An improved method for the synthesis of 3-amino-1H-quinolin-2-one

Article abstract of DOI:10.1081/SCC-120012984

An efficient method for the synthesis of 3-amino-1H-quinolin-2-one is described. Condensation of o-nitrobenzaldehyde with hippuric acid gave 4-(2-nitrobenzylidene)-2-phenyloxazol-5-one. This compound was reduced to give 4-(2-aminobenzylidene)-2-phenyloxaz

Full text of DOI:10.1081/SCC-120012984

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AN IMPROVED METHOD FOR THE SYNTHESIS OF 3-
AMINO-1H-QUINOLIN-2-ONE
a
a
b
Cecilia Juárez-Gordiano , Alicia Hernández-Campos, & Rafael Castillo
a
Departamento de Farmacia, Facultad de Química UNAM, CU, México, DF 04510, México
b
Departamento de Farmacia, Facultad de Química UNAM, CU, México, DF 04510, México
Published online: 16 Aug 2006.
To cite this article: Cecilia Juárez-Gordiano , Alicia Hernández-Campos, & Rafael Castillo (2002): AN IMPROVED METHOD
FOR THE SYNTHESIS OF 3-AMINO-1H-QUINOLIN-2-ONE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:19, 2959-2963
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 19, pp. 2959–2963, 2002
AN IMPROVED METHOD FOR
THE SYNTHESIS OF
3
-AMINO-1H-QUINOLIN-2-ONE
Cecilia Jua
´
´
rez-Gordiano, Alicia Hernandez-Campos,
and Rafael Castillo*
Departamento de Farmacia, Facultad de Quı
´
´
mica
UNAM, CU. Mexico DF 04510, Mexico
´
ABSTRACT
An efficient method for the synthesis of 3-amino-1H-quinolin-
-one is described. Condensation of o-nitrobenzaldehyde with
hippuric acid gave 4-(2-nitrobenzylidene)-2-phenyloxazol-
-one. This compound was reduced to give 4-(2-aminobenzy-
2
5
lidene)-2-phenyloxazol-5-one, which upon isomerization with
light, cyclization and hydrolysis afforded the desired product.
Key Words: 3-Amino-1H-quinolines; Synthesis; Photochem-
ical isomerization
The considerable biological importance of quinolone derivatives, such
[1]
[2]
as antibacterial activity and, more recently, antiviral activity has stimu-
lated work on these heterocycles. This is the case of 3-amino-1H-quinolin-
2-one (6). As part of our studies to prepare new agents with potential
antiviral activity we were in need of 6; however, there are no general
methods available for its preparation in good yields.
*
Corresponding author. Fax: þ(525)6225329; E-mail: rafaelc@servidor.unam.mx
959
2
DOI: 10.1081/SCC-120012984
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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´
JUAREZ-GORDIANO, HERNANDEZ-CAMPOS, AND CASTILLO
´
2
960
One approach reported is based on the condensation of 2-amino-
benzaldehyde with a-nitromethylenecarbonyl compounds with a subsequent
cyclization and reduction of the nitro group to give 6. However, this method
[3]
gives very poor yields. In another approach, the condensation of 2-nitro-
benzaldehyde with aceturic acid gave a mixture of cis and trans 2-methyl-4-
(
2-nitrobenzylidene)oxazol-2-one, which upon separation, reduction of the
[
4]
cis isomer, cyclization, and hydrolysis gave 6 in low yield. The synthesis of
has also been achieved via a Curtius rearrangement; nevertheless, this
6
[
5]
method involves a multistep process giving low yields of 6. And finally,
was obtained by the reduction of methyl anthranilate, followed by
6
oxidation of the corresponding alcohol. Condensation of this with ethyl
nitroacetate gave 3-nitroquinolone, which upon hydrogenation afforded
[6]
the product.
In this paper we describe a short and efficient synthesis of 3-amino-
H-quinolin-2-one according to reaction Sch. 1.
1
The condensation of o-nitrobenzaldehyde (1) and hippuric acid (2) in
ꢀ
acetic anhydride containing pyridine as a base at 75 C gave a 91% yield of
4-(2-nitrobenzylidene)-2-phenyloxazol-5-one (3). Catalytic reduction of 3
with H , Pd/C 5% for 15 min afforded a 93% yield of a red crystalline
2
material identified as 4-(2-aminobenzylidene)-2-phenyloxazol-5-one (4). Its
1
H NMR spectrum showed a broad signal at 6.23 ppm because of the NH2
group. When the hydrogenation time increased to 30 min, 3-benzamido-
3,4-dihydro-1H-quinolin-2-one (7) was obtained. These results support the
idea that the geometry of 4 and 3 is trans in such a way that the reacting
carbonyl and amino groups are on opposite sides of the double bond; for
this reason 5 was not obtained directly under these conditions. Later on, 4
was isomerized and cyclized upon irradiation with a 250-Watt G.E.
sunlamp in acetone as a solvent. In this reaction, the product was
ꢀ
Scheme 1. (a) Ac
5
2
O, pyridine, 75 C; (b) H
%, ethanol, 30 min; (d) Light, acetone; (e) NaOH–H O/EtOH, 80 C.
2
, Pd/C 5%, ethanol, 15 min; (c) H
ꢀ
2
, Pd/C
2

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3
-AMINO-1H-QUINOLIN-2-ONE
2961
3-benzamido-1H-quinolin-2-one (5), which precipitated as soon as it was
formed in 80% yield. Finally, 5 was hydrolyzed in EtOH/H O with NaOH
2
ꢀ
at 80 C for 48 h to afford 6 in 92% yield. All compounds obtained had IR,
1
H NMR, MS spectra and elemental analysis, which are consistent with
the expected structures.
In conclusion, in this communication an efficient method is described
for the synthesis of 6 in only four steps, each of which with good yields. The
important feature of this work is the high selectivity in the condensation
reaction where only one isomer is formed, and not a mixture of isomeric
[
4]
oxazolones, as described in the case of aceturic acid. The catalytic hydro-
genation of 3 was also selective, since only the nitro group was reduced in
preference to the exocyclic double bond. Each reaction step in the synthesis
is simple to carry out, affording good product yields, which are higher than
those previously reported in the literature.
EXPERIMENTAL
Melting points were determined with a Buchi 530 model apparatus
and are uncorrected. IR spectra were taken on a Perkin Elmer spectrometer.
1
H NMR spectra were recorded on a Varian VXR-300 spectrometer, using
TMS as internal standard. Mass spectra (MS) were performed by EI, 70 eV,
using a Hewlett Packard apparatus, model 5988.
4-(2-Nitrobenzylidene)-2-phenyloxazol-5-one (3): A mixture of 1
25.00 g, 0.1654 mol), 2 (36.00 g, 0.2009 mol), acetic anhydride (31.61 mL)
and pyridine (13.54 mL) was stirred for 15 min at 75 C and a dark brown
solid was formed. The mixture was filtered, and the residue was washed with
ethanol. The crude product was purified by recrystallization from toluene to
(
ꢀ
ꢀ
give 44.33 g (0.1506 mol, 91.05%) of yellow crystals, m.p. 162–164 C.
0
1
H NMR (CDCl ): ꢀ 8.68 (dd, J ¼ 7.80 and 1.20 Hz, 1H, H-6 ), 8.18–8.10
3
0
0
0
(
and 1.50 Hz, 1H, H-4 ), 7.61 (s, 1H, H-benzylic), 7.71–7.56 (4H, m, H-2 , 3 ,
m, 2H, H-4 , 5 ), 8.06 (dd, J ¼ 8.40 and 1.20 Hz, 1H, H-3 ), 7.81 (td, J ¼ 7.65
0
0
0
0
0
0
00
00
À1
5
MS: m/z 294 (M , 17%), 105 (100%); Anal. Calcd: C, 65.31; H, 3.43;
, 6 ); IR (KBr): 1850 (C¼O), 1798 (C¼N) 1514 and 1334 (NO ) cm
;
2
þ
N, 9.52. Found: C, 65.27; H, 3.18; N, 9.49.
4-(2-Aminobenzylidene)-2-phenyloxazol-5-one (4): A mixture of 3
15.00 g, 0.0510 mol), ethyl acetate (200 mL) and 5% Pd/C (1.50 g) was
(
hydrogenated (60 psi) in a Parr hydrogenation apparatus for 15 min at
room temperature. The resulting solution was filtered and the solvent,
evaporated. The residue was recrystallized from toluene to give 12.60 g
ꢀ
0.0477 mol, 93.53%) of red crystals, m.p. 172–173 C. H NMR (CDCl ):
3
1
(

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´
JUAREZ-GORDIANO, HERNANDEZ-CAMPOS, AND CASTILLO
´
2
962
0
ꢀ
2
(
8.18 (dd, J ¼ 8.10 and 1.50 Hz, 1H, H-6 ), 8.08 (dd, J ¼ 7.70 and 1.50 Hz,
00
00
00
00
00
H, H-2 , 6 ), 7.75–7.51 (m, 3H, H-3 , 4 , 5 ), 7.47 (s, 1H, H-benzylic), 7.16
0
td, J ¼ 7.72 and 1.50 Hz, 1H, H-5 ), 6.75 (dd, J ¼ 7.90 and 1.20 Hz, 1H,
0
0
H-3 ), 6.65 (td, J ¼ 7.80 and 1.20 Hz, 1H, H-4 ), 6.23 (s, 2H, NH ); IR
2
À1
(
2
KBr): 3402 and 3334 (NH ), 1770 (C¼O), 1646 (C¼N) cm ; MS: m/z
2
þ
64 (M , 100%), 105 (5%); Anal. Calcd: C, 72.72; H, 4.58; N, 10.60.
Found: C, 72.76; H, 4.11; N, 10.18.
-Benzamido-1H-quinolin-2-one
.0378 mol) was suspended in acetone (200 mL) and the mixture was stir-
3
(5):
Compound
4
(10.00 g,
0
red and irradiated with a 250-Watt G.E. sunlamp for 3 days. During this
time red crystals were formed. The mixture was filtered and the residue
was washed with acetone and recrystallized from ethanol to give 8.00 g
ꢀ
0.0303 mol, 80.16%) of 5, m.p. 271–273 C. H NMR: (CDCl –DMSO-d ):
3 6
1
(
ꢀ
12.36 (s, 1H, NH, benzamide), 9.36 (s, 1H, NH quinolone), 8.72 (s, 1H,
0
0
H-4), 7.91 (dd, J ¼ 7.50 and 1.80 Hz, 2H, H-2 , 6 ), 7.64–7.48 (m, 4H, H-5,
0
0
0
H-3 , 4 , 5 ), 7.40–7.31 (m, 2H, H-6, 7), 7.16–7.27 (m, 1H, H-8); IR (KBr):
À1
þ
3
370 (NH), 1682 (C¼O), 1644 (C¼O) cm ; MS: m/z 264 (M , 65%), 78
(
100%); Anal. Calcd: C, 72.72; H, 4.58; N, 10.60. Found: C, 72.28; H,
4.44; N, 10.49.
3-Amino-1H-quinolin-2-one (6): To a solution of NaOH (11.00 g,
.275 mol) in water (59 mL) and ethanol (35 mL) was slowly added 5
6.60 g, 0.0250 mol) and the resulting mixture was stirred at 80 C for 48 h.
0
(
ꢀ
After cooling, water (100 mL) was added and the mixture was extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium sulfate.
Evaporation of the solvent under vacuum gave 3.70 g, (0.0231 mol, 92.40%)
ꢀ
[4,5]
ꢀ
1
of a light yellow solid, m.p. 208–209 C, [lit.
210–211 C]. H NMR
(
(
(
CDCl –DMSO-d ): ꢀ 11.79 (s, 1H, NH), 7.32 (d, J ¼ 7.50, 1H, H-5), 7.19
3
6
d, J ¼ 7.80, 1H, H-8), 7.11 (t, J ¼ 7.50 and 1.50 Hz, 1H, H-7), 7.02
t, J ¼ 7.20 and 1.50 Hz, 1H, H-6), 6.72 (s, 1H, H-4), 5.44 (s, 2H, NH );
2
þ
À1
IR (KBr): 3440 and 3334 (NH ), 1668 (C¼O) cm ; MS: m/z 160 (M ,
2
1
00%), 133 (64%), 105 (41%); Anal. Calcd: C, 67.49; H, 5.03; N, 17.49.
Found: C, 67.11; H, 5.00; N, 17.22.
-Benzamido-3,4-dihydro-1H-quinolin-2-one (7): A mixture of
16.00 g, 0.0544 mol), ethyl acetate (200 mL) and 5% Pd/C (1.50 g) was
shaken under hydrogen (60 psi) in a Parr hydrogenation apparatus for
0 min at room temperature. The catalyst was removed by filtration and
the product crystallized spontaneously in the filtrate to give 11.50 g,
3
3
(
3
ꢀ
1
(
0.0432 mol, 79.41%) of 7, m.p. 166–167 C. H NMR (CDCl ): ꢀ 10.2
3
(
s, 1H, NH quinolone), 8.07 (d, J ¼ 6.60 Hz, 1H, NH benzamide), 7.91
0
0
0
(
dd, J ¼ 6.60 and 1.50 Hz, 2H, H-5, 8), 7.57–7.41 (m, 3H, H-3 , 4 , 5 ),
0
0
7
3
.22–7.12 (m, 2H, 2 , 6 ), 7.01–6.91 (m, 2H, H-6, 7), 4.83–4.71 (m, 1H, H-
), 3.39–3.28 (m, 2H, CH ); IR (KBr): 3300 (NH), 1692 (C¼O) cm ; MS:
À1
2

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3
-AMINO-1H-QUINOLIN-2-ONE
2963
þ
m/z 266 (M , 1%), 145 (100%); Anal. Calcd: C, 72.16; H, 5.30; N, 10.52.
Found: C, 71.88; H, 5.14; N, 10.40.
ACKNOWLEDGMENTS
We are very grateful to Dr. Joseph Muchowski for critical review of
the manuscript. We thank Georgina Duarte, Margarita Guzman, Graciela
Chavez, Maricela Gutierrez, Federico Garcıa and Rosa I. Del Villar for
´ ´ ´
1
recording MS, IR, and H NMR spectra. This work was supported in
part by CONACyT and DGAPA IN204998.
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Received in the USA October 4, 2001

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