Simple preparation of 7-alkylamino-2-methylquinoline-5,8-diones: Regiochemistry in nucleophilic substitution reactions of the 6- or 7-bromo-2-methylquinoline-5,8-dione with amines

Article abstract of DOI:10.1016/j.tet.2004.04.041

7-Alkylamino-2-methylquinoline-5,8-diones (7) were prepared from 6-bromo-2-methylquinoline-5,8-dione (2) not from 7-bromo-2-methylquinoline-5,8- dione (1). The chemistry of the transformation of 6-bromo-2-methylquinoline-5,8- dione (2) and various alkylamines, such as piperidine, 2-methylaziridine, benzylamine, n-butylamine, cyclohexylamine, t-butylamine, and ammonia, to 7-alkylamino compounds 7 as well as the transformation of 7-bromo compound 1 and the alkylamines to 6-alkylamino-2-methylquinoline-5,8-diones 11 was studied. The efficient and simple synthetic routes of the key intermediates, 6- and 7-bromo-2-methylquinoline-5,8-diones (2 and 1), from 5,8-dihydroxy-2- methylquinoline (15) and 5,7-dibromo-8-hydroxy-2-methylquinoline (9), respectively, were developed. We also proposed the mechanism for the unusual regioselectivity on the nucleophilic amination of 6- and 7-bromo-2- methylquinoline-5,8-diones (2 and 1).

Full text of DOI:10.1016/j.tet.2004.04.041

Tetrahedron 60 (2004) 4945–4951
Simple preparation of
7-alkylamino-2-methylquinoline-5,8-diones:
regiochemistry in nucleophilic substitution reactions of the
6- or 7-bromo-2-methylquinoline-5,8-dione with aminesq;qq
*
Han Young Choi and Dae Yoon Chi
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, South Korea
Received 16 February 2004; revised 16 April 2004; accepted 16 April 2004
Abstract—7-Alkylamino-2-methylquinoline-5,8-diones (7) were prepared from 6-bromo-2-methylquinoline-5,8-dione (2) not from
7-bromo-2-methylquinoline-5,8-dione (1). The chemistry of the transformation of 6-bromo-2-methylquinoline-5,8-dione (2) and various
alkylamines, such as piperidine, 2-methylaziridine, benzylamine, n-butylamine, cyclohexylamine, t-butylamine, and ammonia, to
7-alkylamino compounds 7 as well as the transformation of 7-bromo compound 1 and the alkylamines to 6-alkylamino-2-methylquinoline-
5,8-diones 11 was studied. The efficient and simple synthetic routes of the key intermediates, 6- and 7-bromo-2-methylquinoline-5,8-diones
(2 and 1), from 5,8-dihydroxy-2-methylquinoline (15) and 5,7-dibromo-8-hydroxy-2-methylquinoline (9), respectively, were developed. We
also proposed the mechanism for the unusual regioselectivity on the nucleophilic amination of 6- and 7-bromo-2-methylquinoline-5,8-diones
(2 and 1).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
due to their synthetic problems such as preferential C6
substitution or addition of nucleophiles,1,11,13,21 while
7-amino or 7-acetylaminoquinoline-5,8-diones were pre-
pared from the reduction of azide and nitro substituents.19,20
Recently, we published a report, in which, 7-alkylamino-2-
methylquinoline-5,8-diones 7 were synthesized by the new
synthetic route—nucleophilic substitution of amines and
debromination—from 6,7-dibromo-2-methylquinoline-5,8-
dione (3).10 But this method has two drawbacks. First, as
there is a regioselectivity between C6 and C7 in amination
of 6,7-dibro-2-methylquinoline-5,8-dione (3), we could
obtain the C7 aminated product only as moderate yields
(50–60%) in optimized aprotic solvent such as dioxane.
Second, in debromination step, we could not prepare some
kinds of alkylamino compounds such as 2-methylaziridine,
benzylamine and t-butylamine which are unstable in acidic
condition because of the prevalently ongoing dealkylation.
Thus we tried to discover another synthetic route for the
preparation of the 7-alkylamino-2-methylquinoline-5,8-
diones 7 including the alkylamino groups which are
unstable in acidic conditions.
Quinoline- and isoquinoline-5,8-diones have wide spectra
of biological activities as antitumor, antibacterial, antifun-
gal, antimalarial agents.1 – 10 The syntheses and the
biological activities of 6,7-functionalized quinoline-5,8-
diones such as amino, hydroxyl, methoxy, thiol, and
halogen have been reported.1–4,11–17 As 7-amino group is
the most critical segment in determining the antitumor
activity of Streptonigrin, Steptonigrone, and Lavendamycin,18
7-amino-2-methylquinoline-5,8-dione (7g) has been the
focus of synthetic efforts. Recently, Behforouz reported a
short and efficient synthetic method of 7-amino-2-methyl-
quinoline-5,8-dione (7g) as well as Lavendamycin from
7-acetylamino-2-methylquinoline-5,8-dione and b-methyl-
tryptophan.19,20 But to our knowledge, there has been no
report on the syntheses of 7-alkylamino-2-methylquinoline-
5,8-diones 7 as major products except our previous report10
q CDRI Communication No. 6414.
qq Supplementary data associated with this article can be found, in the
online version at doi: 10.1016/j.tet.2004.04.041
Herein, we wish to report the preparation of various
7-alkylamino-2-methylquinoline-5,8-diones 7 by a new
efficient route. It is noteworthy that the conventional
alkylation reactions on 7-amino group do not proceed due
to its lack of nucleophilicity. The C2 methyl group could be
Keywords: Quinoline-5,8-dione; 7-Amino-2-methylquinoline-5,8-dione;
Nucleophilic substitution reactions; Regiochemistry; Alkylamination.
*
Corresponding author. Tel.: þ82-32-860-7686; fax: þ82-32-867-5604;
e-mail address: dychi@inha.ac.kr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.041

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H. Y. Choi, D. Y. Chi / Tetrahedron 60 (2004) 4945–4951
used for coupling with CD ring of Lavendamycin by
reported method.19,20
Scheme 2.
2. Results and discussion
There were many reports on the preparation of 7-amino-
quinoline-5,8-dione (7g) by nucleophilic azide substitution
of 7-bromoquinoline-5,8-dione (1) followed by reduction to
the amino group22,23 and 6-aminoquinoline-5,8-dione (12g)
by direct amine substitution of 6-methoxyquinoline-5,8-
dione21 and we also detected that 7-methoxyquinoline-5,8-
dione yields 7-alkylamino-2-methylquinoline-5,8-dione 7
by nucleophilic amine substitution in low yields.10 Thus to
find an efficient synthetic route for the preparation of
7-alkylamino compounds 7, we have designed a direct
amination reaction of 7-bromoquinoline-5,8-dione (1) as
shown in Scheme 1.
Scheme 3. The direct amination of 7-bromo-2-methylquinoline-5,8-dione
(1).
desired 7-piperidyl compound 7a in a low yield (3%) as
shown in Scheme 3. At this point, the regiochemistry of C6
and C7 positions were thoroughly investigated. Therefore, it
was expected the direct nucleophilic amination of 6-bromo-
2-methylquinoline-5,8-dione (2) would produce 7-amino
compounds 12 and 7 (Scheme 4). The debromination
reactions of 6-bromo-7-alkylamino compounds 12 to 7 were
developed by our group.10
Scheme 1. A proposed new synthetic route for 7-alkylamino-2-methyl-
quinoline-5,8-diones.
2.1. The preparation of 7-bromoquinoline-5,8-dione (1)
Petrow and Sturgeon reported a synthetic route for the
preparation of 1 from 8-hydroxy-5-nitroso-2-methylquino-
line by oxidation of nitroso to nitro group, selective
bromination on the C7 position, reduction of nitro to the
amino group, and oxidation to 7-bromo-2-methylquinoline-
5,8-dione (1).24 This procedure contained five steps and
produced 1 in low yields. We have tried to discover an
efficient and easy synthetic route for 7-bromo-2-methyl-
quinoline-5,8-dione (1). Various synthetic routes were
examined to synthesize 7-bromo compound 1. Among
them, 1 was prepared from very simple starting material,
8-hydroxy-2-methylquinoline (8) in two steps with 66%
yield as shown in Scheme 2. Simple bromination of 8 gave
5,7-dibromo-8-hydroxy-2-methylquinoline (9) in 97% yield
at rt for 5 min. The oxidation using 61% of nitric acid in the
presence of concentrated sulfuric acid provided 1 in 68%
yield.
Scheme 4. Another proposed new synthetic route for 7-alkylamino-2-
methylquinoline-5,8-diones.
2.2. The preparation of 6-bromoquinoline-5,8-dione (2)
As prepared 1, we expected that the direct oxidation by
nitric acid of 6,8-dibromo-5-hydroxy-2-methylquinoline
(14) would give 2 (Scheme 5). Unfortunately, we could
obtain 2 in a trace amount. The difference of the electron
donating abilities between 5-hydroxy and 8-hydroxy groups
showed the different reactivities. Generally, it is known that
the electron rich aromatic compounds are more easily
oxidized. The 8-hydroxy group is thought to have more
powerful electron donating ability by the formation of an
intramolecular hydrogen bond with N1 nitrogen.
Surprisingly, direct nucleophilic amination of 7-bromo
compound 1 using piperidine gave predominantly the
6-piperidyl compounds 10a (55%), 11a (30%), and the
As shown in Scheme 6, we could prepare 2 from

H. Y. Choi, D. Y. Chi / Tetrahedron 60 (2004) 4945–4951
4947
Table 1 shows the results of the various 7-alkylamino
compounds 7 prepared by direct nucleophilic aminations
from 6-bromo-2-methylquinoline-5,8-dione (2). The
reaction in the aprotic solvents such as dichloromethane
gave the maximum yield of 7. The addition of triethylamine
Scheme 5. Oxidation of 6,8-dibromo-5-hydroxy-2-methylquinoline.
Scheme 7.
increased the selectivity of 7-amino products by trapping
the generated HBr that can form the salt with N1
nitrogen. We could also obtain the 6-alkylamino compounds
11 from 6-bromo compound 2 with 40–60% yields by
addition of Lewis acid in polar protic solvent as shown in
Scheme 8.28
Scheme 6.
2,5-dimethoxyaniline in a reasonable yield by Doebner–
Miller reaction25 followed by oxidation using NBS. The
regiochemistry of 6-bromo-2-methylquinoline-5,8-dione
synthesized was identified by comparison with the authentic
compound prepared by the route as shown in Scheme 7.
Using this chemistry only the mono bromo compound 17,
6-bromo-5,8-dimethoxy-2-methylquinoline was obtained
which was oxidized via our recently reported method26
using NBS with catalytic sulfuric acid and water.
2.3. Plausible mechanism for the selective oxidative
bromination of 5,8-dihydroxy-2-methylquinoline to
6-bromo-2-methylquinoline-5,8-dione
According to Scheme 6, 6-bromo-2-methylquinoline-5,8-
dione (2) could efficiently and easily be obtained from 5,8-
dihydroxy-2-methylquinoline (15) in gram-reaction scale.
Scheme 9 shows the plausible mechanism for the selective
oxidative bromination of 15 to 2. This mechanism consists
Table 1. Amination of 6-bromo-2-methylquinoline-5,8-dionea
Solvent (25 mL)
Amine (3 equiv.)
Et3N (mL)
Time (min)
7 (%)
11 (%)
12 (%)
Total yield (%)
MeOH
Piperidine
Piperidine
Piperidine
Piperidine
2-Methylaziridine
2-Methylaziridine
Benzylamine
Benzylamine
n-Butylamine
n-Butylamine
Cyclohexylamine
t-Butylamineb
NH4OH (1.5 mL)
—
—
—
—
—
0.5
—
0.5
—
0.5
0.5
0.5
1.5
10
10
10
10
15
15
10
10
10
10
30
48 h
90
7a (35)
7a (70)
7a (75)
7a (88)
7b (88)
7b (94)
7c (55)
7c (87)
7d (55)
7d (93)
7e (74)
7f (48)
7g (34)
11a (44)
11a (7)
11a (18)
11a (10)
11b (11)
11b (5)
11c (5)
11c (2)
—
—
—
—
—
12a (trace)
12a (trace)
12a (trace)
—
—
—
12c (16)
12c (3)
12d (25)
12d (6)
12e (8)
12f (4)
12g (13)
79
77
93
98
99
99
76
92
80
99
82
52
47
Dioxane
Benzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a
See general procedure in Section 4.
6 equiv. of amine was used.
b

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H. Y. Choi, D. Y. Chi / Tetrahedron 60 (2004) 4945–4951
of the 6- or 7-methoxy-2-methylquinoline-5,8-dione.21
From those results, we could conclude that the chelating
and intramolecular hydrogen bonding effect in polar
protic solvent is important on the regioselectivity, while in
non-polar aprotic solvent, the regiochemistry is mainly
determined by properties of substituents on C6 or C7
position.
We propose the regioselectivity on the basis of electronic
and steric effects. As shown in Scheme 10, the electron
donating ability of methoxy group increases the electron
density at the C7 position in place of ortho-position,
consequently making the nucleophilic attack on the ipso-
position favorable. On the other hand, when the bromine
used as a leaving group, the bulkiness of bromine makes the
ipso-attack difficult, thus it makes the attack at the C7
position in place of ortho-position favorable.
Scheme 8.
of three steps: (1) selective acetylation of 8-hydroxy group
of 15 without base, (2) bromination using NBS onto the C6
position, and (3) oxidation using another equiv of NBS.
Therefore, we added 2 equiv. of NBS because it is used as a
brominating agent as well as oxidant. The key-intermediate,
5,8-dihydroxy-2-methylquinoline (15) could be prepared
from 2,5-dimethoxyaniline via Doebner–Miller reaction
and demethylation using concentrated HBr in 50–60%
yield.27
Scheme 10. Regioselectivity by substituent.
Furthermore, we obtained a different result between the
6-bromo (2) and 7-bromo-2-methylquinoline-5,8-dione (1)
on the nucleophilic amination. The 7-bromo-2-methyl-
quinoline-5,8-dione (1) yielded the 6-alkylamino-7-
bromo-2-methylquinoline-5,8-diones 10 as major products,
while 6-bromo-2-methylquinoline-5,8-dione (2) produced
7-alkylamino-2-methylquinoline-5,8-diones 7 as major
products. We proposed that the different results are due to
the intramolecular hydrogen bonding between the OH at the
C8 and N1 as shown in Schemes 11 and 12.
Scheme 9.
When the base such as triethylamine was added, compound
15 was diacetylated on both 5- and 8-hydroxy and this
diacetylated compound was not oxidized at the NBS
condition. In addition, the direct treatment of NBS in
methanol to 5,8-dihydroxy-2-methylquinoline (15) pro-
vided 2-methylquinoline-5,8-dione (4) in a 77% yield. On
the inverse regioselectivity of nucleophilic amination of 1
and 2, some papers reported the prevalent attack on the C6
position1 is due to the chelation of metal cation between
8-oxygen and 1-nitrogen, and it is generally accepted that
chelating effect is important for regioselectivity.13,28
Actually, we experienced the chelating effect and hydrogen
bonding effect in Table 1 (entry 1) and Scheme 8. We also
detected that the nucleophilic aminations of 7-bromo-2-
methylquinoline-5,8-dione (1) yielded the 6-amino com-
pounds 10 and 11. On the other hand, the neucleophilic
aminations of 6-bromo-2-methylquinoline-5,8-dione (2)
yielded the 7-amino compounds 7 and 12 as major products
in non-polar aprotic solvents. It was reported that the
6-methoxy and 7-methoxy compounds each produced
6-amino and 7-amino compounds on the amine substitution
Scheme 11 shows that the intermediate can be in both in
keto and enol forms, but the enol form will be more stable
due to the intramolecular hydrogen bonding. As a result,
following oxidation reaction of enol form provided
6-alkylamino-7-bromo-2-methylquinoline-5,8-dione 10 as
a major product. But in case of 6-bromo-2-methylquinoline-
5,8-dione (2), because there is no possibility for the more
stabilizing the enol form, the 7-alkylamino-2-methylquino-
line-5,8-diones 7 was obtained as a major product as shown
in Scheme 12.
3. Conclusion
Recently, we reported a synthetic method for the
preparation of various 7-alkylamino-2-methylquinoline-
5,8-diones by nucleophilic amination of 6,7-dibromo-2-
methylquinoline-5,8-dione followed by debromination upon
treatment with hydrobromic acid.10 As this synthetic route
has some drawbacks, we developed the new synthetic route

H. Y. Choi, D. Y. Chi / Tetrahedron 60 (2004) 4945–4951
4949
Scheme 11. Proposed mechanism on the 6-alkylamino-2-methylquinoline-5,8-diones from 7-bromo-2-methylquinoline-5,8-diones.
Scheme 12. Proposed mechanism of 7-alkylamino-2-methylquinoline-5,8-diones from 6-bromo-2-methylquinoline-5,8-diones.
for 7-alkylamino-2-methylquinoline-5,8-diones by nucleo-
philic amination from 6-bromo-2-methylquinoline-5,8-dione,
not from 7-bromo compound. Using this new method, we
could prepare the alkylamino-2-methylquinoline-5,8-diones
that could not be prepared by debromination method. During
the research for the preparation of 7-alkylamino-2-methyl-
quinoline-5,8-dione, we also discovered a new and efficient
synthetic routes for the key intermediates, 6-bromo or
7-bromo-2-methylquinoline-5,8-diones.
(40 mL), and HNO3 (61%, 5 mL) was added for 30 min in
the ice bath. And ice water (300 mL) was added and
extracted with dichloromethane without neutralization and
dried by Na2SO4 and was concentrated in vacuo to give 1
1
(5.81 g, 23.1 mmol, 68%) as a yellowish-white solid: H
NMR (200 MHz, CDCl3) d 8.30 (d, J¼8.2 Hz, 1H), 7.57 (d,
J¼8.2 Hz, 1H), 7.56 (s, 1H), 2.80 (s, 3H); 13C NMR
(50 MHz, CDCl3 þDMSO-d6) d 181.4, 175.9, 164.8, 145.3,
139.4, 139.1, 134.8, 128.1, 126.4, 23.7; MS (EI) 253 (Mþ),
251 (Mþ, 100), 225, 223, 197, 195, 172, 144, 116, 89, 74,
63, 53, 39. Anal. Calcd for C10H6BrNO2: C, 47.65; H, 2.40;
N, 5.56. Found: C, 47.26; H, 2.52; N, 5.51.
4. Experimental
4.1. 5,7-Dibromo-8-hydroxy-2-methylquinoline (9)29
4.2. General procedure for amination of 7-bromo-2-
methylquinoline-5,8-dione (1)
Bromine (10 mL) dissolved in MeOH (100 mL) was added
into the mixture of 8-hydroxy-2-methylquinoline (8, 10.0 g,
62.8 mmol), NaHCO3 (10 g) and MeOH (100 mL). After
stirring for 5 min at rt, Na2SO3 (5 g) was added and then the
mixture was filtered and washed with H2O (200 mL) and
was dried in vacuo to give 9 (19.34 g, 61.0 mmol, 97%) as a
white solid.
4.2.1. 7-Bromo-2-methyl-6-(piperidin-1-yl)quinoline-
5,8-dione (10a).10 7-Bromo-2-methylquinoline-5,8-dione
(1, 700 mg, 2.78 mmol) was dissolved in dichloromethane
(20 mL) and piperidine (0.7 mL) was added. After stirring
for 1 min at rt, H2O (50 mL) was added into the mixture and
extracted with dichloromethane, dried by Na2SO4 and
concentrated in vacuo. The residue was purified by flash
column chromatography (40% EtOAc/hexane) to give 10a
(519 mg, 1.55 mmol, 55%), 2-methyl-6-(piperidin-1-yl)-
quinoline-5,8-dione (11a, 215 mg, 0.84 mmol, 30%),
4.1.1. 7-Bromo-2-methylquinoline-5,8-dione (1).19 5,7-
Dibromo-8-hydroxy-2-methylquinoline
34.1 mmol) was dissolved in concentrated H2SO4
(9,
10.8 g,

4950
H. Y. Choi, D. Y. Chi / Tetrahedron 60 (2004) 4945–4951
2-methyl-7-(piperidin-1-yl)quinoline-5,8-dione (7a, 22 mg,
0.08 mmol, 3%). See the analytical data in Ref. 10.
200 mg, 0.79 mmol) was dissolved in dichloromethane
(10 mL) and triethylamine (0.5 mL) then 2-methylaziridine
(0.19 mL) was added at rt. After stirring for 5 min, H2O
(100 mL) was added and was extracted with dichloro-
methane and dried by Na2SO4 and was concentrated in
vacuo. The residue was purified by flash column chroma-
tography (40% EtOAc/hexane) to give 7b (170 mg,
0.75 mmol, 94%) as a yellow solid: See detail data are in
Ref. 10. 2-Methyl-6-(2-methylaziridin-1-yl)quinoline-5,8-
4.2.2. 2,4-Dibromo-5-aminophenol (13).30 The title com-
pound was prepared by acetylation of 3-aminophenol,
followed by selective 2,4-dibromination and deacetylation.
4.2.3. 6,8-Dibromo-5-hydroxy-2-methylquinoline (14).30
Crotonaldehyde (1.5 mL) was added into the mixture of 2,4-
dibromo-5-aminophenol (13, 1.15 g, 4.31 mmol) and con-
centrated HCl (10 mL) and AcOH (10 mL), then the
reaction mixture was refluxed for 30 min. The reaction
mixture was neutralized by NaHCO3 and extracted by
EtOAc and was concentrated in vacuo. The residue was
purified by flash column chromatography (60% EtOAc/
1
dione (11b, 8 mg, 0.04 mmol, 5%): H NMR (400 MHz,
CDCl3) d 8.28 (d, J¼8.0 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H),
6.39 (s, 1H), 2.77 (s, 1H), 2.40–2.43 (m, 1H), 2.20–2.23
(m, 2H), 1.47 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 183.2, 181.3, 164.9, 157.1, 147.5, 134.5, 126.8,
126.3, 118.9, 36.3, 34.5, 25.2, 17.5; MS (ESI, positive) 229
(Mþþ1, 100). HRMS (EIþ) m/z Calcd for C13H12N2O2
(Mþ) 228.0899, found 228.0889.
1
hexane) to give 14 (691 mg, 2.18 mmol, 51%): H NMR
(200 MHz, CDCl3) d 9.07 (bs, 1H), 8.23 (d, J¼8.4 Hz, 1H),
7.74 (s, 1H), 7.05 (d, J¼8.8 Hz, 1H), 2.49 (s, 3H); 13C NMR
(50 MHz, CDCl3 þDMSO-d6) d 159.7, 149.0, 143.7, 134.3,
131.1, 121.5, 119.6, 113.1, 102.9, 24.8; MS (EI) 319 (Mþ),
317 (Mþ), 315 (Mþ), 156, 128, 101, 64, 51, 32 (100).
HRMS (EIþ) m/z Calcd for C10H7Br2NO (Mþ) 316.8874,
found 316.8894.
4.3.2. 7-Benzylamino-2-methylquinoline-5,8-dione (7c).
1H NMR (200 MHz, CDCl3) d 8.29 (d, J¼8.0 Hz, 1H), 7.50
(d, J¼8.0 Hz, 1H), 7.28–7.40 (m, 5H), 6.42 (bs, 1H), 5.80
(s, 1H), 4.41 (d, J¼6.0 Hz, 1H), 2.73 (s, 3H); 13C NMR
(50 MHz, CDCl3) d 182.0, 180.4, 163.0, 147.9, 146.1,
135.6, 134.5, 129.0, 128.4, 128.2, 128.1, 127.6, 100.9, 46.9,
29.6, 24.9; MS (EI) 278 (Mþ), 276, 261, 194, 174, 117, 91
(100), 77, 65, 51, 39. HRMS (EIþ) m/z Calcd for
C17H14N2O2 (Mþ) 278.1055, found 278.1059.
4.2.4. 5,8-Dihydroxy-2-methylquinoline (15).27 Croton-
aldehyde (11.84 g, 169 mmol, 1.3 equiv.) was added into
the mixture of 2,5-dimethoxyaniline (20 g, 130 mmol) and
concentrated HBr (150 mL), then the reaction mixture was
refluxed for 24 h and the reaction mixture was neutralized
by NaHCO3 and extracted by EtOAc and was concentrated
in vacuo. The residue was purified by flash column
chromatography (40% EtOAc/hexane) to give 15 (7.4 g,
42.3 mmol, 33%): 1H NMR (200 MHz, CDCl3 þDMSO-d6)
d 8.41 (d, J¼8.4 Hz, 1H), 7.26 (d, J¼8.4 Hz, 1H), 6.93 (d,
J¼8.2 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H), 2.70 (s, 3H); 13C
NMR (50 MHz, CDCl3 þDMSO-d6) d 156.6, 144.8, 144.1,
137.4, 131.3, 120.8, 118.0, 108.9, 107.9, 24.6; MS (EI) 175
(Mþ, 100), 146, 118, 87, 74, 52, 39. HRMS m/z (EIþ)
175.0635, Calcd for C10H9NO2 175.0633.
4.3.3. 6-Benzylamino-2-methylquinoline-5,8-dione (11c).
1H NMR (200 MHz, CDCl3) d 8.25 (d, J¼8.0 Hz, 1H),
7.27–7.45 (m, 6H), 6.20 (bs, 1H), 5.95 (s, 1H), 4.39 (d,
J¼5.4 Hz, 1H), 2.77 (s, 3H); 13C NMR (50 MHz, CDCl3) d
181.5, 181.3, 165.4, 148.5, 147.0, 135.4, 134.1, 128.8,
128.0, 127.5, 126.0, 125.0, 102.2, 46.7, 26.3; MS (EI)
278 (Mþ, 100), 261, 201, 187, 174, 117, 91, 77, 65. HRMS
(EIþ) m/z Calcd for C17H14N2O2 (Mþ) 278.1055, found
278.1056.
Compounds 12a, 12c-g, 7d-g.10 See detail data are in
Ref. 10.
4.2.5. 6-Bromo-2-methylquinoline-5,8-dione (2).26 Acetic
anhydride (2 mL) was added into the mixture of 5,8-
dihydroxy-2-methylquinoline (15, 1.0 g, 5.57 mmol) and
dichloromethane (40 mL) and THF (10 mL). After stirring
at rt for 5 min, NBS (1.7 g, 9.55 mmol, 1.68 equiv.) was
added and was stirred for 10 min and then H2O (200 mL)
including NaHCO3 (3 g) added and extracted by dichloro-
methane and was concentrated in vacuo. The residue was
purified by flash column chromatography (60% EtOAc/
4.3.4. 8-Acetoxy-5-hydroxy-2-methylquinoline (18).
Acetic anhydride (2.7 mL, 28.8 mmol, 0.9 equiv.) was
added into the mixture of 5,8-dihydroxy-2-methylquinoline
(15, 5.6 g, 32.0 mmol) and dichloromethane (50 mL). After
stirring at rt for 30 min, the reaction mixture was
concentrated in vacuo. The residue was purified by flash
column chromatography (40% EtOAc/hexane) to give 18
(4.71 g, 22.0 mmol, 69%): 1H NMR (200 MHz, CDCl3
þDMSO-d6) d 9.96 (s, 1H), 8.37 (d, J¼8.4 Hz, 1H), 7.19 (d,
J¼8.4 Hz, 1H), 7.10 (d, J¼8.6 Hz, 1H), 6.74 (d, J¼8.4 Hz,
1H), 2.61 (s, 3H), 2.34 (s, 3H); 13C NMR (50 MHz, CDCl3
þDMSO-d6) d 167.9, 156.9, 149.3, 138.8, 136.8, 129.3,
119.1, 118.9, 116.9, 104.7, 23.3, 18.7; MS (CI) 218 (Mþþ1,
100), 204, 176. Anal. Calcd for C12H11NO3: C, 66.35; H,
5.10; N, 6.45. Found: C, 65.98; H, 5.48; N, 6.28.
1
hexane) to give 2 (1.23 g, 4.89 mmol, 85.7%): H NMR
(200 MHz, CDCl3) d 8.39 (d, J¼8.4 Hz, 1H), 7.65 (s, 1H),
7.59 (d, J¼8.0 Hz, 1H), 2.80 (s, 3H); 13C NMR (50 MHz,
CDCl3 þDMSO-d6) d 178.6, 175.1, 163.3, 144.3, 137.8,
137.0, 133.3, 125.4, 123.7, 22.9.; MS (EI) 253 (Mþ, 100),
251 (Mþ), 225, 223, 197, 195, 144, 116, 89, 63, 53, 39.
Anal. Calcd for C10H6BrNO2: C, 47.65; H, 2.40; N, 5.56.
Found: C, 47.40; H, 2.55; N, 5.53.
4.3.5. 6-Bromo-2-methylquinoline-5,8-dione (2) from
4.3. General procedure for amination of 6-bromo-2-
methylquinoline-5,8-dione (2) at Table 1
8-acetoxy-5-hydroxy-2-methylquinoline
(5.47 g, 30.7 mmol, 2.47 equiv.) was added into the mixture
of 8-acetoxy-5-hydroxy-2-methylquinoline (2.69 g,
(18).
NBS
4.3.1. 2-Methyl-7-(2-methylaziridin-1-yl)quinoline-5,8-
dione (7b).10 6-Bromo-2-methylquinoline-5,8-dione (2,
12.4 mmol) and dichloromethane (70 mL). After stirring
at rt for 30 min, the solvent was removed in vacuo. The

H. Y. Choi, D. Y. Chi / Tetrahedron 60 (2004) 4945–4951
4951
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EtOAc/hexane) giving 2 (2.30 g, 9.0 mmol, 73%).
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Acknowledgements
This work was supported by National Research Laboratory
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