Chemoselective synthesis of quinoline N-oxides from 3-(2-nitrophenyl)-3- hydroxypropanones

Article abstract of DOI:10.1002/jhet.485

The reaction of 3-(2-nitrophenyl)-3-hydroxypropanones with Zn/NH ₄Cl gave the corresponding quinoline N-oxides in 80-90% yields. The reaction initiated the reduction of nitro group to afford the corresponding hydroxylamine, which intramolecularly condensed and followed by dehydration to give quinoline N-oxide. Although treatment of 2-nitrochalcone with Zn/NH ₄Cl in EtOH/H₂O resulted in the formation of quinoline N-oxide in low yield, the reaction of 2-nitrochalcone with Sn/NH₄Cl in refluxing EtOH/H₂O afforded quinoline N-oxide in 80% yield.

Full text of DOI:10.1002/jhet.485

1372
Chemoselective Synthesis of Quinoline N-Oxides from
3-(2-Nitrophenyl)-3-hydroxypropanones
Vol 47
Kentaro Okuma,* Jun-ichi Seto, Noriyoshi Nagahora,
and Kosei Shioji
Department of Chemistry, Faculty of Science, Fukuoka University, Jonan-ku,
Fukuoka 814-0180, Japan
*E-mail: kokuma@fukuoka-u.ac.jp
Received January 20, 2010
DOI 10.1002/jhet.485
Published online 25 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of 3-(2-nitrophenyl)-3-hydroxypropanones with Zn/NH4Cl gave the corresponding quino-
line N-oxides in 80–90% yields. The reaction initiated the reduction of nitro group to afford the corre-
sponding hydroxylamine, which intramolecularly condensed and followed by dehydration to give
quinoline N-oxide. Although treatment of 2-nitrochalcone with Zn/NH4Cl in EtOH/H2O resulted in the
formation of quinoline N-oxide in low yield, the reaction of 2-nitrochalcone with Sn/NH4Cl in refluxing
EtOH/H2O afforded quinoline N-oxide in 80% yield.
J. Heterocyclic Chem., 47, 1372 (2010).
INTRODUCTION
RESULTS AND DISCUSSION
Quinoline ring framework can be found in many
synthetic and natural compounds of biological impor-
tance. Especially, quinoline N-oxides (1) are important
compounds because of their biological activity [1].
The quinoline N-oxide core unit has been found in
drugs exerting microsomal Na, K-ATPase [2], antiviral
[3], or antimalarian activities [4]. The synthetic
method of quinoline N-oxide mainly devoted to the
oxidation of the corresponding quinolines, which were
synthesized from 2-aminochalcones or 2-nitrochalcones
and Sn/HCl or with Pd/C hydrogenation and cycliza-
tion [5]. We have also reported the synthesis of qui-
nolines by the reaction of 2-aminochalcones with NIS
or I2 [6]. Direct palladium-catalyzed arylation of quin-
oline N-oxides to 2-arylquinoline N-oxides was
recently reported [7]. Although Baylis-Hilman adducts
reacted with trifluoroacetic acid to give 3,4-substituted
quinoline N-oxides in 49–82% yields [8], there are
few reports on the direct synthesis of quinoline N-
oxides from chalcones or 3-hydroxy ketones, which
afforded mixtures of quinolines and quinoline N-
oxides [9]. These results prompted us to investigate
the direct synthesis of quinoline N-oxides from 3-
hydroxy ketones (2) or 2-nitrochalcones. Herein, we
would like to report a direct synthesis of quinoline N-
oxides from easily available 3-hydroxy ketones 2 and
2-nitrochalcones.
3-Hydroxy ketones 2 were synthesized by the reaction
of 2-nitrobenzaldehydes (3) and acetophenones (4) in
the presence of sodium carbonate by the method
recently described by Wang et al. [10] (Scheme 1).
We first tried the metal mediated reductive cyclization
of 3-hydroxy-3-(2-nitrophenyl)-1-phenylpropan-1-one 2a
whether 2-phenylquinoline N-oxide 1a or 2-phenylqui-
noline 5a would be formed. The results were shown in
Table 1. Treatment of 2a with Sn/HCl resulted in the
formation of N-oxide 1a and 5a in 26 and 60% yields,
respectively (entry 1). When Zn/HCl was allowed to
react with ketone 2a, N-oxide 1a was obtained in 46%
yield (entry 2). When Sn/NH4Cl was treated with 2a at
60ꢀC for 12 h, N-oxide 1a and quinoline 5a were
obtained in 7 and 6% yields, respectively (entry 4).
Finally, when Zn/NH4Cl was used as reducing reagents
at 60ꢀC, N-oxide 1a was exclusively obtained in 85%
yield (entry 6).
As the optimum conditions (4 equiv Zn/ 3 equiv of
NH4Cl, EtOH/H2O, 60ꢀC) were determined, we then
tried other 3-hydroxy ketones 2 to investigate the scope
and limitation of this method. Treatment of 3-hydroxy-
3-(2-nitrophenyl)-1-p-tolylpropan-1-one (2b) with Zn/
NH4Cl in EtOH/H2O resulted in the formation of 2-(p-
tolyl)quinoline N-oxide (1b) in 90% yield (entry 2).
When methyl, methoxy, or chloro groups were substi-
tuted on aromatic ring (ketones 2c–e), the corresponding
C
V
2010 HeteroCorporation

November 2010
Chemoselective Synthesis of Quinoline N-Oxides from
3-(2-Nitrophenyl)-3-hydroxypropanones
1373
Scheme 1
N-oxides 1c–e were obtained in high yields (entries
2–6). Naphthyl substituted ketone 2g also afforded 2-
naphtylquinoline N-oxide 1g (entry 7). Interestingly,
4-hydroxy-4-(2-nitrophenyl)butan-2-one 2j also reduced
and cyclized to afford 2-methylquinoline N-oxide (1j) in
86% yield (entry 10). Other quinolines were obtained in
high yields (Table 2). Thus, general synthesis of
N-oxides 1 from easily available 3-hydroxy ketones 2
under mild conditions was achieved.
starting quinoline N-oxides were required. The present
method requires shorter reaction time (5–6 h) and rela-
tively lower temperature (60ꢀC).
We then tried the reductive cyclization of 2-nitrochal-
cone (7a) whether N-oxide 1a would be exclusively
formed. Previously, Barros et al. [9] have reported the
reductive cyclization of 2-nitrochalcones with SnCl2/
HCl, which led to the mixtures of 2-substituted quino-
line N-oxides 1 and quinolines 5 in moderate yields. To
the best of our knowledge, only one report on the practi-
cal synthesis of N-oxide 1 from chalcone 7 was
appeared, whereas yields were low [11]. Thus, the
method of exclusive formation of N-oxides 1 from 7
must be required. When chalcone 7a was treated with
Sn/HCl at RT for 1 h, quinoline 5a was isolated in 80%
yield (Table 3, entry 1). Treatment of chalcone 7a, Pd/C
(0.1 equiv), and H2 gas in ethanol (5 h), followed by
refluxing for 13 h resulted in the formation of quinoline
The reaction might proceed as follows: 3-hydroxy ke-
tone 2a was reduced by Zn/NH4Cl to give hydroxyla-
mine 6a which was easily cyclized under these condi-
tions and dehydrated to give quinoline N-oxide 1a
(Scheme 2).
The present method has some advantage over direct
Pd-catalyzed arylation of quinoline N-oxides [7], which
requires Pd(OAc)2 as a catalyst and refluxing toluene
for 16 h in 55–91% yields. Additionally, 3 equiv of
Table 1
Reaction of 2a with metal and acid.
Entry
Metal (eq)
Acid (eq)
Temperature (ꢀC)
Time (h)
1a Yield (%)
5a Yield (%)
1
2
3
4
5
6
7
Sn (3)
Zn (3)
Fe (3)
Sn (3)
Sn (3)
Zn (4)
Fe (5)
HCl (4)
HCl (4)
HCl (4)
NH4Cl (3)
NH4Cl (3)
NH4Cl (3)
NH4Cl (3)
60
RT
1
18
12
12
2
26
46
61
7
60
0a
RT
60
14
6b
20c
0
Reflux
60
Reflux
40
85
0
5
24
0d
a Starting 2a was recovered in 36% yield.
b Starting 2a was recovered in 69% yield.
c Starting 2a was recovered in 25% yield.
d Starting 2a was recovered in 90% yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 2
Reductive cyclization of 2-hydroxy ketones 2.
Entry
1
Substrate
Time (h)
Product
Yield (%)
85
2a
2b
5
1a
1b
2
6
90
3
4
5
2c
2d
2e
6
6
6
1c
1d
1e
88
90
89
6
2f
5
1f
82
7
8
2g
2h
5
5
1g
1h
80
89
9
10
11
2i
2j
4
5
5
1i
1j
89
86
85
2k
1k

November 2010
Chemoselective Synthesis of Quinoline N-Oxides from
3-(2-Nitrophenyl)-3-hydroxypropanones
1375
Scheme 2. Reaction mechanism.
carbonyl moiety at trans position of hydroxylamine 8a
prevent intramolecular cyclization, part of which further
reduced to give aniline 9a, then cyclized to afford quin-
oline 5a (entries 1–4). On the other hand, by using Sn/
NH4Cl, which have lower reducing ability than Sn/HCl,
as reducing reagents, target quinoline N-oxides 1a were
obtained in acceptable yields, while careful tuning of
the reaction time must be required (Scheme 3). Com-
pared to the reductive cyclization of 3-hydroxy ketones
2 (Table 2), the reduction of 2-nitrochalcones required
prolonged reaction time.
In summary, we have synthesized 2-substituted quino-
line N-oxides by one-pot process from 3-hydroxylpropa-
nones or 2-nitrochalcones. This procedure provides a
general synthesis of quinoline N-oxides from easily
available 3-hydroxypropanones or 2-nitrochalcones.
5a in 78% yield (entry 4). In both case, no quinoline N-
oxide 1a was obtained. When Zn/NH4Cl was treated
with 7a at 60ꢀC, N-oxide 1a was obtained in 21% yield
along with 15% of starting chalcone 7a (entry 5). When
the reaction was carried in refluxing ethanol for 24 h by
using Sn/NH4Cl as a reducing reagent, N-oxide 1a and
quinoline 5a were obtained in 80% and 4% yields,
respectively (entry 8). Prolonged heating resulted in the
further reduction of 1a–5a (entries 9–10). Other substi-
tuted nitrochalcones 7b–d also afforded quinoline N-
oxides 1 in good yields, however, small amount of start-
ing chalcones 7b–d were still remained unreacted
(entries 11–13).
EXPERIMENTAL
General. All chemicals were obtained from commercial
suppliers and were used without further purification. Analytical
TLC was carried out on precoated plates (Merck silica gel 60,
F254) and flash column chromatography was performed with
silica (Merck, 70-230 mesh). NMR spectra (1H at 400 MHz;
13C at 100 MHz) were recorded in CDCl3, and chemical shifts
are expressed in ppm relative to internal TMS (d ¼ 0.00) and
CDCl3 (d ¼ 77.00) for 1H- and 13C-NMR. Melting points
were uncorrected.
By using metal/HCl as reducing reagents, 2-nitrochal-
chone 7a was reduced to give hydroxylamine 8a. Since
Table 3
Hydroamination of 2-nitrochalcones with metal.
Yield (%)
Entry
R
Metal (equiv)
Acid
Temperature (ꢀC)
Time (h)
1
5
1
2
3
Ph
Ph
Ph
Sn (3)
Zn (3)
Fe (3)
HCl
HCl
HCl
–
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
Rt
Rt
Rt
1
4
24
18
4
0
80
42
0
0
0
4
5
Ph
Ph
Pd/C (0.1)
Zn (3)
Sn (3)
Sn (3)
Sn (3)
Sn (3)
Sn (3)
Sn (3)
Sn (3)
Sn (3)
reflux
60
60
reflux
reflux
reflux
reflux
reflux
reflux
reflux
0
78
3
21
20
75a
80
78
0
82b
80c
82d
6
7
Ph
Ph
28
20
26
33
72
24
22
24
0
0
8
Ph
Ph
Ph
4
9
12
87
0
10
11
12
13
4-MeC6H4
4-ClC6H4
1-naphtyl
0
0
a Starting chalcone 7a was recovered in 5% yield.
b 1-(4-Methylphenyl)-3-(2-nitrophenyl)-2-en-1-one 7b was recovered in 4% yield.
c 1-(4-Chlorophenyl)-3-(2-ntrophenyl)-2-en-1-one 7c was recovered in 3% yield.
d 1-Naphtyl-3-(2-nitrophenyl)prop-2-en-1-one 7d was recovered in 4% yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1376
K. Okuma, J.-I. Seto, N. Nagahora, and K. Shioji
Vol 47
Scheme 3
7.46 (ddd, J ¼ 7.7, 7.6, 1.2 Hz, 1H), 7.40 (ddd, J ¼ 7.5, 7.5,
1.2 Hz, 1H), 7.28–7.23 (m, 2H), 5.8 4(dd, J ¼ 9.3, 2.0 Hz,
1H), 4.00 (br 1H), 3.64 (dd, J ¼ 17.6, 2.0 Hz, 1H), 3.15 (dd, J
¼ 17.6, 9.3 Hz, 1H), 2.56(s, 3H). 13C-NMR (CDCl3) d ¼
203.9, 147.5, 139.1, 138.9, 137.0, 134.0, 132.4, 132.3, 129.2,
128.6, 128.5, 126.1, 124.7, 66.4, 49.2, 21.8. Calcd for
C16H15NO4 (-H2O); C, 71.90; H, 4.90; N, 5.24. Anal Found;
C, 71.84; H, 5.12; N, 5.11.
3-Hydroxy-1-(4-metoxyphenyl)-3-(2-nitrophenyl)propan-1-
one (2e). Yield: 66%, pale yellow crystals, mp 128–129ꢀC
(ref. [12] mp 128–129ꢀC). 1H-NMR (CDCl3) d ¼ 8.00–7.93
(m, 4H), 7.69 (ddd, J ¼ 7.6, 7.6, 1.2 Hz, 1H), 7.46 (ddd, J ¼
7.6, 7.8, 1.4 Hz, 1H), 6.96 (d, J ¼ 8.1 Hz, 2H), 5.83 (dd, J ¼
9.4, 2.4 Hz, 1H), 4.20 (d, J ¼ 2.6 Hz, 1H), 3.88 (s, 3H), 3.70
(d, J ¼ 17.4, 2.4 Hz, 1H), 3.14 (dd, J ¼ 17.4, 9.4 Hz, 1H).
13C-NMR (CDCl3) d ¼ 198.8, 164.4, 147.6, 138.9, 134.0,
130.9(2C), 129.6, 128.7, 128.5, 124.6, 114.1(2C), 66.4, 55.8,
46.1.
1-(4-Chlorophenyl)-3-hydroxy-3-(2-nitrophenyl)propan-1-
one (2f). Yield: 74%, deep green crystals, mp 92–93ꢀC. 1H-
NMR (CDCl3) d ¼ 7.99 (dd, J ¼ 8.1, 1.2 Hz, 1H), 7.98 (dd, J
¼ 7.6, 1.4 Hz, 1H), 7.92 (d, J ¼ 8.8 Hz, 2H), 7.70 (ddd, J ¼
7.6, 7.6, 1.2 Hz, 1H), 7.49–7.43 (m, 3H), 5.85 (dd, J ¼ 9.3,
2.2 Hz, 1H), 3.87 (d, J ¼ 3.0 Hz, 1H), 3.68 (dd, J ¼ 17.6, 2.2
Hz, 1H,) 3.19 (dd, J ¼ 9.3, 17.6 Hz, 1H). 13C-NMR (CDCl3)
d ¼ 198.8, 147.5, 140.6, 138.7, 134.9, 134.1, 129.9(2C),
129.3(2C), 128.6, 128.6, 124.7, 66.1, 46.8. Calcd for
C15H12ClNO4; C, 58.93; H, 3.96; N, 4.58. Anal. Found; C,
58.69; H, 4.11; N, 4.52.
3-Hydroxy-1-naphthyl-3-(2-nitrophenyl)propan-1-one
(2g). Yield: 61%, greenish brown oil, 1H-NMR(CDCl3) d ¼
8.73 (d, J ¼ 8.6 Hz, 1H), 8.03–7.98 (m, 3H), 7.94 (dd, J ¼
7.2, 1.2 Hz, 1H), 7.89 (dd, J ¼ 8.2, 1.4 Hz, 1H), 7.74 (ddd,
J ¼ 7.6, 7.5, 1.4 Hz, 1H), 7.64 (ddd, J ¼ 7.6, 7.6, 1.4 Hz,
1H), 7.57 (ddd, J ¼ 8.2, 8.2, 1.2 Hz, 1H), 7.51–7.44 (m, 2H),
5.94 (dd, J ¼ 9.3, 2.2 Hz, 1H), 4.04 (d, J ¼ 3.1 Hz, 1H), 3.82
(dd, J ¼ 17.5, 2.2 Hz, 1H), 3.31 (dd, J ¼ 175, 9.3 Hz, 1H).
13C-NMR (CDCl3) d ¼ 204.1, 147.5, 138.9, 134.9, 134.2,
134.1, 133.8, 130.4, 128.8, 128.8, 128.7, 128.6, 128.5, 126.9,
125.9, 124.7, 124.6, 66.7, 49.8. Calcd for C19H15ClNO4
(þH2O); C, 67.25; H, 5.05; N, 4.13. Anal Found; C, 67.49; H,
4.77; N, 4.04.
Materials. Benzaldehydes 3a–3b and ketones 4a–4j were
purchased from TCI and Aldrich. Zn powder (<50 nm) was
purchased from Aldrich. Sn powder (200 mesh) was purchased
from Wako.
Preparation of 3-hydroxy-3-(2-nitrophenyl)-1-phenylpro-
pan-1-one (2a). To a solution of acetophenone (1.20 g, 10.0
mmol) and sodium carbonate (0.55 g, 5.2 mmol) in water (60
mL) was added a solution of 2-nitrobenzaldehyde (1.51 g, 10.0
mmol) in ethanol (15 mL) in dropwise. After stirring for 17 h
at RT, the reaction mixture was extracted with dichlorome-
thane (10 mL ꢁ 3). The combined extract was dried over so-
dium sulfate, filtered, and evaporated to give brown solid,
which was chromatographed over silica gel by elution with
hexane-ethyl acetate (5:1) to afford green crystals of 2a (1.95
g, 7.2 mmol). mp 106–107ꢀC (ref. [11] mp 106–107ꢀC). 1H-
NMR (CDCl3) d ¼ 8.00–7.96 (m, 4H), 7.71 (dd, J ¼ 8.0, 7.4
Hz, 1H), 7.60 (t, J ¼ 7.4, 1.2 Hz, 1H), 7.45–7.50 (m 3H), 5.86
(dd, J ¼ 9.3, 2.4 Hz, 1H), 4.01 (d, J ¼ 3.1 Hz, 1H), 3.73 (dd,
J ¼ 17.7, 2.4 Hz, 1H), 3.22 (dd, J ¼ 17.7, 9.3 Hz, 1H). 13C-
NMR (CDCl3) d ¼ 200.2, 147.5, 138.8, 138.6, 136.6, 134.1,
134.0, 129.0(2C), 128.7, 128.5(2C), 128.4, 124.7, 66.2, 46.7.
Other reactions were carried out in a similar manner.
3-Hydroxy-1-(4-methylphenyl)-3-(2-nitrophenyl)propan-1-
one (2b). Yield: 72%. Deep green crystals. mp 70–71ꢀC. 1H-
NMR (CDCl3) d ¼ 7.97–8.00 (m, 2H), 7.86 (d, J ¼ 7.9 Hz,
2H), 7.69 (dd, J ¼ 7.6, 7.6 Hz, 1H), 7.46 (dd, J ¼ 7.8, 7.6 Hz,
1H), 7.27 (d, J ¼ 7.9 Hz, 2H), 5.84 (dd, J ¼ 9.4, 2.4 Hz, 1H),
4.06 (br, 1H), 3.71 (dd, J ¼ 17.6, 2.4 Hz, 1H), 3.17 (dd, J ¼
17.6, 9.4 Hz, 1H). 13C-NMR (CDCl3) d ¼ 199.9, 147.5, 145.1,
138.9, 134.1, 134.0, 129.7, 128.7(2C), 128.6(2C), 128.5, 124.7,
66.2, 46.5, 22.0. Calcd for C16H15NO4; C, 67.36; H, 5.30; N,
4.91. Anal Found; C, 67.38; H, 5.36; N, 4.92.
1-(5-Bromo-2-hydroxyphenyl)-3-hydroxy-3-(2-nitrophe-
nyl)propan-1-one (2h). Yield: 74%, purple crystals, mp 92–
1
93ꢀC. H-NMR (CDCl3) d ¼ 11.9 (s, 1H), 8.02 (dd, J ¼ 7.9,
1.4 Hz, 1H), 7.98 (d, J ¼ 7.9, 1.3 Hz, 1H), 7.79 (d, J ¼ 2.4
Hz, 1H), 7.73 (ddd, J ¼ 7.9, 7.8, 1.3 Hz, 1H), 7.57 (dd, J ¼
8.9, 2.4 Hz, 1H), 7.50 (ddd, J ¼ 7.9, 7.8, 1.4 Hz, 1H), 6.93 (d,
J ¼ 8.9 Hz, 1H), 5.90 (dd, J ¼ 9.2, 2.1 Hz, 1H), 3.66 (dd,
J ¼ 17.8, 2.1 Hz, 1H), 3.41(br, 1H), 3.30(dd, J ¼ 17.8, 9.2
Hz, 1H). 13C-NMR (CDCl3) d ¼ 204.7, 161.7, 147.4, 139.8,
138.4, 134.3, 132.4, 128.9, 128.6, 124.8, 120.9, 120.6, 111.0,
65.5, 46.9. Calcd for C15H12NO3; C, 67.25; H, 5.05; N, 4.13.
Anal. Found; C, 67.49; H, 4.77; N, 4.04.
3-Hydroxy-1-(3-methylphenyl)-3-(2-nitrophenyl)propan-1-
1
one (2c). Yield: 57%. Deep green oil. H-NMR (CDCl3) d ¼
8.00–7.98 (m, 2H), 7.78–7.75 (m, 2H), 7.70 (ddd, J ¼ 7.6, 7.6,
1.2 Hz, 1H), 7.47 (ddd, J ¼ 7.8, 7.6, 1.4 Hz, 1H), 7.41 (d, J ¼
7.6 Hz, 1H), 7.36 (dd, J ¼ 7.6, 7.5 Hz, 1H), 5.86 (dd, J ¼ 9.3,
2.2 Hz, 1H), 4.04 (br, 1H), 3.73 (dd, J ¼ 17.6, 2.2 Hz, 1H),
3.20 (dd, J ¼ 17.6, 9.3 Hz, 1H), 2.41(s, 3H). 13C-NMR
(CDCl3) d ¼ 191.0, 148.8, 143.0, 138.8, 137.7, 134.2, 133.9,
131.6, 130.6, 129.6, 129.5, 128.8, 127.8, 126.2, 25.2, 21.6.
Calcd for C16H15NO4(-H2O); C, 71.90; H, 4.90; N, 5.24. Anal
Found; C, 71.76; H, 5.12; N, 5.12.
2-Bromo-3-hydroxy-3-(2-nitrophenyl)-1-phenylpropan-1-
one (2i). Yield: 52%, colorless crystals, mp 103–104ꢀC. 1H-
NMR (CDCl3) d ¼ 8.06 (d, J ¼ 8.2 Hz, 1H), 7.94 (d, J ¼ 7.2
Hz, 2H), 7.87 (d, J ¼ 7.9 Hz, 1H), 7.67 (dd, J ¼ 8.2, 7.6 Hz,
1H), 7.55 (dd, J ¼ 7.9, 7.6 Hz, 1H), 7.45–7.40 (m, 3H), 5.02
(d, J ¼ 5.0 Hz, 1H), 4.83 (d, J ¼ 5.0 Hz, 1H). 13C-NMR
(CDCl3) d ¼ 191.4, 147.4, 135.2, 134.3, 134.2, 130.3, 129.8,
3-Hydroxy-1-(2-methylphenyl)-3-(2-nitrophenyl)propan-1-
one (2d). Yield: 68%, greenish brown crystals, mp 55–56ꢀC.
1H-NMR (CDCl3) d ¼ 8.00–7.96 (m, 2H), 7.72–7.66 (m, 2H),
Journal of Heterocyclic Chemistry
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Chemoselective Synthesis of Quinoline N-Oxides from
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1377
129.5, 129.0(2C), 128.5(2C), 124.9, 60.3, 58.1. Anal. Calcd for
C15H12NO3 (-HBr); C, 66.91; H, 4.12; N, 5.20. Found; C,
66.84; H, 4.38; N,5.24.
Hz, 2H), 7.85 (d, J ¼ 8.2 Hz, 1H), 7.77 (dd, J ¼ 8.2, 7.8 Hz,
1H ), 7.73 (d, J ¼ 9.0 Hz, 1H), 7.62 (dd J ¼ 8.4, 7.8 Hz, 1H),
7.50 (d, J ¼ 8.4 Hz, 1H), 7.33 (d, J ¼ 8.2 Hz, 2H), 2.43 (s,
3H). 13C-NMR (CDCl3) d ¼ 145.4, 142.5, 139.9, 130.8, 129.9,
129.7(2C), 129.7(2C), 129.2, 128.5, 128.2, 125.5, 123.5, 120.5,
21.7.
4-Hydroxy-4-(2-nitrophenyl)butan-2-one (2j). Yield: 66%,
yellow crystals, mp 55–56ꢀC (ref. [13] mp 52–55ꢀC). 1H-
NMR (CDCl3) d ¼ 7.91 (d, J ¼ 7.9 Hz, 1H), 7.68 (dd, J ¼
7.9, 7.7 Hz, 1H), 7.45 (dd, J ¼ 8.1, 7.7 Hz, 1H), 5.69 (dd, J ¼
9.4, 2.0 Hz, 1H), 3.15 (dd, J ¼ 17.8, 2.0 Hz, 1H), 2.73 (dd, J
¼ 17.8, 9.4 Hz, 1H), 2.24(s, 3H). 13C-NMR (CDCl3) d ¼
209.1, 147.4, 138.6, 134.1, 128.5, 128.4, 124.7, 65.9, 51.3,
30.7.
3-Hydroxy-3-(b-nitrobenzo[1,3]dioxol-5-yl)-1-phenylpro-
pan-1-one (2k). Yield: 50%, pale yellow crystals, mp 96–
97ꢀC. 1H-NMR(CDCl3) d ¼ 7.96 (d, J ¼ 7.4 Hz, 2H), 7.60
(dd, J ¼ 7.4, 7.4 Hz, 1H), 7.54 (s, 1H), 7.48 (dd, J ¼ 7.4, 7.4
Hz, 2H), 7.43 (s, 1H), 6.13 (s, 2H), 5.88 (dd, J ¼ 9.2, 2.0 Hz,
1H), 4.03 (d, J ¼ 2.2 Hz, 1H), 3.72 (dd, J ¼ 17.6, 2.0 Hz,
1H), 3.11 (dd, J ¼ 17.6, 9.2 Hz, 1H). 13C-NMR (CDCl3) d ¼
200.3, 152.9, 147.4, 141.3, 136.8, 136.6, 134.0, 129.0(2C),
128.5(2C), 107.4, 105.4, 103.2, 66.4, 46.7. Anal. Calcd for
C16H13NO6; C, 60.95; H, 4.16; N, 4.44. Found; C, 60.67; H,
4.36; N, 4.40.
Reductive cyclization of 2a by using tin and hydrochloric
acid. To a solution of 2a (0.136 g, 0.5 mmol) and conc HCl
(0.17 mL, 0.20 mmol) in EtOH (12 mL) was added Sn powder
(0.178 g, 1.5 mmol) in one portion. After being stirred for 1h
at 60ꢀC, the reaction mixture was evaporated, washed with
water, and extracted with CH2Cl2 (5 mL ꢁ 3). The combined
extract was dried over sodium sulfate, filtered, and evaporated
to give pale green oily solid, which was chromatographed over
silica gel by elution with dichloromethane to afford 2-phenyl-
quinoline N-oxide 1a (0.029 g, 0.13 mmol) and 2-phenylquino-
line 5a (0.062 g, 0.30 mmol). mp 79–80ꢀC (ref. [1] mp 78–
79ꢀC).
2-(3-Methylphenyl)quinoline N-oxide (1c). Yield: 88%, or-
1
ange crystals, mp 110–111ꢀC. H-NMR (CDCl3) d ¼ 8.87 (d,
J ¼ 8.8 Hz, 1H), 7.88–7.62 (m, 5H), 7.64 (dd, J ¼ 7.5, 7.5
Hz, 1H), 7.50 (d, J ¼ 8.7 Hz, 1H ), 7.42 (dd J ¼ 7.6, 7.6 Hz,
1H), 7.29 (d, J ¼ 7.6 Hz, 1H), 2.45(s, 3H). 13C-NMR (CDCl3)
d ¼ 145.5, 142.6, 138.2, 133.7, 130.8, 130.5, 130.3, 129.8,
128.6, 128.5, 128.2, 126.9, 125.3, 123.7, 120.6, 21.7. Anal.
Calcd for C13H15NO4; C, 81.86; H, 5.57; N, 5.95. Found; C,
81.52; H, 5.41; N, 5.78.
2-(2-Methylphenyl)quinoline N-oxide (1d). Yield: 90%, or-
ange crystals, mp 109–110ꢀC (ref. [7] mp 103–104ꢀC).1H-
NMR (CDCl3) d ¼ 8.85 (d, J ¼ 8.7 Hz, 1H), 7.90 (d, J ¼ 8.1
Hz, 1H), 7.82–7.71 (m, 2H), 7.66 (dd, J ¼ 8.1, 8.1 Hz, 1H ),
7.43–7.29 (m, 5H), 7.62 (dd, J ¼ 7.8, 7.8 Hz, 1H), 2.27 (s,
3H). 13C-NMR (CDCl3) d ¼ 146.7, 142.0, 137.7, 133.9, 130.4,
130.1, 129.9, 129.3, 129.1, 128.4, 128.0, 125.9, 124.6, 123.8,
120.3, 19.7.
2-(4-Methoxylphenyl)quinoline N-oxide (1e). Yield: 89%,
pale yellow crystals, mp 123–124ꢀC (ref. [7] mp 125–126ꢀC).
1H-NMR (CDCl3) d ¼ 8.86 (d, J ¼ 8.8 Hz, 1H), 8.03 (d, J ¼
9.0 Hz, 2H), 7.86 (d, J ¼ 8.0 Hz, 1H), 7.78 (ddd, J ¼ 8.0, 8.0,
1.4 Hz, 1H), 7.74 (d, J ¼ 8.4 Hz, 1H), 7.63 (ddd J ¼ 8.4, 8.0,
1.2 Hz, 1H), 7.53 (d, J ¼ 8.8 Hz, 1H), 7.05 (d, J ¼ 9.0 Hz,
2H), 3.89(s, 3H). 13C-NMR (CDCl3) d ¼ 160.7, 144.9, 142.5,
131.5(2C), 130.7, 129.5, 128.4, 128.1, 125.9, 125.4, 123.3,
120.4, 113.9(2C), 55.6.
2-(4-Chlorophenyl)quinoline N-oxide (1f). Yield: 82%,
greenish yellow crystals mp 170–171ꢀC. 1H-NMR (CDCl3) d
¼ 8.84 (d, J ¼ 8.8 Hz, 1H), 7.98–7.94 (m, 2H), 7.88 (d, J ¼
8.4 Hz, 1H), 7.80 (dd, J ¼ 8.2, 7.8 Hz, 1H), 7.76 (d, J ¼ 8.8
Hz, 1H), 7.66 (dd, J ¼ 7.8, 7.8 Hz, 1H), 7.52–7.48 (m, 3H).
13C-NMR (CDCl3) d ¼ 144.1, 142.6, 135.8, 132.1, 131.2(2C),
131.0, 129.9, 128.9, 128.8(2C), 128.3, 125.6, 123.1, 120.5.
Anal. Calcd for C15H10ClNO4; C, 70.46; H, 3.94; N, 5.48.
Found; C, 70.51; H, 4.18; N, 5.53.
2-Phenylquinoline N-oxide 1a: yield: 89%, pale yellow crys-
1
tals, mp 74–75ꢀC (ref. [14] mp 76ꢀC). H-NMR (CDCl3) d ¼
8.87 (d, J ¼ 8.8 Hz, 1H), 7.98 (d, J ¼ 7.9 Hz, 2H), 7.87 (d, J
¼ 7.8 Hz, 1H), 7.80–7.75 (m 2H), 7.65 (dd, J ¼ 7.6, 7.4 Hz,
1H), 7.55–7.45 (m 4H). 13C-NMR (CDCl3) d ¼ 144.9, 142.2,
133.5, 130.5, 129.6(2C), 129.5, 129.5, 128.4(2C), 128.3, 128.0,
125.2, 123.3, 120.2.
Reductive cyclization of 2j by using zinc and ammonium
chloride. To a solution of 4-hydroxy-4-(2-nitropohenyl)-2-
butanone 2j (0.142 g, 0.50 mmol) and ammonium chloride
(0.080 g, 1.5 mmol) in ethanol-water (1:1, 40 mL) was added
zinc powder (0.098 g, 1.5 mmol) in one portion. After stirring
for 6 h at 60ꢀC, the reaction mixture was poured into water
(20 mL), and extracted with dichloromethane (10 mL ꢁ 3).
The combined extract was dried over sodium sulfate, filtered,
and evaporated to give pale yellow solid, which was recrystal-
lized from methanol to afford 2-methylquinoline N-oxide 1j
(0.094 g, 0.43 mmol) colorless crystals. mp 54–55ꢀC (ref. [15]
mp 76ꢀC). 1H-NMR (CDCl3) d ¼ 8.80 (d, J ¼ 8.6 Hz, 1H),
7.84 (d, J ¼ 7.8 Hz, 1H), 7.76 (dd, J ¼ 8.6, 8.2 Hz, 1H), 7.66
(d, J ¼ 8.6 Hz, 1H), 7.60 (dd J ¼ 8.6, 8.2 Hz, 1H), 7.33 (d, J
¼ 7.8 Hz, 1H), 2.73 (s, 3H). 13C-NMR (CDCl3) d ¼ 146.0,
141.8, 130.5, 129.4, 128.2, 128.0, 125.4, 123.2, 119.8, 19.0.
Other reactions were carried out in a similar manner.
2-(1-Naphthyl)quinoline N-oxide (1g). Yield: 80%, color-
less crystals, mp 168–169ꢀC (ref. [7] mp 168–169ꢀC). 1H-
NMR (CDCl3) d ¼ 8.88 (d, J ¼ 9.3 Hz, 1H), 8.02–7.91 (m,
3H), 7.85–7.77 (m, 2H), 7.69(ddd, J ¼ 8.1, 6.8 and 1.2 Hz,
1H ), 7.60(d, J ¼ 5.6 Hz, 2H), 7.60(d, J ¼ 5.6 Hz 2H), 7.55–
7.41(m, 4H). 13C-NMR (CDCl3) d ¼ 145.6, 142.1, 133.4,
132.1, 130.7, 130.5, 130.1, 129.9, 128.6, 128.6, 128.1, 127.7,
126.9, 126.2, 125.4, 125.4, 124.7, 124.5, 20.4.
2-(5-Bromo-2-hydroxyphenyl)-quinoline N-oxide (1h). Yield:
89%, pale yellow crystals, mp 167–168ꢀC (ref. [9] mp 167–
168ꢀC). 1H-NMR (CDCl3) d ¼ 11.30 (s, 1H, OH), 8.91 (d, J
¼ 8.8 Hz, 1H), 8.00 (d, J ¼ 8.8 Hz, 1H), 7.96 (d, J ¼ 8.2 Hz,
1H), 7.92 (dd J ¼ 8.5, 7.9 Hz, 1H), 7.75 (dd, J ¼ 8.2, 7.9 Hz,
1H), 7.67 (d, J ¼ 8.5 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J ¼ 8.8
Hz, 1H), 7.05 (d, J ¼ 8.8 Hz, 1H). 13C-NMR (CDCl3) d ¼
159.4, 147.5, 141.1, 135.3, 133.6, 132.2, 129.9, 129.4, 129.2,
128.3, 124.2, 123.5, 122.7, 120.3, 112.0.
2-(4-Methylphenyl)quinoline N-oxide (1b). Yield: 90%, or-
ange crystals, mp 112–113ꢀC (ref. [7] mp 127–128ꢀC). 1H-
NMR (CDCl3) d ¼ 8.86 (d, J ¼ 9.0 Hz, 1H), 7.90 (d, J ¼ 8.2
3-Bromo-2-phenylquinoline N-oxide (1i). Yield: 89%, yel-
low crystals mp 124–125ꢀC (ref. [16] mp 125–127ꢀC). 1H-
NMR (CDCl3) d ¼ 8.64 (d, J ¼ 7.2 Hz, 1H), 7.70 (d, J ¼ 7.6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1378
K. Okuma, J.-I. Seto, N. Nagahora, and K. Shioji
Vol 47
Hz, 1H), 7.60–7.52 (m, 4H), 7.52 (dd, J ¼ 7.8, 7.8 Hz, 2H),
7.44 (dd, J ¼ 7.4, 7.2 Hz, 1H), 7.27 (s, 1H). 13C-NMR
(CDCl3) d ¼ 130.1(2C), 129.9, 129.8, 129.7, 129.0, 128.7(2C),
128.6, 128.2, 128.0, 127.6, 127.1, 120.0, 111.3.
1f (0.115 g, 0.40 mmol): mp 170–171ꢀC. 2-Naphtylquinoline
N-oxide 1g (0.124 g, 0.41 mmol): mp 168–169ꢀC.
6-Phenyl-[1,3]dioxolo[4,5-g]quinoline N-oxide (1k). Yield:
85%, pale yellow crystals, mp 224–225ꢀC. 1H-NMR (CDCl3)
d ¼ 8.22 (s, 1H), 7.91 (dd, J ¼ 8.2, 1.2 Hz, 2H), 7.58 (d, J ¼
8.6 Hz, 1H), 7.52–7.44 (m, 3H), 7.35 (d, J ¼ 8.6 Hz, 1H),
7.09 (s, 1H), 6.17 (s, 2H). 13C-NMR (CDCl3) d ¼ 152.2,
149.5, 133.9, 129.8(2C), 129.5, 129.4, 128.7, 128.4(2C), 127.0,
124.7, 121.9, 103.4, 102.6, 98.5. Anal. Calcd for C16H11NO3;
C, 72.45; H, 4.18; N, 5.28. Found; C, 72.28; H, 4.43; N, 5.27.
Reductive cyclization of 2-nitrochalcone with Sn/HCl. To
a solution of 2-nitrochalchone 7a (0.253 g, 1.0 mmol) and
conc. HCl (0.33 mL, 4.0 mmol) in EtOH (15 mL) was added
Sn powder (0.356 g, 3.0 mmol) in one portion. After stirring
for 1h at RT, the reaction mixture was evaporated to afford
dark solid, which was extracted with EtOAc (5 mL ꢁ 3), dried
over sodium sulfate, filtered, and evaporated to afford yellow
solid. Chromatographic separation of the solid (SiO2, EtOA-
c:hexane ¼ 1:1) gave 2-phenylquinoline 5a (0.164 g, 0.80
mmol).
Reductive cyclization of 2-nitrochalcone with Pd/C. To a
solution of 2-nitrochalcone 7a (0.253 g, 1.0 mmol) in EtOH
(15 mL) was added Pd/C (10%, 0.053 g, 0.05 mmol) in one
portion. After stirring for 3 h under hydrogen atmosphere, the
reaction mixture was refluxed for 8h, and evaporated to give
dark brown oily crystals, which was chromatographed over
silica gel by elution with EtOAc:Hexane (1:5) to give 5a
(0.160 g, 0.78 mmol).
Reductive cyclization of 2-nitrochalcone with Sn/
NH4Cl. To a solution of 2-nitrochalcone 7a (0.127 g, 0.50
mmol) and ammonium chloride (0.080 g, 1.5 mmol) in etha-
nol-water (1:1, 40 mL) was added tin powder (0.178 g, 1.5
mmol) in one portion. After refluxing for 26 h, the reaction
mixture was poured into water (20 mL), and extracted with
dichloromethane (10 mL ꢁ 3). The combined extract was
dried over sodium sulfate, filtered, and evaporated to give pale
yellow crystals, which was chromatographed over silica gel to
afford 2-phenyllquinoline N-oxide 1a (0.088 g, 0.40 mmol)
and 2-phenylquinoline 5a (0.004 g, 0.02 mmol).
REFERENCES AND NOTES
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Other reactions were carried out in a similar manner.
2-(4-Methylphenyl)quinoline N-oxide 1b (0.109 g, 0.41
mmol): mp 112–113ꢀC. 2-(4-Chlorophenyl)quinoline N-oxide
[15] Bjorsvik, H. -R.; Gambarotti, C.; Jensen, V. R.; Gonzalez,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet