Reactive 2-quinolones dearomatized by steric repulsion between 1-methyl and 8-substituted groups

Article abstract of DOI:10.1016/j.tet.2013.04.008

Usual 1-methyl-2-quinolone (MeQone) derivatives are not reactive because of aromatic property in the heterocyclic ring. On the other hand, 8-substituted MeQones have been proved to be highly reactive, which is caused by steric repulsion between the 1-meth

Full text of DOI:10.1016/j.tet.2013.04.008

Accepted Manuscript
Reactive 2-Quinolones Dearomatized by Steric Repulsion between 1-Methyl and 8-
Substited Groups
Xin Chen, Kazuya Kobiro, Haruyasu Asahara, Kiyomi Kakiuchi, Ryuichi Sugimoto,
Kazuhiko Saigo, Nagatoshi Nishiwaki
PII:
S0040-4020(13)00520-6
10.1016/j.tet.2013.04.008
TET 24208
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 November 2012
Revised Date: 31 March 2013
Accepted Date: 2 April 2013
Please cite this article as: Chen X, Kobiro K, Asahara H, Kakiuchi K, Sugimoto R, Saigo K, Nishiwaki N,
Reactive 2-Quinolones Dearomatized by Steric Repulsion between 1-Methyl and 8-Substited Groups,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.04.008.
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ACCEPTED MANUSCRIPT
Reactive 2-Quinolones Dearomatized by Steric Repulsion between
1
-Methyl and 8-Substited Groups
†
†
†
‡
†
Xin Chen, Kazuya Kobiro, Haruyasu Asahara, Kiyomi Kakiuchi, Ryuichi Sugimoto,
†
,†
Kazuhiko Saigo, and Nagatoshi Nishiwaki*
†
School of Environmental Science and Engineering, Kochi University of Technology,
Miyanokuchi, Tosayamada, Kami, Kochi 782-8502, Japan
‡
Graduate School of Materials Science, Nara Institute of Science and Technology,
Takayama, Ikoma, Nara 630-0192, Japan
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
TEL: +81-887-57-2517
FAX: +81-887-57-2520

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Table of Contents
CN
CN
N
R1
NO2
O
R1
H
O
-
HNO2
N1
R2 Me
8
cine-Substitution
R2 Me
1
2
R , R = Me or NO
2
Abstract
Usual 1-methyl-2-quinolone (MeQone) derivatives are not reactive because of aromatic
property in the heterocyclic ring. On the other hand, 8-substituted MeQones have been
proved to be highly reactive, which is caused by steric repulsion between the 1-methyl and
the 8-substituted groups. When 1-methyl-3,6,8-trinitro-2-quinolone was treated with
potassium (or trimethylsilyl) cyanide, cyanation proceeded at the 4-position
regioselectively as a result of cine-substitution. This reaction is initiated with addition of
cyanide species, and the cyanoquinolone is formed by the protonation of the resultant
anionic intermediate followed by elimination of nitrous acid. The high reactivity was
maintained even when one of the nitro groups on the benzene moiety was replaced by a
methyl group, which afforded corresponding cine-substituted products upon treatment with
potassium cyanide.

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Introduction
A Rutaceae family, commonly known as Citrus, reveals high commercial value because
of wide consumption in the world. The family is quite large, including approximately 160
genera and 1900 species with great diversity in morphological characters. The Rutaceae
family plays an important role to supply extraordinary array of phytochemicals such as
1
limonoids, flavonoids, coumarins, alkaloids, volatile oils, and so on. Furthermore,
quinolone alkaloids have been extensively studied by using various synthetic techniques,
2
and various medicinal properties have been reported, such as antitumor activity,
3
4
5
antianemia activity, antikinetoplastid activity, antimicrobial activity, antibacterial
6
7
8
activity, dipeptidyl peptidase IV inhibition, chymase inhibition, and so on.
The 1-methyl-2-quinolone (MeQone) framework is a fundamental partial structure of
these biologically active compounds. Naturally occurring MeQone derivatives have
attracted many researchers’ interest, and their isolations, structural determinations, total
syntheses, and modifications have been important subjects over the past decades. In
addition, unnatural MeQone derivatives have also attracted much attention recently
because of their latent pharmacological and physiological activities. However, the
functionalization of the MeQone skeleton is not easily performed due to the aromatic

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property of the pyridone moiety; the development of facile methods for the
9
functionalization of the MeQone framework is still challenging.
On the other hand, we have found that 1-methyl-3,6,8-trinitro-2-quinolone (1) exhibited
extraordinary high reactivity compared with other MeQone derivatives. Indeed, the
functionalization of the MeQone framework was easily performed by cine-substitution or
1
0
cycloaddition. Among three nitro groups, the 8-nitro group was found to be essential for
the activation of the quinolone 1. The cine-substitution proceeded efficiently to afford
4
2
-functionalized 6,8-dinitro-2-quinolone (3) upon treatment of the quinolone 1 with
1
1
,4-pentanedione (2) in the presence of triethylamine at room temperature. To the
contrary, 1-methyl-3,6-dinitro-2-quinolone (4) caused no change even at an elevated
1
2
temperature (Scheme 1). The quite different reactivity between the quinolones 1 and 4
cannot be rationalized by only electron-withdrawing effect of the 8-nitro group, because it
is far from the reaction site (the 4-position). Hence, we suppose the high reactivity of the
quinolone 1 is caused by steric repulsion between the 1-methyl and the 8-nitro groups, by
which the coplanarity of the pyridone moiety and the benzene ring is disturbed. Indeed,
8
X-ray analysis indicated that the dihedral angle between the N -Me and C -R bonds was
1
8
o
o 12
2
5 (Figure 1) while the corresponding angle of 4 was 0.9 . As a result of disturbing the

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coplanarity, the pyridone moiety serves as an activated nitroalkene rather than an aromatic
1
3
species. This hypothesis prompted us to study the sterical activation of the MeQone
framework sterically by a substituent at the 8-position.
Scheme 1. cine-Substitution of Nitrated 1-Methyl-2-quinolones with 2,4-Pentanedione
OH
O
4
O N
NO2
O
O N
2
H
O
2
O
O
O
O
NEt3
+
+
N 1
MeCN, rt
N
8
O N Me
O N Me
2
2
1
2
2
3 (88%)
4
O N
2
NO2
O
NEt3
No reaction
N 1
8
MeCN, reflux
H
Me
4

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1
2
Figure 1. ORTEP (30% probability ellipsoids) view of the quinolone 1.
Results and Discussion
1
. Prediction of Steric Distortion by DFT Calculation
In order to predict the reactivity of MeQone derivatives, the dihedral angles between the
8
8
N -Me and C -R bonds were estimated by DFT calculations (Table 1). When the R group
1
8
at the 8-position is hydrogen (Compound 4), the benzene and pyridone moieties are almost
coplanar. On the other hand, when the 8-position is substituted by a methyl or nitro group
(5 and 6), the 2-quinolone ring is torsionally strained by the steric compression of the
1
-methyl and 8-methyl/nitro groups. As a result, 1,6-dimethyl-3,8-dinitro-2-quinolone (5)

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and 1,8-dimethyl-3,6-dinitro-2-quinolone (6) are considered to surely reveal high reactivity
as well as the trinitroquinolone 1.
8
Table 1. Dihedral Angles between the N -Me and C -R Bonds
1
8
R6
R6
NO2
O
R8
θ
Me
N
O
N
R8 Me
NO2
6
8
a
Compound
R
R
Dihedral angles θ
o
1
4
5
6
NO
NO
Me
NO
2
NO
2
2
29.0
o
H
1.5
2
o
NO
Me
29.2
o
30.9
2
a
Estimated by DFT calculations using B3LYP/6-31+G (d,p)
2
. Preparation of Nitroquinolones
Firstly, synthetic methods for the nitrated dimethyl-2-quinolones 5 and 6 were studied
1
4
(
Scheme 2). The starting dimethyl-2-quinolones, 1,6-dimethyl-2-quinolone (8) and
1
4
1
,8-dimethyl-2-quinolone (13), were prepared from the commercially available
methylquinolines 7 and 12 according to the synthetic method reported for
1
5a
1
-methyl-2-quinolone. In fact, when 1,6-dimethyl-2-quinolone (8) was nitrated, the nitro

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groups were mainly introduced at the 5 and 7-positions as well as at the 3-position, in
which the electro-donating 6-methyl group serves as an ortho-directing group.
Thus, 1,6-dimethyl-3,5,7-trinitro-2-quinolone (9), 1,6-dimethyl-5,7-dinitro-2-quinolone
(10), and 1,6-dimethyl-3,5-dinitro-2-quinolone (11) were obtained without any detection of
the desired 3,8-dinitroquinolone 5.
In the case of the nitration of 1,8-dimethyl-2-quinolone (13), 8-methyl group served as a
stronger ortho, para-directing group than the acylamino group (the ring nitrogen) to afford
1
,8-dimethyl-3,5,7-trinitro-2-quinolone (14), 1,8-dimethyl-3,5-dinitro-2-quinolone (15) as
the products. In the present reaction, the acylamino group also served as a para-directing
group to give the desired 1,8-dimethyl-3,6-dinitro-2-quinolone (6) in 28% yield.

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Scheme 2. Preparation of Dimethyl-dinitro-2-quinolones
Me
Me
1) Me SO4
H SO /HNO
2 4 3
2
2
) K [Fe(CN) ]
NaOH aq.
o
3
6
N
Me
O
50 C, 1 d
N
7
8 (84%)
NO2
NO2
NO2
Me
O N
NO2
O
Me
+
Me
NO2
O
+
N
O N
2
N
O
N
2
Me
Me
Me
9
(16%)
10 (21%)
11 (45%)
1
) Me SO4
H SO /HNO
2 4 3
2
2
) K [Fe(CN) ]
NaOH aq.
o
3
6
50 C, 1 d
N
N
O
Me
Me Me
12
13 (85%)
NO2
NO2
NO2
NO2 O N
NO2
2
+
+
O N
2
N
O
N
O
N
O
Me Me
Me Me
Me Me
14 (27%)
15 (40%)
6 (28%)
3
. cine-Substitution Using 2,4-Pentanedione (2)
The obtained nitroquinolones 9, 14, 15, and 6 were subjected to the reactions with
,4-pentanedione (2) in the presence of triethylamine. While the 3,6,8-trinitroquinolone 1
2
efficiently underwent the cine-substitution, neither trinitroquinolones 9 nor 14 caused no

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reaction (Table 2, entries 1-3) under the same conditions. In the case of the dinitroquinolone
1
5, the corresponding product 18 was not detected (entry 4).
Table 2. cine-Substitution of Nitro-1,8-dimethyl-2-quinolones with 2,4-Pentanedione
OH
O
R5
R5
R6
R7
NO2
O
R6
R7
H
O
O
O
NEt (1.5 equiv.)
3
+
MeCN, rt, 1 d
N
N
R8 Me
R8 Me
(1.2 equiv.)
5
6
7
8
Entry
R
H
R
R
R
Nitroquinolone
Product Yield/%
1
2
3
4
5
NO2
Me
H
H
NO2
NO2
H
NO2
H
1
9
3
16
17
18
19
88
0
NO2
NO2
NO2
H
Me
Me
Me
14
15
6
0
H
0
NO2
H
92
It is noteworthy that cine-substitution efficiently proceeded to afford 19 in 92% yield
when the substrate 6 was employed, which has only two nitro groups (entry 5). This
experimental fact strongly supports our hypothesis; the steric repulsion between two methyl
groups activates the MeQone framework. However, the quinolones 14 and 15 did not
undergo the cine-substitution despite the presence of a methyl group at the 8-position, in

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5
which the peri-substituent (R ) might prevent the approach of the bulky enolate of 2 to the
4
-position.
4
. Cyanation of the Trinitroquinolone 1
In order to estimate the activating effect of the steric repulsion between the substituents
at the 1- and 8-positions, it is necessary to employ a small nucleophile instead of a bulky
enolate of 2 to avoid the steric hindrance of a substituent at the 5-position. From this
viewpoint, cyanide was employed as a nucleophile. When a solution of potassium cyanide
in methanol was added to a solution of the quinolone 1 in acetonitrile, and heated at 60 °C
for 2 hours, a complex mixture was obtained, from which two products, the
4
-cyano-2-quinolone derivative 21 and the dimeric product 22 were isolated.

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Scheme 3. A Plausible Reaction Mechanism for the Formation of 21 and 22
NO2
Nu
O N
H
O
2
Nu
N
MeO
Nu
H
O N
2
N
NO2
H
H
O N
2
O N Me
2
NO2
O
NO2
4
FDNQ
O N Me
2
N
O
(
Nu = CN, 21)
O N Me
2
route
a'
route
a
Me
N
Nu
H OMe
O
NO2
H
Nu
route
b
O N
2
NO2
O N
2
NO2
O N
2
NC
H
H
N
O
O N
N
O
2
NO2
NO2
NO2
O N Me
2
O N Me
2
N
O
1
O
2
0
O N
N
O N Me
2
2
Me
O
O N
2
Me
CN
N
N
O N
2
NO2
2
NO2
O
O N Me
2
NO2
22
A plausible mechanism for the formation of these products is illustrated in Scheme 3.
The reaction is initiated with the nucleophilic attack of cyanide (Nu = CN) at the 4-position
of the quinolone 1. The cyanoquinolone 21 is afforded when the resultant anion 20 is
protonated, followed by the elimination of a nitrous acid molecule (Scheme 3, route a).
Another route is also acceptable, which involves a proton migration followed by

ACCEPTED MANUSCRIPT
elimination of nitrite anion (route a’). On the other hand, the dimeric product 22 is formed
when the intermediate anion 20 attacks another molecule of the quinolone 1, and the
pyridone moieties aromatize accompanied by the elimination of nitrous acid molecules
(route b). Although this kind of dimerization was observed in the reaction of the quinolone
1
6
1
with tertiary amines, this is the first example to isolate a dimer in the reaction with
C-nucleophiles. The strongly electron-withdrawing ability of the carbonyl and nitro groups
is considered to stabilize the anionic intermediate 20.
The reaction conditions were optimized as shown in Table 3. The reaction temperature
was found to be a crucial factor for the present reaction. When the temperature was lowered
to 0 °C, the total yield of 21 and 22 increased up to 94% (the yield of 21 was increased up
to 80%), accompanied with the simplification of the reaction mixture (entries 2-4). On the
other hand, a longer reaction time did not affect the yields of 21 and 22 (entry 5). Next, the
control of the reaction routes (routes a and b) was attempted by changing the volume of the
solvent. When the reaction was conducted under concentrated conditions, many signals
other than those of 21 and 22 were observed in the reaction mixture without considerable
change in the ratio of 21/22 (entry 6). Moreover, dilution was not so effective for avoiding
the dimerization (entry 7). The solvent effect for the reaction was also investigated; when

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H O was employed as the solvent for dissolving potassium cyanide, many by-products
2
were observed (entry 8). Hence, methanol was found to be a more suitable solvent
dissoluble of potassium cyanide, which was somewhat influential for inhibiting the side
reactions during the whole reaction process.
Table 3. Optimization of Reaction Conditions
δ 7.31
δ 9.27
O
H
δ 7.89
H
Me
CN
CN
N
O N
NO2
2
O N
2
H
O
O N
NO2
2
+
KCN
+
N
O
MeCN/
MeOH (2 mL)
N
N
O
O N
Me
2
0
.5 mmol
O N
2
Me
O N
Me
NO2
2
1
(0.5 mmol)
2
1
22
Temp.
°C
Solv.
Time
Yield/%
Total
Recovery
Entry
/
/mL
20
20
20
20
20
10
50
20
/h
2
2
2
2
4
2
2
2
21
63
73
80
78
69
71
62
73
22
9
yield/%
72
of 1/%
1
2
3
4
5
6
7
60
rt
7
7
7
80
0
14
10
9
94
6
-20
0
88
11
6
78
0
7
78
9
0
7
69
8
b
8
0
14
87
9
a
1
b
Determined by H NMR based on 1. H O was used as the solvent in order to completely
2
dissolve KCN.

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Finally, in order to investigate the cation effect of cyanide compounds, trimethylsilyl
cyanide/cesium fluoride was employed instead of potassium cyanide. To our expectation,
the formation of the dimer 22 was not observed, and the yield of 21 dramatically increased
up to 90%, when the reaction was conducted at room temperature for 1 d (Scheme 4). We
suppose that the anionic intermediate 20 is trapped by a trimethylsilyl group to afford a
stable enolate intermediate, which prevents the nucleophilic attack of the intermediate 20 to
another molecule of the quinolone 1.
Scheme 4. cine-Substitution of Quinolone 1 with Trimethylsilyl Cyanide
CN
MeCN (20 mL)/
O N
2
NO2
O N
2
H
O
H O (1 mL)
2
+
Me SiCN
3
N
O
CsF, rt, 1 d
N
0
.5 mmol
O N
2
Me
O N
2
Me
1
(0.5 mmol)
2
1 (90%)
1
7
While known cyanation methods require multi-step reactions, the present method
enables the cyanation through a shorter synthetic route, which will be a useful synthetic
tool for constructing a library of versatile MeQone derivatives by the chemical conversion
of the cyano and nitro functions.

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5
. Estimation of the Steric Activation Using the Cyanation
The cyanation reactions of nitrated 1,8-dimethyl-2-quinolones using potassium cyanide
were investigated because of smaller size than that of trimethylsilyl cyanide (Table 4).
Although the 3,5,7-trinitroquinolone 14 caused no change upon treatment with
2
,4-pentanedione (2), the reaction with potassium cyanide efficiently proceeded to afford
the cine-substituted product, 4-cyanoquinolone 23, in 83% yield (entry 2). The cyanation
also took place even when the 3,5-dinitroquinolone 15 was employed (entry 3).
Furthermore, the 3,6-dinitroquinolone 6 revealed high reactivity to undergo the
cine-substitution quantitatively (entry 4). These results strongly support our consideration
that the steric repulsion between 1-methyl and 8-methyl groups activated the MeQone by
disturbing the coplanarity (entries 3 and 4).

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Table 4. cine-Substitution of Nitro-1,8-dimethyl-2-quinolones with Potassium Cyanide
R5
R5 CN
MeCN/
MeOH (2 mL)
R6
R7
NO2
O
R6
R7
H
O
+
KCN
rt, 1 d
N
N
0
.5 mmol
R8 Me
R8 Me
0
.5 mmol
5
6
7
8
Entry
R
H
R
R
R
Nitroquinolone
Product
Yield/%
73
1
2
3
4
NO2
H
H
NO2
H
NO2
Me
Me
Me
1
14
15
6
3
NO2
NO2
H
23
24
25
83
H
47
NO2
H
quant.
Conclusion
We have developed a simple method for the cyanation of the 3-nitro-8-substituted
MeQones. When the 8-position was substituted with a nitro group, cine-substitution and
dimerization easily proceeded under mild reaction conditions to afford the cyanoquinolones
2
1 and 22. The reaction could be used for estimating the activation degree of the MeQone
framework. As a result, the presence of an 8-substituent was found to be crucial for causing
the cine-substitution, which activated the MeQone framework by steric repulsion with the
1
-methyl group. These results should be valuable information for the functionalization of
the MeQone framework by activating sterically, and are helpful for finding new
biologically active compounds.

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Experimental
General
The melting points were determined on a Yanaco micro-melting-points apparatus, and were
uncorrected. All the reagents and solvents were commercially available and used as
received. TLC was performed using Merck silica gel 60 F254, and column chromatography
1
was performed using silica gel 60 (Nacalai Tesque, spherical neutral, 150 µm). The H
NMR spectra were measured on a Bruker Ascend-400 at 400 MHz with TMS as an internal
1
3
standard. The C NMR spectra were measured on a Bruker Ascend-400 at 100 MHz, and
1
3
assignments of C NMR spectra were performed by DEPT experiments. The IR spectra
were recorded on a JASCO FT/IR-4200 spectrometer. The mass spectra and the high
resolution mass spectra were measured on a JEOL JMS-DX303HF or JEOL-JMS-700
MStation.
Nitration of 1,6-Dimethyl-2-quinolone
To cold 18 M H SO (11.1 mL, 200 mmol), the quinolone 8 (1.7 g, 10 mmol) was
2
4
gradually added and then 15 M HNO (23.3 mL, 350 mmol) was added gradually. The
3
resultant mixture was heated at 50 °C for 1 d. After cooling down to room temperature,
H O (30 mL) was poured into the reaction mixture. The generated yellow precipitate (2.6 g)
2

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was collected with filtration. Further purification was performed by recrystallization or
column chromatography on silica gel. The nitration of the 1,8-dimethyl-2-quinolone 13 was
conducted in a similar manner.
1
8
2
1
1
,6-Dimethyl-3,5,7-trinitroquinolin-2(1H)-one (9). Eluted with hexane/ethyl acetate =
1
/2; 493 mg, 16% yield; yellow solid; mp 189−191 °C; H NMR (400 MHz, DMSO-d ) δ
6
1
3
.42 (s, 3H), 3.40 (s, 3H), 8.53 (s, 1H), 8.68 (s, 1H); C NMR (100 MHz, DMSO-d ) δ
6
4.9 (CH ), 34.2 (CH ), 111.2 (C), 124.2 (C), 127.1 (CH), 131.7 (C), 131.7 (CH), 138.5 (C),
3
3
+
41.4 (C), 148.8 (C), 152.7 (CO); MS (EI, 70 eV) m/z = 308 (M , 3), 220 (25), 191 (36),
1
3
1
5
15 (100), 105 (55); HRMS (EI, magnetic field) Calcd for C H N O 308.0393, found
11
8
4
7
08.0393.
,6-Dimethyl-5,7-dinitroquinolin-2(1H)-one (10). Eluted with hexane/ethyl acetate = 7/3;
1
53 mg, 21% yield; yellow solid; mp 112−115 °C; H NMR (400 MHz, DMSO-d ) δ 2.37
6
1
3
(
s, 3H), 3.33 (s, 3H), 6.92 (d, J = 10.0 Hz, 1H), 7.74 (d, J = 10.0 Hz, 1H), 8.32 (s, 1H); C
NMR (100 MHz, DMSO-d ) δ 15.6 (CH ), 34.0 (CH ), 114.6 (C), 123.2 (C), 125.3 (CH),
6
3
3
1
29.7 (CH), 131.8 (CH), 132.3 (C), 139.3 (C), 149.2 (C), 160.8 (CO); MS (EI, 70 eV) m/z
+
=
263 (M , 100), 233 (30), 173 (45); HRMS (EI, magnetic field) Calcd for C H N O
11
9
3
5
2
63.0542, found 263.0542.

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1
,6-Dimethyl-3,5-dinitroquinolin-2(1H)-one (11). 1.18 g, 45% yield; yellow needles;
1
recrystallized from MeCN; mp 259−261 °C; H NMR (400 MHz, CD CN) δ 2.44 (s, 3H),
3
13
3
.78 (s, 3H), 7.72 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 8.31 (s, 1H); C NMR (100
MHz, DMSO-d ) δ 16.4 (CH ), 30.9 (CH ), 108.7 (C), 118.7 (CH), 124.8 (C), 128.3 (CH),
6
3
3
+
1
3
2
1
3
2
2
1
7
3
1
1
3
36.5 (CH), 139.2 (C), 142.1 (C), 148.2 (C), 152.9 (CO); MS (EI, 70 eV) m/z = 263 (M ,
8), 142 (41), 115 (57), 69 (100); HRMS (EI, magnetic field) Calcd for C H N O
5
11
9
3
63.0542, found 263.0537.
,8-Dimethyl-3,5,7-trinitroquinolin-2(1H)-one (14). Eluted with hexane/ethyl acetate =
1
/7; 862 mg, 27% yield; yellow solid; mp 188−190 °C; H NMR (400 MHz, DMSO-d ) δ
6
1
3
.85 (s, 3H), 3.82 (s, 3H), 8.53 (s, 1H), 8.60 (s, 1H); C NMR (100 MHz, DMSO-d ) δ
6
3.2 (CH ), 37.7 (CH ), 111.0 (C), 127.9 (CH), 131.3 (C), 131.6 (CH), 133.2 (C), 140.7 (C),
3
3
+
42.8 (C), 145.9 (C), 154.9 (CO); MS (EI, 70 eV) m/z = 308 (M , 10), 130 (29), 101 (32),
5 (46), 69 (100); HRMS (EI, magnetic field) Calcd for C H N O 308.0393, found
11
8
4
7
08.0395.
,8-Dimethyl-3,5-dinitroquinolin-2(1H)-one (15). Eluted with hexane/ethyl acetate = 3/7;
1
.05 g, 40% yield; yellow solid; mp 216−219 °C; H NMR (400 MHz, DMSO-d ) δ 2.84 (s,
6
1
3
H), 3.78 (s, 3H), 6.92 (d, J = 9.6 Hz, 1H), 7.66 (d, J = 9.6 Hz, 1H), 8.39 (s, 1H); C NMR

ACCEPTED MANUSCRIPT
(
100 MHz, DMSO-d ) δ 23.4 (CH ), 36.4 (CH ), 113.2 (C), 125.6 (CH), 129.5 (CH), 129.9
6
3
3
(C), 131.8 (C), 131.8 (CH), 140.0 (C), 146.0 (C), 162.1 (CO); MS (EI, 70 eV) m/z = 263
+
(
M , 100), 159 (28), 130 (20), 75 (17); HRMS (EI, magnetic field) Calcd for C H N O
11
9
3
5
2
1
7
63.0542, found 263.0541.
,8-Dimethyl-3,6-dinitroquinolin-2(1H)-one (6). Eluted with hexane/ethyl acetate = 7/3;
1
37 mg, 28% yield; yellow solid; mp 236−238 °C; H NMR (400 MHz, DMSO-d ) δ 2.84
6
1
3
(
s, 3H), 3.85 (s, 3H), 8.42 (d, J = 2.8 Hz, 1H), 8.80 (d, J = 2.8 Hz, 1H), 9.09 (s, 1H); C
NMR (100 MHz, DMSO-d ) δ 23.2 (CH ), 37.0 (CH ), 118.4 (C), 125.2 (CH), 128.4 (C),
6
3
3
1
31.1 (CH), 136. 7 (CH), 140.3 (C), 142.0 (C), 146.0 (C), 155.4 (CO); MS (EI, 70 eV) m/z
+
=
263 (M , 95), 210 (58), 193 (53), 142 (80), 117 (100); HRMS (EI, magnetic field) Calcd
for C H N O 263.0542, found 263.0541.
11
9
3
5
cine-Substitution Using 2,4-Pentanedione (2)
To a solution of 1,8-dimethyl-3,6-dinitro-2-quinolone (6, 132 mg, 0.5 mmol) and
2
,4-pentanedione (2, 61mg, 0.6 mmol) in acetonitrile (20 mL), 0.025 M solution of
triethylamine (30 mL, 0.75 mmol) was added at room temperature over 30 min and the
solution color turned to brown. The reaction mixture was stirred for a further 1 d. After
concentration, the reaction mixture was dissolved into CHCl (20 mL) and washed with
3

ACCEPTED MANUSCRIPT
H O (20 mL) to remove Et NHNO . The organic layer was dried over (MgSO ), and
2
3
2
4
concentrated to get residue. Then, the residue was purified by recrystallization with hexane
to afford cine-substituted product 19 (145 mg, 0.46 mmol, 92% yield).
(Z)-4-(2-Hydroxy-4-oxopent-2-en-3-yl)-1,8-dimethyl-6-nitroquinolin-2(1H)-one (19).
1
orange solid; mp 192−194 °C; H NMR (400 MHz, CDCl ) δ 1.90 (s, 6H), 2.85 (s, 3H),
3
3
.89 (s, 3H), 6.75 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 16.86 (s, 1H);
C NMR (100 MHz, CDCl ) δ 23.9 (2CH ), 24.3 (CH ), 37.1 (CH ), 109.0 (C), 120.2 (CH),
1
3
3
3
3
3
1
1
22.8 (C), 125.9 (CH), 127.2 (C), 129.6 (CH), 142.3 (C), 146.0 (C), 146.4 (C), 164.0 (CO),
+
90.7 (CO); MS (EI, 70 eV) m/z = 316 (M , 100), 263 (75); HRMS (EI, magnetic field)
Calcd for C H N O 316.1059, found 316.1062.
1
6
16
2
5
General Procedure for Synthesis of 21 and 22
1
5
To a solution of 1-methyl-3,6,8-trinitro-2-quinolone (1) (147 mg, 0.5 mmol) in
acetonitrile (20 mL) was added potassium cyanide (33 mg, 0.5 mmol) at 60 °C, and the
mixture was stirred for 2 h. Then, the solvent was evaporated in vacuo. The residue was
purified by column chromatography on silica gel to afford the cine-substituted product 21
(eluted with hexane/ethyl acetate = 7/3, 87 mg, 0.315 mmol, 63%) and the dimeric product

ACCEPTED MANUSCRIPT
2
2 (eluted with hexane/ethyl acetate = 1/1, 12 mg, 0.023 mmol, 9% based on 1),
respectively.
-Methyl-6,8-dinitro-2-oxo-1,2-dihydroquinoline-4-carbonitrile (21). Yellow powder;
1
−
1 1
mp 168−171 °C; IR (KBr) 2247 cm ; H NMR (400 MHz, DMSO-d ) δ 3.37 (s, 3H), 7.89
6
1
3
(
s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 9.07 (d, J = 2.4 Hz, 1H); C NMR (100 MHz, DMSO-d )
6
δ 34.8 (CH ), 113.6 (CN), 119.4 (C), 121.7 (C), 123.6 (CH), 124.7 (CH), 132.3 (CH), 137.2
3
+
(
C), 138.7 (C), 140.5 (C), 160.1 (CO); MS (EI, 70 eV) m/z = 274 (M , 68), 244 (100), 182
(
63), 127 (61); HRMS (EI, magnetic field) Calcd for C H N O 274.0338, found
11
6
4
5
2
1
74.0337.
,1'-Dimethyl-6,6',8,8'-tetranitro-2,2'-dioxo-1,1',2,2'-tetrahydro-3,4'-biquinoline-4
−
1
1
-
carbonitrile (22). Reddish brown oil; IR (KBr) 2240 cm ; H NMR (400 MHz,
DMSO-d ) δ 3.45 (s, 3H), 3.46 (s, 3H), 7.31 (s, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.81 (d, J =
6
13
2
.4 Hz, 1H), 8.97 (d, J = 2.4 Hz, 1H), 9.18 (d, J = 2.4 Hz, 1H); C NMR (100 MHz,
DMSO-d ) δ 34.9 (CH ), 35.5 (CH ), 112.8 (CN), 119.9 (C), 121.1 (C), 122.6 (C), 123.2
6
3
3
(CH), 124.1 (CH), 125.3 (CH), 125.8 (CH), 125.9 (CH), 136.9 (C), 137.4 (C), 137.5 (C),
1
38.7 (C), 138.9 (C), 140.7 (C), 140.8 (C), 142.7 (C), 159.6 (CO), 160.8 (CO); MS (EI, 70

ACCEPTED MANUSCRIPT
+
eV) m/z = 521 (M , 95), 491 (100); HRMS (EI, magnetic field) Calcd for C H N O
10
2
1
11
7
5
21.0567, found 521.0560.
Cyanation of Trinitroquinolone 1 using Trimethylsilyl Cyanide
1
7
To a solution of 1-methyl-3,6,8-trinitro-2-quinolone (1) (147 mg, 0.5 mmol) and
trimethylsilyl cyanide (50 mg, 05 mmol) in acetonitrile (20 mL), caesium fluoride (76 mg,
0
.5 mmol) in 1 mL H O was added at room temperature, and the mixture was stirred for 1 d
2
1
and concentrated. Then, the residue was detected by H NMR, and the yield of
cine-substituted product 21 was calculated with internal standard (Cl CHCHCl ).
2
2
Cyanation of Nitroquinolones using Potassium Cyanide
,8-Dimethyl-5,7-dinitro-2-oxo-1,2-dihydroquinoline-4-carbonitrile (23).
To a solution of 1,8-dimethyl-3,5,7-trinitro-2-quinolone (14, 154 mg, 0.5 mmol) in
1
acetonitrile (15 mL) was added potassium cyanide (33 mg, 0.5 mmol in 2 mL MeOH) at
room temperature, and the mixture was stirred for 1 d. Then, the reaction mixture was
filtrated, and the filtrate was concentrated under reduced pressure. The residue was
recrystallized with MeOH to afford cine-substituted product 23 (119 mg, 0.41 mmol, 83%
1
yield). Red solid; mp 221−223 °C; H NMR (400 MHz, DMSO-d ) δ 2.78 (s, 3H), 3.69 (s,
6
1
3
3
H), 7.86 (s, 1H), 8.50 (s, 1H); C NMR (100 MHz, DMSO-d ) δ 23.2 (CH ), 38.1 (CH ),
6 3 3

ACCEPTED MANUSCRIPT
1
1
08.3 (CN), 112.0 (C), 115.6 (C), 130.7 (CH), 131.0 (C), 133.6 (C), 136.4 (CH), 138.3 (C),
+
46.8 (C), 160.1 (CO); MS (EI, 70 eV) m/z = 288 (M , 40), 184 (100); HRMS (EI,
magnetic field) Calcd for C H N O 288.0495, found 288.0494.
12
8
4
5
1
,8-Dimethyl-5-nitro-2-oxo-1,2-dihydroquinoline-4-carbonitrile (24).
To a solution of 1,8-dimethyl-3,5-dinitro-2-quinolone (15, 132 mg, 0.5 mmol) in
acetonitrile (15 mL) was added KCN (33 mg, 0.5 mmol in 2 mL MeOH) at room
temperature, and the mixture was stirred for 1 d. Then, the solution was concentrated under
reduced pressure, and purified with column chromatography to afford cine-substituted
product 24 (eluted with hexane/ethyl acetate = 3/7, 57 mg, 0.24 mmol, 47% yield). Yellow
1
solid; mp 215−217 °C; H NMR (400 MHz, DMSO-d ) δ 2.86 (s, 3H), 3.77 (s, 3H), 7.02 (d,
6
13
J = 9.6 Hz, 1H), 8.17 (d, J = 9.6 Hz, 1H), 8.42 (s, 1H); C NMR (100 MHz, DMSO-d ) δ
6
2
3.7 (CH ), 36.4 (CH ), 113.4 (CN), 119.2 (C), 123.0 (C), 125.4 (CH), 129.2 (C), 129.7
3 3
+
(
CH), 132.3 (C), 135.6 (CH), 145.1 (C), 162.3 (CO); MS (EI, 70 eV) m/z = 243 (M , 53),
1
97 (62), 169 (100), 142 (67); HRMS (EI, magnetic field) Calcd for C H N O 243.0644,
12 9 3 3
found 243.0639.
1
,8-Dimethyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-carbonitrile (25).

ACCEPTED MANUSCRIPT
To a solution of 1,8-dimethyl-3,6-dinitro-2-quinolone (6, 132 mg, 0.5 mmol) in
acetonitrile (15 mL) was added KCN (33 mg, 0.5 mmol in 2 mL MeOH) at room
temperature, and the mixture was stirred for 1 d. Then, the solution was concentrated under
reduced pressure. Pure cine-substituted product 25 (166 mg, 0.5 mmol, quant.) was
obtained without further purification without any detectable of by-products. Brown solid;
1
mp 197−198 °C; H NMR (400 MHz, DMSO-d ) δ 2.84 (s, 3H), 3.79 (s, 3H), 7.66 (s, 1H),
6
1
3
8
.39 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H); C NMR (100 MHz, DMSO-d ) δ 23.3
6
(
CH ), 36.8 (CH ), 114.3 (CN), 117.8 (C), 119.4 (CH), 122.0 (C), 128.8 (C), 129.8 (CH),
3 3
+
1
30.7 (CH), 141.6 (C), 145.2 (C), 161.2 (CO); MS (EI, 70 eV) m/z = 243 (M , 100), 228
(
35), 169 (40); HRMS (EI, magnetic field) Calcd for C H N O 243.0644, found
12 9 3 3
2
43.0637.
ACKNOWLEDGEMENTS
We are grateful to Prof. Satoshi Minakata, Osaka University, Japan for his kind
assistance.

ACCEPTED MANUSCRIPT
Supporting Information Statement
Supporting Information. Table of atom coordinates and absolute energies for DFT
1
13
calculations, H NMR and C NMR spectra of compounds 6, 8-11, 13-15, 19, and 21-25
are available.
References
1
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1
0. Nishiwaki, N. Molecules 2010, 15, 5174–5195.
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Asahara, M.; Asaka, N.; Tohda, Y.; Ariga, M. Heterocycles 1999, 51, 567–574.
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1
1
1
1
1
1
4. Wu, Y. -L.; Chuang, C. -P.; Lin, P. -Y. Tetrahedron 2000, 56, 6209–6217.
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1
1
-methyl-2-pyridone: Prill, E. A.; McElvain, S. M. Org. Synth., Coll. 1943, 2, 419–421. (b)
-Methyl-3,6,8-trinitro-2-quinolone was prepared by nitration of 1-methyl-2-quinolone:
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377–1381.
1