Synthesis of substituted aminoquinolines as useful intermediates for preparation of aromatic N-tricyclic systems

Article abstract of DOI:10.3987/COM-06-10782

An effective approach for the synthesis of new substituted mono and diaminoquinolines is described. Two known quinolines 7,8-dichloro-6-nitroquinoline (1) and 7,8-dichloro-6-nitrohydroquinolin-4-one (9) were used as key intermediates.{A figure is presented}.

Full text of DOI:10.3987/COM-06-10782

HETEROCYCLES, Vol. 68, No. 8, 2006
1715
HETEROCYCLES, Vol. 68, No. 8, 2006, pp. 1715 - 1722. © The Japan Institute of Heterocyclic Chemistry
Received, 8th May, 2006, Accepted, 15th June, 2005, Published online, 20th June, 2006. COM-06-10782
SYNTHESIS OF SUBSTITUTED AMINOQUINOLINES AS USEFUL
INTERMEDIATES FOR PREPARATION OF AROMATIC N-TRICYCLIC
SYSTEMS
Antonio Carta,* Michele Palomba, and Paola Corona
Department of Medicinal and Toxicological Chemistry, University of Sassari, Via
Muroni 23, 07100 Sassari, Italy; e-mal: acarta@uniss.it
Abstract – An effective approach for the synthesis of new substituted mono and
diaminoquinolines is described. Two known quinolines 7,8-dichloro-6-
nitroquinoline (1) and 7,8-dichloro-6-nitrohydroquinolin-4-one (9) were used as
key intermediates.
INTRODUCTION
Quinoline ring is well present in natural and synthetic compounds endowed with biological activities.
Nevertheless, its chemistry continues to drawn the attention of many researchers over the world. Several
1
-3
reviews emphasises both synthetic approaches and reactivity of this heterocycle and a well documented
4
,5
application of the pharmacological properties of its derivatives is widely reported. Its outstanding
importance from the medicinal chemistry point of view spans from the antimalarial drugs to the most
6
recent wide spectrum antibacterial quinolones. In this context, in the past, some of us reported the
7
8
synthesis of both novel triazolo[4,5-f]quinolines and their anticancer activity and triazolo[4,5-f] and
9
,10
[4,5-h]quinolinone carboxylic acids as antimicrobial analogues of oxolinic acid
as well as we
1
1
investigated on the synthesis and reactivity of some nitroquinolines. From these studies we were able to
perform versatile procedures to afford 6,7-diaminoquinolines, 7-chloro-6-nitroquinolines and 6-
1
2
aminoquinolines which allowed us to prepare novel triazolo[4,5-g]quinolines,
imidazo[4,5-
and [4,7]phenantrolines. Now, in connection with
these works we required new quinoline derivatives to use as synthons in the building up of novel tricyclic
1
2,13
12-14
15
g]quinolines,
pyrido[2,3-g]quinoxalines
1
2
ring systems. This fact forced us to optimize the synthesis of the previously described 8-chloro-6,7-
diaminoquinoline (5) and 6,7-diaminoquinoline (7) of Scheme 1 and to obtain the new quinolines of
Scheme 2.

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HETEROCYCLES, Vol. 68, No. 8, 2006
RESULTS AND DISCUSSION
1
2
Our previous work on the preparation of the diamine (5) followed a similar scheme as that indicated
below (Scheme 1). Compound (1) was converted into the intermediate (4) by ammonia in ethanol in a
sealed vessel. Catalytic hydrogenation (10% palladised charcoal and hydrogen) of the nitro group was
conditioned upon the temperature of reaction. Thus, at room temperature, compound (5) was uniquely
obtained in 90% yield, whereas operating at 60°C compound (7) was isolated in 50% yield and in this
1
2
11
case hydrogenolysis of chlorine atom at 8 position occurred. In a preceding paper we could observe
the different reactivity of chlorine atom in ortho to a nitro group in the quinoline ring when we attempted
at obtaining the 3-methyl-3H-triazolo[4,5-f] or [4,5-g]quinoline by reaction of 6-chloro-5-nitroquinoline
or 6-chloro-7-nitroquinoline with methylhydrazine respectively. In that case only the 6-chloro-5-
nitroquinoline reacted with methylhydrazine to give rise to a mixture of 3-methytriazolo[4,5-f]quinoline-
1
-oxide and 2-methyltriazolo[4,5-f]quinoline-1-oxide in 5.4:1 ratio, while 6-chloro-7-nitroquinoline did
not yield the expected ring closure but instead produced the sole reduction of the nitro group to a primary
amine.
NH2 (CH CO) O
NHCOCH3
Cl
3
2
rt, 20 h
N
Cl
N
Cl
(60%)
Cl
3 (90%)
2
CH HNNH sealed steel vessel
3
2
1
00 °C, 80 h
EtOH
NH3
NO2
CH3HNNH2
EtOH
NO2
NH2
NH2
EtOH
sealed steel vessel
60 °C, 24 h
N
NH2
N
Cl
sealed steel vessel
N
1
100 °C, 80 h
Cl
(98%)
Cl
1
Cl
(95%)
4
5
H NNH , 10%
Pd-C, EtOH
2
2
H NNH , 10 %
Pd-C, EtOH
(CH CO) O
rt, 20 h
3
2
reflux, 3 h
2
2
reflux, 3 h
NH2
NH2
NHCOCH3
NHCOCH3
N
N
NH2
N
6
(95%)
7 (70%)
Cl
8
(90%)
Scheme 1
With this in mind we have investigated the role played by these different bases in the reaction with
compound (1) using the conditions depicted in Scheme 1. Thus, we have found a new procedure to obtain
the 6-aminoquinoline (6) that is not easy to prepare by a straightforward method because of the difficulty

HETEROCYCLES, Vol. 68, No. 8, 2006
1717
1
6
of introducing a precursor nitro group selectively in this position by a nitrating agent. Our experiments
show that when hydrazine hydrate in ethanol was used in the presence of 10% Pd/charcoal under reflux
for 3h, compound (6) was obtained in 95% yield with total displacement of the chlorine atoms.
Conversely the use of methyhydrazine in ethanol at 100°C for 80 h in a sealed vessel at 100°C yielded
6
0% of compound (2).
O
NH2
N
Cl
H
Cl
0 (70%)
NH3
1
EtOH
sealed steel vessel
sealed steel vessel
2
1
60 °C, 120 h
CH HNNH
3
1
00 °C, 80 h
EtOH
(90%)
O
NH3
OCH CH3
NH2
N
NH2
N
2
NO2
EtOH
NO2
NO2
NH2
NO2
Cl
Et SO
2
4
sealed steel vessel
160 °C, 65 h
+
N
H
Cl
N
Cl
Cl
Cl
Cl
Cl
9
12 (50%)
1
1 (60%)
13 (40%)
NH3
(97%)
NH3
sealed steel vessel
EtOH
NH3
EtOH 160 °C, 24 h
sealed steel vessel
160 °C, 15 h
Cl
EtOH
(95%)
sealed steel vessel
O
NO2
NO2
POCl3
1
60 °C, 48 h
N
NH2
N
NH2
H
Cl
Cl
4 (87%)
1
5 (70%)
1
CH HNNH sealed steel vessel
3
2
EtOH
100 °C, 80 h
O
Cl
N
NH2
NH2
NH2
POCl3
N
H
NH2
Cl
6 (80%)
Cl
17 (50%)
1
Scheme 2
Under the latter same conditions from 4 we obtained compound (5) in 95% yield. Analogously, from
compound (4), under the conditions experienced in the case of 1, we isolated compound (7) in 70% yield
with a similar displacement of chlorine atom. Compounds (2) and (5) were converted in mono (3) and

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HETEROCYCLES, Vol. 68, No. 8, 2006
diacetyl (8) derivatives in very high yields. In our opinion the aquisition of compounds (6,7) operating
with hydrazine in refluxing ethanol in the presence of a catalytic amount of Pd represents a new
convenient procedure for preparation of monoamino and diaminoquinolines where methylhydrazine in the
absence of catalyst acts only as a reducing agent. A similar behaviour was observed in the case of the
1
4
previously described compound (9) when submitted to reaction with methylhydrazine in ethanol at
00°C in a sealed vessel which was converted into the amine (10) in 70% yield (Scheme 2). Similarly
1
from compound (14), under the above conditions, compound (16) was selectively obtained in 80% yield.
Not surprisingly ethylation of (9) with diethyl sulfate occurred at oxygen to give (11) thus demonstrating
3
that the tautomeric equilibrium is prevailing as it is generally observed in the case of reaction with POCl .
In fact either compound (14) or (16) were chlorinated at C-4. However, we must point out that 4-ethoxy
group in (11) is easier displaced by ammonia in ethanol solution than the chlorine at C-7 and gives rise to
a mixture of monoamino (13) and diamino (12) derivatives while in compound (15) nucleophilic
displacement of chlorine to give (12) is almost quantitative (97%). An identical result (90-95% yield) was
obtained starting from (11) and (13) running the same reaction for a prolonged time. These results
represent an improvement in preparation of monoamino and diaminoquinolines for our work in progress.
EXPERIMENTAL
Melting points are uncorrected and were taken in open capillaries in a Digital Electrothermal IA9100
1
melting point apparatus. H-NMR spectra were recorded at 200 MHz using a Varian XL-200
spectrometer. Chemical shifts are reported in ppm (δ) relative to tetramethylsilane as internal standard.
MS spectra were performed on a combined HP 5790 (GC)-HP 5970 (MS) apparatus or with a combined
Liquid Chromatograph-Agilent 1100 series Mass Selective Detector (MSD). Column chromatography
was performed using 70-230 mesh (Merck silica gel 60). The progress of the reactions and the purity of
the final compounds were monitored by TLC using Merck F-254 commercial plates.
Intermediates
7
,8-Dichloro-6-nitroquinoline (1) and 7,8-dichloro-6-nitrodihydroquinolin-4-one (9) were known and
12,14
they were prepared as previously reported
.
Reduction reactions
Method A: using methylhydrazine.
A solution of 1, 4, 9 or 14 (12.0 mmol) and methylhydrazine (3 mL) in 120 mL of ethanol was heated in a
sealed steel vessel at 100 °C for 80 h. The reaction mixture was then cooled to rt and the solvent was
removed in vacuo. The crude solid was thoroughly triturated with ether to give the corresponding 6-
aminoquinoline (2, 5, 10 and 16) in 60, 95, 70 and 80 % yields respectively. Melting points, analytical

HETEROCYCLES, Vol. 68, No. 8, 2006
1719
1
2,14
1
and spectroscopical data of 2, 5, and 16 have been previously reported.
6
-Amino-7,8-dichlorohydroquinolin-4-one (10). mp > 300°C (EtOH); H-NMR (DMSO-d
6
): δ 11.65 (s,
1
H, NH), 8.71 (s, 1H, H-5), 7.99 (d, 1H, J = 7.6 Hz, H-3), 6.09 (d, 1H, J = 7.6 Hz, H-2), 4.57 (s, 2H,
); LC/MS: 229 (M+H); Anal. Calcd for C OCl : C, 47.19; H, 2.64; N, 12.23. Found C, 46.88; H,
.86; N, 12.04.
Method B: using hydrazine and 10% Pd-C.
NH
2
9
H
6
N
2
2
2
A suspension of 1 or 4 (12.0 mmol), 10% Pd-C (0.50 g) and 5 mL of hydrazine monohydrate (98%) in 50
mL of ethanol was refluxed under stirring for 2.5 h. On cooling, the catalyst was filtered off and both
solvent and excess of hydrazine removed in vacuo. The crude solid was thoroughly triturated with
acetone to yield the corresponding de-halogenated 6-aminoquinoline (6 and 7) in 95 and 70 % yield
1
2
respectively. Melting point, analytical and spectroscopical data of 7 have been previously reported.
1
6
-Aminoquinoline (6). mp 98-100°C (EtOH); H-NMR (CDCl
3
+DMSO-d
6
): δ 8.66 (d, 1H, J = 4.8 Hz,
H-2), 8.56 (d, 1H, J = 8.4 Hz, H-4), 8.02 (d, 1H, J = 9.0 Hz, H-8), 7.73 (dd, 1H, J = 4.8 and 8.4 Hz, H-3),
+
7
.50 (d, 1H, J = 9.0 Hz, H-7), 7.04 (s, 1H, H-5), 6.5 (s, 2H, NH
2
); MS M/Z 144 (M ); Anal. Calcd for
9 8 2
C H N
: C, 74.98; H, 5.59; N, 19.43. Found C, 74.63; H, 5.75; N, 19.22.
Preparation of 7,8-dichloro-4-ethoxy-6-nitroquinoline (11). To a suspension of 9 (1.0 g, 3.86 mmol)
and 1.24 g (3.86 mmol) of cesium carbonate (99%) in 20 mL of dehydrated DMF (less than 0.0100% of
water) under stirring was heated at 60 °C and slowly added a solution of ethyl sulfate (0.74 g, 4.8 mmol)
in 6 mL of DMF. After the addition was complete, the reaction mixture was stirred for an additional 4 h,
then poured into 150 g of crushed ice. The solid obtained was collected by filtration and recrystallized
1
from acetone to yield 0.67 g (60%). mp 123-124°C; H-NMR (DMSO-d
6
): δ 8.96 (d, 1H, J = 5.4 Hz, H-2),
8
.65 (s, 1H, H-5), 7.28 (d, 1H, J = 5.4 Hz, H-3), 4.38 (q, 2H, J = 7.0 Hz, CH ), 1.51 (t, 3H, J = 7.0 Hz,
2
+
CH ); MS M/Z 286 (M ); Anal. Calcd for C H N O Cl : C, 46.02; H, 2.81; N, 9.76. Found C, 45.76; H,
3
11
8
2
3
2
3
.10; N, 9.50.
Preparation of 4-chloroquinolines (15 and 17). A solution of 14 or 16 (5.0 mmol) in 20 mL of
phosphorus(V) oxychloride (99%) was refluxed under stirring for 24 h. The reaction mixture was then
cooled to rt and poured into 200 g of crushed ice. The resulting solution was made alkaline with 25%
aqueous ammonia solution. The crude solid obtained was purified by chromatography on silica gel with a
9
:1 mixture of ether-ethanol, to give 15 and 17 respectively.
1
7
8
2
-Amino-4,8-dichloro-6-nitroquinoline (15). (70 %). mp 196-198°C (acetone); H-NMR (DMSO-d ): δ
6
.88 (d, 1H, J = 5.0 Hz, H-2), 8.81 (s, 1H, H-5), 7.62 (d, 1H, J = 5.0 Hz, H-3), 7.23 (s, 2H, NH ); MS M/Z
2
+
57 (M ); Anal. Calcd for C
9
H
5
N
3
O
2
Cl
2
: C, 41.89; H, 1.95; N, 16.28. Found C, 41.76; H, 1.68; N, 15.90.

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HETEROCYCLES, Vol. 68, No. 8, 2006
1
6
,7-Diamino-4,8-dichloroquinoline (17). (50 %). mp 168-170°C (EtOH); H-NMR (CDCl
3
+DMSO-d
6
):
δ 8.51 (d, 1H, J = 5.0 Hz, H-2), 7.24 (s, 1H, H-5), 7.22 (d, 1H, J = 5.0 Hz, H-3), 5.15 (s, 2H, NH
2
), 4.78
+
(
s, 2H, NH
2
); MS M/Z 227 (M ); Anal. Calcd for C
9
H
7
N
3
Cl
2
: C, 47.39; H, 3.09; N, 18.42. Found C,
4
7.70; H, 2.87; N, 18.06.
Displacement by ammonia of chlorine atoms and ethoxy group
A solution of 1, 9, 11 or 15 (12.0-24.0 mmol) in ethanol (120-250 mL) saturated with dry gaseous
ammonia was heated in a sealed steel vessel at 160 °C under stirring for 24 h (in the case of 1 and 9), 15 h
(
in the case of 15) and 120 h (in the case of 11). Then the reaction mixture was cooled to rt, the solvent
was removed in vacuo and the solid residue recrystallized from ethanol, to give 4 (98%), 14 (87%), 12
90 and 97% from 11 and 15 respectively). When the compound (11) was submitted to the same reaction
(
for a shorter time (65 h) a mixture of diamine (12) in 50% yield and monoamine (13) in 40 % yield was
obtained. Purification was achieved by chromatography on silica gel eluting with a 9:1 mixture of
chloroform-methanol, to give in the sequence compounds (13) and (12). Melting points, analytical and
1
2,14
spectroscopical data of 4 or 14 have been previously reported.
,7-Diamino-8-chloro-6-nitroquinoline (12). mp > 300°C (EtOH); H-NMR (DMSO-d
H-5), 8.28 (d, 1H, J = 5.4 Hz, H-2), 7.88 (s, 2H, NH ), 7.00 (s, 2H, NH ), 6.49 (d, 1H, J = 5.4 Hz, H-3);
1
4
6
): δ 9.20 (s, 1H,
2
2
LC/MS: 239 (M+H); Anal. Calcd for C
9
H
7
N
4
O
2
Cl: C, 45.30; H, 2.96; N, 23.48. Found C, 45.66; H, 3.07;
N, 23.21.
1
4
9
2
1
-Amino-7,8-dichloro-6-nitroquinoline (13). mp > 300°C (acetone); H-NMR (CDCl
3
+DMSO-d
6
): δ
.04 (s, 1H, H-5), 8.48 (d, 1H, J = 5.4 Hz, H-2), 7.53 (s, 2H, NH
2
), 6.74 (d, 1H, J = 5.4 Hz, H-3); LC/MS:
58 (M+H); Anal. Calcd for C
6.01.
9 5 3 2 2
H N O Cl : C, 41.89; H, 1.95; N, 16.28. Found C, 46.21; H, 31.80; N,
Preparation of acetylaminoquinolines (3 and 8). A suspension of 2 or 8 (4.5 mmol) in acetic anhydride
15 mL), was stirred to rt overnight, the resulting precipitate was filtered off, washed with water and dried,
to afford in 90% respectively:
N-(7,8-Dichloroquinolin-6-yl)acetamide (3). mp 209-210°C (acetone); H-NMR (DMSO-d
(
1
6
): δ 9.89 (s,
2
4
H, NH), 9.00 (d, 1H, J = 4.8 Hz, H-2), 8.38 (d, 1H, J = 8.4 Hz, H-4), 8.28 (s, 1H, H-5), 7.64 (dd, 1H, J =
+
.8 and 8.4 Hz, H-3); MS M/Z 254 (M ); Anal. Calcd for C11
H
8
N
2
OCl
2
: C, 51.79; H, 3.16; N, 10.98.
Found C, 52.12; H, 3.00; N, 11.33.
1
N-(6-Acetylamino-8-chloroquinolin-7-yl)acetamide (8). mp 253-255°C (acetone); H-NMR (DMSO-
d
6
): δ 9.67 (s, 2H, NH), 9.20 (s, 2H, NH), 8.91 (d, 1H, J = 4.8 Hz, H-2), 8.40 (s, 1H, H-5), 8.24 (d, 1H, J
+
=
8.0 Hz, H-4), 7.51 (dd, 1H, J = 4.8 and 8.0 Hz, H-3); MS M/Z 277 (M ); Anal. Calcd for C13
H
12
N
3
3
O Cl: C, 56.22; H, 4.36; N, 15.13. Found C, 55.90; H, 4.48; N, 14.88.

HETEROCYCLES, Vol. 68, No. 8, 2006
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.
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“
1
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HETEROCYCLES, Vol. 68, No. 8, 2006
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