Synthesis of 2-phenylquinolin-4-amines substituted with diverse amino and aminoalkyl groups

Article abstract of DOI:10.1002/jhet.5570430628

Facile synthetic approaches to 2-phenylquinolin-4-amines containing an aminoalkyl group at N⁴ of the quinolin-4-amine and amino or aminoalkyl groups at the phenyl moiety are presented.

Full text of DOI:10.1002/jhet.5570430628

Nov-Dec 2006
1613
Synthesis of 2-Phenylquinolin-4-amines Substituted with Diverse
Amino and Aminoalkyl Groups
Martial Say, Ekaterina Paliakov, Maged Henary and Lucjan Strekowski*
Department of Chemistry, Georgia State University,
Atlanta, Georgia 30302-4098,
e-mail: lucjan@gsu.edu
Received March 10, 2006
R2
N
R1
R1, R2 = substituted aminoalkylamino
Facile synthetic approaches to 2-phenylquinolin-4-amines containing an aminoalkyl group at N4 of the
quinolin-4-amine and amino or aminoalkyl groups at the phenyl moiety are presented.
J. Heterocyclic Chem., 43, 1613 (2006).
Substituted quinolin-4-amines exhibit a variety of biologi-
cal activities. Many compounds of this class are important
agrochemicals due to their fungicidal, insecticidal, and
pesticidal properties [1]. Others are drugs currently in
clinical use. Thus, quinolin-4-amines are antimalarial,
antiviral, antitumor, anti-inflammatory, analgesic, immuno-
stimulatory, and hypotensive agents [1]. Recently, there has
been an immense interest in 2-arylquinolin-4-amines
substituted with additional amino groups. Such quinolines
can intercalate with poly(dT•dA•dT) and stabilize this triple-
helix DNA structure with high selectivity in the presence of
duplex DNA of any sequence [2]. This feature has
important ramifications for the development of a therapeutic
methodology known as antigene strategy [3]. Specifically,
it has been suggested that the triple-helix formed from the
cellular duplex and an external third strand followed by
stabilization of the resultant triplex can be used to directly
regulate the expression of a selected gene.
ology for the synthesis of N-substituted 2-arylquinolin-4-
amines [4,8-10]. This is illustrated by cyclization of keti-
mine 1 in the presence of lithium 4-methylpiperazide that,
unexpectedly, also results in nucleophilic displacement of the
2-fluorine atom at the phenyl group to give a dipiperazino
derivative 5 in high yield (vide infra) [11]. On the other
hand, a similar reaction of a 4-fluorophenyl ketimine gives a
4-piperazinoquinoline as shown in Scheme 1 by the previ-
ously unpublished synthesis of 6 from 2. This cyclization
methodology is successful for any lithium reagent derived
Scheme 1
Me
O
Ar
CF3
N
CF3
NH2
p-TsOH
Me
R1
R2
2-Arylquinolin-4-amines functionalized with additional
amino groups are also potent antagonists of immuno-
stimulatory bacterial DNA which contains a CpG motif
[4]. Extensive research is being conducted to develop
such substituted quinolin-4-amines into practical drugs for
inducing remission in systemic lupus erythematosus and
rheumatoid arthritis [5,6]. It has also been suggested that,
due to their immunosuppressive properties, such com-
pounds can be useful in the prevention of graft-versus-
host disease in bone transplant patients [7].
R3
1
2
3
4
: R1 = F, R2 = R3 = H
: R1 = R2 = H, R3 = F
: R1 = H, R2 = R3 = F
: R1 = H, R2 = R3 = Me
Li
N
N Me
NMe2
LiHN
Me
N
NMe2
This report pertains to the synthesis of new amino
derivatives of 2-phenylquinolin-4-amines as potential
triple-helix DNA stabilizing and immunosuppressive
agents. The goal was to develop simple methodologies
for the preparation of a large number of compounds for
structure-activity analyses.
N
N
HN
N
R1
R2
R3
R3
N
Me, R3 = H
: R2 = R3 = F
: R2 = R3 = Me
N
=
5
: R1
: R1 = H, R3 = F
7
8
Cyclization of ketimines such as 1-4 (Scheme 1) by the
reactions with lithium dialkylamides is a convenient method-
6

1614
M. Say, E. Paliakov, M. Henary and L. Strekowski
Vol 43
from a secondary amine and with lithium 2-(dimethyl-
amino)ethylamide as illustrated by a high-yield preparation
of new quinolin-4-amines 7 and 8. Unfortunately,
treatment of the ketimines with lithium reagents derived
from other primary amines including the simple homolog
3-(dimethylamino)propylamine results in the formation of
an amidine as the major or sole product [8,9].
A solution to this problem is provided in Scheme 2 by
the synthesis of a 4-chloroquinoline followed by treatment
of this intermediate product with an amine. As part of this
work it was found that 4-chloroquinolines 9-11 are
conveniently prepared by cyclization of the respective
ketimines 1, 2, and 4 with potassium tert-butoxide followed
by hydrolysis of the resultant 4-tert-butoxyquinolines and
then treatment of the intermediate 4-hydroxyquinolines
with a mixture of phosphorus pentachloride and phos-
phorus oxychloride. Since the first two steps are highly
efficient [12], the previously published procedure was
simplified in that the intermediate 4-tert-butoxy and 4-
hydroxyquinolines were used for the third step without
purification. Moreover, the final 4-chloroquinolines are
purified by simple crystallization. Our first attempts of a
nucleophilic displacement of the C4-chlorine by heating
mixtures of 9 or 10 with various amines in the absence of
any additive were largely unsuccessful. It was found,
however, that N-substituted quinolin-4-amines could be
obtained in moderate yields by heating the mixtures in the
presence of phenol. Similar results were obtained by using
boron trifluoride as a catalyst.
Subsequently, it was found that the substitution reaction
proceed with high efficiency and at a relatively low
temperature in the presence of a catalytic amount of tin
tetrachloride. It can be suggested that complexation of the
quinoline N1-atom by this Lewis acid renders the C4-
atom more electrophilic, that is, more reactive toward a
nucleophilic attack. The intermediate ꢀ-adduct may also
be stabilized by the nitrogen-tin interaction.
This methodology for the introduction of an amino
group at the position 4 of the quinoline is general, and a
large number of compounds were prepared in this fashion.
Selected examples are shown in Scheme 2 for illustration.
An additional advantage is the possibility to synthesize N-
substituted quinolin-4-amines for which the amine
precursors are not available commercially. Examples are
compounds 20-22 which were obtained by the reaction of
4-chloroquinolines 9, 10 with the corresponding ꢀ-
hydroxyalkylamines followed by treatment of the
resultant alcohols 14-16 with thionyl chloride to give
alkyl chlorides 17-19, and then the reaction of the alkyl
chlorides with dimethylamine.
The previous observation of facile nucleophilic
displacement of the fluorine atom in the 2-fluorophenyl
substituent, as mentioned above, prompted us to study the
scope and limitations of the use of other fluorophenyl-
substituted quinolines for the synthesis of aminophenyl-
substituted derivatives. Previously, it has also been noted
that a 2-(2,4-difluorophenyl)quinoline 31 is formed upon
cyclization of the corresponding ketimine in the presence of
lithium 2-(dimethylamino)ethylamide [11]. Thus, the 2-
fluoro substituent at the phenyl group was replaced in the
presence of a strongly nucleophilic secondary amide
reagent, while the 2-fluorine atom was retained for the
reaction conducted with less reactive primary lithium
reagent. The quinolines 31 and 7 were used in the initial
studies (Scheme 3). As can be seen, a prolonged treatment
of the 2,4-difluorophenyl derivative 31 with lithium 4-
methylpiperazide resulted in the ipso displacement of the
two fluorine atoms to give product 32 in good yield. On the
other hand, a similar treatment of a 3,4-difluorophenyl
derivative 7 gave the same compound 32 and a 2-(3,4-
dipiperazino)quinoline 33 as the major and minor product,
respectively. In the light of the data already mentioned (see
synthesis of 6, Scheme 1) it can be suggested that the
relatively facile displacement of the 2-fluorine atom in 31 is
Scheme 2
1. t-BuOK/THF
2. 24% HBr
Cl
R1
3. POCl3/PCl5
1, 2, 4
R2
R3
N
HN nR4
9
: R1 = F, R2 = R3 = H
10: R1 = R2 = H, R3 = F
11: R1 = H, R2 = R3 = Me
H2N (CH2)n-R4
SnCl4
R1
N
R3
Me
N
NH
SnCl4
(6
4-8
5
%
)
12-13
14-16
17-19
SOCl2
Me
HNMe2
N
20-22
(55-86%)
N
F
N
23
R1
R3
R4
n
12-22
F
H
F
H
F
H
F
NMe2
NMe2
OH
12
13
14
15
3
3
4
4
H
OH
16
17
18
19
20
21
22
H
F
F
H
F
F
H
OH
Cl
6
4
4
6
4
H
H
F
Cl
Cl
NMe2
H
H
F
F
NMe2
NMe2
4
6

Nov-Dec 2006 2-Phenylquinolin-4-amines Substituted with Diverse Amino and Aminoalkyl Groups
1615
followed by a slow displacement of the 4-fluorine atom.
The presumed initial displacement of the 2-fluorine atom in
31 is consistent with the complex-induced proximity effect
(CIPE) [13]. More specifically, it can be suggested that the
quinoline N1 atom forms a complex with a lithium reagent
resulting in a favorable positioning of this reagent for the
nucleophilic displacement of the adjacent fluorine atom at
the 2-fluorophenyl group. A similar complexation of 7 may
result in lithiation at the unsubstituted adjacent position 2 of
the 3,4-difluorophenyl group. It is suggested that the
resultant 3,4-difluorophenyl-2-lithio derivative undergoes
elimination of fluoride to generate a 2,3-didehydrobenzene
(benzyne). Then, addition reaction of this intermediate with
amide anion followed by ipso displacement of the remaining
4-fluoro substituent by an apparent SNAr mechanism gives
32 which is the observed major product. Again, the
preferential formation of 32 rather than 33 is consistent with
the involvement of the CIPE process.
However, there are major differences between the reactivities
of 4-fluorophenyl and 2-fluorophenyl derivatives toward
secondary and primary lithium amides.
Thus, the facile synthesis of 4-aminophenyl derivatives
such as 24 and 25 is restricted to the reactions of second-
ary lithium amides such as lithium 4-methylpiperazide.
Numerous attempts to force the displacement reactions of
6 and 13 by using lithium amides derived from primary
amines were all unsuccessful. By contrast, as illustrated
in Equation 2, the displacement of the 2-fluorine atom in
12 and 23 to give the corresponding products 26-30 was
successful by using either an alkylamide or dialkylamide
reagent. Also, the synthesis of 2-aminophenyl derivatives
required about a four-fold shorter period of time than the
preparation of the 4-aminophenyl counterparts conducted
under similar conditions.
R
R
R1-Li, THF
23o, 16 h
Scheme 3
(2)
N
N
NMe2
NMe2
HN
N
HN
N
R1
F
(56%)
12, 23
26-30
Me
N
R1
NMe2
=
HN
NMe2 ,
NMe2
26: R =
27: R = R1=
HN
R1
R3
N
N
HN
R2
N
N
N
Li
NMe2 , R1=
Me
Me
N
N
Me
HN
28: R =
31: R1 = R3 = F, R2 = H
32
: R1 = H, R2 = R3 = F
R1
7
N
N
N Me,
NMe2
29: R =
30: R =
HN
=
NMe2
HN
N
R1
Me,
N
HN
=
NMe2
Li
N
N
Me
32
+
(72%)
A different approach to the synthesis of amino
functionalized 2-(2-phenyl)quinolines is presented in
Scheme 4.
32/33 = 3:1
N
N
N
33
Me
The methodology is based on the efficient prepar-
ation of methyl substituted homologs of 4-chloro-2-
phenylquinoline, and the chemistry starting with a
dimethyl derivative 11 is provided as an example.
Compound 11 was brominated at the methyl groups in
the presence of N-bromosuccinimide and a catalytic
amount of dibenzoyl peroxide to give a bis(bromo-
methyl) derivative 34. A subsequent reaction of 34
with 4-methylhomopiperazine was selective in that
only the bromine atoms were displaced resulting in the
formation of a substituted 4-chloroquinoline 35. The
treatment of 35 with 2-(dimethylamino)ethylamine in
the presence of a catalytic amount of tin tetrachloride
gave a polyamino substituted 2-phenylquinoline 36. In
the synthesis of an analogous product 38 the crude
intermediate 4-chloroquinoline 37 was subjected to the
reaction with an amine, resulting in simplification of
the procedure.
N
Me
Additional studies were conducted with 2-(4-fluoro-
phenyl)quinolin-4-amines 6, 13 (Equation 1) and their 2-
fluorophenyl analogs 12, 23 (Equation 2). The expected ipso
displacement pattern was observed in all cases shown.
R
R
Me
N
N Li
(1)
THF, 23o, 16 h
F
N
N
N
6,13
N
Me
24: R =
25: R =
N
N
Me
HN
NMe2

1616
M. Say, E. Paliakov, M. Henary and L. Strekowski
Vol 43
1H nmr, 19F nmr and TLC analysis (hexanes/ether, 19:1).
Compound 4 was crystallized from hexanes, E/Z = 19:1. The
stereochemistry of 4 was determined by nOe studies as
described previously [14].
Scheme 4
Cl
NBS/Bz2O2
11
N
Br
Br
N-[1-(3,4-Difluorophenyl)ethylidene]-2-(trifluoromethyl) aniline
(3).
34
1
This compound was obtained in a 67% yield; H nmr (E/Z
H
N
H
N
mixture): ꢀ 2.15 and 2.56 (2s, 3H), 7.13-7.86 (m, 7H); 19F nmr
(E/Z mixture): ꢀ 24.7, 25.6, 27.3 and 31.9 (4m, 2F), 90.1 and
99.6 (2s, 3F).
Anal. Calcd. for C15H10F5N: C, 60.26; H, 3.36; N, 4.68.
Found: C, 60.11; H, 3.40; N, 4.75.
N
N
R
N
Me
Me
N
N-[1-(3,4-Dimethylphenyl)ethylidene]-2-(trifluoromethyl)aniline
(4).
N
R
N
Me
N
This compound was obtained in an 83% yield; mp 49-51°; 1H
nmr (E isomer): ꢀ 2.15 (s, 3H), 2.30 (s, 3H), 2.31 (s, 3H), 6.73 (d,
J = 8 Hz, 1H), 7.11 (t, J = 8 Hz, 1H), 7.18 (d, J = 8 Hz, 1H), 7.45
(t, J = 8 Hz, 1H), 7.63 (m, 2H), 7.75 (s, 1H); 19F nmr: ꢀ 99.1 (s).
Anal. Calcd. for C17H16F3N: C, 70.09; H, 5.54; N, 4.81.
Found: C, 69.76; H, 5.74; N, 4.90.
N
N
Me
N
Me
35: R = Cl
N
NMe2
H2N
SnCl4
(50%)
NMe2
N
HN
36: R =
Me
Substituted 2-Phenylquinolin-4-amines (5-8).
Synthesis of 5 from 1 has been reported previously [11]. In
the preparation of 6-8 by cyclization of the respective ketimines
2-4 the general procedure [8-10] was modified in that the
reactions were conducted in tetrahydrofuran, under otherwise
identical conditions. Products 6-8 were purified by chroma-
tography eluting with ethyl acetate/hexanes/tri-ethylamine
(10:1:1).
37: R = Cl
H2N
N
O
SnCl4
HN
38: R =
(49%)
N
O
2-(4-Fluorophenyl)-4-(N-methylpiperazino)quinoline (6).
In summary, several methodologies for the synthesis of
polyamino substituted derivatives of 2-phenylquinolin-4-
amine were analyzed. The syntheses with 4-chloroquino-
lines are the most general, as they allow for the
preparation of a large number of the desired products
starting with a single intermediate 4-chloroquinoline.
This compound was obtained in an 80% yield after crystal-
lization from ethyl acetate/hexanes; mp 90-91°; 1H nmr
(deuterated dimethyl sulfoxide): ꢀ 2.31 (s, 3H), 2.64 (m, 4H),
3.30 (m, 4H), 7.44 (s, 1H), 7.51 (t, J = 8 Hz, 1H), 7.69 (t, J = 8
Hz, 1H), 7.80 (d, J = 8Hz, 1H), 8.00 (m, 3H), 8.21 (m, 2H); 19
nmr: ꢀ 55.0 (s); hrms: calcd. for C20H20FN3 m/z 321.1641,
observed m/z 312.1637.
F
EXPERIMENTAL
N-[(2-(Dimethylamino)ethyl]-2-(3,4-difluorophenyl)quinolin-4-
amine (7).
All commercial reagents were used without purification.
Tetrahydrofuran was distilled from sodium benzophenone ketyl
immediately before use. Chromatography was conducted on a
chromatotron with silica gel-coated rotors. Melting points
(Pyrex capillary) are not corrected. Unless reported otherwise,
1H nmr spectra were obtained at 400 MHz at 25° in
deuteriochloroform for free bases and in deuterated dimethyl
sulfoxide for hydrobromide salts with tetramethylsilane as an
internal reference. The 19F nmr spectra were recorded at 282
MHz in the same solvents with hexafluorobenzene as an internal
reference.
This compound was obtained in a 73% yield after crystal-
lization from ethyl acetate/hexanes; yellow needles; mp 130-
131°; 1H nmr: ꢀ 2.37 (s, 6H), 2.77 (t, J = 6 Hz, 2H), 3.41 (q, J1 =
6 Hz, J2 = 7 Hz, 2H), 6.05 (s, exchangeable with D2O, 1H), 6.77
(s, 1H), 7.29 (m, 1H), 7.47 (m, 1H), 7.69 (m, 1H), 7.87 (m, 2H),
7.99 (m, 1H), 8.07 (m, 1H); 19F nmr: ꢀ 23.71 (m, 1F), 23.95 (m,
1F); ms: m/z 101 (100), 240 (50), 168 (50), 327 (80, M+).
Anal. Calcd. for C19H19F2N3: C, 69.70; H, 5.85; N, 12.83.
Found: C, 69.70; H, 5.76; N, 12.70.
N-[2-(Dimethylamino)ethyl]-2-(3,4-dimethylphenyl)quinolin-4-
amine dihydrobromide (8•2HBr•H20).
Ketimines (1-4).
The oily free base was transformed into a hydrobromide by
using a general procedure [10], and the salt was crystallized
from ethanol/hexanes; yield 66%; white solid; mp 299-300°; H
nmr: ꢀ 2.37 (s, 3H), 2.40 (s, 3H), 2.94 (s, 6H), 3.56 (t, J = 6 Hz,
2H), 4.13 (d, J = 6 Hz, 2H), 7.18 (s, 1H), 7.45 (d, J = 8 Hz, 1H),
7.73 (t, J = 8 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 7.94 (s, 1H), 7.99
The synthesis of ketimines 1 [11] and 2 [10] has been reported
previously. Compounds 3 and 4 were prepared in a similar way
by condensation of 2-(trifluoromethyl)aniline with the corre-
sponding substituted acetophenone. The oily product 3 was
purified by Kugelrohr distillation (100-150°/0.3 mmHg). It was
obtained as a mixture of E/Z diastereomers (1:1), as judged by
1

Nov-Dec 2006 2-Phenylquinolin-4-amines Substituted with Diverse Amino and Aminoalkyl Groups
1617
(t, J = 8 Hz, 1H), 8.21 (d, J = 8 Hz, 1H), 8.68 (d, J = 8 Hz, 1H),
9.22 (s, exchangeable with D2O, 1H), 9.90 (s, exchangeable with
D2O, 1H); ms: m/z 101 (30), 128 (30), 217 (50), 233 (30), 249
(50), 261 (80), 273 (20), 319 (100, M+).
Anal. Calcd. for C21H25N3•2HBr•H2O: C, 50.52; H, 5.85; N,
8.42. Found: C, 50.80; H, 5.81; N, 8.44.
triethylamine/methanol/ethyl acetate (5:10:85). The solid product
15 and 16 were crystallized from methanol or ethyl acetate. Oily
products 12-14 and 23 were converted into hydrobromides by
using a general procedure [10], and the salts were crystallized
from ethanol/hexanes.
N-[3-(Dimethylamino)propyl]-2-(2-fluorophenyl)quinoline-4-amine
Dihydrobromide (12•2HBr•0.5H2O).
4-Chloroquinolines (9-11).
This compound was obtained in a 60% yield; mp 152-154°;
1H nmr (deuterated dimethyl sulfoxide): ꢀ 2.10 (m, 2H), 2.80 (s,
6H), 3.22 (m, 2H), 3.71 (m, 2H), 7.20 (s, 1H), 7.55 (m, 2H),
7.90 (t, J = 8 Hz, 1H), 7.95 (m, 2H), 8.00 (m, 2H), 8.65 (d, J = 8
Hz, 1H), 9.50 (s, exchangeable with D2O, 1H), 9.60 (s,
exchangeable with D2O, 1H); 19F nmr: ꢀ 55.0 (s).
Ketimine 1, 2 or 4 (3 mmoles) was added to a solution of
potassium tert-butoxide (1.8 g, 16 mmoles) in anhydrous tetra-
hydrofuran (50 ml), and the mixture was heated under reflux for 2
hours under a nitrogen atmosphere. After cooling the mixture was
treated with water (0.5 ml) and the precipitated inorganic material
was filtered off. The solution containing a 4-tert-butoxyquinoline
was treated with 18% hydrochloric acid (2 ml), and the mixture
was heated under reflux for 1 hour. Concentration of the mixture
on a rotary evaporator to 10 ml followed by treatment with ether
(10 ml) and then refrigeration gave a precipitate of a 4-
hydroxyquinoline hydrobromide. The precipitate was filtered,
washed with ether, and treated with phosphorus oxychloride (5
ml) and phosphorus pentachloride (0.3 g, 1.5 mmoles). The
mixture was heated under reflux for 1 hour, then cooled and
poured onto ice (50 g). Neutralization of the mixture with a
saturated solution of sodium bicarbonate followed by extraction
with ether (3 x 15 ml) and then washing of the extract with water
(2 x 10 ml), drying (Na2SO4) and concentration gave a brown
residue of a 4-chloroquinoline 9, 10 or 11. Colorless crystals were
obtained by crystallization from hexanes.
Anal. Calcd. for C20H22FN3•2HBr•0.5H2O: C, 48.60; H, 5.10;
N, 8.50. Found: C, 48.39; H, 5.27; N, 8.21.
N-[3-(Dimethylamino)propyl]-(4-fluorophenyl)quinolin-4-amine
Dihydrobromide (13•2HBr•2.5 H2O).
This compound was obtained in a 65% yield; mp 218-220°;
1H nmr (deuterated dimethyl sulfoxide): ꢀ 1.90 (m, 2H), 2.20 (s,
6H), 2.40 (t, J = 7 Hz, 2H), 3.40 (t, J = 7 Hz, 2H), 6.91 (s, 1H),
7.35 (m, 4H), 7.62 (m, 1H), 7.85 (d, J = 8 Hz, 1H), 8.15 (d, J = 8
Hz, 1H), 8.25 (m, 2H); 19F nmr: ꢀ 49.0 (s).
Anal. Calcd. for C20H22FN3•2HBr•1.5H2O: C, 46.89; H, 5.31;
N, 8.20. Found: C, 46.99; H, 5.42; N, 8.19.
N-(4-Hydroxybutyl)-2-(2-fluorophenyl)quinolin-4-amine (14).
This compound was used for a further transformation as an
1
4-Chloro-2-(2-fluorophenyl)quinoline (9).
oil; yield 61%; H nmr (deuterated dimethyl sulfoxide): ꢀ 1.80
This compound was obtained in an 82% yield; mp 98-99°; 1H
nmr (deuterated dimethyl sulfoxide): ꢀ 7.41 (m, 2H), 7.60 (m,
1H), 7.81 (t, J = 8 Hz, 1H), 7.93 (t, J = 8 Hz, 1H), 8.04 (d, J = 8
Hz, 1H), 8.09 (s, 1H), 8.22 (m, 1H), 8.24 (d, J = 8 Hz, 1H); 19F
nmr: ꢀ 49.0 (s).
(m, 2H), 3.38 (m, 2H), 3.52 (m, 2H), 4.41 (br s, exchangeable
with D2O), 1H), 6.85 (s, 1H), 7.23 (br s, exchangeable with D2O,
1H), 7.37 (m, 2H), 7.47 (m, 2H), 7.67 (t, J = 8 Hz, 1H), 7.89 (d,
J = 8 Hz, 1H), 8.00 (t, J = 8 Hz, 1H), 8.29 (d, J = 8 Hz, 1H); 19
F
nmr: ꢀ 54.0 (s).
Anal. Calcd. for C15H9ClFN: C, 69.91; H, 3.52; N, 5.43.
Found: C, 69.87; H. 3.35; N, 5.12.
Anal. Calcd. for C19H19FN2O: C, 73.53; H, 6.17; N, 9.02.
Found: C, 73.40; H, 6.28; N, 8.80.
4-Chloro-2-(4-fluorophenyl)quinolines (10).
N-(4-Hydroxybutyl)-2-(4-fluorophenyl)quinolin-4-amine (15).
This compound was obtained in an 80% yield; mp 90-92°
(reported [4]: yield 66%, mp 90-92°).
This compound was obtained in a 76% yield; mp 143-145°;
1H nmr (deuterated dimethyl sulfoxide): ꢀ 1.63 (m, 2H), 1.79 (m,
2H), 3.47 (m, 4H), 6.95 (s, 1H), 7.09 (m, 1H), 7.36, (m, 2H),
7.62 (t, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 8.24 (m, 3H), 9.11
(br s, exchangeable with D2O, 1H), 1.10 (br s, exchangeable
with D2O, 1H); 19F nmr: ꢀ 54.0 (s).
4-Chloro-2-(3,4-dimethylphenyl)quinoline (11).
This compound was obtained in an 80% yield; mp 100-102°;
1H nmr: ꢀ 2.34 (s, 3H), 2.38 (s, 3H), 7.27 (d, J = 8 Hz, 1H), 7.58
(t, J = 8 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H),
7.94 (m, 2H), 8.16 (d, J = 8 Hz, 1H), 8.20 (d, J = 8 Hz, 1H); hr-
fab-ms: calcd for C17H1535ClN (M++1) m/z 268.0893, observed
m/z 268.0898.
Anal. Calcd. for C19H19FN2O: C, 73.53; H, 6.17; N, 9.02.
Found: C, 73.47; H, 6.34; N, 8.69.
N-(6-Hydroxyhexyl)-2-(4-fluorophenyl)quinolin-4-amine (16).
Anal. Calcd. for C17H14ClN•0.25H2O: C, 74.99; H, 5.37; N,
5.14. Found: C, 74.90; H, 5.30; N, 5.18.
This compound was obtained in a 78% yield; mp 100-102°;
1H nmr (deuterated dimethyl sulfoxide): ꢀ 1.50 (m, 6H), 1.70 (m,
2H), 3.40 (m, 4H), 4.40 (br s, exchangeable with D2O, 1H), 6.90
(s, 1H), 7.20 (br s, exchangeable with D2O, 1H), 7.39 (m, 2H),
7.45 (t, J = 8 Hz, 1H), 7.70 (t, J = 8 Hz, 1H), 7.90 (d, J = 8 Hz,
1H), 8.30 (m, 3H); 19F nmr: ꢀ 49.0 (s); hr-ms: calcd for
C21H23FN2O m/z 338.1781, observed m/z 338.1794.
Substituted Quinolin-4-amines (12-16 and 23).
A mixture of 4-chloroquinoline 9 or 10 (0.21 g, 0.8 mmol), an
amine (2.5 mmol) and 2 drops of anhydrous tin tetrachloride was
stirred at 130° under a nitrogen atmosphere for 6 hours. The
resulting dark oil was allowed to cool and then treated with
water (5 ml). Extraction with ethyl acetate (3 x 10 ml) followed
by drying of the extract with magnesium sulfate and concen-
tration gave an oil which was further purified by chroma-
tography on silica gel eluting with ethyl acetate/hexanes (1:3) or
2-(2-Fluorophenyl)-4-(N-methylpiperazino)quinoline Dihydro-
bromide (23).
This compound was obtained in a 68% yield; mp 278-279°
1
(dec); H nmr: ꢀ 2.92 (s, 3H), 3.49 (s, 2H), 3.63 (s, 2H), 3.78 (s,

1618
M. Say, E. Paliakov, M. Henary and L. Strekowski
Vol 43
2H), 4.27 (s, 2H), 7.55 (m, 2H), 7.74 (m, 2H), 7.95 (m, 2H),
8.03 (t, J = 8 Hz, 1H), 8.16 (d, J = 8 Hz, 1H), 8.23 (d, J = 8 Hz,
1H), 10.27 (s, exchangeable with D2O, 1H); ms: m/z 101 (30),
222 (50), 306 (80), 321 (100, M+).
2H), 8.66 (d, J = 8 Hz, 1H), 9.50 (br s, exchangeable with D2O,
2H); 19F nmr: ꢁ 55.0 (s).
Anal. Calcd. for C21H24FN3•2HBr•H2O: C, 48.76; H, 5.46; N,
8.12. Found: C, 48.79; H, 5.70; N, 8.25.
Anal. Calcd. for C20H20FN3•2HBr•H2O: C, 47.92; H, 4.83; N,
8.38. Found: C, 47.93, H, 4.82, N, 8.30.
N-[4-(Dimethylamino)butyl]-2-(4-fluorophenyl)quinolin-4-amine
Dihydrobromide (21•2HBr•2H2O).
N-( -Chloroalkyl)quinolin-4-amines (17-19).
This salt was obtained in a 63% yield; mp 239-240°;1H nmr: ꢁ
1.81 (m, 4H), 2.78 (s, 6H), 3.17 (t J = 6 Hz, 2H), 3.73 (t, J = 6
Hz, 2H), 7.08 (s, 1H), 7.57 (m, 2H), 7.74 (t, J = 8 Hz, 1H), 8.00
(t, J = 8 Hz, 1H), 8.16 (m, 3H), 8.70 (d, J = 8 Hz, 1H), 9.34 (br s,
exchangeable with D2O, 1H), 9.60 (br s, exchangeable with
D2O, 1H); 19F nmr: ꢁ 55.0 (s).
A mixture of an N-(ꢀ-hydroxyalkyl)quinolin-4-amine 14, 15
or 16 (3 mmoles) and thionyl chloride (12 ml) in benzene (10
ml) was heated under reflux for 3 hours. After cooling the
mixture was poured onto ice (25 g), neutralized with a saturated
solution of sodium bicarbonate, and extracted with ethyl acetate
(4 x 20 ml). The extract was dried with magnesium sulfate,
concentrated, and the residue was subjected to chromatography
eluting with pentane/ethyl acetate (7:3).
Anal. Calcd. for C21H24FN3•2HBr•2H2O: C, 47.12; H, 5.65; N,
7.84. Found: C, 47.34; H, 5.86; N, 7.48.
N-[6-(Dimethylamino)hexyl]-4-(4-fluorophenyl)quinolin-4-
amine (22).
N-(4-Chlorobutyl)-2-(2-fluorophenyl)quinolin-4-amine (17).
This compound was obtained as a yellow solid; yield 80%,
mp 107-108°; H nmr (deuterated dimethyl sulfoxide); ꢁ 1.86
This compound was obtained in a 65% yield; mp 100-101°; 1H
nmr (deuterated dimethyl sulfoxide): ꢁ 1.41 (m, 6H), 1.70 (m, 2H),
2.10 (s, 6H), 2.20 (t, J = 6 Hz, 2H), 3.42 (m, 2H), 6.95 (s, 1H), 7.20
(br s, exchangeable with D2O, 1H), 7.35 (m, 3H), 7.65 (t, J = 8 Hz,
1H), 7.90 (d, J = 8 Hz, 1H), 8.30 (m, 3H); 19F nmr: ꢁ 49.0 (s); hr-
ms: calcd for C23H28FN3 m/z 365.2249, observed m/z 365.2257.
Anal. Calcd. for C23H28FN3: C, 75.58; H, 7.72; N, 11.49.
Found: C, 75.64; H, 7.85; N, 11.29.
1
(m, 4H), 3.38 (t, J = 6 Hz, 2H), 3.72 (t, J = 6 Hz, 2H), 6.83 (s,
1H), 7.24 (s, exchangeable with D2O, 1H), 7.34 (m, 2H), 7.49
(m, 2H), 7.66 (t, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.96 (t, J
= 8 Hz, 1H), 8.27 (d, J = 8 Hz, 1H); 19F nmr: ꢁ 54.0 (s); hr-ms:
calcd for C19H1835ClFN2 m/z 328.1141, observed m/z 328.1150.
N-(4-Chlorobutyl)-2-(4-fluorophenyl)quinolin-4-amine (18).
Substituted 2-(Aminophenyl)quinolin-4-amines (24-30, 32, and
33).
1
This compound was obtained as an oil; yield 85%; H nmr
(deuterated dimethyl sulfoxide); ꢁ 1.92 (m, 4H), 3.49 (t, J = 6
Hz, 2H), 3.79 (t, J = 6 Hz, 2H), 7.00 (s, 1H), 7.22 (br s,
exchangeable with D2O, 1H), 7.35 (m, 2H), 7.45 (t, J = 8 Hz,
1H), 7.66 (t, J = 8 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 8.30 (m, 3H);
19F nmr: ꢁ 54.0 (s); hr-ms: calcd for C19H1835ClFN2 m/z
328.1141, observed m/z 328.1145.
A solution of the corresponding amine (2.7 mmol) in tetra-
hydrofuran (3 mL) was treated with a solution of n-buthyl-
lithium in cyclohexane (2 M, 1.4 mL, 2.7 mmol) at –10° for
30 minutes and then with a solution of 6, 7, 12, 13, 23 or 31
(0.3 mmol) in tetrahydrofuran (2 ml). The mixture was stirred
at room temperature for 4 hours for substitution of ortho
fluorine atom in 12 and 23, 24 hours for para substitution in 6
and 13, and 4 days for the reactions of difluorophenyl
derivatives 7 and 31. The mixture was quenched with water (1
mL) and extracted with ethyl acetate (3 x 10 ml). The extract
was concentrated and the residue purified by chromatography
eluting with triethylamine/methanol/ethyl acetate (1:3:16).
Products were transformed into hydrobromide salts according
to a general procedure [10], and the salts were crystallized
from methanol/ether.
N-(6-Chlorohexyl)-2-(4-fluorophenyl)quinolin-4-amine (19).
1
This compound was obtained as an oil; yield 72%; H nmr
(deuterated dimethyl sulfoxide); ꢁ 1.50 (m, 4H), 1.80 (m, 4H),
3.45 (t, J = 6 Hz, 2H), 3.70 (t, J = 6 Hz, 2H), 6.90 (s, 1H), 7.20
Br s, exchangeable with D2O, 1H), 7.35 (m, 2H), 7.45 (t, J = 8
Hz, 1H), 7.70 (t, J = 8 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 8.30 (m,
3H); 19F nmr: ꢁ 50.0 (s); hr-ms: calcd for C21H2235ClFN2 m/z
356.1454, observed m/z 356.1464.
N-[ꢀ-(Dimethylamino)alkyl]quinolin-4-amines (20-22).
4-(N-Methylpiperazino)-2-[4-(N-methylpiperazino)phenyl]-
quinoline Trihydrobromide (24•3HBr•2.5H2O).
A mixture of an N-(ꢀ-chloroalkyl)quinolin-4-amine 17, 18 or
19 (2 mmoles), dimethylamine hydrochloride (1.65 g, 20
mmoles), sodium carbonate (2.1 g, 20 mmoles), and anhydrous
N,N-dimethylformamide (10 ml) was heated to 70° for 4 hours,
then cooled and filtered. The filtrate was concentrated on a rotary
evaporator and the residue was subjected to chromatography
eluting with ethyl acetate/triethylamine (40:1). The oily products
20 and 21 were converted into hydrobromides by using a general
procedure [10], and the salts were crystallized from methanol.
The solid free base 22 was crystallized from ethyl acetate.
1
This salt was obtained in a 74% yield; mp 290-293°; H nmr:
ꢁ 3.00 (s, 6H), 3.20 (m, 4H), 3.67 (m, 8H), 4.21 (m, 4H), 7.30
(d, J = 8 Hz, 2H), 7.54 (s, 1H), 7.72 (t, J = 8 Hz, 1H), 8.00 (t, J =
8 Hz, 1H), 8.20 (m, 3H), 8.30 (d, J = 8 Hz, 1H), 10.00 (br s,
exchangeable with D2O, 1H), 10.20 (br s, exchangeable with
D2O, 1H); hr-ms for free base: calcd for C25H31N5O2 m/z
401.2579, observed m/z 401.2579.
Anal. Calcd. for C25H31N5•3HBr•2.5H2O: C, 43.56; H, 5.70;
N, 10.15. Found: C, 43.92; H, 5.53; N, 9.82.
N-[4-(Dimethylamino)butyl]-2-(2-fluorophenyl)quinolin-4-
amine Dihydrobromide (20•2HBr•H2O).
N-[3-(Dimethylamino)propyl]-2-[4-(N-methylpiperazino)phenyl]-
quinolin-4-amine Trihydrobromide (25•3HBr•2H2O).
1
This salt was obtained in a 60% yield; mp 148-150°; H nmr:
1
ꢁ 1.80 (m, 4H), 2.80 (s, 6H), 3.18 (m, 2H), 3.61 (m, 2H), 7.01 (s,
1H), 7.52 (m, 2H), 7.78 (m, 2H), 7.90 (t, J = 8 Hz, 1H), 8.00 (m,
This salt was obtained in a 61% yield, mp 313-315°; H
nmr: ꢁ 2.22 (s, 6H), 2.97 (s, 3H), 2.41 (t, J = 7 Hz, 2H), 2.56

Nov-Dec 2006 2-Phenylquinolin-4-amines Substituted with Diverse Amino and Aminoalkyl Groups
1619
(m, 2H), 3.25 ( m, 4H), 3.45 (t, J = 7 Hz, 2H), 6.95 (s, 1H),
7.10 (m, 2H), 7.30 (br s, exchangeable with D2O, 1H), 7.40
(t, J = 8 Hz, 1H), 7.61 (t, J = 8 Hz, 1H), 7.82 (d, J = 8 Hz,
1H), 8.10 (m, 3H).
2H), 9.59 (br s, exchangeable with D2O, 1H); ci-ms: m/z 202
(75), 319 (100), 404 (M++1).
Anal. Calcd. for C25H33N5•4HBr•H2O: C, 40.29; H, 5.27; N,
9.39. Found: C, 40.31; H, 5.57; N, 9.09.
Anal. Calcd. for C25H33N5•3HBr•2H2O: C, 44.00; H, 5.91; N,
10.25. Found: C, 43.92; H, 5.77; N, 9.90.
N-[2-(Dimethylamino)ethyl]-2-[2,4-bis(4-methylpiperazino)-
phenyl]quinolin-4-amine Tetrahydrobromide(32•4HBr•2H2O).
N-[3-(Dimethylamino)propyl]-2-[2-[[2-(dimethylamino)ethyl]-
amino]phenyl]quinolin-4-amine (26).
Reaction of 31 with lithium 4-methylpiperazide followed by
treatment of the resultant quinoline 32 with hydrobromic acid
gave the salt 32•4HBr•2H2O in a 56% yield. The same product
was obtained in a 54% yield starting with 7; mp 239-241° (dec);
1H nmr: ꢀ 2.78 (s, 3H), 2.88 (s, 3H), 2.93 (s, 6H), 2.37 (bs, 4H),
3.21-3.48 (br m, 12H), 3.55 (t, J = 6 Hz, 2H), 4.04 (m, 2H), 6.81
(s, 1H), 6.89 (d, J = 8 Hz, 1H), 7.10 (s, 1H), 7.66 (d, J = 8 Hz,
1H), 7.72 (t, J = 8 Hz, 1H), 7.97 (t, J = 8 Hz, 1H), 8.15 (d, J = 8
Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 9.09 (br s, exchangeable with
D2O, 1H), 9.98 (br s, exchangeable with D2O, 1H); esi-ms: m/z
244.77 (100), 488.52 (M++1). The substitution pattern of 32 was
derived from proton decoupling and nOe experiments.
This compound was obtained in a 77% yield, mp 130-131°;
1H nmr (deuterated dimethyl sulfoxide): ꢀ 1.81 (m, 2H), 2.19 (s,
6H), 2.22 (s, 6H), 2.40 (t, J = 6 Hz, 2H), 2.61 (t, J = 6 Hz, 2H),
3.22 (t, J = 6 Hz, 2H), 3.40 (t, J = 6 Hz, 2H), 6.65 (m, 2H), 6.80
(s, 1H), 7.20 (t, J = 8 Hz, 1H), 7.30 (br s, exchangeable with
D2O, 1H), 7.40 (t, J = 8 Hz, 1H), 7.60 (t, J = 8 Hz, 1H), 7.70 (d,
J = 8 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 8.20 (d, J = 8 Hz, 1H),
9.50 (br s, exchangeable with D2O, 1H).
Anal. Calcd. for C24 H33 N5: C, 73.61; H, 8.50; N, 17.88.
Found: C, 73.46; H, 8.88; N, 17.55.
Anal. Calcd. for C29H41N7•4HBr•2H2O: C, 41.11; H, 5.83; N,
11.57. Found: C, 41.16; H, 5.95; N, 11.40.
N-[3-(Dimethylamino)propyl]-2-[2-[[3-(dimethylamino)propyl]-
amino]phenyl]quinolin-4-amine Trihydrobromide (27•3HBr•5H2O).
N-[2-(Dimethylamino)ethyl]-2-[3,4-bis(4-methylpiperazino)-
phenyl]quinolin-4-amine Pentahydrobromide (33•5HBr).
1
This salt was obtained in a 72% yield; mp 212-214°; H nmr:
ꢀ 1.98 (m, 2H), 2.10 (t, J = 6 Hz, 2H), 2.80 (s, 6H), 2.90 (s, 6H),
3.20 (m, 6H), 3.70 (t, J = 6 Hz, 2H), 6.80 (t, J = 8 Hz, 1H), 6.85
(d, J = 8 Hz, 1H), 6.95 (s, 1H), 7.35 (d, J = 8 Hz, 1H), 7.40 (t, J
= 8 Hz, 1H), 7.75 (m, 1H), 8.00 (m, 2H), 8.70 (d, J = 8 Hz, 1H),
9.30 (br s, exchangeable with D2O, 1H), 9.68 (br s,
exchangeable with D2O, 1H).
Quinoline 33 was obtained as a minor product by the reaction
of 7 with lithium 4-methylpiperazide. The salt was obtained in
1
an overally yield of 18%; mp >300° (dec.); H nmr: ꢀ 2.94 (s,
12H), 3.05 (m, 4 H), 3.36-3.59 (bm, 12H), 4.00 (m, 2H), 4.10
(m, 2H), 7.15 (s, 1H), 7.25 (d, J = 8 Hz, 1H), 7.58 (s, 1H), 7.77
(m, 2H), 8.00 (t, J = 8 Hz, 1H), 8.31 (d, J = 8 Hz, 1H), 8.66 (d, J
= 8 Hz, 1H), 9.18 (br s,with D2O, 1H), 9.95 (br s, exchangeable
with D2O, 1H); esi-ms: m/z 244.8 (100), 488.6 (M+ +1). The
substitution pattern of 33 was derived from proton decoupling
and nOe experiments.
Anal. Calcd. for C25H35N5•3HBr•5.5H2O: C, 40.17; H, 6.61;
N; 9.37. Found: C, 40.00; H, 6.80; N, 9.25.
N-[3-(Dimethylamino)propyl]-2-[2-(4-methylpiperazino)phenyl]-
quinolin-4-amine Trihydrobromide(28•3HBr•1.5H2O).
1
Anal. Calcd. for C29H41N7•5HBr: C, 39.04; H, 5.20; N, 10.98.
Found: C, 39.34; H, 5.45; N, 10.80.
This salt was obtained in a 75% yield; mp 225-228°; H nmr:
ꢀ 1.10 (t, J = 6Hz, 2H), 2.15 (t, J = 6 Hz, 2H), 2.80 (s, 9H), 3.20
(m, 4H), 3.31 (t, J = 6 Hz, 2H), 3.50 (m, 2H), 3.81 (t, J = 6 Hz,
2H), 7.10 (s, 1H), 7.40 (m, 2H), 7.65 (t, J = 8 Hz, 1H), 7.75 (m,
2H), 8.00 (t, J = 8 Hz, 1H), 8.10 (d, J = 8 Hz, 1H), 8.70 (d, J = 8
Hz, 1H), 9.40 (br s, exchangeable with D2O, 1H), 9.80 (br s,
exchangeable with D2O, 1H).
2-[3,4-Bis(bromomethyl)phenyl]-4-chloroquinoline (34).
A mixture of 11 (1.0 g, 3.75 mmoles), N-bromosuccinimide
(1.47 g, 8.25 mmoles), and benzoyl peroxide (0.15 g) in
carbon tetrachloride (50 ml) was heated under reflux for 6
hours. After cooling, a precipitate of succinimide was filtered
off, and the solution was concentrated. The resultant yellow
residue was crystallized from hexanes to give 34 in a 52%
Anal. Calcd. for C25H33N5•3HBr•1.5H2O: C, 44.60; H, 5.84;
N, 10.40. Found: C, 44.75; H, 6.17; N, 10.30.
N-(4-Methylpiperazino)-2-[2-[2-(dimethylamino)ethyl]phenyl]-
quinolin-4-amine Trihydrobromide (29•3HBr•H2O).
1
yield; mp104-107° (dec); H nmr: ꢀ 4.73 (s, 2H), 4.78 (s, 2H),
7.52 (d, J = 8 Hz, 1H), 7.63 (m, 1H), 7.78 (m, 1H), 7.95 (s,
1H), 8.05 (d, J = 8 Hz, 1H), 8.11 (s, 1H), 8.19 (d, J = 8 Hz,
1H), 8.24 (d, J = 8 Hz, 1H).
Anal. Calcd. for C17H12Br2ClN: C, 47.98; H, 2.84; N, 3.29.
Found: C, 47.80; H, 2.75; N, 3.20.
1
This salt was obtained in a 69% yield; mp 314-315° (dec); H
nmr: ꢀ 2.86 (s, 6H), 2.94 (s, 3H), 3.18 (s, 2H), 3.59 (m, 2H),
3.63 (m, 4H), 4.27 (s, 2H), 6.89 (t, J = 7 Hz, 1H), 6.98 (d, J = 8
Hz, 1H), 7.47 (m, 3H), 7.74 (t, J = 7 Hz, 1H) 7.98 (t, J = 7 Hz,
1H), 8.19 (m, 2H), 10.39 (br s, exchangeable with D2O, 1H); ci-
ms: m/z 195.7 (35), 319.4 (100), 390 (M++1).
4-Chloro-2-[3,4-bis[N-methylhomopiperazino)methyl]phenyl]-
quinoline Pentahydrobromide (35•5HBr•4H2O).
Anal. Calcd. for C24H31N5•3HBr•H2O: C, 44.32; H, 5.58; N,
10.77. Found: C, 43.92; H, 5.58; N, 10.54.
A mixture of 34 (85.1 mg, 0.2 mmole) and N-methylhomo-
piperazine (400 mg, 4 mmoles) was stirred at room temperature
for 24 hours and then concentrated on a rotary evaporator.
Chromatography of the residue eluting with ethyl acetate/
methanol/triethylamine (5:4:1) gave 37 as an oil. The hydro-
bromide salt was obtained in an overall yield of 47%; mp 220-
N-(4-Methylpiperazino)-2-[(2-[3-(dimethylamino)propyl)phenyl]-
quinolin-4-amine Tetrahydrobromide (30•4HBr•H2O).
1
This salt was obtained in a 65% yield; mp 187-189° (dec); H
nmr: ꢀ 2.65 (m, 2H), 2.76 (s, 9H), 2.88 (m, 2H), 2.97 (m, 4H),
3.16 (m, 6H), 6.83 (t, J = 8 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 7.43
(m, 3H), 7.75 (t, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 1H), 8.20 (m,
1
221° (dec); H nmr (free base, deuteriochloroform): ꢀ 1.86 (m,
4H), 2.38 (m, 6H), 2.69 (t, J = 5 Hz, 4H), 2.72 (m, 12H), 3.84 (s,

1620
M. Say, E. Paliakov, M. Henary and L. Strekowski
Vol 43
2H), 3.86 (s, 2H), 7.51 (d, J = 8 Hz, 1H), 7.60 (s, 1H), 7.76 (m,
1H), 7.96 (m, 1H), 7.98 (d, J = 8 Hz, 1H), 8.09 (d, J = 8 Hz, 1H),
8.19 (m, 2H).
Anal. Calcd. for C29H38N5Cl•5HBr•4H2O: C, 35.95; H, 5.31;
N, 7.23. Found: C, 35.95; H, 5.30; N, 7.56.
exchangeable with D2O, 1H), 9.71 (br s, exchangeable with
D2O, 1H), 10.20 (br s, exchangeable with D2O, 1H); hr-ms (free
base): calcd for C33H47N7O m/z 557.3842, observed m/z
557.3859.
Anal. Calcd. for C33H47N7O•4HBr•1.5H2O: C, 43.63; H, 5.99;
N, 10.79. Found: C, 43.52; H, 6.13; N, 10.39.
N-[2-(Dimethylamino)ethyl]-2-[3,4-bis[(N-methylhomopiper-
azino)methyl]phenyl]quinolin-4-amine Hexahydrobromide
(36•6 HBr•6H2O).
REFERENCES
Reaction of 35 with 2-(dimethylamino)ethylamine in the
presence of tin tetrachloride was conducted and the product was
purified by using a general procedure described above to give a
[1] F. Palacios, D. Aparicio, G. Rubiales, A. M. Ochoa de Retana
and Martinez de Marigorta in Targets in Heterocyclic Systems.
Chemistry and Properties, O. A. Attanasi and D. Spinelli, Eds., Italian
Chemical Society, Roma, Italy, 1997, Vol. 1, p. 187.
[2] J. B. Chaires, J. Ren, M. Henary, O. Zegrocka, G. R. Bishop
and L. Strekowski, J. Am. Chem. Soc., 125, 7272 (2003).
[3] C. Helene, Eur. J. Cancer, 27, 1466 (1991).
[4] L. Strekowski, M. Say, M. Henary, P. Ruiz, L. Manzel, D. E.
Macfarlane and A. Bojarski, J. Med. Chem., 46, 1242 (2003).
[5] R. Fox, Semin. Arthritis Rheum., 23, 82 (1993).
[6] D. J. Wallace, Rheum. Dis. Clin. North Amer., 20, 243
(1994).
1
salt of 36 in a yield of 50%; mp 224-225°; H nmr: ꢀ 2.25 (m,
4H), 2.89 (s, 6H), 2.94 (s, 6H), 3.39-3.79 (br m, 14H), 3.90 (m,
4H), 4.17 (m, 2H), 4.68 (m, 2H), 4.82 (m, 2H), 7.36 (s, 1H),
7.78 (t, J = 8 Hz, 1H), 8.03 (m, 2H), 8.23 (m, 2H), 8.56 (d, J = 8
Hz, 2H) 8.65 (s, 1H).
Anal. Calcd. for C33H49N7•6HBr•6H2O: C, 34.84; H, 5.94; N,
8.62. Found: C, 34.82; H, 5.86; N, 8.38.
N-[2-(Morpholino)ethyl]-2-[3,4-bis[(4-methylpiperazino)methyl]-
phenyl]quinolin-4-amine Tetrahydrobromide (38•4HBr•1.5H2O).
[7] K. R. Schultz and A. L. Gilman, Leuk. Lymphoma, 24, 201
(1997).
This salt was obtained by using a modified procedure
described above for the synthesis of the salt of 36. Thus,
compound 34 was treated with 4-methylpiperazine and the
resultant product 37, without purification, was subjected to the
reaction with 4-(2-aminoethyl)morpholine under otherwise
identical conditions. The resultant compound 38 was purified
by chromatography eluting with ethyl acetate/methanol/
triethylamine and then converted into hydrobromide by using a
general procedure. After crystallization from 95% ethanol the
overall yield of 38•4HBr•1.5H2O was 49%; mp 188-191° (dec);
1H nmr: ꢀ 2.51 (m, 2H), 2.81 (m, 8H), 2.92 (m, 4H), 3.09 (s,
6H), 3.15 (m, 4H), 3.60 (m, 4H), 3.82 (m, 8H), 4.15 (m, 2H),
7.19 (s, 1H), 7.65 (d, J = 8 Hz, 1H), 7.75 (t, J = 8 Hz, 1H), 7.94
(m, 3H), 8.23 (d, J = 8 Hz, 1H), 8.60 (m, 1H), 9.25 (br s,
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