An Efficient Synthesis of 2,4-Disubstituted Quinolines by Electrophile-Mediated Cyclization Reactions of 2-Isocyanostyrene Derivatives

Article abstract of DOI:10.1246/bcsj.77.553

A novel quinoline synthesis starting with 2-isocyanostyrene derivatives is described. The treatment of 2-isocyanostyrene derivatives with aldehydes (or acetone) in the presence of a catalytic amount of diethyl ether-boron trifluoride afforded quinoline derivatives carrying a 1-hydroxyalkyl substituent at the 2-position. The use of acetaldehyde diethyl acetal or phenyloxirane as an electrophile under the same conditions gave the corresponding quinoline derivatives, carrying the 1-ethoxyethyl or 2-hydroxy-2-phenylethyl substituent at the 2-position, respectively. 2-Isocyanostyrene derivatives reacted with N,N-dimethyliminium salts without any catalyst to give 2-(1-dimethylaminoalkyl)quinolines.

Full text of DOI:10.1246/bcsj.77.553

Ó 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 553–559 (2004)
553
An Efficient Synthesis of 2,4-Disubstituted Quinolines by Electrophile-
Mediated Cyclization Reactions of 2-Isocyanostyrene Derivatives
ꢀ
Kazuhiro Kobayashi, Kenichi Takagoshi, Shizuka Kondo, Osamu Morikawa, and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552
Received August 21, 2003; E-mail: kkoba@chem.tottori-u.ac.jp
A novel quinoline synthesis starting with 2-isocyanostyrene derivatives is described. The treatment of 2-isocyano-
styrene derivatives with aldehydes (or acetone) in the presence of a catalytic amount of diethyl ether–boron trifluoride
afforded quinoline derivatives carrying a 1-hydroxyalkyl substituent at the 2-position. The use of acetaldehyde diethyl
acetal or phenyloxirane as an electrophile under the same conditions gave the corresponding quinoline derivatives, carry-
ing the 1-ethoxyethyl or 2-hydroxy-2-phenylethyl substituent at the 2-position, respectively. 2-Isocyanostyrene deriva-
tives reacted with N,N-dimethyliminium salts without any catalyst to give 2-(1-dimethylaminoalkyl)quinolines.
We recently showed that 1-(2-isocyanophenyl)pyrroles re-
acted with aldehydes (or ketones), acetals, or oxiranes in the
Table 1. Preparation of 2-(1-Hydroxyalkyl)quinolines 2
Entry
1
R0COR00 2 (Yield/%)a)
EtCHO 2a (52)
i-PrCHO 2b (58)
EtCHO 2c (66)
i-PrCHO 2d (82)
MeCOMe 2e (6)
presence of catalytic amounts of diethyl ether–boron trifluoride
to afford pyrrolo[1,2-a]quinoxalines carrying an oxyalkyl sub-
stituent, such as 1-hydroxyalkyl,1,2 1-alkoxyalkyl,2 or 2-hy-
droxyalkyl,2 at the 4-position, respectively. We also described
that 4-(1-dialkylaminoalkyl)pyrrolo[1,2-a]quinoxalines could
be prepared by treating 1-(2-isocyanophenyl)pyrroles with var-
ious iminium salts without any catalyst.3 In an attempt to broad-
en the scope of these reactions, we examined an analogous elec-
trophile-mediated cyclization using 2-isocyanostyrene deriva-
tives 1 with the expectation that the reaction might produce qui-
nolines carrying one of these functionalized substituents at the
2-position,4 2–6. In this paper, we would like to report on the
results of that study. A large number of general synthetic meth-
ods of quinoline derivatives have been reported.5 However, the
availability of a new method for their general preparation
would seem to be attractive because of their importance in syn-
thetic,6 medicinal,7,8 and natural-product chemistries.9
The treatment of 2-isocyanostyrene derivatives 1 with alde-
hydes in dichloromethane at 0 ꢁC in the presence of a 0.1 molar
amount of diethyl ether–boron trifluoride led to the formation
of quinoline rings with the introduction of a 1-hydroxyalkyl
group at the 2-position (Scheme 1), and the corresponding de-
sired products 2 were obtained in the yields summarized in
Table 1. The reactions of 2-isocyano-ꢀ-phenylstyrene (1a)
gave moderate-to-fair yields of the desired products (entries 1
and 2). However, when methoxy group(s) were substituted on
1
2
3
4
5
6
7
1a (R = Ph)
1a
1b [R = 4-(MeO)C6H4]
1b
1b
1c [R = 3,4-(MeO)2C6H3]
1d (R = Me)
EtCHO
EtCHO
2f (72)
2g (39)
a) Isolated yields after purification by preparative TLC on
SiO2.
the ꢀ-phenyl group, somewhat better results were obtained (en-
tries 3, 4, and 6). Although the reaction of 1b with acetone un-
der the same conditions gave the desired product 2e, the yield
was very low (entry 5). Furthermore, the use of 2-isocyano-
ꢀ-methylstyrene (1d) gave a rather poor result (entry 7). This
may be due to the lower nucleophilicity of the methylethenyl
group.
The preparation of 2-(1-ethoxyethyl)quinolines 3a and 3c
was achieved by the treatment of 2-isocyanostyrene derivatives
1a and 1c with acetaldehyde diethyl acetal in the presence of
diethyl ether–boron trifluoride under conditions similar to those
described for the preparation of 2, as shown in Scheme 2. How-
ever, the yields of these products were low to moderate.
Subsequently, a similar treatment of 2-isocyanostyrene de-
rivatives 1 with phenyloxirane was carried out. The reaction
was found to give 2-(2-hydroxy-2-phenylethyl)quinolines 4,
as illustrated in Scheme 3. While the reaction using 2-isocya-
no-ꢀ-(4-methoxyphenyl)styrene (1b) gave a moderate yield
of the desired product 4b, ꢀ-(3,4-dimethoxyphenyl)-2-isocya-
nostyrene (1c) gave a much better result.
The portionwise addition of a catalyst, which was very effec-
tive for preparing substituted pyrrolo[1,2-a]quinoxalines,1,2
could not be used in any cases of the above-mentioned present
reactions, because TLC analyses of the reactions showed that
the starting materials were completely consumed within 20
min in all cases.
Scheme 1.
Published on the web March 12, 2004; DOI 10.1246/bcsj.77.553

554 Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
Synthesis of 2,4-Disubstituted Quinolines
Scheme 2.
Scheme 4.
attempt was made to isolate (quinolin-2-ylmethyl)ammonium
iodides. The reaction mixtures were directly treated with satu-
rated anhydrous sodium hydrogencarbonate to give the corre-
sponding 2-(dimethylaminomethyl)quinolines 6a and 6f (en-
tries 1 and 5). The reaction of isocyanide 1c with N,N-dimethyl-
propylideneammonium iodide10 proceeded sluggishly, even at
room temperature to afford only a low yield of 2-[1-(dimethyl-
amino)propyl]quinoline 6g, after a workup with saturated anhy-
drous sodium hydrogencarbonate (entry 6).
The present reactions leading to 2-functionalized quinolines
2–6 are thought to proceed via an attack of the isocyano carbon
of o-isocyanostyrenes 1 to activated electrophiles, followed by
an intramolecular combination of the resulting cation center
and the ꢁ-carbon atom of the styrenes, in a similar manner as
illustrated for the formation of pyrrolo[1,2-a]quinolines from
1-(2-isocyanophenyl)pyrroles in our previous papers.1–3
In summary, an efficient synthesis of quinolines carrying a
functionalized substituent at the 2-position, which are other-
wise accessible with difficulty, based on the electrophile-medi-
ated cyclization of 2-isocyanostyrene derivatives, has been
demonstrated. The ready availability of the starting isocya-
nides, which were prepared from commercially available o-
aminoacetophenone, and the ease of operation make the present
quinoline synthesis attractive.
Scheme 3.
As expected, 2-(1-dimethylammonioalkyl)- and 2-(1-di-
methylaminoalkyl)quinolines, 5 and 6, could be obtained by
the treatment of 2-isocyanostyrenes 1 with iminium salts with-
out any catalyst, as illustrated in Scheme 4. Thus, reactions of
2-isocyanostyrene derivatives 1b, 1c, and 1e with N,N-di-
methylmethyleneammonium iodide (Eschenmoser’s salt) un-
derwent smoothly at 0 ꢁC, and the addition of anhydrous diethyl
ether, followed by filtration, gave the corresponding (quinolin-
2-ylmethyl)ammonium iodide (5b, 5c, and 5e) in fair-to-good to
excellent yields, as summarized in Table 2 (entries 2–4). These
salts were then treated with saturated anhydrous sodium hydro-
gencarbonate to give 2-(dimethylaminomethyl)quinolines 6 in
excellent yields, after extraction with dichloromethane, fol-
lowed by purification by column chromatography on silica
gel. In the reactions of 1a and 1f with Eschenmoser’s salt, no
Experimental
General. The melting points were determined on a Laboratory
Devices MEL-TEMP II melting-point apparatus and are uncorrect-
Table 2. Preparation of 2-(1-Aminoalkyl)quinolines 5 and 6
Entry
Isocyanide 1
R in iminium salt
Temp/ꢁC
5 (Yield/%)a)
6 (Yield/%)b)
1
2
3
4
5
6
1a
1b
1c
H
H
H
H
H
Et
0
0
0
0
0
rt
—
5b (76)
5c (95)
5e (74)
—
6a (49)c)
6b (95)
6c (95)
6e (95)
6f (55)c)
6g (28)c)
1e [Ar = 2,6-(MeO)2C6H3]
1f [Ar = 2,4,6-(MeO)3C6H2]
1c
—
a) Isolated yields after recrystallization. b) Isolated yields after purification by chromatography on SiO2.
c) Overall yields from 1.

K. Kobayashi et al.
Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
555
ed. The IR spectra were recorded on a Perkin-Elmer 1600 Series
1
and 5.83 (combined 1H, 2s), 6.84 (2H, d, J ¼ 8:9 Hz), 7.15–7.4
(7H, m), and 8.15–8.6 (1H, m). Found: C, 75.81; H, 6.00; N,
5.32%. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53%.
1-Isocyano-2-[1-(4-methoxyphenyl)ethenyl]benzene (1b): An
FT IR spectrometer. The H NMR spectra were determined using
SiMe4 as an internal reference with a JEOL JNM-GX270 FT
NMR spectrometer operating at 270 MHz in CDCl3. Low-resolu-
tion mass spectra were recorded on a JEOL AUTOMASS 20 spec-
trometer (Center for Joint Research and Development, this Univer-
sity). High-resolution mass spectra were performed on a JEOL
JMS-AX505 HA spectrometer (Faculty of Agriculture, this Uni-
versity). Thin-layer chromatography (TLC) was carried out on
Merck Kieselgel 60 PF254. All of the solvents used were dried over
appropriate drying agents and distilled under argon prior to use. All
of the reactions were carried out under argon.
oil; Rf 0.65 (1:2 EtOAc–hexane); IR (neat) 2123 and 1607 cmꢂ1
;
1H NMR ꢂ 3.80 (3H, s), 5.27 (1H, d, J ¼ 1:0 Hz), 5.77 (1H, d, J ¼
1:0 Hz), 6.84 (2H, d, J ¼ 8:9 Hz), 7.18 (2H, d, J ¼ 8:9 Hz), and
7.3–7.45 (4H, m); MS m=z (%) 235 (Mþ, 100). Found: m=z
235.1012. Calcd for C16H13NO: M, 235.0997.
1-(2-Aminophenyl)-1-(3,4-dimethoxyphenyl)ethanol: An oil;
Rf 0.20 (1:2 EtOAc–hexane); IR (neat) 3477, 3379, and 1614
cmꢂ1; 1H NMR ꢂ 1.86 (3H, s), 3.5–4.2, 3.82, and 3.84 (combined
9H, br, s, and, s, respectively), 6.64 (1H, d, J ¼ 6:6 Hz), 6.7–6.8
(2H, m), 6.85 (1H, t, J ¼ 7:6 Hz), 7.06 (1H, d, J ¼ 2:0 Hz), 7.13
(1H, t, J ¼ 7:6 Hz), and 7.37 (1H, d, J ¼ 7:6 Hz). Found: C,
70.29; H, 6.96; N, 5.08%. Calcd for C16H19NO3: C, 70.31; H,
7.01; N, 5.12%.
Starting Materials. The starting isocyanides 1 were prepared
from 1-amino-2-(1-arylethenyl)benzenes or 1-amino-2-(1-methyl-
ethenyl)benzene (commercially available) by formylation with for-
mic acid in refluxing toluene, followed by dehydration of the re-
ꢁ
sulting formamides with POCl3/Et3N in THF at 0 C. 1-Amino-
2-(1-arylethenyl)benzenes were prepared by the action of arylmag-
nesium bromides, generated from appropriate aryl bromide and
magnesium, upon o-aminoacetophenone, followed by thermolytic
dehydration11 of the resulting 1-(2-aminophenyl)-1-arylethanols.
The physical, spectral, and analytical data for new compounds
follow.
1-Amino-2-[1-(3,4-dimethoxyphenyl)ethenyl]benzene: mp
ꢁ
cmꢂ1; H NMR ꢂ 3.56 (2H, br s), 3.84 (3H, s), 3.87 (3H, s), 5.26
(1H, d, J ¼ 1:3 Hz), 5.69 (1H, d, J ¼ 1:3 Hz), 6.68 (1H, d, J ¼
8:2 Hz), 6.7–6.8 (2H, m), 6.86 (1H, dd, J ¼ 8:2 and 2.0 Hz),
6.96 (1H, d, J ¼ 2:0 Hz), 7.05–7.2 (2H, m). Found: C, 75.09; H,
6.88; N, 5.28%. Calcd for C16H17NO2: C, 75.27; H, 6.71; N,
5.49%.
145–147 C (hexane–Et2O); IR (KBr disk) 3464, 3372, and 1607
1
1-(2-Aminophenyl)-1-phenylethanol: mp 88–90 ꢁC (hexane–
Et2O); IR (KBr disk) 3527, 3464, 3370, and 1621 cmꢂ1; 1H NMR ꢂ
1.87 (3H, s), 3.73 (3H, br), 6.64 (1H, d, J ¼ 7:4 Hz), 6.86 (1H, t,
J ¼ 7:4 Hz), 7.11 (1H, t, J ¼ 7:4 Hz), 7.2–7.35 (3H, m), and
7.35–7.45 (3H, m). Found: C, 78.82; H, 7.10; N, 6.30%. Calcd
for C14H15NO: C, 78.84; H, 7.09; N, 6.57%.
N-{2-[1-(3,4-Dimethoxyphenyl)ethenyl]phenyl}formamide:
mp 125–127 ꢁC (toluene); IR (KBr disk) 3340 and 1694 cmꢂ1
;
1H NMR ꢂ 3.84 (3H, s), 3.88 (3H, s), 5.23 and 5.26 (combined
1H, 2s), 5.79 and 5.85 (combined 1H, 2s), 6.7–6.95 (3H, m),
7.1–7.45 (4H, m), 8.15–8.6 (2H, m). Found: C, 71.96; H, 6.13;
N, 4.93%. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94%.
1-[1-(3,4-Dimethoxyphenyl)ethenyl]-2-isocyanobenzene
(1c): mp 79–81 ꢁC (Et2O–hexane–CH2Cl2); IR (KBr disk) 2124
and 1601 cmꢂ1; 1H NMR ꢂ 3.85 (3H, s), 3.88 (3H, s), 5.31 (1H, s),
5.79 (1H, s), 6.70 (1H, dd, J ¼ 8:2 and 2.0 Hz), 6.78 (1H, d, J ¼
8:2 Hz), 6.87 (1H, d, J ¼ 2:0 Hz), and 7.3–7.45 (4H, m); MS
m=z (%) 265 (Mþ, 100). Found: C, 76.71; H, 5.43; N, 5.20%. Calcd
for C17H15NO2: C, 76.96; H, 5.70; N, 5.28%.
1-Amino-2-(1-phenylethenyl)benzene: mp 83–85 ꢁC (hex-
1
ane–Et2O); IR (KBr disk) 3476, 3381, and 1615 cmꢂ1; H NMR
ꢂ 3.03 (2H, br), 5.35 (1H, d, J ¼ 1:3 Hz), 5.79 (1H, d, J ¼ 1:3
Hz), 6.70 (1H, d, J ¼ 7:9 Hz), 6.79 (1H, td, J ¼ 7:9 and 1.3 Hz),
7.15 (1H, td, J ¼ 7:9 and 1.3 Hz), and 7.25–7.4 (6H, m). These
spectral data were identical to those reported in the literature.12
N-[2-(1-Phenylethenyl)phenyl]formamide:
(hexane–Et2O); IR (KBr disk) 3266, 1694, and 1668 cmꢂ1
mp 86–89 ꢁC
;
1H NMR ꢂ 5.32 and 5.36 (combined 1H, 2s), 5.89 and 5.95 (com-
bined 1H, 2s), 7.05–7.4 (10H, m), and 8.15–8.55 (1H, m). Found:
C, 80.67; H, 5.87; N, 5.99%. Calcd for C15H13NO: C, 80.69; H,
5.87; N, 6.27%.
N-[2-(1-Methylethenyl)phenyl]formamide:
mp 60–61 ꢁC
(toluene–hexane); IR (KBr disk) 3275 and 1667 cmꢂ1; H NMR
ꢂ 2.05 and 2.07 (combined 3H, 2s), 5.00 and 5.03 (combined
1H, 2s), 5.36 and 5.40 (combined 1H, 2s), 7.05–7.3 (4H, m),
7.61 (1H, br), and 8.3–8.7 (1H, m). Found: C, 74.54; H, 7.02; N,
8.64%. Calcd for C10H11NO: C, 74.51; H, 6.88; N, 8.69%.
1-Isocyano-2-(1-methylethenyl)benzene (1d): An oil; Rf 0.78
1
1-Isocyano-2-(1-phenylethenyl)benzene (1a): An oil; Rf 0.75
1
(1:2 EtOAc–hexane); IR (neat) 2122 cmꢂ1; H NMR ꢂ 5.40 (1H,
s), 5.87 (1H, s), and 7.25–7.4 (9H, m); MS m=z (%) 205 (Mþ,
87) and 204 (100). Found: m=z 205.0916. Calcd for C15H11N: M,
205.0891.
1
(1:2 EtOAc–hexane); IR (neat) 2122 cmꢂ1; H NMR ꢂ 2.10 (3H,
1-(2-Aminophenyl)-1-(4-methoxyphenyl)ethanol: An oil; Rf
s), 5.07 (1H, s), 5.29 (1H, s), and 7.2–7.35 (4H, m); MS m=z (%)
143 (Mþ, 100). Found: m=z 143.0719. Calcd for C10H9N: M,
143.0735.
0.25 (1:2 EtOAc–hexane); IR (neat) 3456, 3382, and 1611 cmꢂ1
;
1H NMR ꢂ 1.86 (3H, s), 3.7–3.85 and 3.78 (combined 6H, br and
s), 6.64 (1H, dd, J ¼ 7:9 and 1.3 Hz), 6.8–6.9 (3H, m), 7.12 (1H,
t, J ¼ 7:9 Hz), 7.30 (2H, d, J ¼ 8:9 Hz), and 7.37 (1H, d, J ¼
7:9 Hz). Found: C, 73.86; H, 7.14; N, 5.66%. Calcd for
C15H17NO2: C, 74.05; H, 7.04; N, 5.76%.
1-(2-Aminophenyl)-1-(2,6-dimethoxyphenyl)ethanol:
ꢁ
mp
95–97 C (hexane–Et2O); IR (KBr disk) 3479, 3443, 3345, 1635,
1
and 1611 cmꢂ1; H NMR ꢂ 2.03 (3H, s), 3.65 (6H, s), 4.39 (1H,
br s), 5.83 (2H, br s), 6.55–6.65 (4H, m), 6.95–7.05 (2H, m), and
7.21 (1H, t, J ¼ 8:2 Hz). Found: C, 70.25; H, 6.94; N, 5.04%.
Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12%.
1-Amino-2-[1-(2,6-dimethoxyphenyl)ethenyl]benzene: mp
134–138 ꢁC (hexane–Et2O); IR (KBr disk) 3451, 3361, 1628,
and 1612 cmꢂ1 1H NMR ꢂ 3.75 (6H, s), 4.01 (2H, br s), 5.39
;
(1H, d, J ¼ 2:1 Hz), 5.64 (1H, d, J ¼ 2:1 Hz), 6.55–6.7 (4H, m),
7.00 (1H, t, J ¼ 7:6 Hz), 7.12 (1H, d, J ¼ 7:6 Hz), and 7.19
(1H, t, J ¼ 8:2 Hz). Found: C, 75.16; H, 6.80; N, 5.41%. Calcd
for C16H17NO2: C, 75.27; H, 6.71; N, 5.49%.
1-Amino-2-[1-(4-methoxyphenyl)ethenyl]benzene: An oil;
Rf 0.75 (1:2 EtOAc–hexane); IR (neat) 3466, 3375, and 1607
1
cmꢂ1; H NMR ꢂ 3.58 (2H, br), 3.80 (3H, s), 5.23 (1H, s), 5.69
(1H, m), 6.85 (1H, d, J ¼ 8:6 Hz), 7.15–7.4 (6H, m), and 7.30
(1H, d, J ¼ 8:6 Hz). Found: C, 79.87; H, 6.61; N, 6.16%. Calcd
for C15H15NO: C, 79.97; H, 6.71; N, 6.22%.
N-{2-[1-(4-Methoxyphenyl)ethenyl]phenyl}formamide: mp
72–73 C (toluene); IR (KBr disk) 3314, 1694, and 1605 cmꢂ1
ꢁ
;
1H NMR ꢂ 3.80 (3H, s), 5.20 and 5.23 (combined 1H, 2s), 5.78

556 Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
Synthesis of 2,4-Disubstituted Quinolines
N-{2-[1-(2,6-Dimethoxyphenyl)ethenyl]phenyl}formamide:
mp 163–165 ꢁC (toluene); IR (KBr disk) 3326, 1693, and 1613
1H NMR ꢂ 0.79 (3H, d, J ¼ 6:6 Hz), 1.15 (3H, d, J ¼ 6:6 Hz),
2.1–2.25 (1H, m), 4.78 (1H, br s), 4.86 (1H, br s), 7.25 (1H, s),
7.45–7.55 (6H, s), 7.72 (1H, t, J ¼ 8:3 Hz), 7.90 (1H, d, J ¼ 8:3
Hz), and 8.14 (1H, d, J ¼ 8:3 Hz); MS m=z (%) 277 (Mþ, 3.2)
and 194 (100). Found: C, 82.05; H, 6.97; N, 4.81%. Calcd for
C19H19NO: C, 82.28; H, 6.90; N, 5.05%.
cmꢂ1 1H NMR ꢂ 3.78 and 3.81 (combined 6H, 2s), 5.46 and
;
5.48 (combined 1H, 2d, J ¼ 1:3 Hz each), 5.52 and 5.55 (com-
bined 1H, 2d, J ¼ 1:3 Hz each), 6.57 and 6.59 (combined 2H, d,
J ¼ 8:6 Hz each), 7.0–7.25 (4H, m), 7.32 and 7.39 (combined
1H, 2d, J ¼ 7:6 Hz each), and 8.25–8.7 (2H, m). Found: C,
71.97; H, 6.33; N, 4.85%. Calcd for C17H17NO3: C, 72.07; H,
6.05; N, 4.94%.
1-[1-(2,6-Dimethoxyphenyl)ethenyl]-2-isocyanobenzene (1e):
mp 123–124 ꢁC (hexane–Et2O–CH2Cl2); IR (KBr disk) 2128 and
1634 cmꢂ1; 1H NMR ꢂ 3.71 (6H, s), 5.62 (1H, d, J ¼ 1:5 Hz), 5.82
(1H, d, J ¼ 1:5 Hz), 6.57 (2H, d, J ¼ 8:6 Hz), and 7.15–7.35 (5H,
m); MS m=z (%) 265 (Mþ, 51) and 250 (100). Found: C, 76.74; H,
5.61; N, 5.21%. Calcd for C17H15NO2: C, 76.96; H, 5.70; N,
5.28%.
2-(1-Hydroxypropyl)-4-(4-methoxyphenyl)quinoline (2c): A
viscous oil; Rf 0.13 (1:5 EtOAc–hexane); IR (neat) 3390 and
1614 cmꢂ1
;
1H NMR ꢂ 1.01 (3H, t, J ¼ 7:3 Hz), 1.7–1.85 (1H,
m), 2.0–2.1 (1H, m), 3.90 (3H, s), 4.90 (2H, br s), 7.05 (2H, d, J ¼
8:9 Hz), 7.24 (1H, s), 7.4–7.55 (3H, m), 7.71 (1H, t, J ¼ 8:2 Hz),
7.93 (1H, d, J ¼ 8:2 Hz), and 8.13 (1H, d, J ¼ 8:2 Hz); MS m=z
(%) 293 (Mþ, 1.5) and 265 (100). Found: C, 77.79; H, 6.72; N,
4.88%. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77%.
2-(1-Hydroxy-2-methylpropyl)-4-(4-methoxyphenyl)quino-
ꢁ
line (2d): mp 117–118 C (hexane–Et2O); IR (KBr disk) 3382
1
1-(2-Aminophenyl)-1-(2,4,6-trimethoxyphenyl)ethanol: mp
ꢁ
and 1609 cmꢂ1; H NMR ꢂ 0.79 (3H, d, J ¼ 6:8 Hz), 1.14 (3H,
147–149 C (hexane–Et2O–CH2Cl2); IR (KBr disk) 3479, 3379,
1
d, J ¼ 6:8 Hz), 2.0–2.5 (1H, m), 3.89 (3H, s), 4.76 (1H, br s),
4.84 (1H, br s), 7.06 (2H, d, J ¼ 8:6 Hz), 7.23 (1H, s), 7.4–7.55
(3H, m), 7.71 (1H, t, J ¼ 8:2 Hz), 7.93 (1H, d, J ¼ 8:2 Hz), and
8.13 (1H, d, J ¼ 8:2 Hz); MS m=z (%) 307 (Mþ, 6.6), 306 (19),
and 236 (100). Found: C, 77.96; H, 6.88; N, 4.32%. Calcd for
C20H21NO2: C, 78.15; H, 6.89; N, 4.56%.
and 1606 cmꢂ1; H NMR ꢂ 2.00 (3H, s), 3.64 (6H, s), 3.80 (3H,
s), 4.3–4.6 (1H, br), 5.4–5.6 (2H, br), 6.18 (2H, s), 6.55–6.65
(2H, m), and 6.9–7.0 (2H, m). Found: C, 67.30; H, 7.01; N,
4.70%. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62%.
1-Amino-2-[1-(2,4,6-trimethoxyphenyl)ethenyl]benzene: mp
ꢁ
102–103 C (hexane–Et2O); IR (KBr disk) 3445, 3362, and 1602
1
2-(1-Hydroxy-1-methylethyl)-4-(4-methoxyphenyl)quino-
line (2e): A viscous oil; Rf 0.05 (1:5 EtOAc–hexane); IR (neat)
;
3390 and 1604 cmꢂ1 1H NMR ꢂ 1.57 (1H, br s), 1.63 (6H, s),
3.91 (3H, s), 7.07 (2H, d, J ¼ 8:4 Hz), 7.35 (1H, s), 7.4–7.5 (3H,
m), 7.71 (1H, t, J ¼ 8:3 Hz), 7.92 (1H, d, J ¼ 8:3 Hz), and 8.12
(1H, d, J ¼ 8:3 Hz); MS m=z (%) 293 (Mþ, 8.9) and 278 (100).
Found: C, 77.72; H, 6.61; N, 4.62%. Calcd for C19H19NO2: C,
77.79; H, 6.53; N, 4.77%.
cmꢂ1; H NMR ꢂ 3.72 (6H, s), 3.80 (3H, s), 4.00 (2H, br s), 5.37
(1H, d, J ¼ 1:5 Hz), 5.60 (1H, d, J ¼ 1:5 Hz), 6.15 (2H, s),
6.55–6.7 (2H, m), 6.99 (1H, td, J ¼ 7:6 and 1.6 Hz), and 7.10
(1H, dd, J ¼ 7:6 and 1.6 Hz). Found: C, 71.61; H, 6.07; N,
4.91%. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91%.
N-{2-[1-(2,4,6-Trimethoxyphenyl)ethenyl]phenyl}formamide:
mp 115–117 ꢁC (toluene); IR (KBr disk) 3390 and 1698 cmꢂ1
;
1H NMR ꢂ 3.76, 3.78, and 3.80 (combined 9H, 3s), 5.4–5.55
(2H, m), 6.135 and 6.144 (combined 2H, 2s), 7.0–7.4 (4H, m),
and 8.2–8.7 (2H, m). Found: C, 68.87; H, 6.30; N, 4.45%. Calcd
for C18H19NO4: C, 68.99; H, 6.11; N, 4.47%.
4-(3,4-Dimethoxyphenyl)-2-(1-hydroxypropyl)quinoline
ꢁ
(2f): mp 109–110 C (hexane–Et2O); IR (KBr disk) 3390 and
1
1604 cmꢂ1; H NMR ꢂ 1.02 (3H, t, J ¼ 7:4 Hz), 1.75–1.85 (1H,
m), 2.0–2.1 (1H, m), 3.92 (3H, s), 3.98 (3H, s), 3.95–4.05 (2H,
m), 7.0–7.1 (3H, m), 7.27 (1H, s), 7.49 (1H, ddd, J ¼ 7:3, 6.9,
and 1.3 Hz), 7.73 (1H, ddd, J ¼ 8:6, 7.3 and 1.3 Hz), 7.96 (1H,
d, J ¼ 7:3 Hz), and 8.14 (1H, d, J ¼ 8:6 Hz); MS m=z (%) 323
(Mþ, 6.6) and 295 (100). Found: C, 74.22; H, 6.70; N, 4.32%.
Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33%.
1-Isocyano-2-[1-(2,4,6-trimethoxyphenyl)ethenyl]benzene
(1f): mp 128–129 ꢁC (hexane–Et2O–CH2Cl2); IR (KBr disk)
1
2123 and 1601 cmꢂ1; H NMR ꢂ 3.69 (6H, s), 3.82 (3H, s), 5.58
(1H, d, J ¼ 1:3 Hz), 5.76 (1H, d, J ¼ 1:3 Hz), 6.14 (2H, s), and
7.15–7.35 (4H, m); MS m=z (%) 295 (Mþ, 98) and 280 (100).
Found: C, 73.03; H, 5.93; N, 4.82%. Calcd for C18H17NO3: C,
73.20; H, 5.80; N, 4.74%.
2-(1-Hydroxypropyl)-4-methylquinoline (2g): A viscous oil;
Rf 0.16 (1:5 EtOAc–hexane); IR (neat) 3382 and 1604 cmꢂ1
;
Typical Procedure for the Preparation of 2-(1-Hydroxyal-
kyl)quinolines 2. 2-(1-Hydroxypropyl)-4-phenylquinoline (2a):
To a stirred solution of 1a (0.21 g, 1.0 mmol) and propanal (58
1H NMR ꢂ 0.93 (3H, t, J ¼ 7:3 Hz), 1.75–1.85 (1H, m), 1.95–
2.05 (1H, m), 2.71 (3H, s), 4.8–4.85 (2H, m), 7.17 (1H, s), 7.55
(1H, t, J ¼ 8:0 Hz), 7.70 (1H, d, J ¼ 8:0 Hz), 7.98 (1H, d, J ¼
8:0 Hz), and 8.07 (1H, d, J ¼ 8:0 Hz); MS m=z (%) 201 (Mþ,
0.15), 199 (7.5), 184 (19), and 173 (100). Found: C, 77.54; H,
7.61; N, 6.86%. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96%.
Isocyanides 1a and 1c were allowed to react with acetaldehyde
diethyl acetal in the presence of diethyl ether–boron trifluoride (0.1
eq.) as described for the preparation of 2a. Similar workups and pu-
rification gave 3a and 3c, respectively.
ꢁ
mg, 1.0 mmol) in CH2Cl2 (5 mL) at 0 C under argon was added
Et2O BF3 (14 mg, 0.10 mmol). After 20 min, CH2Cl2 (10 mL)
ꢃ
and aqueous saturated NaHCO3 (15 mL) were added. The layers
were separated. The aqueous layer was extracted with CH2Cl2
twice (10 mL each). The combined extracts were washed with
brine, dried over anhydrous K2CO3, and evaporated. The residue
was purified by column chromatography on SiO2 (1:3 EtOAc–
hexane) to give 2a (0.14 g, 52%): a viscous oil; Rf 0.18 (1:3
2-(1-Ethoxyethyl)-4-phenylquinoline (3a): A viscous oil; Rf
0.35 (1:5 EtOAc–hexane); IR (neat) 1591 and 1108 cmꢂ1
;
1
EtOAc–hexane); IR (neat) 3381 and 1591 cmꢂ1; H NMR ꢂ 1.01
(3H, t, J ¼ 7:3 Hz), 1.75–1.85 (1H, m), 1.95–2.05 (1H, m), 4.90
(2H, br s), 7.27 (1H, s), 7.45–7.55 (6H, m), 7.72 (1H, t, J ¼ 8:2),
7.88 (1H, d, J ¼ 8:3 Hz), and 8.14 (1H, d, J ¼ 8:3 Hz); MS m=z
(%) 263 (Mþ, 0.16), 261 (1.9), 246 (13), and 235 (100). Found:
C, 82.08; H, 5.37; N, 6.27%. Calcd for C18H17NO: C, 82.10; H,
5.32; N, 6.08%.
1H NMR ꢂ 1.22 (3H, t, J ¼ 7:4 Hz), 1.58 (3H, d, J ¼ 6:9 Hz),
3.45–3.6 (2H, m), 4.75 (1H, q, J ¼ 7:4 Hz), 7.45–7.6 (7H, m),
7.70 (1H, t, J ¼ 8:2 Hz), 7.91 (1H, d, J ¼ 8:2 Hz), and 8.13
(1H, d, J ¼ 8:2 Hz); MS m=z (%) 277 (Mþ, 0.09) and 233 (100).
Found: C, 82.14; H, 6.93; N, 5.05%. Calcd for C19H19NO: C,
82.28; H, 6.90; N, 5.05%.
2-(1-Hꢁydroxy-2-methylpropyl)-4-phenylquinoline (2b): mp
4-(3,4-Dimethoxyphenyl)-2-(1-ethoxyethyl)quinoline (3c): A
viscous oil; Rf 0.35 (1:2 EtOAc–hexane); IR (neat) 1620, 1608,
115–116 C (hexane–Et2O); IR (KBr disk) 3382 and 1591 cmꢂ1
;

K. Kobayashi et al.
Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
557
1593, 1256, and 1107 cmꢂ1; 1H NMR ꢂ 1.24 (3H, t, J ¼ 6:9 Hz),
1.58 (3H, d, J ¼ 6:6 Hz), 3.45–3.6 (2H, m), 3.92 (3H, s), 3.98 (3H,
s), 4.75 (1H, q, J ¼ 6:9 Hz), 7.0–7.15 (3H, m), 7.48 (1H, t, J ¼ 8:2
Hz), 7.54 (1H, s), 7.70 (1H, t, J ¼ 8:2 Hz), 7.98 (1H, d, J ¼ 8:2
Hz), and 8.12 (1H, d, J ¼ 8:2 Hz); MS m=z (%) 337 (Mþ, 0.07)
and 293 (100). Found: C, 74.73; H, 6.65; N, 4.05%. Calcd for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15%.
ilar to that described for the preparation of 5b. The reaction mix-
ture was treated with saturated aqueous NaHCO3 (10 mL) and ex-
tracted with CH2Cl2 twice (10 mL each). The combined extracts
were dried over anhydrous K2CO3 and evaporated. The residue
was purified by column chromatography on SiO2 (1:5 EtOAc–hex-
ane) to give 6a (0.13 g, 49%): a viscous oil; Rf 0.02 (1:5 EtOAc–
1
hexane); IR (neat) 1614 cmꢂ1; H NMR ꢂ 2.37 (6H, s), 3.80 (2H,
Isocyanides 1b and 1c were allowed to react with phenyloxirane
in the presence of diethyl ether–boron trifluoride (0.1 eq.), as de-
scribed for the preparation of 2a. Similar workups and purification
gave 4b and 4c, respectively.
s), 7.15–7.3 (3H, m), 7.4–7.55 (4H, m), 7.69 (1H, t, J ¼ 8:6 Hz),
7.90 (1H, d, J ¼ 8:6 Hz), and 8.15 (1H, d, J ¼ 8:6 Hz); MS m=z
(%) 263 (M + 1, 56), 262 (Mþ, 24), and 219 (100). Found: C,
82.32; H, 7.00; N, 10.37%. Calcd for C18H18N2: C, 82.41; H,
6.92; N, 10.68%.
2-(2-Hydroxy-2-phenylethyl)-4-(4-methoxyphenyl)quinoline
(4b): A viscous oil; Rf 0.33 (1:5 EtOAc–hexane); IR (neat) 3390
and 1607 cmꢂ1; 1H NMR ꢂ 3.17 (2H, d, J ¼ 5:9 Hz), 3.90 (3H, s),
4.76 (1H, d, J ¼ 5:9 Hz), 5.14 (1H, m), 7.04 (2H, d, J ¼ 8:6 Hz),
7.2–7.3 (6H, m), 7.36 (2H, d, J ¼ 8:6 Hz), 7.48 (1H, dd, J ¼ 8:2
and 7.3 Hz), 7.71 (1H, dd, J ¼ 8:2 and 7.3 Hz), 7.93 (1H, dd, J ¼
8:2 and 1.3 Hz), and 8.12 (1H, d, J ¼ 8:2 Hz); MS m=z (%) 355
(Mþ, 5.2), 353 (25), and 234 (100). Found: C, 81.13; H, 5.96; N,
3.94%. Calcd for C24H21NO2: C, 81.10; H, 5.96; N, 3.94%.
4-(3,4-Dimethoxyphenyl)-2-(2-hydroxy-2-phenylethyl)quino-
line (4c): A viscous oil; Rf 0.10 (1:5 EtOAc–hexane); IR (neat)
2-[(Dimethylamino)methyl]-4-(4-methoxyphenyl)quinoline
(6b). Iodonium salt 5b (0.25 g, 0.6 mmol) was treated with satu-
rated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 twice
(10 mL each). The combined extracts were dried over anhydrous
K2CO3 and evaporated. The residue was purified by column chro-
matography on silica gel (1:5 EtOAc–hexane) to give 6b (0.17 g,
95%): a viscous oil; Rf 0.08 (1:5 EtOAc–hexane); IR (neat) 1609
cmꢂ1 1H NMR ꢂ 2.37 (6H, s), 3.80 (2H, s), 3.90 (3H, s), 7.04
;
(2H, d, J ¼ 8:6 Hz), 7.4–7.55 (4H, m), 7.68 (1H, t, J ¼ 7:3 Hz),
7.94 (1H, d, J ¼ 7:3 Hz), and 8.14 (1H, d, J ¼ 7:3 Hz); MS m=z
(%) 292 (Mþ, 0.07) and 249 (100). Found: C, 77.97; H, 6.96; N,
9.57%. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58%.
4-(3,4-Dimethoxyphenyl)-2-[(dimethylamino)methyl]quino-
line (6c). This compound was prepared from 5c in a manner sim-
ilar to that described for the preparation of 6b. 6c: a viscous oil; Rf
1
3390 and 1603 cmꢂ1; H NMR ꢂ 3.18 (2H, d, J ¼ 6:3 Hz), 3.90
(3H, s), 3.97 (3H, s), 4.76 (1H, d, J ¼ 6:3 Hz), 5.1–5.2 (1H, m),
6.95–7.05 (3H, m), 7.2–7.3 (6H, m), 7.49 (1H, t, J ¼ 8:6 Hz),
7.72 (1H, t, J ¼ 8:6 Hz), 7.95 (1H, t, J ¼ 8:6 Hz), and 8.13 (1H,
d, J ¼ 8:6 Hz); MS m=z (%) 385 (Mþ, 5.2), 383 (75), and 264
(100). Found: C, 77.77; H, 6.13; N, 3.59%. Calcd for C25H23NO3:
C, 77.90; H, 6.01; N, 3.63%.
1
0.05 (1:5 EtOAc–hexane); IR (neat) 1603 cmꢂ1; H NMR ꢂ 2.40
(6H, s), 3.85 (2H, s), 3.92 (3H, s), 3.98 (3H, s), 6.95–7.15 (3H,
m), 7.49 (1H, td, J ¼ 7:9 and 1.3 Hz), 7.55 (1H, s), 7.70 (1H, td,
J ¼ 7:9 and 1.3 Hz), 7.97 (1H, dd, J ¼ 7:9 and 1.3 Hz), and
8.12 (1H, dd, J ¼ 7:9 and 1.3 Hz); MS m=z (%) 322 (Mþ, 0.22)
and 279 (100). Found: C, 74.53; H, 7.02; N, 8.67%. Calcd for
C20H22N2O2: C, 74.51; H, 6.88; N, 8.69%.
Typical Procedure for the Preparation of (Quinolinyl-
methyl)ammonium Iodides 5.
[4-(4-Methoxyphenyl)quino-
lin-2-ylmethyl]dimethylammonium Iodide (5b): To a stirred
solution of N,N-dimethylmethyleneammonium iodide (Eschen-
ꢁ
moser’s salt; 0.24 g, 1.3 mmol) in CH2Cl2 (4 mL) at 0 C under
argon was added dropwise a solution of 1b (0.28 g, 1.3 mmol) in
CH2Cl2 (1 mL). After 1.5 h anhydrous Et2O (20 mL) was added.
The white precipitate was collected by filtration and rꢁecrystallized
from EtOH to give 5b (0.41 g, 76%): mp 204–206 C; IR (KBr
4-(2,6-Dimethoxyphenyl)-2-[(dimethylamino)methyl]quino-
line (6e). This compound was prepared from 5d in a manner sim-
ilar to that described for the preparation of 6b. 6d: a viscous oil; Rf
1
0.05 (1:5 EtOAc–hexane); IR (neat) 1605 cmꢂ1; H NMR ꢂ 2.36
disk) 3400–2250 and 1611 cmꢂ1
;
1H NMR ꢂ 3.04 (6H, s), 3.90
(6H, s), 3.63 (6H, s), 3.82 (2H, s), 6.69 (2H, d, J ¼ 8:3 Hz),
7.35–7.65 (5H, m), and 8.12 (1H, d, J ¼ 8:2 Hz); MS m=z (%)
322 (Mþ, 2.8) and 279 (100). Found: C, 74.32; H, 6.87; N,
8.65%. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69%.
2-[(Dimethylamino)methyl]-4-(2,4,6-trimethoxyphenyl)-
quinoline (6f). This compound was prepared from 1f and Eschen-
moser’s salt under conditions similar to those described for the
preparation of 6a. 6f: a viscous oil; Rf 0.20 (acetone); IR (neat)
(3H, s), 4.60 (2H, s), 7.07 (2H, d, J ¼ 9:1 Hz), 7.25 (1H, s), 7.5–
7.65 (3H, m), 7.73 (1H, s), 7.77 (1H, t, J ¼ 7:6 Hz), 8.04 (1H, t,
J ¼ 7:6 Hz), and 8.20 (1H, d, J ¼ 7:6 Hz). Found: C, 54.04; H,
4.98; N, 6.47%. Calcd for C19H21IN2O: C, 54.30; H, 5.04; N,
6.67%.
[4-(3,4-Dimethoxyphenyl)quinolin-2-ylmethyl]dimethylam-
monium Iodide (5c): mp 215–221 ꢁC (EtOH); IR (KBr disk)
3400–2500 and 1605 cmꢂ1
;
1H NMR ꢂ 3.00 (6H, s), 3.97 (3H,
1613 cmꢂ1 1H NMR ꢂ 2.35 (6H, s), 3.62 (6H, s), 3.80 (2H, s),
;
s), 4.01 (3H, s), 4.58 (2H, s), 7.02 (1H, d, J ¼ 8:2 Hz), 7.1–7.2
(2H, m), 7.27 (1H, s), 7.59 (1H, t, J ¼ 8:2 Hz), 7.78 (1H, t, J ¼
8:2 Hz), 7.91 (1H, s), 8.11 (1H, d, J ¼ 8:2 Hz), and 8.17 (1H, d,
J ¼ 8:2 Hz). Found: C, 53.06; H, 4.88; N, 5.96%. Calcd for
C20H23IN2O2: C, 53.34; H, 5.15; N, 6.22%.
3.90 (3H, s), 6.26 (2H, s), 7.36 (1H, t, J ¼ 8:2 Hz), 7.45 (1H, s),
7.50 (1H, d, J ¼ 8:2 Hz), 7.62 (1H, t, J ¼ 8:2 Hz), and 8.10
(1H, d, J ¼ 8:2 Hz); MS m=z (%) 352 (Mþ, 0.11) and 309 (100).
Found: C, 71.27; H, 6.90; N, 7.77%. Calcd for C21H24N2O3: C,
71.57; H, 6.86; N, 7.95%.
[4-(2,6-Dimethoxyphenyl)quinolin-2-ylmethyl]dimethylam-
monium Iodide (5e): mp 111–115 ꢁC (EtOH); IR (KBr disk)
4-(3,4-Dimethoxyphenyl)-2-[1-(dimethylamino)propyl]quino-
line (6g). To a stirred solution of N,N-dimethylpropylideneammo-
nium iodide, generated in situ from propanal (38 mg, 0.65 mmol),
dimethylamine hydrochloride (53 mg, 0.65 mmol), NaI (0.21 g, 1.4
mmol), Me3SiCl (0.15 g, 1.4 mmol), and Et3N (0.14 g, 1.4 mmol)
in MeCN (1.4 mL) under the Risch’s conditions,10 at room temper-
ature was added dropwise a solution of 1c (0.17 g, 0.65 mmol) in
MeCN (2 mL). After 2 h the reaction mixture was worked up in a
similar manner as described for the preparation of 6a. The crude
product was purified by column chromatography on SiO2 (acetone)
3400–2500 and 1603 cmꢂ1 1H NMR ꢂ 3.06 (6H, s), 3.67 (6H,
;
s), 4.59 (2H, s), 6.72 (2H, d, J ¼ 8:2 Hz), 7.4–7.6 (5H, m), 7.73
(1H, t, J ¼ 8:2 Hz), and 8.20 (1H, d, J ¼ 8:2 Hz). Found: C,
53.24; H, 5.16; N, 6.20%. Calcd for C20H23IN2O2: C, 53.34; H,
5.15; N, 6.22%.
2-[(Dimethylamino)methyl]-4-phenylquinoline (6a). Isocya-
nide 1a (0.21 g, 1.0 mmol) was allowed to reacted with Eschen-
moser’s salt (0.19 g, 1.0 mmol) in CH2Cl2 (5 mL) in a manner sim-

558 Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
Synthesis of 2,4-Disubstituted Quinolines
to give 6g (64 mg, 28%): a viscous oil; Rf 0.20 (acetone); IR (neat)
1604 cmꢂ1; 1H NMR ꢂ 0.80 (3H, t, J ¼ 7:3 Hz), 1.9–2.1 (2H, m),
2.31 (6H, s), 3.45 (1H, dd, J ¼ 8:9 and 4.6 Hz), 3.92 (3H, s), 3.97
(3H, s), 6.95–7.15 (3H, m), 7.41 (1H, s), 7.47 (1H, t, J ¼ 8:2 Hz),
7.69 (1H, t, J ¼ 8:2 Hz), 7.96 (1H, d, J ¼ 8:2 Hz), and 8.16 (1H, d,
J ¼ 8:2 Hz); MS m=z (%) 350 (Mþ, 0.04) and 292 (100). Found: C,
75.33; H, 7.52; N, 7.76%. Calcd for C22H26N2O2: C, 75.40; H,
7.48; N, 7.99%.
Lett., 44, 255 (2003); B. C. Ranu, A. Hajra, S. S. Ley, and U. Jana,
Tetrahedron, 59, 813 (2003), and references cited therein.
6
For utilities of quinolines as intermediates for the design of
biologically active compounds: G. Jones, ‘‘Comprehensive Heter-
ocyclic Chemistry,’’ ed by A. R. Katritzky and C. W. Rees, Perga-
mon, Oxford (1984), Vol. 2, p. 395; T. Suresh, R. N. Kumar, and P.
S. Mohan, Heterocycl. Commun., 9, 83 (2003).
7
For biological importance of quinoline derivatives: J. A.
Joule, K. Mills, and G. F. Smith, ‘‘Heterocyclic Chemistry,’’ 3rd
ed, Chapman & Hall, London (1995), p. 120; T. Shoda, S.
Taketomi, and A. Baba, Eur. Patent, 634169 (1995); Chem. Abstr.,
122, 187610b (1995); M. Antini, A. Cappelli, S. Vomero, G.
Giorgi, T. Langer, M. Hamon, N. Merahi, B. M. Emerit, A.
Cagnotto, M. Skorupska, T. Mennini, and J. C. Pinto, J. Med.
Chem., 38, 2692 (1995); P. K. Desai, P. Desai, D. Macchi, C. M.
Desai, and D. Patel, Indian J. Chem., 35B, 871 (1996); X.-M.
Cheng, C. Lee, S. Klutchko, T. Winters, E. E. Reynolds, K. M.
Welch, M. A. Flynn, and A. M. Doherty, Bioorg. Med. Chem. Lett.,
6, 2999 (1996); G. A. M. Giardina, H. M. Sarau, C. Farina, A. D.
Medhurst, M. Grugni, L. F. Raveglia, D. B. Schmidt, R. Rigolio,
M. Luttmann, V. Vecchietti, and D. W. P. Hay, J. Med. Chem.,
40, 1794 (1997); B. Kalluraya and S. Sreevinasa, Farmaco, 53,
399 (1998); A. von Sprecher, M. Gerspacher, A. Beck, S. Kimmel,
H. Weinstner, G. P. Anderson, U. Niederhauser, N. Subramanian,
and M. A. Bray, Bioorg. Med. Chem. Lett., 8, 965 (1998); D.
We thank Mrs. Miyuki Tanmatsu of this Department for her
work in determining the mass spectra and performing combus-
tion analyses. This work was supported in part by a Grant-in-
Aid for Scientific Research No. 15550092 from the Ministry
of Education, Culture, Sports, Science and Technology.
References
1
K. Kobayashi, T. Matoba, S. Irisawa, T. Matsumoto, O.
Morikawa, and H. Konishi, Chem. Lett., 1998, 551.
K. Kobayashi, S. Irisawa, T. Matoba, T. Matsumoto, K.
2
Yoneda, O. Morikawa, and H. Konishi, Bull. Chem. Soc. Jpn.,
74, 1109 (2001).
3
K. Kobayashi, T. Matsumoto, S. Irisawa, K. Yoneda, O.
Morikawa, and H. Konishi, Heterocycles, 55, 973 (2001).
Recently, 2-functionalized quinoline derivatives have been
4
´
prepared by reactions of 2-metalated quinolines, which were gen-
erated by direct lithiation of quinolines4a or halogen–metal
exchange of 2-haloquinolines,4b,c with electrophiles: a) P. Gros,
Doube, M. Blouin, C. Brideau, C.-C. Chen, S. Desmarais, D.
Eithier, J. P. Falgueyret, R. W. Frieson, M. Girard, V. Girard, J.
Guay, D. Riendeau, P. Tagari, and R. N. Young, Bioorg. Med.
Chem. Lett., 8, 1255 (1998); M. E. Zwaagstra, H. Timmerman,
A. C. van de Stolpe, F. J. de Kanter, M. Tamura, Y. Wada, and
M. Q. Zhang, J. Med. Chem., 41, 1428 (1998); M. Croisy-Delcey,
A. Croisy, D. Carrez, C. Huel, A. Chaironi, P. Ducrot, E. Bisagni,
L. Jin, and G. Leclercq, Bioorg. Med. Chem., 8, 2629 (2000); V. K.
Dua, S. N. Sinha, S. Biswas, N. Valecha, S. K. Puri, and V. P.
Sharma, Bioorg. Med. Chem., 12, 3587 (2002); S. Gallo, S. Atifi,
`
Y. Fort, and P. Caubere, J. Chem. Soc., Perkin Trans. 1, 1997,
3597. b) I. Gomez, E. Alonso, D. J. Ramon, and M. Yus, Tetrahe-
´
´
´
dron, 56, 4043 (2000). c) S. Dumouchel, F. Mongin, F. Trecourt,
´
and G. Queguiner, Tetrahedron Lett., 44, 2033 (2003).
For recent reports on the general synthesis of quinoline de-
5
rivatives: D. S. Coffey, S. A. May, and A. M. Ratz, ‘‘Progress in
Heterocyclic Chemistry,’’ ed by G. W. Gribble and T. L. Gilchrist,
Pergamon, London (2001), Vol. 13, p. 243; H. Tokuyama, M. Sato,
T. Ueda, and T. Fukuyama, Heterocycles, 55, 105 (2001); M. A.
´
A. Mahamoud, C. Santelli-Rouvier, K. Wolfart, J. Molnar, and
J. Barbe, Eur. J. Med. Chem., 38, 19 (2003); D. Varlet, E.
Fourmaintraux, P. Depreux, and D. Lesieur, Heterocycles, 60,
385 (2003); L. Strekowski, M. Say, M. Henary, P. Ruiz, L. Manzel,
D. E. Macfarlene, and A. J. Bojarski, J. Med. Chem., 46, 1242
(2003), and references cited therein.
8
tives: A. Fournet, A. A. Barrios, V. Munoz, R. Hocquemiller, A.
Cave, and J. Bruneton, Antimicrob. Agents Chemother., 37, 859
(1993); A. Fournet, M. E. Ferreira, A. Rojas de Arias, S. Torres
de Ortiz, S. Fuentes, H. Nakayama, and A. Schinini, Antimicrob.
Agents Chemother., 40, 2447 (1996); J. C. Gantier, A. Fournet,
M. H. Munos, and R. Hocquemiller, Planta Med., 40, 285
(1996); K. Mekouar, J. F. Mouscadet, D. Desmaele, F. Subra, H.
¨
´
Leh, D. Savoure, C. Auclair, and J. d’Angelo, J. Med. Chem.,
41, 2846 (1998); F. Zouhiri, J. F. Mouscadet, K. Mekouar, D.
`
Fakhfakh, X. Franck, R. Hocquemiller, and B. Figadere, J. Orga-
nomet. Chem., 624, 131 (2001); H. Amii, Y. Kishikawa, and K.
Uneyama, Org. Lett., 3, 1109 (2001); M. Karikomi, H. Tsukuda,
and T. Toda, Heterocycles, 55, 1249 (2001); N. J. Tom and E.
M. Ruel, Synthesis, 2001, 1351; M. Shimizu, A. Oishi, Y. Taguchi,
T. Sano, Y. Gama, and I. Shibuya, Heterocycles, 55, 1971 (2001);
C. S. Cho, J. S. Kim, T.-J. Kim, and S. C. Shim, Chem. Commun.,
2001, 2576; J. N. Kim, H. J. Lee, K. Young, and H. S. Kim, Tetra-
hedron Lett., 42, 3737 (2001); M. A. Fakhfakh, X. Frank, A.
For biological activities of 2-substituted quinoline deriva-
´
`
Fournet, R. Hocquemiller, and B. Figadere, Tetrahedron Lett.,
42, 3847 (2001); X. G. Li, X. Cheng, and Q. L. Zhou, Synth.
Commun., 32, 2477 (2002); G. Dominguez, L. Casarrubios, J.
Rodoriguez-Noriega, and J. Perez-Castells, Helv. Chim. Acta, 85,
2856 (2002); M. A. Fakhfakh, X. Franck, A. Fournet, R.
`
´
Hocquemiller, and B. Figadere, Synth. Commun., 32, 2863
Desmaele, D. Savoure, H. Leh, F. Subra, M. Le Bret, C. Auclair,
¨
(2002); S. Cacchi, G. Fabrizi, A. Goggiamani, M. Moreno-Man˜as,
and A. Vallribera, Tetrahedron Lett., 43, 5537 (2002); J. N. Kim,
Y. M. Chung, and Y. J. Im, Tetrahedron Lett., 43, 6209 (2002);
H. Z. S. Huma, R. Halder, S. S. Kalra, J. Das, and J. Iqbal, Tetra-
hedron Lett., 43, 6485 (2002); B. S. Lee, J. H. Lee, and D. Y. Chi,
J. Org. Chem., 67, 7884 (2002); R. E. Swenson, T. J. Sowin, and H.
Q. Zhang, J. Org. Chem., 67, 9182 (2002); B. Jiang and Y.-G. Si, J.
Org. Chem., 67, 9449 (2002); A. Arcadi, M. Chiarini, S. D.
Giuseppe, and F. Marinelli, Synlett, 2003, 203; S. J. Song, S. J.
Cho, D. K. Park, T. W. Kwon, and S. A. Jenekhe, Tetrahedron
and J. d’Angelo, J. Med. Chem., 43, 1533 (2000); H. Nakayama,
M. E. Ferreira, A. Rojas de Arias, N. V. de Bilbao, A. Schinini,
and A. Fournet, Phytother. Res., 15, 630 (2001); A. Fournet, R.
Mahieux, M. A. Fakhfakh, X. Frank, R. Hocquemiller, and B.
`
Frigdere, Bioorg. Med. Chem. Lett., 13, 891 (2003).
For natural occurrence of biologically active quinoline de-
rivatives: A. Fournet, B. Vagnuer, P. Richomme, and J. Bruneton,
9
Can. J. Chem., 67, 2116 (1989); A. Fournet, R. Hocquemiller, F.
´
Roblot, A. Cave, P. Richomme, and J. Bruneton, J. Nat. Prod.,
56, 1547 (1993); J. P. Michael, Nat. Prod. Rep., 12, 465 (1995);

K. Kobayashi et al.
Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
559
M. Balasubramanian and J. G. Kway, ‘‘Comprehensive Heterocy-
clic Chemistry II,’’ ed by A. R. Katritzky, C. W. Rees, and E. F.
Scriven, Pergamon Press, Oxford (1996), Vol. 5, Chap. 5.06,
p. 245; J. P. Michael, Nat. Prod. Rep., 14, 605 (1997); J. P.
Michael, Nat. Prod. Rep., 19, 742 (2002); L. M. Nogle and W.
H. Gerwick, J. Nat. Prod., 66, 217 (2003).
10 M. Arend and N. Risch, Synlett, 1997, 974.
11 R. Smith and K. Livinghouse, Tetrahedron, 41, 3559
(1985).
12 M. Harmata and M. Kahraman, Synthesis, 1995, 713.