A methodology for the synthesis of highly functionalized 2- and 4-aminoquinoline derivatives

Article abstract of DOI:10.1016/j.tet.2008.05.014

A methodology for the synthesis of 2- and 4-aminoquinoline derivatives, which takes advantage of selective activation of 2- or 4-substituent of 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1, has been developed. Since a procedure for formation of 3-aminoquinolinones from the 4-quinolinone 1 was described previously, the new methodology comprises a general methodology for the selective syntheses of three isomeric 2-, 3- and 4-aminoquinoline derivatives starting with the common 4-quinolinone 1.

Full text of DOI:10.1016/j.tet.2008.05.014

Tetrahedron 64 (2008) 6698–6704
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A methodology for the synthesis of highly functionalized
2- and 4-aminoquinoline derivatives
*
Bo Hyun Hwang, Sung Hee Park, Eun Bok Choi, Chwang Siek Pak, Hyeon Kyu Lee
Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusung, Taejon 305-606, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A methodology for the synthesis of 2- and 4-aminoquinoline derivatives, which takes advantage of
selective activation of 2- or 4-substituent of 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1, has been
developed. Since a procedure for formation of 3-aminoquinolinones from the 4-quinolinone 1 was de-
scribed previously, the new methodology comprises a general methodology for the selective syntheses of
three isomeric 2-, 3- and 4-aminoquinoline derivatives starting with the common 4-quinolinone 1.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 February 2008
Received in revised form 2 May 2008
Accepted 2 May 2008
Available online 9 May 2008
Keywords:
2-Aminoquinolinone
4-Aminoquinoline
2-Methylsulfanyl-3-acyl-1H-quinolin-4-one
1. Introduction
4-substituent in 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1 into
good leaving groups would enable subsequent treatment with
Quinoline and quinolinone derivatives are important heterocy-
clic compounds that constitute core structures of many naturally
occurring substances that have interesting biological and phar-
maceutical properties.1 In this family, 2- and 4-aminoquinoline
derivatives are especially important in that they possess a wide
range of pharmaceutical activities including antimalarial,2 anti-
HIV,3 anti-Alzheimer disease,4 melanin-concentrating hormone
1 receptor (MCHR) antagonist,5 and Src kinase inhibitor.6 Conse-
quently, the development of efficient methods for the synthesis of
these heterocyclic compounds has continued to be an important
goal. Although some methods are currently available for the
preparation of these targets,1,7 the design of new and simple routes
for the preparation of aminoqinolines and aminoquinolones, par-
ticularly those that are highly functionalized, remains a significant
challenge. In our continuing efforts aimed at the synthesis of 4-
quinolinone analogs for biological testing,8 a need arose for various
aminoquinolines. Herein, we report the results of an investigation
that led to a new strategy for facile preparation of highly func-
tionalized 2- and 4-aminoquinoline beginning with the common
2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1 (Fig. 1).
various amines to afford the corresponding 2- and 4-aminoquino-
line. To test this proposal in the context of the synthesis of 4-ami-
noquinoline 4, 1 was converted to 4-methanesulfonyloxyquinoline
2 in good yield by reaction with methanesulfonyl chloride under
basic conditions (Fig. 2).
Reaction of morpholine with 2 led to the formation of the de-
sired 4-morpholino-quinoline 4 along with 4-quinolinone 1 as side
product. The competitive, undesired process leading to 1 likely
takes place by attack of the amine at the 4-sulfonyl sulfur atom of
2 instead of the C-4 carbon. Consistent with this explanation is the
finding that N-methanesulfonyl morpholine was also produced in
this reaction. The yields of 4-morpholino-quinoline 4 were highly
R1
R
OMs O
N
N
2O
c
X
X
X
X
a
O
O
N
SMe
SMe
4
2
X
N
H
SMe
O
O
O
O
b
d
2. Results and discussion
1
R1
N
H
SMe
O
N
H
N
R2
In devising a strategy for the synthesis of 2- and 4-amino-
quinoline, we envisioned that selective transformation of 2- and
5
3
Figure 1. Syntheses of 2-aminoquinolin-4-one 5 and 4-aminoquinoline 4 from 2-
methylsulfanyl-3-acyl-1H-quinolin-4-one 1. (a) CH3SO2Cl, Et3N, CH2Cl2; (b) H2O2,
AcOH; (c) R1R2NH, base/solvent; (d) R1R2NH, THF.
* Corresponding author. Tel.: þ82 42 860 7016; fax: þ82 42 861 0307.
E-mail address: leehk@krict.re.kr (H.K. Lee).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.014

B.H. Hwang et al. / Tetrahedron 64 (2008) 6698–6704
6699
R1
R
2O
O
O
OMs O
N
O
O
a
b
X
X
X
X
+
N
H
SMe
N
SMe
N
SMe
N
H
SMe
1
2
4
1
Figure 2. Synthesis of 4-amino-4-quinolinone 4 from 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1. (a) CH3SO2Cl, Et3N, CH2Cl2, rt; (b) R1R2NH, K2CO3, CH2Cl2, reflux.
dependent on both the reaction conditions and the nature of sub-
stituents in 2. For example, reaction of morpholine with 2 in the
presence of Et3N in CH2Cl2 gave the desired 4-morphorinoquino-
line 4 in only 12% yield and undesired 4-quinolinone 1 as major
product (70%). In contrast, the yield of 4 increased significantly
(91%) when reaction of morpholine with 2 was performed in the
presence of K2CO3 as base. Also, reactions of 2 with benzylamine
and isobutylamine, employing K2CO3 as the base, produced the
corresponding 4-aminoquinolines 4 as major products. Quinolines
2 containing strong electron withdrawing substituents were highly
reactive as exemplified by the observation that reactions of 2d with
amines were completed in 3 h and high yields (Table 1, entries
10 and 11). In contrast to reactions with alkylamines, 4-meth-
anesulfonyloxyquinoline 2a is unreactive with aromatic amines,
such as aniline. 6-Chloro-8-trifluoromethyl-4-methanesulfonyloxy-
quinoline 2c bearing electron withdrawing substituents is also
resistant to the reaction with aniline under the same reaction
condition only producing small amount of undesired 1c and
recovery of most of 2c. The results of these exploratory studies
are summarized in Table 1.
In the next phase of this effort, a route for the synthesis of
2-amino-4-quinolinones 5 from 2-methylsulfanyl-3-acyl-1H-qui-
nolin-4-one 1 was investigated. For this purpose, 2-methylsul-
fanyl-3-acyl-1H-quinolin-4-one 1 was converted to 2-methylsul-
finyl-3-acyl-1H-quinolin-4-one 3, the latter is more susceptible to
nucleophilic substitution reactions with amines. The requisite
sulfoxides 3 were obtained in good yields by oxidation of the cor-
responding sulfides 1 with hydrogen peroxide in acetic acid
(Fig. 3).9 Treatment of 2-methylsulfinyl-1H-quinolin-4-one 3 with
various alkylamines at room temperature in THF leads to smooth
formation of the corresponding 2-amino-4-quinolinones 5.10 We
obtained 2-aminoquinolin-4-one 5 from the corresponding 3 with
the same substituents of 4-aminoquinoline 4 and amines system-
atically to show the usefulness of the present method to obtain 4
and 5 selectively from the common starting compound 1 (compare
Table 2, entries 1–11 with Table 1, entries 1–11).
Independent of the nature of substituents on the 2-methyl-
sulfinyl-3-acyl-1H-quinolin-4-one ring system, substitution re-
actions with diverse amines take place to provide the corresponding
2-amino-4-quinolinones 5 in good yields. For example, 3-benzoyl-
2-methylsulfinyl-1H-quinolin-4-ones react with amines to form the
corresponding 3-benzoyl-2-amino-1H-quinolin-4-ones 5 in good
yields (Table 2, entries 15 and 17). Sterically bulky amines such as
tert-butylamine and N-methyl-N-phenylamine also smoothly react
with 3 affording the corresponding 2-amino-3-acyl-1H-quinolin-4-
ones 5 (Table 2, entries 13 and 18). The analogous substitution
reactions of 3 with aromatic amines take place only slowly at room
temperature, but they can be driven to completion when run in
refluxing 1,2-dichlorobenzene (Table 2, entries 12 and 13). The
results arising from these studies, summarized in Table 2, show that
the reactions of 2-methylsulfinyl-3-acyl-1H-quinolin-4-ones 3 with
amines stand as a versatile and convenient method to prepare
2-amino-3-acyl-1H-quinolin-4-ones. Especially important is the
fact that this approach to 2-aminoquinolinone synthesis compares
favorably with the previously reported method involving conden-
sation of
a
-benzoylketenedithioacetal with 2-aminobenzoates,7
which has only limited versatility.
Earlier, we described the preparation of 3-aminoquinolinone 8
by hydrolysis of oxazoloquinoline 7, which was prepared from the
O
O
O
O
O
O
b
R3
a
R3
R3
R1
X
X
X
N
H
SMe
N
H
SMe
O
N
H
N
R2
5
1
3
Figure 3. Synthesis of 2-amino-4-quinolinone 5 from 2-methylsulfanyl-3-acyl-1H-
quinolin-4-one 1. (a) H2O2, AcOH (69–98%); (b) R1R2NH, THF/rt (for alkylamines) or
1,2-dichlorobenzene/reflux (for aromatic amines) (see Table 2).
Table 1
Summary of reactions of 4-methanesulfonyloxyquinolines 2 with amines to yield 4-aminoquinolines 4
R1
R
2O
OMs O
N
O
O
K2CO3
CH2Cl2
+
+
X
X
R1R2NH
X
N
SMe
N
SMe
N
H
SMe
4
1
2
Entry
Number
X
R1R2NH
Time (day)
Yield (%)a
4
1
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
PhCH2NH2
Morpholine
(CH3)2CHCH2NH2
PhCH2NH2
Morpholine
(CH3)2CHCH2NH2
PhCH2NH2
Morpholine
(CH3)2CHCH2NH2
PhCH2NH2
(CH3)2CHCH2NH2
3
1
3
3
2
2
3
3
51
45
c
91b
75
c
6-Cl
6-Cl
6-Cl
6-Cl-8-CF3
6-Cl-8-CF3
6-Cl-8-CF3
5-NO2-8-Cl
5-NO2-8-Cl
47
90
66
66
43
c
4
25
66b
61b
95
7
c
9
10
11
3
3 h
3 h
c
c
4j
4k
90b
a
Amine (3.0 equiv) was used.
Amine (1.2 equiv) was used.
Trace amount of 1 was obtained.
b
c

6700
B.H. Hwang et al. / Tetrahedron 64 (2008) 6698–6704
Table 2
3.2. A representative procedure for the synthesis of 2-
methylsulfanyl-3-acetyl-4-methanesulfonyloxyquinolines (2)
Summary of the reactions of 2-methylsulfinyl-3-acyl-1H-quinolin-4-one 3 with
amines to form 2-amino-4-quinolinones 5
O
O
O
O
To a solution of 2-methylsulfanyl-3-acetyl-1H-quinolin-4-one
(1a) (800 mg, 3.43 mmol) and Et3N (714
CH2Cl2 (10 mL) was added slowly methanesulfonyl chloride
(319
L, 4.12 mmol) at 0 ꢀC. The reaction mixture was stirred
mL, 5.14 mmol) in dry
R3
THF or
R3
R1
X
X
+
R1R2NH
1,2-Dichlorobenzene
N
H
SMe
O
N
H
N
R2
m
at 0 ꢀC for 0.5 h and then at ambient temperature for 4.5 h.
The reaction was quenched with H2O and extracted with diethyl
ether twice. The combined organic layer was washed successively
with saturated aq NaHCO3 and brine, and dried over anhydrous
MgSO4 and concentrated in vacuo to give a residue, which was
subjected to flash chromatography on silica gel (n-hexane/ ethyl
acetate¼3/1) to afford the desired product 2a (830 mg, 78%) as a
white solid.
3
5
Entry
Number
X
R3
R1R2NH
Yield (%)a
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
6-Cl
6-Cl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
PhCH2NH2
Morpholine
(CH3)2CHCH2NH2
PhCH2NH2
Morpholine
(CH3)2CHCH2NH2
PhCH2NH2
Morpholine
(CH3)2CHCH2NH2
PhCH2NH2
(CH3)2CHCH2NH2
PhNH2
85
66
87
73
63
60
90
76
75
50
50
75b
79b
82
76
70
66
70
6-Cl
6-Cl-8-CF3
6-Cl-8-CF3
6-Cl-8-CF3
5-NO2-8-Cl
5-NO2-8-Cl
H
8-Me
8-Cl
H
8-Me
3.2.1. 2-Methylsulfanyl-3-acetyl-4-methanesulfonyloxyquino-
line (2a)
9
10
11
12
13
14
15
16
17
18
5j
Yield: 78%; white needle; mp: 117–119 ꢀC; 1H NMR (CDCl3,
5k
5m
5n
5o
5p
5q
5r
300 MHz)
d
8.14 (d, J¼8.7 Hz, 1H), 7.99 (d, J¼8.4 Hz, 1H), 7.76 (t,
Ph(Me)NH
i-PrNH2
J¼7.1 Hz, 1H), 7.56 (t, J¼7.1 Hz, 1H), 3.32 (s, 3H), 2.74 (s, 3H),
2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) 200.19, 156.40, 149.50,
148.40, 131.58, 127.97, 127.09, 126.76, 123.43, 120.53, 39.36, 31.90,
13.75; MS (EI): m/z 311 (Mþ), 296 (40), 232 (100), 218 (67), 217
(21), 202 (44), 199 (27), 198 (38), 172 (20), 130 (21), 114
(21); HRMS (EI): m/z calcd for C13H13NO4S2 311.0286, found
311.0286.
Ph
i-BuNH2
Me
Ph
Me
Me2NH
Morpholine
t-BuNH2
H
7,8-F2
5s
a
Reaction was performed in THF solvent at rt for 24 h.
Reaction was performed in 1,2-dichlorobenzene solvent under reflux for 24 h.
b
3.2.2. 6-Chloro-2-methylsulfanyl-3-acetyl-4-
methanesulfonyloxyquinoline (2b)
ketoxime 6 of 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1 via an
indium(III) chloride promoted Beckmann rearrangement.8 Thus,
when combined with our previous work in this area, the current
effort rounds out a complete plan for the selective synthesis of the
isomeric 2-, 3-, and 4-aminoquinoline derivatives starting from the
common 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1 (Fig. 4).
In summary, a facile method has been developed for the
synthesis of 2- and 4-aminoquinoline derivatives beginning with
the common 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1. The
procedures involve initial selective activation of 2- or 4-substituent
present in 1 and subsequent reaction with amines. Since a
procedure to produce 3-aminoquinolinones from 4-quinolinone 1
has been described earlier,8 the chemistry reported above com-
pletes the development of sequences for the selective synthesis of
isomeric 2-, 3-, and 4-aminoquinoline derivatives starting with the
common 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1.
Yield: 86%; white solid; mp: 175–177 ꢀC; 1H NMR (CDCl3,
300 MHz)
d
8.08 (s,1H), 7.92 (d, J¼9.0 Hz,1H), 7.68 (d, J¼9.0 Hz,1H),
3.33 (s, 3H), 2.71 (s, 6H); 13C NMR (75 MHz, CDCl3) 199.77, 156.98,
147.82, 147.28, 132.74, 132.48, 129.51, 127.87, 122.45, 121.39, 39.44,
31.80, 13.76; MS (EI): m/z 345 (13), 330 (25), 266 (100), 252 (54),
251 (31), 236 (37), 232 (45), 148 (14); HRMS (EI): m/z calcd for
C13H12ClNO4S2 344.9896, found 344.9894.
3.2.3. 6-Chloro-8-trifluoromethyl-2-methylsulfanyl-3-acetyl-4-
methanesulfonyloxyquinoline (2c)
Yield: 90%; white solid; mp: 228–229 ꢀC; 1H NMR (CDCl3,
300 MHz) d 8.23 (s,1H), 8.03 (s,1H), 3.36 (s, 3H), 2.73 (s, 3H), 2.72 (s,
3H); 13C NMR (75 MHz, CDCl3) 199.14, 159.01, 147.07, 143.82, 131.44,
130.96, 130.89, 128.52, 126.74, 122.39, 39.54, 31.66, 13.95; MS m/z
413 (7), 398 (20), 334 (100), 314 (41), 300 (46), 284 (34), 272 (14),
181 (12), 143 (11), 79 (12); HRMS (EI): m/z calcd for
C
14H11ClF3NO4S2 412.9770, found 412.9759.
3. Experimental section
3.1. General
3.2.4. 5-Nitro-8-chloro-2-methylsulfanyl-3-acetyl-4-
methanesulfonyloxyquinoline (2d)
Yield: 69%; yellow solid; mp: 160–162 ꢀC; 1H NMR (CDCl3,
Flash column chromatography was performed on silica gel
(230–400 mesh, Merck). THF was refluxed over sodium in the
presence of benzophenone and distilled prior to use. CH2Cl2 was
distilled from calcium hydride. All other reagent grade chemicals
were obtained from commercial sources and used as-received. 2-
Methylsulfanyl-3-acyl-1H-quinolin-4-ones were prepared by using
the literature procedure.9
300 MHz)
d
7.90 (d, J¼8.7 Hz, 1H), 7.76 (d, J¼8.4 Hz, 1H), 3.27 (s,
3H), 2.78 (s, 3H), 2.73 (s, 3H); 13C NMR (75 MHz, CDCl3) 197.57,
161.63, 145.03, 137.75, 130.82, 129.72, 122.34, 38.27, 31.53, 14.32;
MS m/z 390 (Mþ), 311 (100), 297 (17), 235 (16), 232 (15), 79
(13); HRMS (EI): m/z calcd for C13H11ClN2O6S2 389.9749, found
389.9748.
O
O
O
O
NOH
SMe
O
NH2
N
c
a
b
X
X
X
X
N
H
SMe
N
H
SMe
N
H
N
7
SMe
1
6
8
Figure 4. Synthesis of 3-amino-4-quinolinone 8 from 2-methylsulfanyl-3-acyl-1H-quinolin-4-one 1.8 (a) NH2OH, EtOH; (b) InCl3, CH3CN; (c) 5% HCl, reflux.

B.H. Hwang et al. / Tetrahedron 64 (2008) 6698–6704
6701
3.3. Preparation of 2-methylsulfanyl-3-acetyl-4-
aminoquinolines (4): a representative procedure for
amination of 2-methylsulfanyl-3-acetyl-4-
methanesulfonyloxyquinoline (2)
(24), 128 (27); HRMS (EI): m/z calcd for C16H17ClN2O2S 336.0699,
found 336.0687.
3.3.6. 6-Chloro-2-methylsulfanyl-3-acetyl-4-isobutylamino-
quinoline (4f)
To a mixture of 2a (310 mg, 1 mmol) and potassium carbonate
Yield: 66%; light brown solid; mp: 101–103 ꢀC; 1H NMR (CDCl3,
(400 mg, 3.9 mmol) in 30 mL of methylene chloride was added
300 MHz)
d
7.88 (s, 1H), 7.75 (d, J¼8.7 Hz, 1H), 7.53 (d, J¼8.7 Hz, 1H),
morpholine (100
mL, 1.2 mmol). The reaction mixture was stirred at
7.08 (br s, 1H), 3.30 (dd, J¼5.4, 0.9 Hz, 1H), 2.70 (s, 3H), 2.65 (s, 3H),
1.95–1.84 (m, 1H), 1.00 (s, 3H), 0.99 (s, 3H); 13C NMR (75 MHz,
CDCl3) 203.18, 158.36, 150.94, 146.74, 131.13, 130.17, 129.15, 122.62,
119.64, 115.74, 56.48, 32.36, 30.07, 21.13, 14.02; MS m/z 322 (Mþ),
322 (19), 307 (100), 279 (42), 264 (30), 251 (24), 233 (17), 163 (11);
HRMS (EI): m/z calcd for C16H19ClN2O2S 322.0907, found 322.0900.
reflux until the starting material was totally consumed (1 day). The
reaction was quenched with H2O and extracted with methylene
chloride three times. The methylene chloride extracts were dried
over anhydrous MgSO4 and concentrated in vacuo giving a residue,
which was subjected to flash chromatography on silica gel using
a gradient elution of n-hexane/ethyl acetate (10/1) to give product
4b (260 mg, 90%).
3.3.7. 6-Chloro-8-trifluoromethyl-2-methylsulfanyl-3-acetyl-4-
benzylamino-quinoline (4g)
3.3.1. 2-Methylsulfanyl-3-acetyl-4-benzylamino-quinoline (4a)
Yield: 66%; white solid; mp: 110–111 ꢀC; 1H NMR (CDCl3,
Yield: 51%; white solid; mp: 141–143 ꢀC; 1H NMR (CDCl3,
300 MHz) d 8.05 (s, 1H), 7.91 (s, 1H), 7.38–7.35 (m, 3H), 7.27–7.24
300 MHz)
d
7.87 (d, J¼7.8 Hz, 2H), 7.65–7.60 (m, 1H), 7.36–7.26
(m, 2H), 6.86 (br s, 1H), 4.55 (d, J¼5.7 Hz, 2H), 2.68 (s, 3H), 2.61 (s,
3H); 13C NMR (75 MHz, CDCl3) 203.08, 159.58, 149.74, 143.22,
137.70, 129.78, 129.70, 129.19, 128.32, 128.17, 127.66, 126.84, 120.40,
118.27, 53.22, 32.20, 14.07; MS m/z 424 (Mþ), 409 (52), 391 (12), 106
(9), 91 (100), 65 (19); HRMS (EI): m/z calcd for C20H16ClF3N2OS
424.0624, found 424.0482.
(m, 6H), 6.59 (br s, 1H), 4.57 (d, J¼5.4 Hz, 2H), 2.69 (s, 3H), 2.63 (s,
3H); 13C NMR (75 MHz, CDCl3) 203.79, 157.21, 150. 45, 148.24,
138.38, 130.57, 129.02, 128.75, 128.01, 127.66, 124.25, 122.85, 118.66,
117.59, 53.06, 32.23, 13.89; MS m/z 322 (Mþ), 218 (100), 171 (42),
89 (30); HRMS (EI): m/z calcd for C19H18N2OS 322.1140, found
322.1158.
3.3.8. 6-Chloro-8-trifluoromethyl-2-methylsulfanyl-3-acetyl-4-
morpholino-quinoline (4h)
3.3.2. 2-Methylsulfanyl-3-acetyl-4-morpholino-quinoline (4b)
Yield: 91%; white solid; mp: 151–156 ꢀC; 1H NMR (CDCl3,
Yield: 66%; light yellow solid; mp: 157–160 ꢀC; 1H NMR (CDCl3,
300 MHz)
d
8.03 (d, J¼8.7 Hz, 1H), 7.95 (d, J¼8.4 Hz, 1H), 7.65 (t,
300 MHz)
d
8.17 (s, 1H), 7.94 (s, 1H), 3.89 (t, J¼4.4 Hz, 4H), 3.23 (t,
J¼7.1 Hz, 1H), 7.43 (t, J¼7.1 Hz, 1H), 3.87 (t, J¼4.5 Hz, 4H), 3.02 (t,
J¼4.5 Hz, 4H), 2.68 (s, 3H), 2.66 (s, 3H); 13C NMR (75 MHz, CDCl3)
204.29, 155.82, 150.92, 149.56, 130.31, 130.19, 129.13, 125.38, 124.30,
123.60, 67.75, 52.36, 33.18, 31.13,13.57; MS m/z 302 (Mþ), 287 (100),
251 (59), 229 (38), 202 (32),128 (48),127 (38); HRMS (EI): m/z calcd
for C16H18N2O2S 302.1089, found 302.1070.
J¼4.2 Hz, 4H), 2.68 (s, 3H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3)
203.00, 158.25, 149.81, 143.83, 130.77, 129.61, 129.36, 129.28, 127.33,
125.04, 67.34, 52.20, 32.95, 30.92, 13.54; MS m/z 404 (Mþ), 389
(100), 369 (27), 355 (67), 327 (41), 311 (28), 211 (28); HRMS (EI):
m/z calcd for C17H16ClF3N2O2S 404.0573, found 404.0553.
3.3.9. 6-Chloro-8-trifluoromethyl-2-methylsulfanyl-3-acetyl-4-
isobutylamino-quinoline (4i)
3.3.3. 2-Methylsulfanyl-3-acetyl-4-isobutylamino-quinoline (4c)
Yield: 75%; light brown solid; mp: 65–66 ꢀC; 1H NMR (CDCl3,
Yield: 61%; white solid; mp: 135–137 ꢀC; 1H NMR (CDCl3,
300 MHz)
d
7.92 (d, J¼8.7 Hz, 1H), 7.82 (d, J¼8.1 Hz, 1H), 7.61 (t,
300 MHz)
d
8.09 (s, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 3.33 (t, J¼5.9 Hz,
J¼8.1 Hz, 1H), 7.32 (t, J¼8.3 Hz, 1H), 7.24 (br s, 1H), 3.32 (t, J¼5.9 Hz,
2H), 2.70 (s, 3H), 2.66 (s, 3H), 1.95–1.86 (m, 1H), 1.00 (s, 3H), 0.98 (s,
3H); 13C NMR (75 MHz, CDCl3) 203.23, 157.94, 152.05, 148.29,
130.59, 128.64, 123.70, 123.28, 118.39, 115.21, 56.62, 32.32, 30.06,
20.12, 14.02; MS m/z 288 (Mþ), 271 (58), 245 (20), 149 (48), 81 (53);
HRMS (EI): m/z calcd for C16H20N2OS 288.1296, found 288.1269.
2H), 2.74 (s, 3H), 2.66 (s, 3H), 1.96–1.89 (m, 1H), 1.01 (s, 3H), 0.99 (s,
3H); 13C NMR (75 MHz, CDCl3) 202.62, 160.40, 151.68, 143.37,
129.76, 129.68, 127.40, 127.34, 120.04, 115.47, 56.83, 32.45, 30.14,
20.08, 14.24; MS m/z 390 (Mþ), 375 (100), 357 (18), 347 (29), 329
(23), 299 (18), 281 (11), 210 (8); HRMS (EI): m/z calcd for
C17H18ClF3N2OS 390.0780, found 390.0769.
3.3.4. 6-Chloro-2-methylsulfanyl-3-acetyl-4-benzylamino-
quinoline (4d)
3.3.10. 5-Nitro-8-chloro-2-methylsulfanyl-3-acetyl-4-
benzylamino-quinoline (4j)
Yield: 47%; white solid; mp: 125–127 ꢀC; 1H NMR (CDCl3,
Yield: 95%; yellow solid; mp: 128–130 ꢀC; 1H NMR (CDCl3,
300 MHz)
d
7.85 (s, 1H), 7.79 (d, J¼9.0 Hz,1H), 7.55 (d, J¼9.0 Hz, 1H),
300 MHz)
d
7.77 (d, J¼8.1 Hz,1H), 7.67 (d, J¼8.4 Hz,1H), 7.32–7.27 (m,
7.37–7.32 (m, 3H), 7.26–7.24 (m, 2H), 6.39 (t, J¼5.4 Hz, 1H, –NH–),
4.53 (d, J¼5.7 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H); 13C NMR (75 MHz,
CDCl3) 203.63, 157.59, 149.21, 146.67, 138.05, 131.12, 130.26, 129.83,
129.08, 128.15, 127.73, 122.23, 119.57, 118.37, 52.99, 32.20, 13.84; MS
m/z 356 (Mþ), 341 (72), 323 (17), 265 (9), 163 (10), 106 (10), 91
(100), 65 (15); HRMS (EI): m/z calcd for C19H17ClN2OS 356.0750,
found 356.0531.
3H), 7.04–7.01 (m, 2H), 4.26 (d, J¼5.7 Hz, 2H), 2.78 (s, 3H), 2.60 (s,
3H); 13C NMR (75 MHz, CDCl3) 202.20, 161.46, 150.93, 147.17, 144.94,
138.20, 137.06, 128.99, 128.92, 128.24, 127.61, 120.55, 111.36, 53.30,
31.98, 14.41; MS m/z 401 (Mþ), 386 (10), 106 (6), 91 (100), 65 (7);
HRMS (EI): m/z calcd for C19H16ClN3O3S 401.0601, found 401.0589.
3.3.11. 5-Nitro-8-chloro-2-methylsulfanyl-3-acetyl-4-
isobutylamino-quinoline (4k)
3.3.5. 6-Chloro-2-methylsulfanyl-3-acetyl-4-morpholino-
quinoline (4e)
Yield: 90%; yellow solid; mp: 120–123 ꢀC; 1H NMR (CDCl3,
300 MHz)
d
8.34 (br s, 1H), 7.73 (d, J¼8.4 Hz, 1H), 7.76 (d, J¼8.1 Hz,
Yield: 90%; white solid; mp: 135–137 ꢀC; 1H NMR (CDCl3,
1H), 2.98 (t, J¼5.9 Hz, 2H), 2.76 (s, 3H), 2.74 (s, 3H), 1.78–1.67 (m,
1H), 0.85 (s, 3H), 0.83 (s, 3H); 13C NMR (75 MHz, CDCl3) 201.63,
162.07, 153.24, 147.29, 144.98, 138.34, 128.87, 120.12, 115.65, 110.22,
55.81, 32.57, 30.02, 19.80, 14.67; MS m/z 367 (Mþ), 352 (57), 324
(80), 292 (33), 280 (89), 263 (100), 250 (42), 236 (24), 163 (26);
HRMS (EI): m/z calcd for C16H18ClN3O3S 367.0757, found 367.0749.
300 MHz)
d
7.98 (s, 1H), 7.88 (d, J¼9.0 Hz,1H), 7.58 (d, J¼9.0 Hz, 1H),
3.88 (t, J¼4.4 Hz, 4H), 3.26 (t, J¼4.4 Hz, 4H), 2.66 (s, 3H), 2.66 (s,
3H); 13C NMR (75 MHz, CDCl3) 203.61, 156.23, 149.81, 147.64,
130.94, 130.71, 130.60, 130.41, 124.19, 123.16, 67.64, 52.06, 32.94,
13.36; MS m/z 336 (Mþ), (27), 321 (100), 285 (29), 263 (27), 163

6702
B.H. Hwang et al. / Tetrahedron 64 (2008) 6698–6704
3.4. Preparation of 2-methylsulfinyl-3-acyl-1H-quinolin-4-
ones (3): a representative procedure for oxidation of 2-
methylsulfanyl-3-acyl-1H-quinolin-4-ones (1)
(s, 3H), 1.81 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 202.077,
176.205, 161.983, 134.309, 133.241, 129.319, 126.523, 126.179,
123.730, 114.778, 44.040, 36.909, 8.008; MS (EI): m/z 297 (Mþ), 280,
264, 253, 225, 206, 179, 148, 114, 75; HRMS (EI): m/z calcd for
To a well stirred suspension of 2-methylsulfanyl-3-acyl-1H-qui-
nolin-4-one (1a) (1.17 g, 5 mmol) in acetic acid (30 mL) was added
hydrogen peroxide (35%,1.1 mL, 12.5 mmol). Stirring was continued
for 24 h at room temperature. The reaction mixture was poured
into ice-water and precipitated solid was collected by filtration. The
solid product was washed with water several times and dried. The
solid was pure enough to use in next step or can be purified by re-
crystallization (EtOH) or chromatography on silica gel.
C13H12ClNO3S 297.0226, found 297.0213.
3.4.7. 7,8-Difluoro-2-methylsulfinyl-3-acetyl-1H-quinolin-4-
one (3g)
Yield: 80%; mp: 187–189 ꢀC; TLC Rf 0.14 (hexane/EtOAc¼3/1); 1H
NMR (300 MHz, CDCl3) d 10.84 (br s, 1H), 8.21 (m, 1H), 7.33 (m, 1H),
3.02 (s, 3H), 2.81 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 198.74,
175.23, 162.19, 153.55, 153.48, 151.51, 151.44, 141.01, 140.89, 138.99,
138.87,128.70,128.67,128.62,128.59,124.88,123.60,123.56,123.53,
123.50,115.68,115.53,115.27, 43.75, 31.56 (because of coupling with
fluorine atoms, more peaks appeared than the actual numbers of
carbon atom); MS (EI): m/z 285 (Mþ), 268, 254, 239, 224, 194, 180,
166, 150, 125, 112, 57; HRMS (EI): m/z calcd for C12H9F2NO3S
285.0271, found 285.0991.
3.4.1. 2-Methylsulfinyl-3-acetyl-1H-quinolin-4-one (3a)
Yield: 98%; mp: 228–229 ꢀC; TLC Rf 0.07 (hexane/EtOAc¼3/1);
1H NMR (300 MHz, CDCl3)
d
10.60 (br s, 1H), 8.46 (d, J¼7.8 Hz, 1H),
7.76 (t, J¼8.1 Hz,1H), 7.55 (m, 2H), 3.01 (s, 3H), 2.82 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 198.964, 176.654, 141.192, 137.115, 133.576,
127.759, 127.213, 126.543, 118.516, 114.535, 43.685, 31.413; MS (EI):
m/z 249 (Mþ), 232, 218, 191, 158, 130, 114, 89; HRMS (EI): m/z calcd
for C12H11NO3S 249.0460, found 249.0475.
3.4.8. 2-Methylsulfinyl-3-benzoyl-1H-quinolin-4-one (3h)
Yield: 83%; mp: 239–240 ꢀC; TLC Rf 0.34 (hexane/EtOAc¼3/1);
1H NMR (300 MHz, CDCl3)
d
10.42 (br s, 1H), 8.39 (d, J¼8.1 Hz, 1H),
3.4.2. 6-Chloro-2-methylsulfinyl-3-acetyl-1H-quinolin-4-one (3b)
Yield: 88%; mp: 241–243 ꢀC; TLC Rf 0.36 (hexane/EtOAc¼3/1);
7.76 (m, 3H), 7.52 (m, 5H), 3.18 (s, 3H); 13C NMR (125 MHz, CDCl3)
193.98, 175.70, 159.81, 138.23, 137.56, 133.65, 132.74, 129.04,
d
1H NMR (300 MHz, CDCl3)
d
10.65 (br s, 1H), 8.42 (d, J¼2.1 Hz, 1H),
128.08, 127.57, 127.34, 126.30, 118.40, 44.42, 30.91; MS (EI): m/z 311
(Mþ), 296, 264, 248, 220, 202, 190, 165, 105, 77, 57; HRMS (EI): m/z
calcd for C17H13NO3S 311.0616, found 311.0610.
7.70 (dd, J¼8.7, 2.4 Hz, 1H), 7.55 (d, J¼9.0 Hz, 1H), 3.02 (s, 3H), 2.81
(s, 3H); 13C NMR (125 MHz, CDCl3)
d
198.996, 175.667, 161.567,
135.735, 134.163, 133.070, 129.094, 127.054, 120.309, 114.850,
45.639, 31.137; MS (EI): m/z 283 (Mþ), 266, 252, 222, 192, 88, 75, 55;
HRMS (EI): m/z calcd for C12H10ClNO3S 283.007, found 283.0069.
3.5. Preparation of 2-amino-3-acyl-1H-quinolin-4-one (5)
A representative procedure for amination of 2-methylsulfinyl-3-
acyl-1H-quinolin-4-one (3) with alkylamines. A solution of 2-meth-
ylsulfinyl-3-acetyl-1H-quinolin-4-one (3a) (1.2 g, 4.9 mmol) and
benzylamine (0.53 g, 4.9 mmol) in 20 mL of anhydrous THF was
stirred at room temperature for 24 h and concentrated in vacuo
giving a residue, which was dissolved in ethyl acetate. The ethyl
acetate solution was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated, in vacuo giving a residue, which
was subjected to flash chromatography on silica gel with n-hexane/
ethyl acetate to give pure product 5a (1.2 g, 85%).
3.4.3. 6-Chloro-8-trifluoromethyl-2-methylsulfinyl-3-acetyl-1H-
quinolin-4-one (3c)
Yield: 89%; mp: 202–203 ꢀC; TLC Rf 0.63 (hexane/EtOAc¼3/1);
1H NMR (300 MHz, CDCl3)
d
11.21 (br s, 1H), 8.63 (d, J¼2.7 Hz, 1H),
8.00 (d, J¼2.4 Hz, 1H), 3.01 (s, 3H), 2.81 (s, 3H); 13C NMR (125 MHz,
CDCl3)
d 198.285, 174.385, 162.345, 132.549, 131.884, 131.519,
131.452, 131.141, 130.181, 124.399, 115.096, 43.549, 31.403; MS (EI):
m/z 351 (Mþ), 334, 320, 293, 90, 268, 143, 84, 64; HRMS (EI): m/z
calcd for C13H9ClF3NO3S 350.9944, found 350.9927.
A representative procedure for amination of 2-methylsulfinyl-3-
acyl-1H-quinolin-4-one (3) with aromatic amine. A solution of 2-
methylsulfinyl-3-acetyl-1H-quinolin-4-one (3a) (1.0 g, 4 mmol)
3.4.4. 5-Nitro-8-chloro-2-methylsulfinyl-3-acetyl-1H-quinolin-4-
one (3d)
Yield: 69%; mp: 263–264 ꢀC; TLC Rf 0.37 (hexane/EtOAc¼3/1);
and aniline (483 mL, 4 mmol) in 20 mL of anhydrous 1,2-di-
1H NMR (300 MHz, CDCl3)
d
11.30 (br s, 1H), 7.89 (d, J¼8.4 Hz, 1H),
chlorobenzene was stirred at reflux for 24 h and concentrated in
vacuo to give a residue, which was dissolved in ethyl acetate. The
ethyl acetate solution was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated in vacuo giving a residue, which
was subjected to flash chromatography on silica gel with n-hexane/
ethyl acetate to give pure product 5m (0.84 g, 75%).
7.43 (d, J¼8.1 Hz, 1H), 3.04 (s, 3H), 2.75 (s, 3H); 13C NMR (125 MHz,
CDCl3)
d 198.334, 173.060, 162.522, 148.098, 135.240, 133.069,
126.252, 120.269, 120.200, 116.101, 43.734, 31.600; MS (EI): m/z 328
(Mþ), 311, 297, 270, 251, 229, 109, 74; HRMS (EI): m/z calcd for
C
12H9ClN2O5S 327.9921, found 327.9927.
3.4.5. 8-Methyl-2-methylsulfinyl-3-acetyl-1H-quinolin-4-one (3e)
Yield: 80%; mp: 208–210 ꢀC; TLC Rf 0.38 (hexane/EtOAc¼3/1);
3.5.1. 2-Benzylamino-3-acetyl-1H-quinolin-4-one (5a)
Yield: 85%; mp: 213–215 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 12.00
1H NMR (300 MHz, CDCl3)
d
10.79 (br s, 1H), 8.31 (d, J¼8.1 Hz, 1H),
(br s, 1H), 8.26 (d, J¼7.8 Hz, 1H), 7.75 (br s, 1H), 7.45–7.34 (m, 6H),
7.23 (t, J¼7.4 Hz, 1H), 6.90 (d, J¼8.1 Hz, 1H), 4.64 (d, J¼5.5 Hz, 2H),
2.80 (s, 3H); 13C NMR (75 MHz, CDCl3) 201.37, 177.14, 156.29, 136.18,
135.31, 132.21, 129.59, 128.67, 127.01, 126.86, 124.28, 123.88, 115.41,
101.78, 45.35, 33.47; MS (EI): m/z 292 (Mþ), 277 (29), 201 (36), 172
(45), 106 (73), 91 (100); HRMS (EI): m/z calcd for C18H16N2O2
292.1212, found 292.1213.
7.58 (d, J¼7.2 Hz, 1H), 7.43 (t, J¼8.1 Hz, 1H), 3.03 (s, 3H), 2.83 (s, 3H),
2.65 (s, 2H); 13C NMR (125 MHz, CDCl3)
d
202.343, 178.737, 160.629,
135.976, 134.575, 128.060, 126.805, 126.392, 125.327, 114.415,
43.863, 31.607, 17.713; MS (EI): m/z 263 (Mþ), 246, 232, 200, 182,
113, 98, 69, 56; HRMS (EI): m/z calcd for C13H13NO3S 263.0616,
found 263.0613.
3.4.6. 8-Chloro-2-methylsulfinyl-3-propionyl-1H-quinolin-4-
one (3f)
3.5.2. 2-Morpholino-3-acetyl-1H-quinolin-4-one (5b)
Yield: 66%; mp: 200–202 ꢀC; 1H NMR (CDCl3, 300 MHz)
d
13.84
(s,1H), 8.18 (d, J¼8.2 Hz,1H), 7.68 (m, 2H), 7.33 (m,1H), 3.87 (m, 4H),
3.41(m, 4H), 2.77 (s, 3H); 13C NMR(125 MHz, CDCl3)
204.27,168.58,
159.64, 148.73, 133.11, 127.22, 123.98, 123.76, 117.72, 105.10, 66.50,
Yield: 78%; mp: 186–187 ꢀC; TLC Rf 0.67 (hexane/EtOAc¼3/1);
1H NMR (300 MHz, CDCl3)
d
11.18 (br s, 1H), 8.36 (d, J¼8.1 Hz, 1H),
d
7.89 (d, J¼7.8 Hz, 1H), 7.46 (t, J¼8.1 Hz, 1H), 3.46–3.17 (m, 2H), 3.04

B.H. Hwang et al. / Tetrahedron 64 (2008) 6698–6704
6703
51.75, 28.11; MS (EI): m/z 272 (Mþ), 257, 227, 215,197,172,145, 86, 58;
HRMS (EI): m/z calcd for C15H16N2O3 272.1161, found 272.1191.
2H), 2.76 (s, 3H), 2.11–2.04 (m, 1H), 1.12 (s, 3H), 1.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) 201.26, 174.35, 155.68, 132.05, 131.60, 129.81,
129.76, 129.17, 127.34, 101.34, 48.59, 33.46, 28.33, 20.43; MS (EI):
m/z 360 (Mþ), 345 (76), 317 (100), 297 (70), 279 (21), 72 (31); HRMS
(EI): m/z calcd for C16H16N2O2F3Cl 360.0852, found 360.0849.
3.5.3. 2-Isobutylamino-3-acetyl-1H-quinolin-4-one (5c)
Yield: 87%; mp: 203–205 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 11.65
(br s, 1H), 8.41 (br s, 1H), 8.2 (d, J¼8.0 Hz, 1H), 7.51–7.47 (m, 1H),
7.25–7.22 (m, 2H), 3.19 (t, J¼5.8 Hz, 2H), 2.80 (s, 3H), 2.06–2.02 (m,
1H), 1.05 (s, 3H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl3) 201.08,
177.35, 155.97, 132.33, 126.86, 124.10, 123.66, 115.62, 101.52, 48.74,
33.54, 30.97, 28.01, 20.31; MS (EI): m/z 258 (Mþ), 243 (33), 215
(100), 202 (30), 197 (35), 187 (29); HRMS (EI): m/z calcd for
3.5.10. 2-Benzylamino-5-nitro-8-chloro-3-acetyl-1H-quinolin-4-
one (5j)
Yield: 50%; mp: 260–261 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 12.13
(br s, 1H), 7.97 (br s, 1H), 7.54 (d, J¼13.5 Hz, 1H), 7.46–7.39 (m, 5H),
7.10 (d, J¼13.5 Hz, 1H), 4.70 (d, J¼9.0 Hz, 2H), 2.71 (s, 3H); 13C NMR
(75 MHz, CDCl3) 201.49, 155.88, 134.39, 133.99, 131.49, 129.96,
129.34, 127.36, 122.21, 117.74, 101.89, 45.94, 33.46; MS (EI): m/z 371
(Mþ), 353 (8), 323 (7), 247 (4), 206 (6), 91 (100), 65 (11); HRMS (EI):
m/z calcd for C18H14ClN3O4 371.0673, found 371.0693.
C
15H18N2O2 258.1368, found 258.1363.
3.5.4. 2-Benzylamino-6-chloro-3-acetyl-1H-quinolin-4-one (5d)
Yield: 73%; mp: 231–232 ꢀC; TLC Rf 0.45 (hexane/EtOAc¼1/1);
1H NMR (300 MHz, CDCl3)
d 12.00 (br s, 1H), 8.22 (s, 1H), 7.65 (br s,
1H), 7.40 (m, 6H), 6.84 (d, J¼8.4 Hz, 1H), 4.64 (d, J¼5.7 Hz, 2H), 2.78
3.5.11. 2-Isobutylamino-5-nitro-8-chloro-3-acetyl-1H-quinolin-4-
(s, 3H); 13C NMR (125 MHz, CDCl3)
d
201.45, 175.96, 156.36, 135.23,
one (5k)
134.73, 132.40, 129.87, 129.80, 128.92, 126.98, 126.80, 125.63, 117.10,
101.85, 45.55, 33.54, 29.87; MS (EI): m/z 326 (Mþ), 311, 283, 235,
206, 179, 106, 91, 65; HRMS (EI): m/z calcd for C18H15ClN2O2
326.0822, found 326.0818.
Yield: 50%; mp: 203–210 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 11.75 (br
s,1H), 7.99 (br s,1H), 7.63 (d, J¼8.4 Hz,1H), 7.13 (d, J¼8.4 Hz,1H), 3.23
(t, J¼5.9 Hz, 2H), 2.68 (s, 3H), 2.15–2.10 (m, 1H), 1.14 (s, 3H), 1.12 (s,
3H); 13C NMR (75 MHz, CDCl3) 201.29, 172.81, 155.21, 133.93, 131.49,
121.98, 117.66, 101.42, 48.79, 33.34, 31.12, 28.32, 20.54; MS (EI): m/z
337 (Mþ), 294 (34), 276 (66), 247 (100), 219 (36),129 (33),114 (35), 57
(57);HRMS(EI):m/zcalcdforC15H16N3O4Cl337.0827, found 337.0817.
3.5.5. 2-Morphorino-6-chloro-3-acetyl-1H-quinolin-4-one (5e)
Yield: 63%; mp: 220–222 ꢀC; TLC Rf 0.26 (hexane/EtOAc¼1/1);
1H NMR (300 MHz, CDCl3)
d 13.71 (s, 1H), 8.13 (s, 1H), 7.61 (m, 2H),
3.85 (t, J¼4.8 Hz, 4H), 3.41 (t, J¼4.8 Hz, 4H), 2.76 (s, 3H); 13C NMR
3.5.12. 2-Phenylamino-3-acetyl-1H-quinolin-4-one (5m)
(125 MHz, CDCl3)
d
204.55, 167.66, 159.82, 147.29, 133.76, 129.42,
Yield: 75%; mp: 210–211 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 13.11
128.93, 123.13, 118.54, 106.38, 66.59, 51.83, 28.23; MS (EI): m/z 306
(Mþ), 291, 289, 261, 249, 233, 206, 179, 164, 86, 58; HRMS (EI): m/z
calcd for C15H15ClN2O3 306.0771, found 306.0386.
(br s, 1H), 8.31 (d, J¼8.0 Hz, 1H), 7.70 (br s, 1H), 7.70–7.55 (m, 2H),
7.54–7.42 (m, 2H), 7.38–7.35 (m, 2H), 7.30–7.25 (m, 1H), 6.89 (d,
J¼7.8 Hz, 1H), 2.85 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 201.73,
177.31, 154.36, 135.81, 134.50, 132.34, 130.76, 128.15, 127.12, 126.31,
124.40, 101.50, 33.39; MS m/z 278 (Mþ), 263, 235, 205, 187, 120, 77,
65; HRMS (EI): m/z calcd for C17H14N2O2 278.1055, found 278.1048.
3.5.6. 2-Isobutylamino-6-chloro-3-acetyl-1H-quinolin-4-one (5f)
Yield: 60%; mp: 254–255 ꢀC; TLC Rf 0.43 (hexane/EtOAc¼1/1);
1H NMR (CDCl3, 300 MHz)
d
11.67 (br s, 1H), 8.22 (d, J¼2.3 Hz, 1H),
8.04 (br s, 1H), 7.43 (d, J¼8.5 Hz, 1H), 7.14 (d, J¼8.5 Hz, 1H), 3.17 (t,
3.5.13. 2-(N-Methyl-N-phenylamino)-8-methyl-3-acetyl-1H-
J¼6.3 Hz, 2H), 2.77 (s, 3H), 2.05 (m, 3H), 1.08 (s, 3H), 1.06 (s, 3H); 13
C
quinolin-4-one (5n)
NMR (75 MHz, CDCl3) 201.21, 176.02, 155.93, 135.01, 132.43, 129.68,
126.79, 125.55, 117.11, 101.58, 48.87, 33.53, 28.15, 20.47; MS (EI): m/z
292 (Mþ), 263 (100), 245 (23), 235 (32); HRMS (EI): m/z calcd for
Yield: 79%; mp: 229–230 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 13.02
(br s, 1H), 8.17 (d, J¼7.8 Hz, 1H), 7.86 (br s, 1H), 7.60–7.55 (m, 2H),
7.47–7.41 (m, 3H), 7.31 (d, J¼7.2 Hz,1H), 7.16 (t, J¼7.8 Hz,1H), 2.89 (s,
C
15H17ClN2O2 292.0979, found 292.1278.
3H), 2.11 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 201.84, 177.65, 153.98,
134.66,134.375,133.33,130.79,128.15,125.92,125.11,123.41,122.25,
101.26, 33.37, 30.94, 15.58; MS (EI): m/z 292 (Mþ), 277, 249, 201, 77;
HRMS (EI): m/z calcd for C18H16N2O2 292.1212, found 292.1209.
3.5.7. 2-Benzylamino-6-chloro-8-trifluoromethyl-3-acetyl-1H-
quinolin-4-one (5g)
Yield: 90%; mp: 167–170 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 12.16
(br s, 1H), 8.48 (s, 1H), 7.76 (br s, 1H), 7.68 (s, 1H), 7.45–7.36 (m, 5H),
4.65 (d, J¼5.7 Hz, 2H), 2.80 (s, 3H); 13C NMR (75 MHz, CDCl3)
201.48, 174.39, 156.26, 134.14, 131.98, 131.46, 129.83, 129.76, 129.28,
129.16, 127.43, 126.95, 101.74, 45.54, 33.56; MS (EI): m/z 394 (Mþ),
379 (21), 303 (7), 105 (49), 91 (95), 65 (24); HRMS (EI): m/z calcd for
3.5.14. 2-Isopropylamino-8-chloro-3-propionyl-1H-quinolin-4-
one (5o)
Yield: 82%; mp: 167–168 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 11.69
(br d, J¼6.3 Hz, 1H), 8.22 (d, J¼8.0 Hz, 1H), 7.96 (br s, 1H), 7.57 (d,
J¼7.9 Hz, 1H), 7.21 (t, J¼8.1 Hz, 1H), 3.89–3.82 (m, 1H), 3.27 (q,
J¼7.2 Hz, 2H), 1.49 (s, 3H), 1.46 (s, 3H), 1.17 (t, J¼7.2 Hz, 3H); 13C
C
19H14N2O2F3Cl 394.0696, found 394.0701.
NMR (125 MHz, CDCl3)
d 204.72, 176.30, 154.72, 132.93, 131.55,
3.5.8. 2-Morphorino-6-chloro-8-trifluoromethyl-3-acetyl-1H-
126.20, 125.82, 123.72, 119.68, 100.73, 43.47, 37.85, 22.84, 9.03; MS
(EI): m/z 292 (Mþ), 227, 263, 249, 221, 194, 179, 50; HRMS (EI): m/z
calcd for C15H17ClN2O2 292.0979, found 292.0206.
quinolin-4-one (5h)
Yield: 76%; mp: 150–152 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 13.69
(s, 1H, –NH–), 8.29 (s, 1H), 7.93 (s, 1H), 3.82 (t, J¼2.4 Hz, 4H), 3.54 (t,
J¼2.4 Hz, 4H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) 204.28,167.42,
159.11, 144.06, 132.01, 132.06, 127.68, 127.28, 119.19, 106.10, 66.49,
51.62, 31.12, 27.95; MS (EI): m/z 374 (Mþ), 361 (40), 359 (100), 339
(17), 331 (12), 317 (15), 86 (43); HRMS (EI): m/z calcd for
3.5.15. 2-Isobutylamino-3-benzoyl-1H-quinolin-4-one (5p)
Yield: 76%; mp: 301–303 ꢀC; 1H NMR (CDCl3þDMSO-d6,
300 MHz)
d
10.61 (t, J¼4.8 Hz, 1H), 9.85 (s, 1H), 8.12 (d, J¼7.5 Hz,
1H), 7.51–7.44 (m, 4H), 7.37–7.30 (m, 3H), 7.20–7.15 (m, 1H), 3.30
C
16H14N2O3F3Cl 374.0645, found 374.06521.
(dd, J¼6.6, 5.4 Hz, 2H), 2.06–2.02 (m, 1H), 1.10 (s, 3H), 1.08 (s, 3H);
13C NMR (125 MHz, CDCl3þDMSO-d6)
d 198.06, 176.61, 156.13,
3.5.9. 2-Isobutylamino-6-chloro-8-trifluoromethyl-3-acetyl-1H-
quinolin-4-one (5i)
143.72, 138.13, 131.83, 129.47, 127.62, 127.06, 126.37, 124.22, 122.96,
116.50, 100.47, 49.13, 28.13, 20.30; MS (EI): m/z 320 (Mþ), 305, 227,
263, 249, 235, 199, 187, 120, 91, 66; HRMS (EI): m/z calcd for
Yield: 75%; mp: 119–122 ꢀC; 1H NMR (CDCl3, 300 MHz)
d
11.76
(br s, 1H), 8.49 (s, 1H), 7.79 (br s, 1H), 7.76 (s, 1H), 3.15 (t, J¼6.0 Hz,
C20H20N2O2 320.1525, found 320.1499.

6704
B.H. Hwang et al. / Tetrahedron 64 (2008) 6698–6704
3.5.16. 2-Dimethylamino-8-methyl-3-acetyl-1H-quinolin-4-
one (5q)
Supplementary data
Yield: 70%; mp: 130–131 ꢀC; 1H NMR (CDCl3, 300 MHz)
d
13.72
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.05.014.
(br s, 1H), 7.99 (d, J¼7.2 Hz, 1H), 7.51 (d, J¼7.2 Hz, 1H), 7.16 (t,
J¼7.4 Hz, 1H), 3.03 (s, 6H), 2.66 (s, 3H), 2.62 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 204.856, 168.672, 148.249, 135.422, 133.345,
122.677, 121.779, 117.587, 42.483, 31.135, 27.846, 17.767; MS (EI):
m/z 244 (Mþ), 229, 211, 201, 186, 159, 130, 103, 77; HRMS (EI): m/z
calcd for C14H16N2O2 244.1212, found 244.1208.
References and notes
1. Larsen, R. D.; Marcoux, J.-F. Progress in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Pergamon: Oxford, UK, 2000; Vol. 12, p 237.
2. Raynes, K. J.; Stocks, P. A.; O’Neill, P. M.; Park, B. K.; Ward, S. A. J. Med. Chem.
1999, 42, 2747.
3. (a) Wilson, W. D.; Zhao, M.; Patterson, S. E.; Wydra, R. L.; Janda, L.; Strekowski,
L. Med. Chem. Res. 1992, 2, 102; (b) Strekowski, L.; Mokrosz, J. L.; Honkan, V. A.;
Czarny, A.; Cegla, M. T.; Wydra, R. L.; Patterson, S. E.; Schinazi, R. F. J. Med. Chem.
1991, 34, 1739.
4. Proctor, G. R.; Harvey, A. L. Curr. Med. Chem. 2000, 7, 295.
5. (a) Jiang, J.; Hoang, M.; Young, J. R.; Chaung, D.; Eid, R.; Turner, C.; Lin, P.; Tong,
X.; Wang, J.; Tan, C.; Feighner, S.; Palyha, O.; Hreniuk, D. L.; Pan, J.; Sailer, A. W.;
MacNeil, D. J.; Howard, A.; Shearman, L.; Stribling, S.; Camacho, R.; Van der
Ploeg, L. H. T.; Goulet, M. T.; DeVita, R. J. Bioorg. Med. Chem. Lett. 2006, 16, 5270;
(b) Jiang, J.; Lin, P.; Hoang, M.; Chang, L.; Tan, C.; Feighner, S.; Palyha, O. C.;
Hreniuk, D. L.; Pan, J.; Sailer, A. W.; Morin, N. R.; MacNeil, D. J.; Howard, A. D.;
Van der Ploeg, L. H. Y.; Goulet, M. T.; DeVita, R. J. Bioorg. Med. Chem. Lett. 2006,
16, 5275.
6. Boschelli, D. H.; Wang, Y. D.; Ye, F.; Wu, B.; Zhang, N.; Dutia, M.; Powell, D. W.;
Wissner, A.; Weber, J. M.; Boschelli, F. J. Med. Chem. 2001, 44, 822.
7. Wang, M.-X.; Liu, Y.; Huang, Z.-T. Tetrahedron Lett. 2001, 42, 2553.
8. Yoo, K. H.; Choi, E. B.; Lee, H. K.; Yeon, G. H.; Yang, H. C.; Pak, C. S. Synthesis
2006, 1599.
3.5.17. 2-Morphorino-3-benzoyl-1H-quinolin-4-one (5r)
Yield: 66%; mp: 315–317 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 12.68 (s,
1H), 8.20 (d, J¼8.4 Hz,1H), 7.74–7.68(m, 4H), 7.57 (d, J¼7.2 Hz, 1H), 7.44
(d, J¼7.2 Hz, 2H), 7.35–7.30 (m,1H), 3.24 (m, 4H), 3.12 (m, 4H); 13CNMR
(125 MHz,CDCl3)d199.22,168.34,158.86,149.37,137.67,133.13,133.04,
129.87, 127.99, 126.99, 123.88, 123.29, 117.26, 102.70, 65.79, 50.04; MS
(EI): m/z 334 (Mþ), 333, 316, 289, 275, 257, 248, 220, 213, 201, 145, 91,
77; HRMS (EI): m/z calcd for C20H18N2O3 334.1317, found 334.1314.
3.5.18. 2-tert-Butylamino-3-acetyl-7,8-difluoro-1H-quinolin-4-
one (5s)
Yield: 70%; mp: 227–228 ꢀC; TLC Rf 0.71 (hexane/EtOAc¼3/1);
1H NMR (300 MHz, CDCl3)
d 11.94 (br s, 1H), 8.03 (m, 1H), 7.77 (br s,
1H), 7.05 (q, J¼7.2 Hz, 1H), 2.75 (s, 3H), 1.62 (s, 9H); 13C NMR
(125 MHz, CDCl3)
d 201.08, 175.51, 155.27, 152.80, 152.72, 150.79,
9. (a) Pak, C. S.; Choi, E. B. Synthesis 1992, 1291; (b) Choi, E. B.; Yeon, G. H.; Lee, H.
K.; Yang, H. C.; Yoo, C. Y.; Pak, C. S. Synthesis 2003, 2771.
150.71, 137.14, 137.01, 126.99, 126.96, 126.89, 123.08, 123.05, 123.02,
122.98, 121.26, 111.88, 111.74, 101.43, 51.77, 33.48, 30.30 (because of
coupling with fluorine atoms, more peaks appeared than the actual
numbers of carbon atom); MS (EI): m/z 294 (Mþ), 279, 261, 237, 223,
196, 119, 86, 57; HRMS (EI): m/z calcd for C15H16F2N2O2 294.1180,
found 294.1176.
10. We depicted the structure of 5 as 2-amino-1H-quinolin-4-one based on the
structure of 1 as 2-ethylsulfanyl-1H-quinolin-4-one, which was unambiguously
determined by X-ray analysis (Ref. 9b). But some of 5 (5b, 5e, 5h, 5j, 5q, 5r)
seem to exist as 2-amino-quinolin-4-ol 10, since they show only one carbonyl
carbon (204–198 ppm) in 13C NMR spectra.
Acknowledgements
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This research was supported by grants from the Ministry of
Science and Technology of Korea and the Center for Biological
Modulators of the 21st Century Frontier R&D program, the Ministry
of Science and Technology of Korea (CBM32-A1200-00-00-00).
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10
2-Amino-1H-quinolin-4-one 2-Amino-quinolin-4-ol 2-Ethylsulfanyl-1H-quinolin-4-one