One-step synthesis of ethyl quinaldates by lewis acid catalyzed three-component coupling reaction of aromatic amines, aliphatic aldehydes and ethyl glyoxylate

Article abstract of DOI:10.3987/COM-05-S(K)48

A convenient, efficient and simple one-pot method for the synthesis of quinaldates was developed by three-component coupling reaction of an arylamine (1), ethyl glyoxylate and an aliphatic aldehyde (2) in the presence of Lewis acid catalyst. The reaction

Full text of DOI:10.3987/COM-05-S(K)48

HETEROCYCLES, Vol. 66, 2005
611
HETEROCYCLES, Vol. 66, 2005, pp. 611 – 619. © The Japan Institute of Heterocyclic Chemistry
Received, 31st August, 2005, Accepted, 18th October, 2005, Published online, 21st October, 2005. COM-05-S(K)48
ONE-STEP SYNTHESIS OF ETHYL QUINALDATES BY LEWIS ACID
CATALYZED THREE-COMPONENT COUPLING REACTION OF
AROMATIC AMINES, ALIPHATIC ALDEHYDES AND ETHYL
GLYOXYLATE
Takashi Inada, Takayuki Nakajima, and Isao Shimizu*
Department of Applied Chemistry, Graduate School of Science and Engineering,
Waseda University, Okubo 3-4-1, Shinjuku-ku, Tokyo 169-8555,
Japan.E-mail:shimizui@waseda.jp
Abstract – A convenient, efficient and simple one-pot method for the synthesis of
quinaldates was developed by three-component coupling reaction of an arylamine
(1), ethyl glyoxylate and an aliphatic aldehyde (2) in the presence of Lewis acid
catalyst. The reaction proceeded most effectively using Yb(OTf)3 as a catalyst.
INTRODUCTION
2-Quinolinecarboxylic acid (quinaldic acid) and its derivatives form as tryptophan metabolites,1,2 and the
quinaldyl moiety exist widely in natural products or synthetic biologically active compounds, such as
thiostrepton2 and enzyme inhibitors.3 Quinaldates are also used as chelating ligands, which are important
for development of molecular catalysts4 or designing functional materials such as precipitating agents.5
Several synthetic methods of quinaldic acid are known, however, preparation of substituted quinaldates is
scarcely reported.6 We have paid an attention to facile method for substituted quinaldates toward
development of biologically active compounds or functional materials. Recently we have reported a
synthesis of substituted quinolines by three-component coupling reaction of anilines, aromatic aldehydes
and aliphatic aldehydes using iridium catalyst.7 The method is applicable to the synthesis of quinaldates
by replacing aromatic aldehydes with ethyl glyoxylate (EG), and we examined the reaction using several
Lewis acids and metal catalysts. As reported in this paper we have found that Lewis acids catalyze the
three-component coupling reaction effectively, and ytterbium triflate is active catalyst for quinaldate
synthesis.
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

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RESULTS AND DISCUSSION
The results of several Lewis acid catalyzed synthesis of the quinaldate (3a) from p-anisidine (1a), ethyl
glyoxylate (EG) and n-valeraldehyde (2a) are listed in Table 1. At first the reaction of 1a, 2a with EG was
carried out as follows. The mixture of 1a (1.0 mmol) and EG (1.2 mmol) was stirred at room temperature
in DMSO. To the mixture 1.0 mol% of SnCl2 and 2a (1.1 mmol) were added, and the resulting mixture
was heated at 90 oC under oxygen for 16 h to give ethyl 6-methoxy-3-propylquinaldate (3a) in 88% yield
after chromatographic purification. Similarly reaction using ZnCl2 and TiCl4 catalysts gave 3a in high
yields. Instead of ordinary metal chloride Lewis acids, lanthanoid triflates are also effective catalysts.
Among them, Yb(OTf)3 catalyzed the reaction most actively to give 3a in 94% yield. When 0.5 mol% of
Yb(OTf)3 was used, the product was obtained in 87% yield. However, 5 mol% of the catalyst was
employed, the yield was decreased in 83% yield.
NH2
O
O
Catalyst
MeO
+
+
H
CO2Et
H
DMSO
90 oC, 16 h
under O2
N
CO2Et
OMe
1a
2a
3a
EG
Table 1 Effect of catalysts on three-component
coupling reaction
Yield / % a)
Entry
Catalyst
SnCl2
1
2
3
4
5
6
7
(1.0 mol%)
88
88
81
88
83
94
87
ZnCl2
TiCl4
(1.0 mol%)
(1.0 mol%)
(1.0 mol%)
(5.0 mol%)
(1.0 mol%)
La(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3 (0.5 mol%)
a) Isolated yield based on arylamine (1a).
Various substituted quinaldates were obtained in good yields using ytterbium-catalyzed three-component
coupling reaction in a one pot (Table 2). The reactions using p-methoxy- or p-methyaniline were carried
out similarly as in the reaction in Table 1, and the reactions proceeded smoothly to give the products in
good yields except for in the case of acetaldehyde (Entry 2) as an aliphatic aldehyde. However, in the
case of arylamines wtih electron-withdrawing substituent such as p-Br, p-F and p-CO2Me, the results
were unsatisfactory. The reaction is considered to proceed involving imine formation from 1 and EG, and
in the case of electron deficient anilines the formation of corresponding imines was slow. Therefore

HETEROCYCLES, Vol. 66, 2005
613
o
preformation of the imines at higher temperature (120 C) before addition of the catalyst and aliphatic
aldehyde 2 is preferable.8
Yb(OTf)3
NH2
R2
O
O
(1.0 mol%)
R2
+
+
H
CO2Et
H
N
CO2Et
R1
DMSO
R1
90 oC, 16 h
under O2
1
EG
2
3
Table 2 Synthesis of quinaldates by ytterbium-catalyzed three-component
coupling reaction
R1
R1
R2
R2
3 (Yield / %) a)
3 (Yield / %) a)
Entry
Entry
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
n-Pr
H
3a (94)
3b (45)
3c (84)
3d (99)
3e (92)
3f (91)
H
o-OMe
p-Me
p-Br
Et
Et
Et
Et
Et
3g (34)
3h (41)
3i (90)
3j (90)
3k (73)
3l (53)
1
2
3
4
5
6
7
8
Me
Et
9
10b)
11b)
12b)
i-Pr
Bn
p-F
p-CO2Me Et
a) Isolated yield based on arylamine (1). b) Preformation of the imine at 120 oC was carried
out prior to addtion of 2 and Yb(OTf)3.
When aniline was employed, the quinaldate (3g) was obtained in 34% yield. In this case substitution
reaction at C-6 was observed to yield the diester (4) and triester (5) in 15% and 22% yields respectively
based on aniline. The structures of 4 and 5 were elucidated by NMR and HRMS spectrum.
NH2
Yb(OTf)3 (1.0 mol%)
O
O
+
+
DMSO, 90 oC, 16 h
under O2
H
CO2Et
H
CO2Et
EtO2C
3g (34 %)
+
+
N
CO2Et
EtO2C
N
N
CO2Et
4 (15 %)
5 (22 %)
Scheme 1 Three-component coupling reaction of aniline, EG and butanal
The mechanism for the formation of quinaldates (3g, 4 and 5) from aniline can be explained in Scheme 2.
At first formation of imine from aniline and EG followed by reaction of butanal gives the aldehyde C,
which is cyclized under acidic conditions by intramolecular Friedel-Crafts type reaction to give D.

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HETEROCYCLES, Vol. 66, 2005
Dehydration of D gives the dihydroquinaldate E, which is dehydrogenated to give the quinaldate (3g).
The formation of 4 and 5 seems to be explained by Friedel-Crafts type reaction of 3g with EG. The
reaction starting with 3g and EG was examined separately in order to confirm the process from 3g to 4
and 5 via F, but no reaction proceeded under the same reaction conditions of three component coupling
reaction. Therefore the C-C bond forming reaction at C-6 in the quinaldate is supposed to proceed prior to
dehydration of E to 3g. The precise mechanism for the formation of 4 and 5 is not clear, but the reaction
of E with EG is plausible. Thus, reaction of E with EG gives F followed by dehydration to afford the
intermediate G, which is isomerized to furnish the (quinolin-6-yl)acetate derivative (4). Furthermore,
Friedel-Crafts type reaction of E proceeds with the intermediate G followed by loss of two hydrogen
molecules to afford the bis(quinolin-6-yl)acetate (5).9
OH
O
Et
Et
H
NH2
O
+
H
CO2Et
- H2O
N
CO2Et
N
CO2Et
Yb
A
B
H
O
O
-H2
Et
CO2Et
- H2O
Et
CO2Et
Et
Et
N
H
N
H
N
H
CO2Et
N
CO2Et
3g
D
C
E
CO2Et
Et
Et
CO2Et
N
OH
N
- H2O
Et
CO2Et
H
Et
CO2Et
E
EtO2C
EtO2C
N
N
H
G
Et
-2 H2
EtO2C
F
N
CO2Et
5
Et
CO2Et
EtO2C
N
4
Scheme 2 Plausible reaction mechanism for the formation of 3g, 4 and 5
SUMMARY
We have developed an efficient one-pot synthesis of 2-ethoxycarbonylquinoline derivatives (quinaldates)
from aromatic amines, ethyl glyoxylate (EG) and aliphatic aldehydes in the presence of a catalytic
amount of Yb(OTf)3, which provides a promising method for preparation of substituted quinaldates.

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615
EXPERIMENTAL
1
13
All melting points were measured on a Yamato Model MP-21 and were uncorrected. H NMR and C
NMR spectra were recorded in CDCl3 as a solvent using TMS as an internal standard on JEOL Lambda
500 spectrometers. Multiplicities are indicated as br (broadened), s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet). High-resolution mass (HRMS) spectroscopy and elemental analysis were
performed by the Material Characterization Central Laboratory of Waseda University.
General procedure for the synthesis of 3a – 3i. A mixture of arylamine (1) (1.0 mmol), ethyl glyoxylate
(1.2 mmol, 0.273 mL, Polymer form 47% in toluene) in DMSO (3 mL) was stirred at rt for 1 h. Then
alkyl aldehyde (2) (1.1 mmol) and Yb(OTf)3 (6.2 mg, 0.01 mmol) were added to the mixture successively,
and the resulting mixture was stirred at 90 ºC for 16 h under oxygen. The reaction mixture was washed
with phosphate buffered saline solution (PBS, 50 mL) and extracted with AcOEt (20 mL × 3). The
organic layer was dried over MgSO4. Removal of the solvent in vacuo, followed by chromatography on
silica gel column (AcOEt / hexane = 5 / 95), afforded 3.
1
Ethyl 6-methoxy-3-propylquinaldate (3a): pale yellow oil (257 mg, 94 %), H NMR (500 MHz,
CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H, CH3), 1.43 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.69 (m, 2H, CH2), 2.93 (m,
2H, CH2), 3.90 (s, 3H, OCH3), 4.48 (q, J = 7.1 Hz, 2H, OCH2CH3), 6.99 (d, J = 2.7 Hz, 1H, aromatic H),
7.30 (dd, J = 9.2, 2.7 Hz, 1H, aromatic H), 7.88 (s, 1H, aromatic H), 8.02 (d, J = 9.2 Hz, 1H, aromatic
H), 13C NMR (125 MHz, CDCl3) δ 13.9 (s, CH3), 14.2 (s, OCH2CH3), 24.3 (s, CH2), 34.8 (s, CH2), 55.5
(s, OCH3), 61.8 (s, OCH2CH3), 104.0, 122.4, 130.1, 131.3, 134.7, 135.9, 141.9, 147.5, 158.9 (s, aromatic
C); 166.9 (s, CO), HRMS (FAB) calcd for C16H20NO3 [M + H]+ 274.1443, found 274.1444.
Ethyl 6-methoxyquinaldate (3b): colorless crystals (from AcOEt / hexane, 104 mg, 45 %), mp 127-128
1
ºC, H NMR (500 MHz, CDCl3) δ 1.46 (t, J = 7.1 Hz, 3H, OCH2CH3), 3.93 (s, 3H, OCH3), 4.52 (q, J =
7.1 Hz, 2H, OCH2CH3), 7.08 (d, J = 2.7 Hz, 1H, aromatic H), 7.40 (dd, J = 9.3, 2.7 Hz, 1H, aromatic
H), 8.11 – 8.13 (m, 2H, aromatic H), 8.17 (d, J = 9.3 Hz, 1H, aromatic H), 13C NMR (125 MHz, CDCl3)
δ 14.4 (s, OCH2CH3), 55.6 (s, OCH3), 62.0 (s, OCH2CH3), 104.6, 121.5, 123.4, 130.8, 132.3, 135.6, 143.8,
145.8, 159.4 (s, aromatic C); 165.6 (s, CO), HRMS (FAB) calcd for C13H14NO3 [M + H]+ 232.0974,
found 232.0985, Anal. Calcd for C15H19NO: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.42; H, 5.48; N,
6.15.
1
Ethyl 6-methoxy-3-methylquinaldate (3c): pale yellow oil (206 mg, 84 %), H NMR (500 MHz,
CDCl3) δ 1.43 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.61 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 4.47 (q, J = 7.1 Hz,

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HETEROCYCLES, Vol. 66, 2005
2H, OCH2CH3), 6.93 – 6.94 (m, 1H, aromatic H), 7.28 (dd, J = 9.3, 2.7 Hz, 1H, aromatic H), 7.84 (s, 1H,
13
aromatic H), 8.02 (d, J = 9.3 Hz, 1H, aromatic H), C NMR (125 MHz, CDCl3) δ 14.2 (s, OCH2CH3),
19.9 (s, CH3), 55.5 (s, OCH3), 61.7 (s, OCH2CH3), 103.8, 122.3, 130.2, 130.7, 131.3, 136.6, 141.9, 146.9,
159.1 (s, aromatic C); 166.6 (s, CO), HRMS (FAB) calcd for C14H16NO3 [M + H]+ 246.1130, found
246.1123.
Ethyl 6-methoxy-3-ethylquinaldate (3d): pale yellow oil (257 mg, 99 %), 1H NMR (500 MHz, CDCl3)
δ 1.28 (t, J = 7.5 Hz, 3H, CH3), 1.42 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.97 (q, J = 7.5 Hz, 2H, CH2), 3.87 (s,
3H, OCH3), 4.47 (q, J = 7.1 Hz, 2H, OCH2CH3), 6.97 (d, J = 2.7 Hz, 1H, aromatic H), 7.28 (dd, J = 9.3,
13
2.7 Hz, 1H, aromatic H), 7.87 (s, 1H, aromatic H), 8.01 (d, J = 9.0 Hz, 1H, aromatic H), C NMR (125
MHz, CDCl3) δ 14.2 (s, OCH2CH3), 15.1 (s, CH3), 25.8 (s, CH2), 55.4 (s, OCH3), 61.7 (s, OCH2CH3),
104.0, 122.3, 130.2, 131.2, 134.9, 136.1, 141.8, 147.4, 158.9 (s, aromatic C); 166.8 (s, CO), HRMS
(FAB) calcd for C15H18NO3 [M + H]+ 260.1287, found 260.1287.
1
Ethyl 6-methoxy-3-isopropylquinaldate (3e): pale yellow oil (251 mg, 92 %), H NMR (500 MHz,
CDCl3) δ 1.30 (d, J = 6.8 Hz, 6H, CH3), 1.40 (t, J = 7.1 Hz, 3H, OCH2CH3), 3.48 (m, 1H, CH), 3.86 (s,
3H, OCH3), 4.46 (q, J = 7.1 Hz, 2H, OCH2CH3), 7.00 (d, J = 2.7 Hz, 1H, aromatic H), 7.27 (dd, J = 9.2,
2.7 Hz, 1H, aromatic H), 7.97 – 7.99 (m, 2H, aromatic H), 13C NMR (125 MHz, CDCl3) δ 14.1 (s,
OCH2CH3), 23.7 (s, CH3), 28.9 (s, CH2), 55.4 (s, OCH3), 61.7 (s, OCH2CH3), 104.3, 122.4, 130.1, 130.9,
132.0, 140.0, 141.6, 148.1, 158.7 (s, aromatic C); 167.2 (s, CO), HRMS (FAB) calcd for C16H20NO3 [M +
H]+ 274.1443, found 274.1415.
Ethyl 6-methoxy-3-benzylquinaldate (3f): pale yellow crystals (from AcOEt / hexane, 292 mg, 91 %),
1
mp 96-97 ºC, H NMR (500 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H, CH3), 3.84 (s, OCH3), 4.35 (q, J =
7.1 Hz, 2H, CH2), 4.36 (s, 2H, CH2), 7.11 – 7.13 (m, 2H, aromatic H), 7.16 – 7.18 (m, 1H, aromatic H),
7.23 – 7.25 (m, 2H, aromatic H), 7.29 (dd, J = 9.2, 2.7 Hz, 1H, aromatic H), 7.75 (s, 1H, aromatic H),
13
8.01 (d, J = 9.2 Hz, 1H, aromatic H) C NMR (125 MHz, CDCl3) δ 14.1 (s, OCH2CH3), 38.4 (s, CH2),
55.5 (s, OCH3), 61.8 (s, OCH2CH3), 104.2, 122.7, 126.3, 128.5, 129.2, 130.1, 131.3, 133.3, 136.6, 139.6,
142.0, 147.4, 159.1 (s, aromatic C); 166.7 (s, CO), HRMS (FAB) calcd for C20H20NO3 [M + H]+
322.1443, found 322.1452, Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C, 74.53; H,
5.76; N, 4.06.
Ethyl 3-ethylquinaldate (3g): pale yellow oil (78 mg, 34 %), 1H NMR (500 MHz, CDCl3) δ 1.30 (t, J =
7.5 Hz, 3H, CH3), 1.43 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.96 (q, J = 7.5 Hz, 2H, CH2), 4.49 (q, J = 7.1 Hz,

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2H, OCH2CH3), 7.50 – 7.53 (m, 1H, aromatic H), 7.62 – 7.65 (m, 1H, aromatic H), 7.73 (dd, J = 8.2, 1.3
Hz, 1H, aromatic H), 7.99 (s, 1H, aromatic H), 8.12 (d, J = 9.0 Hz, 1H, aromatic H), 13C NMR (125 MHz,
CDCl3) δ 14.2 (s, OCH2CH3), 15.0 (s, CH3), 25.6 (s, CH2), 61.9 (s, OCH2CH3), 126.9, 127.8, 128.8, 129.2,
129.7, 135.2, 136.1, 145.7, 150.4 (s, aromatic C); 166.8 (s, CO), HRMS (FAB) calcd for C14H16NO2 [M +
H]+ 230.1181, found 230.1182.
Ethyl 8-methoxy-3-ethylquinaldate (3h): pale yellow oil (106 mg, 41 %), 1H NMR (500 MHz, CDCl3)
δ 1.28 (t, J = 7.5 Hz, 3H, CH3), 1.43 (t, J = 7.1 Hz, 3H, OCH2CH3), 3.00 (q, J = 7.5 Hz, 2H, CH2), 4.03 (s,
3H, OCH3), 4.47 (q, J = 7.1 Hz, 2H, OCH2CH3), 6.97 (dd, J = 7.7, 0.7 Hz, 1H, aromatic H), 7.31 (dd, J =
13
8.2, 0.7 Hz, 1H, aromatic H), 7.44 − 7.48 (m, 1H, aromatic H), 7.98 (s, 1H, aromatic H), C NMR (125
MHz, CDCl3) δ 14.1 (s, OCH2CH3), 15.0 (s, CH3), 25.6 (s, CH2), 55.9 (s, OCH3), 61.8 (s, OCH2CH3),
107.2, 118.6, 128.4, 130.1, 136.2, 136.3, 137.7, 148.8, 155.6 (s, aromatic C); 166.6 (s, CO), HRMS
(FAB) calcd for C15H18NO3 [M + H]+ 260.1287, found 260.1286.
1
Ethyl 6-methyl-3-ethylquinaldate (3i): pale yellow oil (219 mg, 90 %), H NMR (500 MHz, CDCl3)
δ 1.28 (t, J = 7.5 Hz, 3H, CH2CH3), 1.42 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.47 (s, 3H, CH3), 2.95 (q, J =
7.5 Hz, 2H, CH2), 4.47 (q, J = 7.1 Hz, 2H, OCH2CH3), 7.44 – 7.46 (m, 2H, aromatic H), 7.88 (s, 1H,
13
aromatic H), 8.00 (d, J = 8.6 Hz, 1H, aromatic H), C NMR (125 MHz, CDCl3) δ 14.1 (s, OCH2CH3),
15.1 (s, CH2CH3), 21.6 (s, CH3), 25.6 (s, CH2), 61.7 (s, OCH2CH3), 125.6, 128.9, 129.3, 131.5, 135.4,
137.9, 144.2, 149.3 (s, aromatic C); 166.8 (s, CO), HRMS (FAB) calcd for C15H18NO2 [M + H]+
244.1338, found 244.1324.
General procedure for the synthesis of 3j – 3l. A mixture of arylamine (1) (1.0 mmol), ethyl glyoxylate
(1.2 mmol, 0.273 mL, Polymer form 47 % in toluene) and DMSO (3 mL) was stirred at 120 ºC for 1 h.
Then alkyl aldehyde (3) (1.1 mmol) and Yb(OTf)3 (6.2 mg, 0.01 mmol) were added to the mixture, and
the resulting mixture was stirred at 90 ºC for 16 h under oxygen (balloon). The reaction mixture was
washed with PBS buffer solution (50 mL) and extracted with AcOEt (20 mL × 3). The organic layer was
dried over MgSO4. Removal of the solvent in vacuo, followed by chromatography on silica gel column
(AcOEt / Hexane = 5 / 95), afforded 3.
1
Ethyl 6-bromo-3-ethylquinaldate (3j): pale yellow oil (275 mg, 90 %), H NMR (500 MHz, CDCl3)
δ 1.30 (t, J = 7.5 Hz, 3H, CH3), 1.44 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.97 (q, J = 7.5 Hz, 2H, CH2), 4.49 (q,
J = 7.1 Hz, 2H, OCH2CH3), 7.71 (dd, J = 9.0, 2.1 Hz, 1H, aromatic H), 7.91 – 7.92 (m, 2H, aromatic
13
H), 7.98 (d, J = 9.0 Hz, 1H, aromatic H), C NMR (125 MHz, CDCl3) δ 14.2 (s, OCH2CH3), 14.9 (s,

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HETEROCYCLES, Vol. 66, 2005
CH3), 25.6 (s, CH2), 62.1 (s, OCH2CH3), 122.0, 129.0, 129.8, 131.4, 132.8, 135.0, 136.4, 144.2, 150.8 (s,
aromatic C); 166.5 (s, CO), HRMS (FAB) calcd for C14H15NO2Br [M + H]+ 308.0286, found 308.0289.
1
Ethyl 6-fluoro-3-ethylquinaldate (3k): pale yellow oil (180 mg, 73 %), H NMR (500 MHz, CDCl3)
δ 1.31 (t, J = 7.5 Hz, 3H, CH3), 1.44 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.99 (q, J = 7.5 Hz, 2H, CH2), 4.50 (q,
J = 7.1 Hz, 2H, OCH2CH3), 7.36 (dd, J = 8.8, 2.7 Hz, 1H, aromatic H), 7.41 – 7.45 (m, 1H, aromatic
13
H), 7.96 (s, 1H, aromatic H), 8.14 (dd, J = 9.2, 5.3 Hz, 1H, aromatic H), C NMR (125 MHz, CDCl3)
δ 14.2 (s, OCH2CH3), 15.0 (s, CH3), 25.6 (s, CH2), 62.0 (s, OCH2CH3), 109.9 (d, JCF = 23 Hz, aromatic
C), 119.7 (d, JCF = 27 Hz, aromatic C), 129.6 (d, JCF = 9.7 Hz, aromatic C), 132.4 (d, JCF = 9.7 Hz,
aromatic C), 135.5 (d, JCF = 5.6 Hz, aromatic C), 136.4, 142.8 (s, aromatic C), 149.8 (d, JCF = 3.2 Hz,
aromatic C), 161.3 (d, JCF = 256 Hz, aromatic C), 166.6 (s, CO); HRMS (FAB) calcd for C14H15NO2F [M
+ H]+ 248.1087, found 248.1080.
Ethyl 6-methoxycarbonyl-3-ethylquinaldate (3l): colorless crystals (from hexane, 152 mg, 53 %), mp
1
84-85 ºC, H NMR (500 MHz, CDCl3) δ 1.32 (t, J = 7.5 Hz, 3H, CH3), 1.44 (t, J = 7.1 Hz, 3H,
OCH2CH3), 2.98 (q, J = 7.5 Hz, 2H, CH2), 3.96 (s, 3H, OCH3), 4.51 (q, J = 7.1 Hz, 2H, OCH2CH3), 8.11
(s, 1H, aromatic H), 8.15 (d, J = 8.8 Hz, 1H, aromatic H), 8.23 (dd, J = 8.8, 1.6 Hz, 1H, aromatic H), 8.53
(d, J = 1.6 Hz, 1H, aromatic H), 13C NMR (125 MHz, CDCl3) δ 14.2 (s, OCH2CH3), 14.9 (s, CH3), 25.5 (s,
CH2), 52.5 (s, OCH3), 62.1 (s, OCH2CH3), 127.9, 128.7, 129.2, 130.0, 130.1, 136.0, 137.3, 147.4, 152.6 (s,
aromatic C); 166.4, 166.5 (s, CO), HRMS (FAB) calcd for C16H18NO4 [M + H]+ 288.1236, found
288.1251, Anal. Calcd for C15H19NO: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.69; H, 5.79; N, 4.89.
Ethyl 6-(ethoxycarbonylmethyl)-3-ethylquinaldate (4): pale yellow oil (47 mg, 15 %, obtained along
with 3g), 1H NMR (500 MHz, CDCl3) δ 1.20 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.29 (t, J = 7.5 Hz, 3H, CH3),
1.42 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.96 (q, J = 7.5 Hz, 2H, CH2CH3), 3.75 (s, 2H, CH2), 4.13 (q, J = 7.1
Hz, 2H, OCH2CH3), 4.48 (q, J = 7.1 Hz, 2H, OCH2CH3), 7.58 (dd, J = 8.8, 1.8 Hz, 1H, aromatic H), 7.65
(d, J = 1.8 Hz, 1H, aromatic H), 7.96 (s, 1H, aromatic H), 8.08 (d, J = 8.8 Hz, 1H, aromatic H), 13C NMR
(125 MHz, CDCl3) δ 14.1, 14.2 (s, OCH2CH3), 15.0 (s, CH3), 25.6 (s, CH2CH3), 52.5 (s, OCH3), 61.0,
61.9 (s, OCH2CH3), 126.9, 128.7, 129.8, 130.9, 134.0, 135.6, 135.9, 144.8, 150.2 (s, aromatic C); 166.7,
171.0 (s, CO), HRMS (FAB) calcd for C18H22NO4 [M + H]+ 316.1549, found 316.1550.
Ethyl 2,2-bis(2-ethoxycarbonyl-3-ethylquinolin-6-yl)acetate (5): pale yellow oil (119 mg, 22 %,
1
obtained along with 3g), H NMR (500 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.29 (t, J =
7.5 Hz, 6H, CH3), 1.43 (t, J = 7.1 Hz, 6H, OCH2CH3), 2.96 (q, J = 7.5 Hz, 4H, OCH2CH3), 4.26 (q, J =

HETEROCYCLES, Vol. 66, 2005
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7.1 Hz, 2H, OCH2CH3), 4.49 (q, J = 7.1 Hz, 4H, OCH2CH3), 5.35 (s, 1H, CH), 7.64 (dd, J = 9.0, 2.0 Hz,
2H, aromatic H), 7.72 (d, J = 2.0 Hz, 2H, aromatic H), 7.99 (s, 2H, aromatic H), 8.11 (d, J = 9.0 Hz, 2H,
13
aromatic H), C NMR (125 MHz, CDCl3) δ 14.1, 14.2 (s, OCH2CH3), 15.0 (s, CH3), 25.6 (s, CH2CH3),
56.8 (s, CH), 61.7, 62.0 (s, OCH2CH3), 126.4, 128.8, 130.1, 130.3, 135.9, 136.4, 137.9, 144.9, 150.7 (s,
aromatic C); 166.7, 171.6 (s, CO), HRMS (FAB) calcd for C32H35N2O6 [M + H]+ 543.2495, found
543.2495.
ACKNOWLEDGEMENTS
This work was supported by Waseda University Grant for Special Project Research (No. 2005B-157).
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