One-pot approach to 2,3-disubstituted-2,3-dihydro-4-quinolones from 2-alkynylbenzamides

Article abstract of DOI:10.1021/jo201636a

Concise and efficient syntheses of various trans-2,3-disubstituted-2,3- dihydro-4-quinolones have been achieved via tandem Hofmann-type rearrangement of 2-alkynylbenzamides, nucleophilic addition of alcohols to the isocyanate intermediates, intermolecular

Full text of DOI:10.1021/jo201636a

NOTE
pubs.acs.org/joc
One-Pot Approach to 2,3-Disubstituted-2,3-dihydro-4-quinolones
from 2-Alkynylbenzamides
Noriko Okamoto,†,‡ Kei Takeda,‡ Minoru Ishikura,§ and Reiko Yanada*,†
†Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
‡Department of Synthetic Organic Chemistry, Graduate School of Medical Sciences, Hiroshima University, 1-2-3 Kasumi,
Minami-Ku, Hiroshima 734-8553, Japan
§Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
S Supporting Information
b
ABSTRACT: Concise and efficient syntheses of various trans-
2,3-disubstituted-2,3-dihydro-4-quinolones have been achieved
via tandem Hofmann-type rearrangement of 2-alkynylbenza-
mides, nucleophilic addition of alcohols to the isocyanate
intermediates, intermolecular [2+2]-cycloaddition with carbonÀ
carbon triple bonds and aldehydes, and intramolecular aminocyclization of nitrogen of carbamates to the α,β-unsaturated
ketones.
umerous synthetic methodologies for quinolone syntheses
have been reported1 because the ring system constitutes a
hypervalent iodine (1 equiv) at 60 °C for 2 h, which is a
procedure required to ensure the completion of the Hofmann-
type rearrangement, benzaldehyde (1.5 equiv) and a Brønsted or
Lewis acid catalyst were added. Without the addition of an
external acid (Table 1, entry 1) and with Cu(OTf)2 (Table 1,
entry 2), the reaction stopped at the carbamate stage to give only
2a. Most of the other acids afforded the desired quinolone
derivative 4a with high trans-selectivity together with 2a and
ketone 5a,15 presumably produced from the acetic acid-catalyzed
hydrolysis of alkyne 2a, with various yields and in variable ratios.
N
basic structural unit of a large number of natural products,2
synthetic intermediates,3 and bioactive molecules including
antimitotic,4 antiviral,5 antibacterial,6 and anticancer7 agents
and HIV-1 integrase inhibitors.8 Similarly, 2,3-dihydro-4-quino-
lones possess attractive pharmacological properties9 and also are
used as important synthetic intermediates for the biologically
active compounds.10,11As part of our continuing interest in the
syntheses of biologically active compounds using a tandem
strategy, we have recently reported a procedure for the one-pot
platinum(II)-catalyzed synthesis of indoles and isoquinolines via
isocyanates, which were derived from a Hofmann-type rearran-
The best result was obtained with PhI(OCOCH3)2 and BF3
Et2O (1 equiv), which afforded 4a in 73% yield with high trans-
selectivity (Table 1, entry 7).
3
gement of amides 1 using a hypervalent iodine reagent.12
A
Having in hand the optimized conditions for the formation of
4a, we further explored the scope of this reaction, particularly in
regard to the substituents R1 and R4, alcohol R2OH, and
aldehyde R3CHO (Table 2). In most cases, moderate yields
and high trans-selectivities of 2,3-disubstituted-2,3-dihydro-4-
quinolones 416 were observed. In the presence of either elec-
tron-donating or moderately electron-withdrawing substituents
R4 on the aromatic ring of 2-alkynylbenzamides 1, the yields of
desired products 4 ranged from 72À81% (Table 2, entries 1À3).
However, the presence of the strongly electron-withdrawing
nitro group on the aromatic ring slowed the [2+2]-cycloaddition
reaction, giving carbamate 2e exclusively (Table 2, entry 4). The
use of benzyl alcohol as the nucleophile afforded only N-Cbz-
protected 4-quinolone 4f (Table 2, entry 5). When aliphatic
aldehydes were used, 4-quinolones were also obtained with high
trans-selectivities (Table 2, entries 10 and 11). 2-Alkynylbenza-
mides 1, bearing an aromatic substituent on the terminus of the
alkyne, also gave the corresponding 4-quinolone 4 in good yields
(Table 2, entries 14 and 15). When p-cyanobenzaldehyde or p-
significant feature of this strategy is that relatively stable alkyny-
lamides could be used as a starting material to efficiently furnish
the indoles and isoquinolines in combination with the Hofmann-
type rearrangement. As an extension of this approach, we now
report our successful stereoselective synthesis of trans-2,3-dihy-
dro-4-quinolones 4 featuring a tandem strategy that involves (1)
Hofmann-type rearrangement of 2-alkynylbenzamides 1 fol-
lowed by a nucleophilic addition of an alcohol to an isocyanate
intermediate (1 f 2), (2) acid-catalyzed intermolecular [2+2]-
cycloaddition with carbonÀcarbon triple bonds of carbamates 2
and aldehydes (2 f 3), and (3) acid-catalyzed intramolecular
aminocyclization to the α,β-unsaturated ketones (3 f 4)
(Scheme 1).
A key to the success of this approach is whether an acid
catalyst, required for the [2+2]-cycloaddition13,14 and the ami-
nocyclization, can tolerate the presence of coproducts generated
in the Hofmann-type rearrangement by the hypervalent iodine
reagent. To explore this possibility, we examined the reaction
using 1a, readily available from Sonogashira coupling of 2-iodo-
benzamide and 1-hexyne, as a substrate (Table 1). After the
treatment of 1a with EtOH (4 equiv) in the presence of
Received: August 5, 2011
Published: September 22, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201636a J. Org. Chem. 2011, 76, 9139–9143
|

The Journal of Organic Chemistry
NOTE
nitrobenzaldehyde were used as the aldehyde at 60 °C, inter-
molecular [2+2]-cycloaddition proceeded stereoselectively to
give only the corresponding trisubstituted enones 3q or 3r with
high (E)-selectivity13 accompanied by ketone 5a (Table 2,
entries 16 and 18). The configuration of the enone double bond
of 3 was assigned on the basis of NOESY experiments. Fortu-
nately, the same reactions at 90 °C gave the desired 4-quinolones
4q and 4r in high yields with trans-selectivities (Table 2, entries
17 and 19). To determine whether the trans-selectivity of the
formation of 4 depends on the E:Z-configuration of enone 3, we
undertook the following experiment (Scheme 2). The stereo-
isomeric mixture of the enone 3q (E:Z = 3:1) was derived from
the enone 3q (E:Z = 25:1, Table 2, entry 16) after being stored at
room temperature for five months. Following the addition of
reaction to afford 4s (Table 2, entry 20). This reaction can be
easily conducted on a scale of 7 mmol of 1f (1.015 g) in a slightly
higher yield (Table 2, entry 21). The reaction with benzophe-
none instead of aldehydes failed to give any of the desired cyclic
compound 4t at all (Table 2, entry 22).
In conclusion, we have demonstrated the synthesis of various
trans-2,3-disubstituted-2,3-dihydro-4-quinolones from 2-alky-
nylbenzamide derivatives by a one-pot tandem process that
involves a Hofmann-type rearrangement of 2-alkynylbenza-
mides, a nucleophilic addition of alcohols to the resulting
isocyanate intermediates, an intermolecular [2+2]-cycloaddition
with an alkyne triple bond and aldehydes, and an intramolecular
aminocyclization to the α,β-unsaturated ketones.
BF3 Et2O (1 equiv) in DCE and stirring of the mixture at 90 °C
3
for 24 h, the reaction afforded only trans-4q in 80% yield. Thus,
the predominant trans-4q formation is not dependent on the E:
Z-configuration of 3q, and is presumably produced from normal
1,4-addition of carbamate nitrogen to α,β-unsaturated carbonyl
compound 3. Terminal alkyne 1f was also suitable for this
’ EXPERIMENTAL SECTION
General Experimental Methods. 1H NMR and 13C NMR
spectra were recorded on a 600 MHz spectrometer. Chemical shifts
are reported in δ (ppm) from tetramethylsilane as an internal standard.
Data are reported as follows: chemical shifts, relative integration value,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m
= multiplet), and coupling constants (Hz). Infrared spectra were
obtained using an FT spectrometer. Analytical thin layer chromatogra-
phy was performed on Merck silica gel 60 F254 TLC plates. Compouds
1a,17 1e,17 2a,13d 4a,13d 4l,13d 4r,13d and 5a13d are all known compounds.
Experimental procedures and data for compounds 1b, 1c, 1d, and 1f
have been reported in our previous paper.12a
Scheme 1. One-Pot Synthesis of 2,3-Disubstituted-2,3-dihy-
dro-4-quinolones 4 from Amides 1
Ethyl 2-(Hex-1-ynyl)5-nitrophenylcarbamate (2e). White
solid (56 mg, 97%): mp 84À85 °C; 1H NMR (CDCl3) δ 9.05 (1H, s),
7.81 (1H, dd, J = 8.4, 2.4 Hz), 7.50 (1H, s), 7.45 (1H, d, J = 8.4 Hz), 4.29
(2H, q, J = 7.3 Hz), 2.56 (2H, t, J = 7.2 Hz), 1.69À1.64 (2H, m),
1.55À1.49 (2H, m), 1.36 (3H, t, J = 7.3 Hz), 0.99 (3H, t, J = 7.6 Hz); 13C
NMR (CDCl3) δ 152.8, 147.5, 139.8, 131.9, 118.1, 116.9, 112.2, 103.0,
74.7, 61.9, 30.3, 22.0, 19.4, 14.4, 13.5; IR (CHCl3, cmÀ1) 3398, 3035,
Table 1. Optimization of the Reaction Conditionsa
entry
hypervalent iodine
acid (1 equiv)
Cu(OTf)2
time (h)
4a (%)b (trans:cis)c
5a (%)
2a (%)
1
2
3
4
5
6
7
8
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCH3)2
PhI(OCOCH3)2
PhI(OCOCH3)2
PhI(OCOCH3)2
20
20
20
20
24
24
18
18
trace
5
0
0
4
4
5
0
9
48
64
0
0
BF3 Et2O
60 (20:1)
43 (18:1)
trace
3
AgSbF6
SbF5
0
4
AgOTf
5 (20:1)
73 (40:1)
48 (28:1)
10
0
BF3 Et2O
3
BF3 Et2O
12
3
(0.5 equiv)
9
PhI(OCOCH3)2
BF3 Et2O
24
15 (27:1)
8
35
3
(0.1 equiv)
10
11
12
PhI(OCOCH3)2
PhI(OCOCH3)2
PhI(OTs)(OH)
TfOH
24
24
20
8 (27:1)
18 (24:1)
32 (18:1)
4
27
4
8
0
0
In(OTf)3
BF3 Et2O
3
a Amide (0.2 mmol), hypervalent iodine (0.2 mmol), EtOH (0.8 mmol), benzaldehyde (0.3 mmol), and acid (0.2 mmol) in ClCH2CH2Cl (1 mL) were
used except in entries 8 and 9. b Isolated yields. c Ratios were determined by 1H NMR analysis.
9140
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NOTE
Table 2. One-Pot Synthesis of 4-Quinolone 4 from Benzamide 1
entry
alkyne
R1
R2
R3
R4
temp (°C)
time (h)
4
(trans:cis) (%)
5 (%)
2 or 3 (E:Z) (%)
1
1a
1b
1c
1d
1a
1a
1a
1a
1a
1a
1a
1a
1b
1e
1e
1a
1a
1a
1a
1f
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Ph
Ph
Bu
Bu
Bu
Bu
H
Et
Et
Et
Et
Bn
Et
Et
Et
Et
Et
Et
Me
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
o-MeC6H4
m-MeC6H4
p-MeOC6H4
p-FC6H4
H
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
90
60
90
60
60
90
20
16
16
24
20
20
20
24
20
20
20
20
20
16
16
32
24
24
24
20
20
22
4b
4c
4d
4e
4f
81 (22:1)
72 (7:1)
80 (38:1)
0
0
0
2
OMe
F
0
0
3
5d 7
0
4
NO2
H
0
2e 97
5
73 (8:1)
82 (20:1)
76 (33:1)
68 (98:1)
76 (25:1)
61 (20:1)
87 (99:1)
72 (28:1)
52 (11:1)
73 (trans)
66 (trans)
0
0
0
6
H
4g
4h
4i
0
0
7
H
0
0
8
H
0
0
9
H
4j
0
0
10
11
12
13
14
15
16
17
18
19
20
21a
22
hexyl
H
4k
4l
23
0
cyclohexyl
Ph
H
0
0
H
4m
4n
4o
4p
4q
4q
4r
4r
4s
4s
4t
0
0
Ph
OMe
H
0
0
p-MeC6H4
p-MeC6H4
p-CNC6H4
p-CNC6H4
p-NO2C6H4
p-NO2C6H4
p-MeC6H4
p-MeC6H4
(PhCOPh)
0
0
H
0
0
H
5a 19
3q 55 (25:1)
H
82 (trans)
0
0
0
H
5a 24
3r 59 (25:1)
H
80 (trans)
85
0
0
0
0
0
H
0
1f
H
H
88
0
1a
Bu
H
0
5a trace
a The reaction was conducted with a 7 mmol (1.015 g) scale of 1f.
Scheme 2. Conversion of Enone 3q to trans-4q
30.6, 28.2, 22.9, 14.5, 13.8; IR (CHCl3, cmÀ1) 3277, 3036, 3009, 1730,
1632, 1599, 1582, 1528, 1516, 1449, 1346, 1250, 1196, 1163, 1059. MS
(EI): m/z = 396 (M+). HRMS (EI): m/z calcd for C22H24N2O5:
396.1685; found: 396.1689.
General Procedure for One-Pot Synthesis of 2,3-Disubsti-
tuted-2,3-dihydro-4-quinolones 4 from 2-Alkynylbenzamides 1.
To a solution of 2-alkynylbenzamide 1 (0.20 mmol) and PhI(OAc)2
(0.22 mmol) in 1,2-dichloroethane (1.0 mL) was added alcohol (0.80 mmol),
and the mixture was stirred at 60 °C for 2 h. Then, aldehyde (0.30 mmol) and
1738, 1533, 1347, 1237, 1197, 819. MS (EI): m/z = 290 (M+). HRMS
(EI): m/z calcd for C15H18N2O4: 290.1267; found: 290.1274.
(E)-Ethyl 2-(2-(4-Cyanobenzylidene)hexanoyl)phenyl-
carbamate (3q). Pale yellow oil (41 mg, 55%): 1H NMR (CDCl3) δ
10.10 (1H, s), 8.41 (1H, d, J = 8.9 Hz), 7.70À7.69 (3H, m), 7.56 (1H, t,
J = 7.9 Hz), 7.44 (2H, d, J = 7.6 Hz), 7.06 (1H, t, J = 7.9 Hz), 6.81 (1H, s),
4.24 (2H, q, J = 6.9 Hz), 2.68 (2H, t, J = 7.9 Hz), 1.54À1.49 (2H, m),
1.42À1.31 (5H, m), 0.91 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 201.2,
153.8, 145.6, 141.1, 140.1, 136.0, 134.3, 132.7, 132.3, 129.5, 123.0, 121.2,
120.0, 118.5, 111.8, 61.3, 30.6, 28.1, 22.9, 14.5, 13.8; IR (CHCl3, cmÀ1) 3230,
3034, 3009, 1728, 1630, 1582, 1524, 1449, 1238, 683. MS (EI): m/z = 376
(M+). HRMS (EI): m/z calcd for C23H24N2O3: 376.1787; found: 376.1780.
(E)-Ethyl 2-(2-(4-Nitrobenzylidene)hexanoyl)phenylcar-
bamate (3r). Pale yellow oil (47 mg, 59%): 1H NMR (CDCl3) δ 10.13
(1H, s), 8.42 (1H, d, J = 8.2 Hz), 8.27 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J =
7.6 Hz), 7.57 (1H, t, J = 7.9 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.07 (1H, t, J =
7.6 Hz), 6.85 (1H, s), 4.24 (2H, q, J = 6.9 Hz), 2.70 (2H, t, J = 7.9 Hz),
1.54À1.51 (2H, m), 1.41À1.37 (2H, m), 1.33 (3H, t, J = 6.9 Hz), 0.91
(3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 201.1, 153.8, 147.2, 146.1,
142.0, 141.1, 135.3, 134.4, 132.7, 129.7, 123.8, 122.8, 121.2, 120.1, 61.3,
BF3 Et2O (0.20 mmol) was added, and the mixture was stirred at 60 or 90 °C
3
for 16À32 h. After the completion of the reaction was confirmed by TLC, the
reaction mixture was directly chromatographed on silica gel using hexane:
ethyl acetate (10:1 to 5:1) as an eluent to afford the 2,3-disubstituted-2,3-
dihydro-4-quinolone 4.
Ethyl 3-Butyl-4-oxo-2-p-tolyl-3,4-dihydroquinoline-1(2H)-
carboxylate (4b). Pale yellow oil (59 mg, 81%): 1H NMR (CDCl3) δ
7.90À7.89 (2H, m), 7.47 (1H, t, J = 7.9 Hz), 7.08À7.04 (3H, m), 7.00
(2H, d, J = 7.6 Hz), 5.98 (1H, s), 4.46À4.32 (2H, m), 3.12 (1H, t, J = 7.6
Hz), 2.22 (3H, s), 1.81À1.71 (2H, m), 1.62À1.54 (1H, m), 1.50À1.43
(1H, m), 1.41À1.34 (5H, m), 0.92 (3H, t, J = 6.9 Hz); 13C NMR
(CDCl3) δ 195.9, 155.1, 141.1, 137.0, 135.3, 134.4, 129.2, 129.1, 127.3,
126.5, 123.8, 123.5, 62.7, 59.6, 51.1, 29.7, 29.2, 22.5, 20.8, 14.5, 13.8; IR
(CHCl3, cmÀ1) 3036, 3007, 2961, 2932, 1706, 1682, 1601, 1479, 1460,
1396, 1381, 1321, 1298, 1269, 1242, 1196, 1049. MS (EI): m/z= 365 (M+).
HRMS (EI): m/z calcd for C23H27NO3: 365.1991; found: 365.1991.
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NOTE
Ethyl 3-Butyl-7-methoxy-4-oxo-2-p-tolyl-3,4-dihydroqui-
noline-1(2H)-carboxylate (4c). Pale yellow oil (57 mg, 72%): H
62.8, 59.4, 55.2, 51.1, 29.7, 29.3, 22.5, 14.5, 13.9; IR (CHCl3, cmÀ1
)
2961, 2934, 1682, 1601, 1514, 1479, 1462, 1396, 1381, 1321, 1298, 1271,
1252, 1034, 714. MS (EI): m/z = 381 (M+). HRMS (EI): m/z calcd for
C23H27NO4: 381.1940; found: 381.1935.
1
NMR (CDCl3) δ 7.78 (1H, d, J = 8.9 Hz), 7.39 (1H, s), 7.00 (2H, d, J =
8.2 Hz), 6.94 (2H, d, J = 8.2 Hz), 6.55 (1H, dd, J = 8.6, 2.4 Hz), 5.89 (1H,
s), 4.38À4.23 (2H, m), 3.76 (3H, s), 2.98À2.95 (1H, m), 2.16 (3H, s),
1.68À1.27 (9H, m), 0.84 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ
194.8, 164.6, 155.0, 143.0, 137.1, 135.7, 129.4, 129.3, 126.5, 117.4, 111.1,
107.8, 62.8, 59.9, 55.5, 50.9, 30.0, 29.3, 22.6, 20.9, 14.5, 13.9; IR
(CHCl3, cmÀ1) 3036, 3009, 1706, 1696, 1603, 1447, 1310, 1272. MS
(EI): m/z = 395 (M+). HRMS (EI): m/z calcd for C24H29NO4:
395.2097; found: 395.2091.
Ethyl 3-Butyl-7-fluoro-4-oxo-2-p-tolyl-3,4-dihydroquino-
line-1(2H)-carboxylate (4d). Pale yellow oil (61 mg, 80%): 1H NMR
(CDCl3) δ7.91 (1H, t, J=7.6Hz), 7.72(1H, d,J=10.3Hz), 7.04(4H, q, J=
7.8 Hz), 6.77 (1H, td, J = 8.2, 1.8 Hz), 5.97 (1H, s), 4.45À4.34 (2H, m), 3.09
(1H, t, J = 7.2 Hz), 2.24 (3H, s), 1.76À1.69 (2H, m), 1.59À1.54 (1H, m),
1.47À1.34 (6H, m), 0.92 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 194.5,
167.2, 165.6, 154.7, 143.2, 143.1, 137.3, 135.1, 130.1, 130.0, 129.4, 126.4,
120.0, 111.7, 111.6, 110.6, 110.4, 63.1, 59.9, 50.8, 29.7, 29.2, 22.5, 20.9, 14.4,
13.9; IR (CHCl3, cmÀ1) 3037, 3008, 2962, 2933, 1711, 1684, 1610, 1585,
1487, 1443, 1397, 1381, 1305, 1266. MS (EI): m/z=383(M+). HRMS(EI):
m/z calcd for C23H26NO3F: 383.1897; found: 383.1888.
Benzyl 3-Butyl-4-oxo-2-p-tolyl-3,4-dihydroquinoline-1(2H)-
carboxylate (4f). Pale yellow oil (62 mg, 73%): 1H NMR (CDCl3) δ
7.88 (2H, d, J = 6.9 Hz), 7.46 (1H, t, J = 7.6 Hz), 7.40À7.34 (5H, m),
7.08À7.05 (3H, m), 6.99 (2H, d, J = 7.6 Hz), 5.97 (1H, s), 5.43 (1H, d, J =
12.4 Hz), 5.29 (1H, d, J = 12.4 Hz), 3.08 (1H, t, J = 7.6 Hz), 2.22 (3H, s),
1.70À1.66 (2H, m), 1.48À1.45 (1H, m), 1.40À1.35 (1H, m), 1.30À1.24
(2H, m), 0.85 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 195.8, 155.0,
141.0, 137.2, 135.7, 135.3, 134.5, 129.3, 128.7, 128.5, 128.3, 127.4, 126.6,
124.0, 123.8, 123.6, 68.4, 60.0, 51.1, 29.8, 29.2, 22.5, 20.9, 13.9; IR
(CHCl3, cmÀ1) 3036, 3009, 2960, 1706, 1684, 1602, 1480, 1461, 1389,
1339, 1321, 1297, 1268, 1021. MS (EI): m/z = 427 (M+). HRMS (EI):
m/z calcd for C28H29NO3: 427.2147; found: 427.2142.
Ethyl 3-Butyl-4-oxo-2-o-tolyl-3,4-dihydroquinoline-1(2H)-
carboxylate (4g). White solid (60 mg, 82%): mp 69À70 °C;
1H NMR (CDCl3) δ 7.98À7.95 (2H, m), 7.55À7.52 (1H, m),
7.16À7.06 (3H, m), 6.90 (1H, t, J = 7.6 Hz), 6.82 (1H, d, J = 8.2 Hz),
6.07 (1H, s), 4.38À4.24 (2H, m), 2.85 (1H, t, J = 7.2 Hz), 2.41 (3H, s),
1.80À1.72 (2H, m), 1.63À1.58 (1H, m), 1.47À1.30 (6H, m), 0.91 (3H, t,
J = 7.6 Hz); 13C NMR (CDCl3) δ 196.1, 154.8, 142.3, 137.3, 135.5, 134.7,
131.2, 127.6, 127.4, 126.1, 125.7, 123.8, 123.6, 123.3, 62.8, 58.4, 51.6, 30.9,
29.2, 22.6, 19.6, 14.4, 13.9; IR (CHCl3, cmÀ1) 3038, 3007, 1702, 1698, 1693,
1681, 1674, 1601, 1480, 1460, 1373, 1320, 1295, 1270. MS (EI): m/z = 365
(M+). HRMS (EI): m/z calcd for C23H27NO3: 365.1991; found: 365.1997.
Ethyl 3-Butyl-4-oxo-2-m-tolyl-3,4-dihydroquinoline-1(2H)-
carboxylate (4h). Pale yellow oil (55 mg, 76%): 1H NMR (CDCl3) δ
7.89 (2H, dd, J = 7.9, 1.7 Hz), 7.50À7.47 (1H, m), 7.09À7.06 (2H, m),
7.00 (1H, s), 6.97À6.95 (2H, m), 5.98 (1H, s), 4.45À4.42 (1H, m),
4.36À4.33 (1H, m), 3.15À3.12 (1H, m), 2.23 (3H, s), 1.79À1.73 (2H, m),
1.60À1.57 (1H, m), 1.49À1.45 (1H, m), 1.41À1.36 (5H, m), 0.92 (3H, t, J
= 7.6 Hz); 13C NMR (CDCl3) δ 195.9, 155.1, 141.3, 138.4, 138.2, 134.5,
128.5, 128.2, 127.5, 127.4, 123.8, 123.7, 123.6, 62.8, 59.8, 51.2, 29.8, 29.3,
22.5, 21.5, 14.5, 13.9; IR (CHCl3, cmÀ1) 3038, 3008, 1700, 1686, 1681,
1602, 1480, 1461, 1380, 1322, 1297, 1269. MS (EI): m/z = 365 (M+).
HRMS (EI): m/z calcd for C23H27NO3: 365.1991; found: 365.1989.
Ethyl 3-Butyl-2-(4-methoxyphenyl)-4-oxo-3,4-dihydroquino-
line-1(2H)-carboxylate (4i). Pale yellow oil (52 mg, 68%): 1H NMR
(CDCl3) δ 7.90 (1H, dd, J = 7.6, 1.4 Hz), 7.85 (1H, d, J = 7.6 Hz), 7.47
(1H, td, J = 7.9, 1.8 Hz), 7.12À7.06 (3H, m), 6.73 (2H, d, J = 8.2 Hz),
5.96 (1H, s), 4.45À4.34 (2H, m), 3.70 (3H, s), 3.11À3.08 (1H, m),
1.77À1.72 (2H, m), 1.61À1.55 (1H, m), 1.49À1.44 (1H, m),
1.39À1.35 (5H, m), 0.92 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ
196.1, 158.7, 155.1, 141.1, 134.5, 130.4, 127.9, 127.4, 123.8, 123.5, 113.9,
Ethyl 3-Butyl-2-(4-fluorophenyl)-4-oxo-3,4-dihydroquinoline-
1(2H)-carboxylate (4j). Pale yellow oil (56 mg, 76%): H NMR
1
(CDCl3) δ 7.90 (1H, d, J = 7.6 Hz), 7.85 (1H, d, J = 7.6 Hz), 7.49 (1H, t,
J = 7.9 Hz), 7.18À7.15 (2H, m), 7.09 (1H, t, J = 7.6 Hz), 6.89 (2H, t, J =
8.6 Hz), 5.98 (1H, s), 4.47À4.33 (2H, m), 3.11À3.08 (1H, m),
1.81À1.71 (2H, m), 1.62À1.53 (1H, m), 1.50À1.43 (1H, m),
1.41À1.34 (5H, m), 0.92 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ
195.7, 162.8, 161.1, 155.1, 140.9, 134.6, 134.3, 134.3, 128.4, 128.4, 127.5,
124.0, 123.8, 123.4, 115.6, 115.5, 63.0, 59.4, 51.2, 29.8, 29.2, 22.5, 14.5,
13.9; IR (CHCl3, cmÀ1) 3036, 3009, 1684, 1602, 1512, 1480, 1461,
1380, 1323, 1297, 1269, 1163. MS (EI): m/z = 369 (M+). HRMS (EI):
m/z calcd for C22H24NO3F: 369.1740; found: 369.1732.
Ethyl 3-Butyl-2-hexyl-4-oxo-3,4-dihydroquinoline-1(2H)-
carboxylate (4k). Pale yellow oil (44 mg, 61%): 1H NMR (CDCl3)
δ 7.98 (1H, dd, J = 7.9, 1.7 Hz), 7.81 (1H, br), 7.54À7.51 (1H, m), 7.15
(1H, t, J = 7.2 Hz), 4.79À4.77 (1H, m), 4.36À4.28 (2H, m), 2.45À2.42
(1H, m), 1.61À1.54 (3H, m), 1.51À1.46 (1H, m), 1.43À1.17 (15H, m),
0.92À0.82 (6H, m); 13C NMR (CDCl3) δ 196.7, 154.9, 140.5, 134.3,
127.3, 124.2, 123.8, 123.5, 62.4, 57.5, 52.2, 31.6, 31.6, 29.5, 29.2, 28.8, 26.1,
22.5, 14.5, 14.0, 13.9; IR (CHCl3, cmÀ1) 3037, 3009, 1680, 1601, 1539,
1521, 1506, 1480, 1461, 1374, 1321, 1295. MS (EI): m/z = 359 (M+).
HRMS (EI): m/z calcd for C22H33NO3: 359.2460; found: 359.2463.
Methyl 3-Butyl-4-oxo-2-phenyl-3,4-dihydroquinoline-1(2H)-
carboxylate (4m). Pale yellow oil (49 mg, 72%): 1H NMR (CDCl3) δ
7.90 (2H, dd, J = 7.9, 1.7 Hz), 7.51À7.48 (1H, m), 7.22À7.14 (5H, m),
7.09 (1H, t, J = 7.6 Hz), 6.00 (1H, s), 3.93 (3H, s), 3.13 (1H, td, J = 7.6,
2.1 Hz), 1.80À1.74 (2H, m), 1.60À1.56 (1H, m), 1.49À1.45 (1H, m),
1.41À1.36 (2H, m), 0.92 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ
195.7, 155.6, 141.1, 138.3, 134.6, 128.6, 127.5, 126.6, 124.0, 123.6, 123.5,
60.2, 53.7, 51.2, 29.8, 29.2, 22.5, 13.9; IR (CHCl3, cmÀ1) 3036, 3009,
1715, 1706, 1684, 1480, 1441. MS (EI): m/z = 337 (M+). HRMS (EI):
m/z calcd for C21H23NO3: 337.1678; found: 337.1670.
Ethyl 3-Butyl-7-methoxy-4-oxo-2-phenyl-3,4-dihydroqui-
noline-1(2H)-carboxylate (4n). Pale yellow oil (40 mg, 52%): 1H
NMR (CDCl3) δ 7.85 (1H, d, J = 8.9 Hz), 7.48 (1H, s), 7.25À7.15 (5H,
m), 6.63 (1H, dd, J = 8.9, 2.1 Hz), 5.99 (1H, s), 4.47À4.42 (1H, m),
4.36À4.31 (1H, m), 3.85 (3H, s), 3.07À3.05 (1H, m), 1.77À1.72 (2H,
m), 1.60À1.56 (1H, m), 1.49À1.43 (1H, m), 1.40À1.34 (5H, m), 0.92
(3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ 194.6, 164.6, 155.0, 143.0,
138.7, 129.5, 128.6, 127.4, 126.6, 117.4, 111.1, 107.7, 62.8, 60.1, 55.5,
50.9, 30.0, 29.3, 22.5, 14.5, 13.9; IR (CHCl3, cmÀ1) 3036, 3009, 1706,
1700, 1675, 1603, 1498, 1448, 1311, 1271. MS (EI): m/z = 381 (M+).
HRMS (EI): m/z calcd for C23H27NO4: 381.1940; found: 381.1940.
Methyl 4-Oxo-3-phenyl-2-p-tolyl-3,4-dihydroquinoline-1(2H)-
carboxylate (4o). White solid (54 mg, 73%): mp 131À132 °C; 1H
NMR (CDCl3) δ 8.00 (1H, dd, J = 7.9, 1.7 Hz), 7.82 (1H, d, J = 7.6 Hz),
7.53 (1H, t, J = 7.9 Hz), 7.31À7.13 (8H, m), 7.05 (2H, d, J = 8.2 Hz),
6.13 (1H, s), 4.42 (1H, d, J = 1.4 Hz), 3.62 (3H, s), 2.25 (3H, s); 13C
NMR (CDCl3) δ 193.6, 155.3, 141.9, 137.4, 137.3, 135.2, 135.0, 129.4,
129.0, 127.7, 127.7, 127.4, 126.6, 125.0, 124.4, 124.2, 62.6, 56.1, 53.4,
20.9; IR (CHCl3, cmÀ1) 3035, 1718, 1684, 1603, 1481, 1441, 1330, 1306.
MS (EI): m/z = 371 (M+). HRMS (EI): m/z calcd for C24H21NO3:
371.1521; found: 371.1523.
Ethyl 4-Oxo-3-phenyl-2-p-tolyl-3,4-dihydroquinoline-1(2H)-
carboxylate (4p). Pale yellow oil (51 mg, 66%): 1H NMR (CDCl3) δ
8.00 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 8.2 Hz), 7.52 (1H, t, J = 7.6 Hz),
7.30À7.12 (8H, m), 7.05 (2H, d, J = 7.6 Hz), 6.14 (1H, s), 4.43 (1H, s),
4.12À4.05 (2H, m), 2.25 (3H, s), 1.04 (3H, t, J = 6.9 Hz); 13C NMR
(CDCl3) δ 193.8, 154.8, 142.0, 137.4, 137.4, 135.3, 134.9, 129.4, 129.0,
127.8, 127.6, 127.3, 126.7, 125.1, 124.6, 124.1, 62.5, 56.0, 20.9, 14.2; IR
9142
dx.doi.org/10.1021/jo201636a |J. Org. Chem. 2011, 76, 9139–9143

The Journal of Organic Chemistry
NOTE
(CHCl3, cmÀ1) 3037, 3009, 1710, 1684, 1602, 1481, 1461, 1396, 1323,
1302. MS (EI): m/z = 385 (M+). HRMS (EI): m/z calcd for
C25H23NO3: 385.1678; found: 385.1683.
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Ethyl 3-Butyl-2-(4-cyanophenyl)-4-oxo-3,4-dihydroquinoline-
1(2H)-carboxylate (4q). White solid (62 mg, 82%): mp 137À
1
138 °C; H NMR (CDCl3) δ 7.89 (1H, dd, J = 7.9, 1.7 Hz), 7.87
(1H, d, J = 8.9 Hz), 7.54À7.51 (3H, m), 7.31 (2H, d, J = 8.9 Hz), 7.12
(1H, t, J = 7.6 Hz), 6.04 (1H, s), 4.46À4.43 (1H, m), 4.38À4.36 (1H, m),
3.11 (1H, td, J = 7.6, 2.1 Hz), 1.80À1.75 (2H, m), 1.59À1.56 (1H, m),
1.49À1.45 (1H, m), 1.41À1.36 (5H, m), 0.92 (3H, t, J = 7.2 Hz); 13C
NMR (CDCl3) δ 194.9, 154.9, 144.1, 140.8, 134.9, 132.5, 127.6, 127.5,
124.3, 123.7, 123.2, 118.3, 111.6, 63.2, 59.8, 51.1, 29.7, 29.2, 22.5, 14.5,
13.9; IR (CHCl3, cmÀ1) 3037, 3009, 1715, 1685, 1602, 1480, 1462,
1378, 1322, 1296. MS (EI): m/z = 376 (M+). HRMS (EI): m/z calcd for
C23H24N2O3: 376.1787; found: 376.1780.
Ethyl 4-Oxo-2-p-tolyl-3,4-dihydroquinoline-1(2H)-carboxy-
late (4s). White solid (53 mg, 85%): mp 114À115 °C; 1H NMR
(CDCl3) δ 7.89 (1H, dd, J = 7.6, 1.4 Hz), 7.79 (1H, d, J = 8.2 Hz),
7.47À7.44 (1H, m), 7.09À7.05 (3H, m), 7.01 (2H, d, J = 8.2 Hz), 6.18
(1H, s), 4.42À4.34 (2H, m), 3.30À3.29 (2H, m), 2.22 (3H, s), 1.38 (3H, t,
J = 7.2 Hz); 13C NMR (CDCl3) δ 193.0, 154.5, 141.7, 137.2, 135.2, 134.5,
129.3, 126.8, 126.5, 125.0, 124.4, 124.0, 62.9, 55.8, 42.4, 20.9, 14.5; IR
(CHCl3, cmÀ1) 3036, 3009, 1685, 1603, 1481, 1462, 1397, 1381, 1269. MS
(EI): m/z = 309 (M+). HRMS (EI): m/z calcd for C19H19NO3: 309.1365;
found: 309.1364.
Ethyl 5-Fluoro-2-hexanoylphenylcarbamate (5d). Pale yel-
low oil (4 mg, 7%): 1H NMR (CDCl3) δ 11.45 (1H, br), 8.29 (1H, dd,
J = 12.4, 2.7 Hz), 7.91 (1H, dd, J = 8.9, 6.2 Hz), 6.75À6.71 (1H, m), 4.23
(2H, q, J = 7.1 Hz), 2.96 (2H, t, J = 7.2 Hz), 1.73À1.71 (2H, m),
1.38À1.34 (4H, m), 1.32 (3H, t, J = 7.2 Hz), 0.92 (3H, t, J = 6.9 Hz); 13C
NMR (CDCl3) δ 203.4, 167.1, 153.8, 144.3, 144.2, 133.3, 133.3, 117.8,
108.6, 108.5, 106.3, 106.1, 61.4, 39.9, 31.4, 24.3, 22.5, 14.4, 13.9; IR
(CHCl3, cmÀ1) 3036, 3009, 1730, 1653, 1591, 1529, 1458, 1251. MS
(EI): m/z = 281 (M+). HRMS (EI): m/z calcd for C15H20NO3F:
281.1427; found: 281.1428.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all the new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: ryanada@ps.hirokoku-u.ac.jp.
(15) Jacubert, M.; Provot, O.; Peyrat, J.-F.; Hamze, A.; Brion, J.-D.;
Alami, M. Tetrahedron 2010, 66, 3775–3787.
(16) The stereochemistry of the product 4 was determined by the
values of the vicinal coupling constants between protons at the 2- and
3-positions.
(17) Wu, M.-J.; Chang, L.-J.; Wei, L.-M.; Lin, C.-F. Tetrahedron
1999, 55, 13193–13200.
’ ACKNOWLEDGMENT
We are grateful to Dr. M. Nishi at Setsunan University for
obtaining LRMS and HRMS data. This work was partially
supported by a Grant-in-Aid for Scientific Research (C) from
JSPS KAKENHI (23590032). N.O. is grateful for the Research
Foundation by Hiroshima International University.
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