); 7.47 (t, 1H, JHH = 8.2 Hz); 7.39 (m, 2H). 7.04
(t, 1H, JHH = 7.3 Hz). 13C NMR (DMSO-d6): d 149.6; 140.5; 140.5;
4.1.45. Methyl 1-[3-(trifluoromethyl)phenylamino]-
3
140.3; 136.7; 129.8; 128.7 (2C); 128.3; 126.3; 124.8; 121.8;
118.5 (2C); 118.4. ESI-MS 222.2 (M+H). Anal. Calcd for C14H11N3ꢂ
0.1 H2Oꢂ0.06 hexane: C, 75.57; H, 5.32; N, 18.41. Found: C, 75.71;
H, 5.34; N, 18.05.
isoquinoline-3-carbo-xylate (32)
A mixture of 31 (200 mg, 0.902 mmol) and 3-trifluoromethyla-
niline (582 mg, 3.61 mmol) was heated 15 min at 150 °C using
Biotage Initiator microwave synthesizer. The resulting reaction
mixture was dissolved in ethyl acetate (50 ml) and washed with
saturated Na2CO3 (2ꢁ 50 ml) and H2O (2ꢁ 50 ml). The organic
phase was dried (Na2SO4) and evaporated to dryness. The crude
product was purified by flash chromatography (silica gel) eluting
with CH2Cl2 to give 32 (229 mg, 73%). 1H NMR (DMSO-d6): d 9.62
4.1.41. N-3-(Trifluoromethylphenyl)quinoxalin-2-amine (14b)
1H NMR (DMSO-d6): d 10.30 (s, 1H); 8.60 (s, 1H); 8.54 (s, 1H);
3
3
7.18 (d, 1H, JHH = 8.2 Hz); 7.90 (dd, 1H, JHH = 8.2, 1.1 Hz); 7.75
3
3
(dd, 1H, JHH = 8.2, 1.0 Hz); 7.69 (t, 1H, JHH = 8.2 Hz); 7.61 (t, 1H,
3JHH = 8.0 Hz). 7.52 (t, 1H, 3JHH = 8.2 Hz): 7.36 (d, 1H, 3JHH = 7.7 Hz).
(s, 1H); 9.03 (s, 1H); 8.69 (d, 1H, JHH = 7.2 Hz); 8.31 (d, 1H,
3
13C NMR (DMSO-d6): d 149.3; 141.1; 140.4; 140.1; 137.0; 130.2;
3JHH = 8.2 Hz); 8.06 (s, 1H), 8.03 (m, 1H); 7.79 (m, 2H); 7.54 (t,
129.9; 129.5 (q, JCF = 31.2 Hz); 128.5; 126.5; 125.4; 124.2 (1JCF
=
1H, JHH = 7.9 Hz); 7.31 (d, 1H, JHH = 7.7 Hz); 3.94 (s, 3H). 13C
2
3
3
3
3
272.1 Hz); 121.9; 117.9 (q, JCF = 3.9 Hz); 114.4 (q, JCF = 4.4 Hz).
ESI-MS 290.2 (M+H). Anal. Calcd for C15H10F3N3ꢂ0.1H2Oꢂ0.08EtOAc:
C, 61.73; H, 3.67; N, 14.10. Found: C, 61.86; H, 3.27; N, 13.69.
NMR (DMSO-d6): d 166.2; 152.1; 142.3; 139.0; 136.9; 131.1;
2
1
129.9 (q, JCF = 31.2 Hz); 129.4; 129.1 (2C); 124.9 (q, JCF
=
3
272.5 Hz); 123.7; 123.3; 120.4; 118.0 (q, JCF = 3.5 Hz); 116.8;
3
116.5 (q, JCF = 3.5 Hz); 52.4. ESI-MS 347.1 (M+H). Anal. Calcd for
4.1.42. Methyl 2-formylbenzoate (28)
C18H13F3N2O2: C, 62.43; H, 3.78; N, 8.09. Found: C, 62.35; H,
A
mixture of 27 (100 mg, 0.666 mmol), MeI (189 mg,
3.71; N, 8.11.
1.33 mmol), K2CO3 (55 mg, 0.400 mmol), and DMF (0.5 ml) was
heated 10 min at 150 °C using Biotage Initiator microwave synthe-
sizer. The resulting reaction mixture was dissolved in ethyl acetate
(50 ml) and washed with HCl (1 M, 3ꢁ 50 ml). The organic phase
was dried (Na2SO4) and evaporated to dryness. The crude product
was purified by flash chromatography (silica gel) eluting with
EtOAc/PE 1:10 to give 28 (104 mg, 95%). 1H NMR (DMSO-d6): d
10.42 (s, 1H); 7.94–7.85 (m, 2H), 7.80–7.75 (m, 2H), 3.92 (s, 3H).
13C NMR (DMSO-d6): d 192.8 (CHO); 166.9 (CO2Me); 136.7;
133.7; 132.8; 132.4; 130.2; 128.8; 53.1.
4.1.46. N-(Cyclohexylmethyl)-1-[3-(trifluoromethyl)-phenyl-
amino]-isoquinoline-3-carboxamide (33a)
A mixture of 32 (145 mg, 0.419 mmol), cyclohexanemethyl-
amine (285 mg, 2.51 mmol) and potassium tert-butoxide (94 mg,
0.837 mmol) was heated 60 min at 250 °C using Biotage Initiator
microwave synthesizer. The resulting reaction mixture was dis-
solved in ethyl acetate (50 ml) and washed with saturated Na2CO3
(2ꢁ 50 ml) and H2O (2ꢁ 50 ml). The organic phase was dried
(Na2SO4) and evaporated to dryness. The crude product was puri-
fied by flash chromatography (silica gel) eluting with EtOAc/PE
1:5 to give 33a (85 mg, 47%). 1H NMR (DMSO-d6): d 9.70 (s, 1H);
4.1.43. Methyl 1-oxo-1,2-dihydroisoquinoline-3-carboxylate
(30)
A mixture of 28 (1.63 g, 9.93 mmol), hippuric acid (2.13 g,
11.9 mmol), NaOAc (977 mg, 11.9 mmol), and Ac2O (10 ml) was
heated 20 min at 100 °C using microwave synthesizer. The resulting
3
3
8.59 (d, 1H, JHH = 8.4 Hz); 8.16 (s, 1H); 8.09 (d, 1H, JHH = 8.3 Hz);
3
8.06 (d, 1H, JHH = 8.0 Hz); 8.97 (m, 2H); 7.79 (m, 2H); 7.82 (t, 1H,
3JHH = 7.5 Hz); 7.77 (t, 1H, 3JHH = 8.2 Hz); 7.58 (t, 1H, 3JHH = 7.9 Hz);
7.39 (d, 1H, 3JHH = 7.7 Hz); 3.19 (t, 2H, 3JHH = 8.3 Hz); 1.72–1.54 (m,

948
R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
5H); 1.50 (m, 1H), 1.29–1.10 (m, 3H); 1.00–0.88 (m, 2H). 13C NMR
ified with concd HCl (a white precipitate was immediately
formed). The precipitate was filtered off and dried under vacuum
to yield 900 mg of acid 37 (yield 75%). 1H NMR (DMSO-d6): d
13.68 (s, 1H); 8.97 (d, 1H, J = 8.55 Hz); 8.86 (s, 1H); 8.41 (d, 1H,
J = 8,30 Hz); 8.05–8.01 (m, 1H); 7.92–7.89 (m, 1H). 13C NMR
(DMSO-d6): d 167.3; 155.0; 145.2; 135.6; 133.6; 129.9; 126.8;
126.3; 126.0; 122.2.
(DMSO-d6): d 163.0; 151.1; 141.3; 140.8; 137.0; 130.7; 129.3;
2
1
129.2 (q, JCF = 31.4 Hz); 128.4; 127.8; 124.2 (q, JCF = 272.1 Hz);
124.2; 123.4; 119.7; 118.3 (q, 3JCF = 3.7 Hz); 116.5 (q, 3JCF = 3.6 Hz);
112.5; 44.7; 37.4; 30.2 (2C); 25.9; 25.2 (2C). ESI-MS 428.2 (M+H).
Anal. Calcd for C24H24F3N3O2ꢂ0.1 toluene: C, 67.94; H, 5.72; N,
9.62. Found: C, 67.90; H, 5.99; N, 9.56.
The following analogues (33b–c) were prepared using the pro-
cedure outlined for 33a above (32 as starting material).
4.1.51. N-Benzyl-1-chloroisoquinoline-4-carboxamide (39a)
1-Chloroisoquinoline-4-carboxylic acid (37) (150 mg, 0.66
mmol), toluene (1.5 ml) and SOCl2 (96.9 ll, 1.33 mmol) were
placed in a 2 ml microwave reaction vessel, and the vessel was
sealed with a septum and placed into the microwave cavity
(Biotage Initiator). Microwave irradiation was used to increase
the temperature to 120 °C; the reaction mixture was then kept at
4.1.47. N-(Cyclohexyl)-1-[3-(trifluoromethyl)phenyl-amino]-
isoquinoline-3-carboxamide (33b)
3
1H NMR (DMSO-d6): d 9.73 (s, 1H); 8.62 (d, 1H, JHH = 8.4 Hz);
8.26 (s, 1H); 8.07–7.98 (m, 3H); 7.84–7.73 (m, 3H); 7.61 (t, 1H,
3
3JHH = 7.9 Hz); 7.40 (d, 1H, JHH = 7.6 Hz); 3.84 (m, 1H); 1.94–1.83
(m, 2H); 1.73–1.53 (m, 3H); 1.44–1.15 (m, 5H). 13C NMR
this temperature for 10 min. Another portion of SOCl2 (97 ll,
(DMSO-d6): d 164.0; 151.2; 141.3; 140.9; 137.0; 130.8; 129.3;
1.33 mmol) was placed in a microwave reaction vessel and heated
at 120 °C for 10 min. The SOCl2 and toluene was removed under
vacuum and the crude acid chloride 38 was used in the next reac-
tion without further purification. Aforementioned acid chloride 38,
2
1
129.2 (q, JCF = 31.4 Hz); 128.4; 127.9; 124.3 (q, JCF = 272.6 Hz);
124.8; 123.4; 119.7; 118.3 (q, 3JCF = 3.9 Hz); 116.8 (q, 3JCF = 4.4 Hz);
112.4; 47.1; 32.1 (2C); 25.0; 24.1 (2C). ESI-MS 414.2 (M+H). Anal.
Calcd for
C23H22F3N3O: C, 66.82; H, 5.36; N, 10.16. Found:
benzylamide (193 ll, 1.77 mmol) and toluene (1.5 ml) were heated
C, 66.48; H, 5.66; N, 10.01.
for 10 min at 80 °C under microwave irradiation. The resultant
mixture was diluted with H2O and EtOAc. The organic layer was
extracted with saturated NaHCO3, water, dried over Na2SO4, and
solvent removed under vacuum to yield 227 mg crude 39a.
4.1.48. N-(Benzyl)-1-[3-(trifluoromethyl)phenyl-amino]-
isoquinoline-3-carboxamide (33c)
3
1H NMR (DMSO-d6): d 9.72 (s, 1H); 8.63 (d, 1H, JHH = 8.3 Hz);
3
3
8.40 (t, 1H, JHH = 6.1 Hz); 8.20 (s, 1H); 8.13 (d, 1H, JHH = 7.8 Hz);
4.1.52. N-Benzyl-1-[3-(trifluoromethyl)phenyl-amino]isoquino-
line-4-carboxamide (40a)
3
8.08–8.03 (m, 2H); 7.82 (t, 1H, JHH = 7.5 Hz); 7.76 (t, 1H,
3
3JHH = 7.6 Hz); 7.50 (t, 1H, JHH = 7.9 Hz); 7.40–7.30 (m, 5H); 7.28
Crude 39a and 3-(trifluoromethyl)-aniline (500 ll, 4.02 mmol)
3
(m, 1H); 4.59 (d, 2H, JHH = 6.1 Hz). 13C NMR (DMSO-d6): d 164.3;
were mixed in a closed microwave reaction vessel. The vessel was
placed in a microwave oven and irradiated at 150 °C for 15 min.
The reaction mixture was dissolved in EtOAc and washed with sat-
urated NaHCO3 (twice), water, dried over anhydrous Na2SO4, and
dried under vacuum. The residue was recrystallized from toluene
to give 147 mg of product 40a as a white solid (53% yield for 3 steps
from 37). 1H NMR (DMSO-d6): d 9.71 (s, 1H); 9.05 (t, 1H, J = 5.93 Hz);
8.62 (d, 1H); 8.45–8.43 (m, 2H); 8.35 (s, 1H); 8.21 (10, d, 1H,
J = 8.15 Hz); 7.81–7.78 (m, 1H); 7.71–7.68 (m, 1H); 7.59–7.56 (m,
1H); 7.41–7.34 (m, 6H); 7.27–7.25 (m, 1H); 4.55–4.54 (d, 1H,
J = 5.8 Hz). 13C NMR (DMSO-d6): d 166.9; 153.4; 141.4; 140.6;
151.2; 141.3; 140.9; 138.9; 136.9; 130.8; 129.3; 129.2 (q,
2JCF = 31.4 Hz); 128.4; 128.2 (2C); 127.9; 127.0 (2C); 126.5; 124.1
1
3
(q, JCF = 272.8 Hz); 124.8; 123.4; 119.8; 118.0 (q, JCF = 4.0 Hz);
3
116.5 (q, JCF = 3.7 Hz); 112.8; 42.5; ESI-MS 422.1 (M+H). Anal.
Calcd for
C24H18F3N3O: C, 68.40; H, 4.31; N, 9.97. Found:
C, 68.02; H, 4.26; N, 9.80.
4.1.49. 4-Bromo-1-chloroisoquinoline (36)
4-Bromoisoquinoline (34) (200 mg, 0.961 mmol), Na2WO4ꢂH2O
(32 mg, 0.096 mmol), AcOH (5 ml) and 30% H2O2 (297 ll, 88 mmol)
were added in the reaction flask and the mixture was stirred at
80 °C for 3 h. After cooling 50 ml of CH2Cl2 was added and the
organic phase washed with saturated NaHCO3 and water. After
drying the organic phase with anhydrous Na2SO4 and removal of
the solvent under vacuum, 240 mg of crude N-oxide 35 was ob-
tained. The crude 35 was dissolved in mixture of dimethylformam-
ide (1.5 ml) and toluene (4.5 ml) and phosphorus oxychloride
2
139.5: 134.4; 131.7; 129.3; 129.1 (q, JCF = 31.3 Hz); 128.2 (2C);
1
127.0 (2C); 126.6; 126.5; 124.3 (q, JCF = 272.3 Hz); 125.0; 123.9;
3
3
119.5; 118.1 (q, JCF = 3.8 Hz); 117.8; 116.5 (q, JCF = 4.3 Hz); 42.4.
ESI-MS 422.3 (M+H). Anal. Calcd for C24H18F3N3O: C, 68.40; H,
4.31; N, 9.97. Found: C, 68.23; H, 4.56; N, 9.71.
4.1.53. N-(Cyclohexylmethyl)-1-chloroisoquinoline-4-
(176 ll, 1.92 mmol,) was added in ice cooled reaction mixture un-
carboxamide (39b)
der argon. The reaction mixture was stirred at rt for 1 h and then
partitioned between EtOAc and water. The organic layer was
washed with saturated NaHCO3 (twice), water, dried over anhy-
drous Na2SO4, and solvent removed under vacuum. The residue
(270 mg) was purified by silica gel flash chromatography (2.5%
EtOAc–petroleum ether) to give 115 mg (total yield 49%) of 36 as
a white solid. 1H NMR (CDCl3): d 8.48 (s, 1H); 8.35 (d, 1H,
J = 8.5 Hz); 8.20 (d, 1H, J = 8.5 Hz); 7.87 (t, 1H, J = 7.6 Hz); 7.77 (t,
1H, J = 7.6 Hz).
A
mixture of crude 1-chloroisoquinoline-4-carboxylic acid
chloride 38 (prepared from 0.66 mmol of 37 as described above),
cyclohexanemethylamine (173 l, 1.33 mmol) and toluene (1.5
l
ml) were introduced into a pressurised microwave reaction tube
(2 ml) equipped with a magnetic stirrer, which was irradiated first
at 80 °C for 10 min and then 100 °C for 10 min in a Biotage Initiator
microwave synthesizer. The reaction mixture was diluted with
H2O and EtOAc and the organic layer was extracted twice with sat-
urated NaHCO3, once with water, dried over Na2SO4, and solvent
removed under vacuum. The residue was purified by flash chroma-
tography using 20% EtOAc–petroleum ether to give 82 mg (41%
yield from 37) of 39b. 1H NMR (DMSO-d6): d 8.34–8.30 (m, 3H);
7.79 (t, 1H, J = 8.1 Hz); 7.71 (t, 1H, J = 8.1 Hz); 6.38 (s, 1H); 3.36
(t, 2H, J = 6.4 Hz); 1.84–1.55 (m, 5H); 1.35–1.15 (m, 4H); 1.07–
1.00 (m, 2H). 13C NMR (DMSO-d6): d 166.6; 153.7; 139.5; 135.0;
132.3; 129.2; 128.5; 126.7; 126.7; 125.5; 46.4; 38.1; 31.0; 26.4;
25.9.
4.1.50. 1-Chloroisoquinoline-4-carboxylic acid (37)
1.40 g (5.77 mmol) of 36 in dry THF (30 ml) was cooled to
ꢀ80 °C under argon then and solution of t-BuLi (12.70 mmol,
7.47 ml of 1.7 M solution in hexane) was added dropwise via
syringe and stirred at ꢀ80 °C for 20 min. The reaction mixture
was poured onto crushed dry ice under nitrogen, 50 ml of water
was added and solution was made basic using 1 M NaOH solution.
The aqueous solution was washed with EtOAc (3ꢁ 50 ml) and acid-

R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
949
4.1.54. N-(Cyclohexylmethyl)-1-[3(trifluoromethyl)-
4.1.58. N-(2-Methoxyphenyl)-1-[3-(trifluoromethyl)-
phenylamino]-isoquinoline-4-carboxamide (40b)
phenylamino]iso-quinoline-4-carboxamide (40d)
39b (82 mg, 0.270 mmol) and 3-(trifluoromethyl)-aniline
Crude 39d and 3-(trifluoromethyl)-aniline (500 ll, 4.02 mmol)
(350
l
l, 2.80 mmol) were mixed in a closed microwave reaction ves-
were mixed in a closed microwave reaction vessel. The vessel
was placed in a microwave oven and irradiated at 150 °C for
15 min. The reaction mixture was dissolved in EtOAc and washed
with saturated NaHCO3 (twice), water, dried over anhydrous
Na2SO4, and dried under vacuum. The residue was purified by flash
chromatography using 5–20% EtOAc–petroleum ether and then
recrystallized from toluene to give 69 mg (18% yield from 37)
40d as a white solid. 1H NMR (DMSO-d6): d 10.43 (s, 1H); 9.78 (s,
1H); 8.65 (d, 1H, J = 8.45 Hz); 8.45–8.40 (m, 3H); 8.24 (d, 1H,
J = 8.25 Hz); 7.86–7.82 (m, 1H); 7.75–7.72 (m, 1H); 7.61–7.58 (m,
1H); 7.53 (s, 1H); 7.39–7.36 (m, 1H); 7.27–7.24 (m, 1H); 6.69
(dd, 1H, J = 8.18 Hz, J = 2.03 Hz); 3.77 (s, 3H). 13C NMR (DMSO-
d6): d 166.2; 159.9; 154.2; 142.0; 141.7; 141.1; 134.8; 131.6;
sel. The vessel was placed in a microwave oven and irradiated at
150 °C for 15 min. The reaction mixture was dissolved in EtOAc
and washed with saturated NaHCO3 (twice), water, dried over anhy-
drous Na2SO4, and dried under vacuum. The residue (116 mg) was
recrystallized from toluene to give 84 mg of product 40b as a white
solid (yield 73%). 1H NMR (DMSO-d6): d 9.70 (s, 1H); 8.61 (d, 1H,
J = 8.40 Hz); 8.44 (s, 1H); 8.38 (d, 1H, J = 8.40 Hz); 8.31 (s, 1H);
8.25 (s, 1H); 8.21 (d, 1H, J = 8.25 Hz); 7.81–7.78 (m, 1H); 7.71–7,68
(5, m, 1H); 7.59–7.56 (m,1H); 7.35 (d, 1H, J = 7.70 Hz); 3.17–3.15
(m, 2H); 1.79–0.94 (m, 11 H). 13C NMR (DMSO-d6): d 166.8; 153.2;
141.4; 140.3; 134.4; 130.6; 129.3; 129.1 (q, JCF = 31.3 Hz); 126.5;
125.1; 124.3 (q, JCF = 272.3 Hz); 123.8; 123.2; 120.1; 118.0;
117.8; 116.3; 45.1; 37.5; 30.5 (2C); 26.0; 25.4 (2C). ESI-MS 428.3
(M+H). Anal. Calcd for C24H24F3N3Oꢂ0.6 H2O: C, 65.77; H, 5.80; N,
9.59. Found: C, 65.64; H, 5.50; N, 9.47.
2
1
2
129.8 (2C); 129.8 (q, JCF = 31.3 Hz); 127.4; 125.5; 124.9 (q,
2JCF = 272.3 Hz); 124.7; 124.1; 120.4; 119.0; 118.5; 117.3; 112.7;
109.5; 106.1; 55.5. ESI-MS 438.3 (M+H). Anal. Calcd for
C
24H18F3N3O2ꢂ0.1 H2O: C, 65.90; H, 4.15; N, 9.61. Found: C, 65.49;
H, 3.94; N, 9.38.
4.1.55. N-(Cyclohexyl)-1-chloroisoquinoline-4-carboxamide
(39c)
A mixture of 1-chloroisoquinoline-4-carboxylic acid chloride 38
(prepared from 0.885 mmol of 37 as described above), cyclohexyl-
4.1.59. N-(Morpholinyl)-1-chloroisoquinoline-4-carboxamide
(39e)
1-Chloroisoquinoline-4-carboxylic acid (37) (200 mg, 0.884
mmol), toluene (1.5 ml), and SOCl2 (258 ll, 3.54 mmol) were
placed in a 2 ml microwave reaction vessel, and the vessel was
sealed with a septum and placed into the microwave cavity. Micro-
wave irradiation was used to increase the temperature to 120 °C;
the reaction mixture was then kept at this temperature for
15 min. The SOCl2 and toluene was removed under vacuum and
the crude acid chloride 38 was used in the next reaction without
further purification. Aforementioned acid chloride 38, morpholine
amine (202 ll, 1.77 mmol) and toluene (1.5 ml) were introduced
into a pressurised microwave reaction vessel (2 ml) equipped with
a magnetic stirrer, which was irradiated at 80 °C for 10 min in a
Biotage Initiator microwave synthesizer. The reaction mixture
was diluted with H2O and EtOAc and the organic layer was washed
with saturated NaHCO3 (twice), water, dried over Na2SO4, and sol-
vent removed under vacuum to yield 131 mg crude 39c.
4.1.56. N-(Cyclohexyl)-1-[3-(trifluoromethyl)phenyl-
amino]isoquinoline-4-carboxamide (40c)
(154 ll, 1.77 mmol) and toluene (1.5 ml) were heated for 10 min at
80 °C and then another 10 min at 100 °C. The resultant mixture
was partitioned between H2O and EtOAc. The organic layer was
extracted with saturated NaHCO3, water, dried over Na2SO4, and
solvent removed under vacuum to yield 171 mg crude 39e.
Crude 40c 3-(trifluoromethyl)-aniline (500 ll, 4.02 mmol) were
mixed in a closed microwave reaction vessel. The vessel was placed
in a microwave oven and irradiated at 150 °C for 15 min. The reac-
tion mixture was dissolved in EtOAc and washed with saturated
NaHCO3 (twice), water, dried over anhydrous Na2SO4, and dried
under vacuum. The residue (116 mg) was purified by flash chroma-
tography using 15–20% EtOAc–petroleum ether to give 86 mg (24%
yield from 37) 40c as a white solid. 1H NMR (DMSO-d6): d 9.68 (s,
1H); 8.60 (d, 1H, J = 8.40 Hz); 8.44 (s, 1H); 8.36–8.30 (m, 2H); 8.3
(s, 1H); 8.26–8.24 (m, 1H); 7.85–7.83 (m, 1H); 7.71–7.68 (m,
1H); 7.59–7.56 (m, 1H); 7.35 (d, 1H, J = 7.65); 3.83–3.81 (m, 1H);
1.90–1.89 (m, 2H); 1.76–1.73 (m, 2H); 1.60 (d, 1H, J = 12.35 Hz);
1.37–1.27 (m, 4H); 1.17–1.11 (m, 1H). 13C NMR (DMSO-d6) d
165.6; 153.8; 142.2; 140.9; 135.0; 131.3; 130.0; 129.8 (q,
4.1.60. N-(Morpholinyl)-1-[3-(trifluoromethyl)phenyl-
amino]isoquinoline-4-carboxamide (40e)
Crude 39e and 3-(trifluoromethyl)aniline (500 ll, 4.02 mmol)
were mixed in a closed microwave reaction vessel. The vessel
was placed in a microwave oven and irradiated at 150 °C for
15 min. The reaction mixture was dissolved in EtOAc and washed
with saturated NaHCO3 (twice), water, dried over anhydrous
Na2SO4, and dried under vacuum. The residue (203 mg) was puri-
fied by flash chromatography using 13–100% EtOAc–petroleum
ether and then recrystallized from toluene to give 146 mg (41%
yield from 37) 40e as a white solid. 1H NMR (DMSO-d6): d 9.67
(s, 1H); 8.64 (d, 1H, J = 8.45 Hz); 8.35 (s, 1H); 8.27 (d, 1H,
J = 8.20 Hz); 8.04 (s, 1H); 7.83–7.79 (m, 2H); 7.73–7.70 (m, 1H);
7.58–7.55 (m, 1H); 7.34 (d, 1H, J = 7.65 Hz); 3.74–3.30 (m, 8H)
13C NMR (DMSO-d6): d 166.7; 152.7; 141.5; 138.6; 133.7; 130.9;
2
2JCF = 31.3 Hz); 127.2; 125.7; 124.9 (q, JCF = 272,3 Hz); 124.4;
123.9; 121.0; 118.7; 118.5; 117.0; 48.7; 33.0 (2C); 25.8; 25.4
(2C). ESI-MS 414.2 (M+H). Anal. Calcd for C23H22F3N3O: C, 66.82;
H, 5.36; N, 10.16. Found: C, 66.48; H, 5.62; N, 10.23.
2
1
4.1.57. N-(2-Methoxyphenyl)-1-chloroisoquinoline-4-
carboxamide (39d)
A mixture of 1-chloroisoquinoline-4-carboxylic acid chloride 38
((prepared from 0.885 mmol of 37 as described above), m-anisi-
129.2; 129.1 (q, JCF = 31.4 Hz); 126.8; 124.2 (q, JCF = 272.2 Hz);
3
124.2; 123.8; 123.6; 119.6; 117.9 (q, JCF = 4.0 Hz); 117.8; 116.4
(q, 3JCF = 4.0 Hz); 117.1; 66.2 (4C). ESI-MS 402.3 (M+H). Anal. Calcd
for C21H18F3N3O2ꢂ0.1 H2O: C, 62.84; H, 4.52; N, 10.47. Found:
C, 62.34; H, 4.66; N, 10.41.
dine (198 ll, 1.77 mmol) and toluene (1.5 ml) were introduced
into a pressurised microwave reaction vessel (2 ml) equipped with
a magnetic stirrer, which was irradiated at 80 °C for 10 min in a
Biotage Initiator microwave synthesizer. The reaction mixture
was partitioned between H2O and EtOAc and the organic layer
was washed with saturated NaHCO3 (twice), water, dried over
Na2SO4, and solvent removed under vacuum to yield 381 mg crude
39d.
4.1.61. 2-Phenylsulfanyl-quinoline (41a)
A
mixture of 2-chloroquinoline 11 (200 mg, 1.22 mmol),
sodium thiophenolate (455 mg, 4.89 mmol) and DMSO (1.0 ml)
was heated 15 min at 150 °C using Biotage Initiator microwave
synthesizer. The resulting reaction mixture was dissolved in ethyl
acetate (50 ml) and washed with saturated Na2CO3 (2ꢁ 50 ml) and

950
R. Saari et al. / Bioorg. Med. Chem. 19 (2011) 939–950
H2O (2ꢁ 50 ml). The organic phase was dried (Na2SO4) and evapo-
rated to dryness. The crude product was purified by flash chroma-
tography (silica gel) eluting with dichloromethane to give 41a
153.9; 139.8; 138.5; 130.8; 129.6 (2C); 127.1; 126.3; 125.0;
124.3; 121.8 (2C); 119.9; 116.3. ESI-MS 222.2 (M+H). Anal. Calcd
for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.32; H, 5.14;
N, 6.14.
3
(180 mg, 83%). 1H NMR (DMSO-d6): d 8.19 (d, 1H, JHH = 8.2 Hz);
3
3
7.55 (d, 1H, JHH = 7.9 Hz); 7.81 (d, 1H, JHH = 8.4 Hz); 7.73–7.66
3
(m, 3H); 7.56–7.51 (m, 4H); 7.07 (d, 1H, JHH = 7.1 Hz). 13C NMR
Acknowledgements
(DMSO-d6): d 160.2; 147.4; 136.9; 134.7 (2C); 130.2; 129.8 (2C);
129.7; 129.4; 127.9; 127.5; 125.8; 125.6; 119.2. ESI-MS 238.1
(M+H). Anal. Calcd for C15H11NS: C, 75.92; H, 4.67; N, 5.9; S,
13.51. Found: C, 75.91; H, 4.63; N, 5.71; S, 13.20.
This work was supported by National Technology Agency of
Finland and The Academy of Finland (Grant 110277). The authors
are grateful to Mrs. Minna Glad for technical assistance.
The following molecules (41c and 41e) were prepared using the
procedure outlined for 41a above (42 and 19 as starting materials).
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4
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3
3
4JHH = 2.0 Hz); 8.04 (d, 1H, JHH = 8.4 Hz); 7.94 (d, 1H, JHH
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8.1 Hz); 7.80–7.76 (m, 1H); 7.65–7.62 (m, 1H); 7.41–7.33 (m,
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Dessi, C.; Curzu, M. M.; Chelucci, G.; Pani, L.; Pinna, G. A. J. Med. Chem. 2006, 49,
7502.
8. Luongo, L.; Palazzo, E.; Tambaro, S.; Giordano, C.; Gatta, L.; Scafuro, M. A.; Rossi,
F. S.; Lazzari, P.; Pani, L.; de Novellis, V.; Malcangio, M.; Maione, S. Neurobiol.
Dis. 2010, 37, 177.
9. Giblin, G. M. P.; O’Shaughnessy, C. T.; Naylor, A.; Mitchell, W. L.; Eatherton, A. J.;
Slingsby, B. P.; Rawlings, D. A.; Goldsmith, P.; Brown, A. J.; Haslam, C. P.;
Clayton, N. M.; Wilson, A. W.; Chessell, I. P.; Wittington, A. R.; Green, R. J. Med.
Chem. 2007, 50, 2597.
10. Giblin, G. M. P.; Billinton, A.; Briggs, M.; Brown, A. J.; Chessell, I. P.; Clayton, N.
M.; Eatherton, A. J.; Goldsmith, P.; Haslam, C.; Johnson, M. R.; Mitchell, W. L.;
Naylor, A.; Perboni, A.; Slingsby, B. P.; Wilson, A. W. J. Med. Chem. 2009, 52,
5785.
4.1.63. 1-Phenylsulfanyl-isoquinoline (41e)
3
1H NMR (CDCl3): d 8.37 (d, 1H, JHH = 8.4 Hz); 8.24 (d, 1H,
3JHH = 5.6 Hz); 7.77 (d, 1H, 3JHH = 8.2 Hz); 7.68 (t, 1H, 3JHH = 8.1 Hz);
7.62–7.67 (m, 3H); 7.43–7.37 (m, 4H). 13C NMR (CDCl3): d 159.3;
142.4; 136.0; 134.6 (2C); 130.8; 129.1 (2C); 128.5; 127.3; 127.2
(2C); 125.0; 118.4. ESI-MS 238.2 (M+H). Anal. Calcd for
C15H11NS: C, 75.92; H, 4.67; N, 5.90. Found: C, 76.25; H, 4.79; N,
5.83.
4.1.64. 3-Phenoxy-quinoline (41b)
A mixture of 3-bromoquinoline 42 (250 mg, 1.20 mmol), phenol
(226 mg, 2.40 mmol), KOH (135 mg, 2.40 mmol), Cu-powder
(43 mg, 0.67) and 1,4-dioxane (4.0 ml) was heated 45 min at
200 °C using Biotage Initiator microwave synthesizer. The resulting
reaction mixture was dissolved in ethyl acetate (50 ml) and washed
with saturated Na2CO3 (2ꢁ 50 ml) and H2O (2ꢁ 50 ml). The organic
phase was dried (Na2SO4) and evaporated to dryness. The crude
product was purified by flash chromatography (silica gel) eluting
with EtOAc/PE 1:30 to give 41b (199 mg, 75%). 1H NMR (CDCl3): d
11. McGaraughty, S.; Chu, K. L.; Dart, M. J.; Yao, B. B.; Meyer, M. D. Neuroscience
2009, 158, 1652.
12. Chu, G.; Saeui, C. T.; Worm, K.; Weaver, D. G.; Goodman, A. J.; Broadrup, R. L.;
Cassel, J. A.; DeHaven, R. N.; LaBuda, C. J.; Koblish, M.; Brogdon, B.; Smith, S.;
Bourdonnec, B. L.; Dolle, R. E. Bioorg. Med. Chem. Lett. 2009, 19, 5931.
13. Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Goldsmith, P.; Haslam,
C. P.; Mitchell, W. L.; Nicholson, N. H.; Page, L. W.; Patel, S.; Roomans, S.;
Slingsby, B. P.; Swarbrick, M. E. Bioorg. Med. Chem. Lett. 2010, 20, 465.
14. Salo, O. M. H.; Raitio, K. H.; Savinainen, J. R.; Nevalainen, T.; Lahtela-Kakkonen,
M.; Laitinen, J. T.; Järvinen, T.; Poso, A. J. Med. Chem. 2005, 48, 7166.
15. Reux, B.; Nevalainen, T.; Raitio, K. H.; Koskinen, A. M. P. Bioorg. Med. Chem.
2009, 17, 4441.
16. Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funakoshi, T.; Chaki, S.; Nagase, Y.;
Iida, I.; Yamaguchi, J.; Semple, G.; Tran, T.; Sekiguchi, Y. Bioorg. Med. Chem.
2006, 14, 3307.
17. Greenlee, W.; Gangly, A.; Wasley, J., W. F. U.S. Patent 6040448, 2000.
18. Banerjee, R.; Rachid, Z.; McNamee, J.; Jean-Claude, B. J. Med. Chem. 2003, 46,
5546.
19. Roche, O.; Rodríguez Sarmiento, R. M. Bioorg. Med. Chem. Lett. 2007, 17, 3670.
20. Bain, D.; Perkin, W.; Robinson, H. J. J. Chem. Soc., Trans. 1914, 105, 2392.
21. Tucker, S. C.; Brown, J. M.; Oakes, J.; Thornthwaite, D. Tetrahedron 2001, 57,
2545.
22. Denni-Dischert, D.; Marterer, W.; Banziger, M.; Yusuff, N.; Batt, D.; Ramsey, T.;
Geng, P.; Michael, W.; Wang, R. B.; Francis, Taplin; Versace, R.; Cesarz, D.;
Perez, L. B. Org. Process Res. Dev. 2006, 10, 70.
3
3
8.82 (d, 1H, JHH = 2.7 Hz); 8.11 (d, 1H, JHH = 8.4 Hz); 7.67 (d, 1H,
3
3JHH = 8.2 Hz); 7.63 (t, 1H, JHH = 8.3 Hz); 7.54–7.49 (m, 2H); 7.41
(m, 2H); 7.20 (t, 1H, 3JHH = 7.4 Hz); 7.10 (m, 2H). 13C NMR (CDCl3):
d 156.3; 151.1; 145.1; 144.6; 130.1 (2C); 129.2; 128.6; 127.9;
127.3; 127.0; 124.3; 120.2; 119.2 (2C). ESI-MS 222.2 (M+H). Anal.
Calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.39; H,
5.01; N, 6.34.
Compound 41d was prepared using the procedure outlined for
41b using 19 as starting material.
4.1.65. 1-Phenoxy-isoquinoline (41d)
23. Cherng, Y. Tetrahedron 2002, 58, 4931.
3
1H NMR (CDCl3): d 8.44 (d, 1H, JHH = 9.1 Hz); 7.97 (d, 1H,
24. Brewster, R. Q.; Groening, T. Org. Synth. Coll. Vol. 1943, 2, 445.
25. Savinainen, J. R.; Kokkola, T.; Salo, O. M. H.; Poso, A.; Järvinen, T.; Laitinen, J. T.
Br. J. Pharmacol. 2005, 145, 636.
26. Savinainen, J. R.; Saario, S. M.; Niemi, R.; Järvinen, T.; Laitinen, J. T. Br. J.
Pharmacol. 2003, 140, 1451.
3JHH = 5.8 Hz); 7.79 (d, 1H, 3JHH = 8.2 Hz); 7.72 (t, 1H, 3JHH = 8.2 Hz);
7.62 (t, 1H, 3JHH = 8.2 Hz); 7.62–7.67 (m, 3H); 7.45 (m, 2H); 7.30 (d,
3
1H, JHH = 6.1 Hz); 7.28–7.22 (m, 3H). 13C NMR (CDCl3): d 160.6;