A convenient synthesis of quinolines by reactions of o-isocyano-β- methoxystyrenes with nucleophiles

Article abstract of DOI:10.1016/j.tet.2004.09.069

2,4-Disubstituted quinolines have been synthesized by reactions of o-isocyano-β-methoxystyrenes, which can be easily prepared from commercially available o-aminophenyl ketones in three steps, with alkyl(or aryl)lithiums in generally good yields. Subsequently, o-isocyano-β- methoxystyrenes have also proved to react efficiently with lithium dialkylamides to afford the corresponding 4-substituted N,N-dialkylquinolin-2-amines in satisfactory yields. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.09.069

Tetrahedron 60 (2004) 11639–11645
A convenient synthesis of quinolines by reactions of
o-isocyano-b-methoxystyrenes with nucleophiles
*
Kazuhiro Kobayashi, Keiichi Yoneda, Kazuna Miyamoto, Osamu Morikawa
and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552, Japan
Received 23 July 2004; accepted 13 September 2004
Available online 18 October 2004
Abstract—2,4-Disubstituted quinolines have been synthesized by reactions of o-isocyano-b-methoxystyrenes, which can be easily prepared
from commercially available o-aminophenyl ketones in three steps, with alkyl(or aryl)lithiums in generally good yields. Subsequently, o-
isocyano-b-methoxystyrenes have also proved to react efficiently with lithium dialkylamides to afford the corresponding 4-substituted N,N-
dialkylquinolin-2-amines in satisfactory yields.
q 2004 Elsevier Ltd. All rights reserved.
There has been substantial interest in quinoline derivatives,
because some of them are known to occur in nature,1 and
exhibit a wide variety of biological activities.2 Moreover,
they have been utilized as intermediates for the design of
biologically active compounds.3 Therefore, a large number
of general methods for the preparation of substituted
quinolines have recently been reported,4 and any new
general route to quinoline derivatives is of interest and
value. In this paper we wish to report in full on the results of
our investigation,5,6 which offer a simple and general
method for preparing 2,4-disubstituted quinolines and
4-substituted N,N-dialkylquinolin-2-amines by reactions of
o-isocyano-b-methoxystyrenes with alkyl(or aryl)lithiums
and lithium dialkylamides, respectively.7 2-Alkylated
quinoline derivatives8 and quinolin-2-amines9 have been
reported to exhibit notable biological activities.
stereoisomers in each case. The ratios of stereoisomers were
1
determined by H NMR spectral data (see Section 2).
The reactions of o-isocyano-b-methoxystyrenes 1 with
aryl(or alkyl)lithiums 2 were conducted as shown in Scheme
2. Thus, after treatment of the isocyanides 1 with
organolithiums 2 (1.5 equiv) at K78 8C in 1,2-dimethoxy-
ethane (DME), the mixtures were allowed to warm to room
temperature. Usual aqueous workup, followed by purifi-
cation using preparative TLC on silica gel, gave 2,4-
disubstituted quinolines 3. The results summarized in
Table 1 demonstrate that the good yields of the desired
2,4-disubstituted quinolines 3a–3i were obtained in general
(entries 1–9), though somewhat poorer yields of the desired
products 3j and 3k were obtained by using o-isocyano-b-
methoxy-a-methylstyrene (1c) (entries 10 and 11). When
the reactions were conducted in THF, rather diminished
1. Results and discussion
o-Isocyano-b-methoxystyrenes 1 were prepared in three
steps from commercially available 2-aminophenylketones
as shown in Scheme 1. Thus, formylation of 2-aminophenyl
ketones with formic acid afforded the corresponding
formamides, which were dehydrated by treatment with
phosphoryl chloride/triethylamine to afford 2-isocyanophenyl
ketones. Wittig reaction of these isocyano ketones with
(methoxymethyl)triphenylphosphonium ylide gave o-iso-
cyano-b-methoxystyrene derivatives 1, as a mixture of
Keywords: Isocyanide; Lithium amide; Organolithium; Quinoline; Styrene.
* Corresponding author. Tel./fax: C81 857 31 5263;
e-mail: kkoba@chem.tottori-u.ac.jp
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.069

11640
K. Kobayashi et al. / Tetrahedron 60 (2004) 11639–11645
Scheme 3.
were allowed to warm to room temperature (Method A).
Scheme 2.
Usual aqueous workup, followed by purification using
preparative TLC on silica gel, gave 4-substituted N,N-
dialkylquinolin-2-amines 5. The results are summarized in
Table 2. Two equivalents each of lithium dialkylamides
generated from bulky secondary amines, such as diisopro-
pylamine or dicyclohexylamine, were used for satisfactory
production of the desired products (entries 2, 3 and 11). In
order to obtain satisfactory yields of 5h and 5i (entries 9 and
10), the reaction temperature was raised to only 0 8C
(Method B) considering the lability of chloride under the
reaction conditions (entry 8). Although the reactions using
o-isocyano-b-methoxy-a-phenylstyrenes 1a and 1b gave
the desired quinoline-2-amines 5a–5i in moderate to fair
yields (entries 1–7, 9 and 10), the use of o-isocyano-b-
methoxy-a-methylstyrene (1c) afforded the desired pro-
ducts 5j and 5k only in rather poor yields (entries 11 and
12). In these cases rather complex reaction mixtures
including small quantities of the starting 1c were obtained.
Table 1. Preparation of 2,4-disubstituted quinolines 3 according to Scheme 2
Entry
Isocyanide 1
Organolithium 2
3 (Yield/%)a
1
2
3
4
5
6
7
8
1a (R1ZPh, R2ZH)
1a
1a
1a
1a
1a
2a (R3Zn-Bu)
2b (R3Zsec-Bu)
2c (R3Ztert-Bu)
2d (R3ZPh)
2e (R3Zp-Tol)
2f (R3Z2-thienyl)
2g (R3Z2-furyl)
2c
3a (79)
3b (84)
3c (89)
3d (91)
3e (88)
3f (74)
3g (75)
3h (87)
3i (85)
3j (58)
3k (55)
1a
1b (R1ZPh, R2ZCl)
1b
9
10
11
2d
2c
2d
1c (R1ZMe, R2ZH)
1c
a Isolated yields after purification by preparative TLC on silica gel.
yields of the desired products were obtained. For example,
the reaction of 1a with 2a in THF under the same conditions
as described above in DME led to the formation of rather
complex reaction mixture and the desired product 3a was
obtained only in 41% yield. This is probably attributable to
the lability of THF to organolithiums. It should be noted that
the reaction of 1a with PhMgBr gave an intractable mixture
of products, from which no more than a trace amount of 3a
was obtained.
Subsequently, the possibility of the preparation of 2-
sulfenylated quinoline derivatives was examined. Scheme 4
shows that benzenethiolate is usable as a nucleophile in the
present method but under reflux conditions in THF to afford
2-phenylthio-4-phenylquinoline (6) in low yield. This
reaction gave a rather complicated reaction mixture
including a fair amount of the starting 1a.
The production of quinoline derivatives 3, 5, and 6 may be
We anticipated that the use of lithium dialkylamide in place
of alkyl(or aryl)lithiums would be expected to afford N,N-
dialkylquinolin-2-amine derivatives, and the reactions of
o-isocyano-b-methoxystyrenes 1 with lithium dialkyl-
amides 4 were carried out as shown in Scheme 3. Thus,
isocyanides 1 were treated with lithium amides 4 (1.2 equiv
in general), generated by the treatment of secondary amines
with butyllithium, in THF at K78 8C, and then the mixtures
Scheme 4.
Table 2. Preparation of quinolin-2-amines 5 according to Scheme 3
Entry
Isocyanide 1
Lithium amide 4
Equiv
Method
5 (Yield/%)a
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
4a (NR32ZNEt2)
1.2
2.0
2.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.0
1.2
A
A
A
A
A
A
A
A
B
B
A
A
5a (60)
5b (61)
5c (45)
5d (64)
5e (72)
5f (55)
5g (77)
5h (35)
5h (50)
5i (52)
5j (16)
5k (15)
4b (NR32ZNi-Pr2)
4c (NR32ZNc-Hex2)
4d (NR32Zpyrrolidin-1-yl)
4e (NR32Zpiperidin-1-yl)
4f (NR32Zmorpholin-1-yl)
4g (NR32Z4-methylpiperazin-1-yl)
4d
4d
4e
4b
4e
9
10
11
12
a Isolated yields after purification by preparative TLC on silica gel.

K. Kobayashi et al. / Tetrahedron 60 (2004) 11639–11645
11641
THF at 0 8C. 2-Isocyanobenzophenone: 87% yield from
2-aminobenzophenone; a pale-yellow solid; mp 95–96 8C
(hexane–CH2Cl2); IR (KBr disk) 2123, 1660 cmK1 1H
;
NMR d 7.45–7.7 (7H, m), 7.81 (2H, dd, JZ8.3, 1.6 Hz).
Calcd for C14H9NO: C, 81.14; H, 4.38; N, 6.76. Found: C,
81.11; H, 4.33; N, 7.01. 5-Chloro-2-isocyanobenzophenone:
88% yield from 2-amino-5-chlorobenzophenone; a pale-
yellow solid; mp 84–85 8C (hexane–CH2Cl2); IR (KBr disk)
2125, 1662 cmK1; 1H NMR d 7.4–7.7 (6H, m), 7.82 (2H, dd,
JZ8.2, 1.3 Hz). Calcd for C14H8ClNO: C, 69.58; H, 3.34;
N, 5.80. Found: C, 69.28; H, 3.51; N, 5.53. 2-Isocyano-
acetophenone: 74% from 20-aminoacetophenone; a yellow
Scheme 5.
1
oil; IR (neat) 2124, 1696 cmK1; H NMR d 2.72 (3H, s),
7.45–7.6 (3H, m), 7.78 (1H, dd, JZ7.9, 1.6 Hz). The last
isocyanide was rather unstable and used in the next step
without any purification after workup. All other chemicals
used in this study are commercially available.
interpreted as illustrated in Scheme 5. The a-addition of a
nucleophile to the isocyano carbon of 1 resulted in
formation of the imidoyl anion intermediate 7. This anion
attacks to the a-carbon atom of the methoxyvinyl moiety of
7 to afford the benzyl anion intermediate 8, which, after a
loss of methoxide, provides 3, 5, and 6. The yields of the
products are thought to depend upon the nucleophilicity of
the nucleophiles. The poorer results of the reactions using 1c
is presumed to be ascribed to the lower stability of the
corresponding intermediate benzyl anions compared to
those from 1a and 1b.
2.3. Typical procedure for the preparation of
isocyanostyrenes 1
2.3.1. 1-Isocyano-2-(2-methoxy-1-phenylethenyl)ben-
zene (1a). To a stirred suspension of (methoxymethyl)tri-
phenylphosphonium chloride (0.96 g, 2.9 mmol) in THF
(15 mL) at 0 8C under argon was added butyllithium
(2.9 mmol; 1.6 M solution in hexanes) dropwise; the mixture
was stirred for 15 min. To this ylide solution 2-isocyano-
benzophenone (0.50 g, 2.4 mmol) in THF (5 mL) was
added. The mixture was allowed to warm to room
temperature and stirring was continued for 30 min. The
reaction was quenched by adding water (20 mL) and the
organic materials were extracted with Et2O three times
(20 mL each). The combined extracts were washed with
water three times and then brine, dried over anhydrous
K2CO3, and evaporated. The crude product was purified by
chromatography on silica gel to give 1a (0.42 g, 72%) as a
pale-yellow viscous oil; a mixture of stereoisomers (E/ZZ
ca. 1:1): Rf 0.66 (1:3 EtOAc–hexane); IR (neat) 2123,
1636 cmK1; 1H NMR d 3.81 (1.5H, s), 3.83 (1.5H, s), 6.38
(0.5H, s), 6.69 (0.5 H, s), 7.05–7.5 (9H, m); MS m/z 235
(MC, 97), 165 (100). Calcd for C16H13NO: M, 235.0997.
Found: m/z 235.0994.
In conclusion, we have demonstrated that the reactions of
o-isocyano-b-methoxystyrene derivatives with nucleophiles,
such as alkyl(or aryl)lithiums, lithium dialkylamides, or
lithium benzenethiolate, provide a new method for the
preparation of 2,4-disubstituted quinolines. The present
method may find some value in organic synthesis because of
its efficiency, the ready availability of the starting materials
and the ease of operation.
2. Experimental
2.1. General
The melting points were determined on a Laboratory
Devices MEL-TEMP II melting-point apparatus and are
uncorrected. The IR spectra were recorded on a Perkin–
Elmer 1600 Series FT IR spectrometer. The 1H 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-resolution mass
spectra were recorded on a JEOL AUTOMASS 20
spectrometer (Center for Joint Research and Development,
this University). High-resolution mass spectra were per-
formed on a JEOL JMS AX505 HA spectrometer (Faculty
of Agriculture, this University). 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.
2.3.2. 4-Chloro-1-isocyano-2-(2-methoxy-1-phenylethe-
nyl)benzene (1b). A pale-yellow viscous oil; a mixture of
stereoisomers (E/ZZca. 1:1): Rf 0.61 (1:3 EtOAc–hexane);
IR (neat) 2123, 1636 cmK1; 1H NMR d 3.82 (1.5H, s), 3.84
(1.5H, s), 6.40 (0.5 H, s), 6.69 (0.5H, s), 7.10 (1H, dd, JZ
7.9, 1.6 Hz), 7.2–7.4 (7H, m); MS m/z 269 (MC, 100). Calcd
for C16H12ClNO: M, 269.0607. Found: m/z 269.0624.
2.3.3. 1-Isocyano-2-(2-methoxy-1-methylethenyl)ben-
zene (1c). A pale-yellow oil; a mixture of stereoisomers
(E/ZZca. 7:3): Rf 0.31 (1:10 EtOAc–hexane); IR (neat)
2.2. Starting materials
1
2124, 1666 cmK1; H NMR d 1.91 (2.1H, d, JZ1.3 Hz),
2.00 (0.9H, d, JZ1.3 Hz), 3.63 (2.1H, s), 3.73 (0.9 H, s),
6.13 (0.7H, q, JZ1.3 Hz), 6.23 (0.3H, q, JZ1.3 Hz), 7.15–
7.4 (4H, m); MS m/z 173 (MC, 60), 130 (100). Calcd for
C11H11NO: M, 173.0841. Found: m/z 173.0861.
2-Isocyanophenyl ketones were prepared from the corre-
sponding commercially available 2-aminophenyl ketones
by formylation with formic acid in toluene at reflux
temperature, followed by dehydration with POCl3/Et3N in

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K. Kobayashi et al. / Tetrahedron 60 (2004) 11639–11645
2.4. Typical procedure for the preparation of 2,4-
disubstituted quinolines 3
2.4.7. 2-(2-Furyl)-4-phenylquinoline (3g).13a A pale-
yellow solid; mp 109–111 8C (hexane–Et2O) (lit.,13b 100–
102 8C); IR (KBr disk) 3091, 1595, 1550, 1495, 1084, 1007,
776, 764, 742, 702 cmK1; 1H NMR d 6.59 (1H, dd, JZ3.3,
1.7 Hz), 7.23 (1H, dd, JZ3.3, 1.0 Hz), 7.4–7.6 (6H, m),
7.63 (1H, dd, JZ1.7, 1.0 Hz), 7.71 (1H, ddd, JZ8.2, 7.3,
1.3 Hz), 7.77 (1H, s), 7.86 (1H, dd, JZ8.2, 1.3 Hz), 8.19
(1H, dd, JZ8.2, 1.3 Hz); MS m/z 271 (MC, 100).
2.4.1. 2-Butyl-4-phenylquinoline (3a). To a stirred solution
of isocyanostyrene 1a (0.12 g, 0.51 mmol) in DME
(2.5 mL) at K78 8C under argon was added dropwise
butyllithium (0.77 mmol; 1.57 M in hexane solution). After
stirring for 30 min at this temperature, the mixture was
allowed to warm to room temperature and stirring was
continued for an additional 30 min. Saturated aqueous
ammonium chloride (15 mL) was added and the mixture
was extracted with Et2O three times (15 mL each). The
combined extracts were washed with brine, dried over
anhydrous Na2SO4, and evaporated. The residue was
purified by preparative TLC on silica gel to give 3a
(0.11 g, 79%) as a pale-yellow viscous oil: Rf 0.67 (1:3
EtOAc–hexane); IR (neat) 3058, 2955, 1592, 1557, 1490,
2.4.8. 6-Chloro-2-(1,1-dimethylethyl)-4-phenylquinoline
(3h). A pale-yellow viscous oil; Rf 0.81 (1:3 hexane–
AcOEt); IR (neat) 3060, 2961, 1590, 1550, 1484, 1137,
701 cmK1 1H NMR d 1.48 (9H, s), 7.4–7.6 (6H, m
;
including s at d 7.45), 7.60 (1H, dd, JZ8.9, 2.3 Hz), 7.80
(1H, d, JZ2.3 Hz), 8.05 (1H, d, JZ8.9 Hz); MS m/z 295
(MC, 37), 280 (100). Calcd for C19H18ClN: C, 77.15; H,
6.13; N, 4.74. Found: C, 76.96; H, 5.95; N, 4.55.
1
765, 701 cmK1; H NMR d 0.97 (3H, t, JZ7.3 Hz), 1.47
2.4.9. 6-Chloro-2,4-diphenylquinoline (3i).14a A pale
yellow solid; mp 114–117 8C (hexane–Et2O) (lit.,14b 127–
129 8C); IR (KBr disk) 3026, 1590, 1544, 1483, 1357, 826,
776, 756, 704, 690 cmK1; 1H NMR d 7.4–7.6 (8H, m), 7.66
(1H, dd, JZ8.9, 2.3 Hz), 7.84 (1H, s), 7.86 (1H, d, JZ
2.3 Hz), 8.15–8.2 (3H, m); MS m/z 315 (MC, 100).
(2H, sextet, JZ7.3 Hz), 1.75–1.9 (2H, m), 3.01 (2H, t, JZ
7.9 Hz), 7.24 (1H, s), 7.43 (1H, ddd, JZ8.2, 7.3, 1.3 Hz),
7.5–7.6 (5H, m), 7.68 (1H, ddd, JZ8.2, 7.3, 1.3 Hz), 7.86
(1H, dd, JZ8.2, 1.3 Hz), 8.11 (1H, dd, JZ8.2, 1.3 Hz); MS
m/z 261 (MC, 1.1), 246 (6.9), 232 (19), 219 (100). Calcd for
C19H19N: C, 87.31; H, 7.33; N, 5.36. Found: C, 87.09; H,
7.20; N, 5.36.
2.4.10. 2-(1,1-Dimethylethyl)-4-methylquinoline (3j).15
pale-yellow viscous oil; Rf 0.84 (1:3 hexane–AcOEt); IR
A
2.4.2. 2-(1-Methylpropyl)-4-phenylquinoline (3b). A
pale-yellow viscous oil; Rf 0.74 (1:3 EtOAc–hexane); IR
(neat) 3061. 2956, 1602, 1558, 1507, 1480, 1448, 758 cmK1
;
(neat) 3056, 2960, 1592, 1557, 1491, 772, 701 cmK1; H
1
1H NMR d 1.46 (9H, s), 2.69 (3H, s), 7.35 (1H, s), 7.48 (1H,
ddd, JZ8.2, 6.9, 1.3 Hz), 7.65 (1H, ddd, JZ8.2, 6.9,
1.3 Hz), 7.93 (1H, dd, JZ8.2, 1.3 Hz), 8.05 (1H, dd, JZ8.2,
1.3 Hz); MS m/z 199 (MC, 54), 184 (100).
NMR d 0.93 (3H, t, JZ7.3 Hz), 1.40 (3H, d, JZ6.9 Hz),
1.65–2.0 (2H, m), 2.95–3.15 (1H, m), 7.23 (1H, s), 7.43 (1H,
ddd, JZ8.2, 7.3, 1.3 Hz), 7.5–7.55 (5H, m), 7.68 (1H, ddd,
JZ8.2, 7.3, 1.3 Hz), 7.86 (1H, dd, JZ8.2, 1.3 Hz), 8.12
(1H, dd, JZ8.2, 1.3 Hz); MS m/z 261 (MC, 3.3), 246 (45),
233 (100). Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36.
Found: C, 87.07; H, 7.29; N, 5.20.
2.4.11. 4-Methyl-2-phenylquinoline (3k).16 A pale-yellow
viscous oil; Rf 0.65 (1:3 hexane–AcOEt); the spectral data
for this compound were identical to those reported
previously.17
2.4.3. 2-(1,1-Dimethylethyl)-4-phenylquinoline (3c). A
pale-yellow solid; mp 85–88 8C (hexane); IR (KBr disk)
2.5. Typical procedure for the preparation of quinolin-2-
amine derivatives 5
3058, 1962, 1602, 1589, 1553, 1488, 778, 761, 706 cmK1
;
1H NMR d 1.50 (9H, s), 7.42 (1H, ddd, JZ8.2, 7.3, 1.3 Hz),
7.44 (1H, s), 7.45–7.55 (5H, m), 7.66 (1H, ddd, JZ8.2, 7.3,
1.3 Hz), 7.84 (1H, dd, JZ8.2, 1.3 Hz), 8.12 (1H, dd, JZ8.2,
1.3 Hz); MS m/z 261 (MC, 43), 246 (100). Calcd for
C19H19N: C, 87.31; H, 7.33; N, 5.36. Found: C, 87.48; H,
7.09; N, 5.27.
2.5.1. 2-Diethylamino-4-phenylquinoline (5a). To a stir-
red solution of lithium diethylamide (0.51 mmol; generated
by the standard method from diethylamine and butyl-
lithium) at K78 8C under argon was added a solution of
isocyanostyrene 1a (0.10 g, 0.43 mmol) in THF (1.0 mL).
After stirring for 30 min at this temperature, the mixture was
allowed to warm to room temperature and stirring was
continued for an additional 30 min. Similar workup as
described for the above typical procedure followed by
purification by preparative TLC on silica gel to give 5a
(71 mg, 60%) as a pale-yellow viscous oil; Rf 0.70 (1:3
EtOAc–hexane); IR (neat) 3060, 2969, 1610, 1597, 1548,
2.4.4. 2,4-Diphenylquinoline (3d). A pale-yellow solid; mp
120–122 8C (hexane) (lit.,10 114 8C); the spectral data for
this product were identical to those reported previously.11
2.4.5. 2-(4-Methylphenyl)-4-phenylquinoline (3e). A
pale-yellow solid; 116–117 8C (hexane–Et2O) (lit.,12
106 8C); the spectral data for this product were identical
to those reported previously.11
1
1450, 1426, 1360, 1246, 770, 701 cmK1; H NMR d 1.26
(6H, t, JZ6.9 Hz), 3.68 (4H, q, JZ6.9 Hz), 6.74 (1H, s),
7.08 (1H, ddd, JZ8.2, 6.9, 1.3 Hz), 7.4–7.55 (6H, m), 7.57
(1H, dd, JZ8.2, 1.3 Hz), 7.72 (1H, dd, JZ8.6, 1.3 Hz); MS
m/z 276 (MC, 29), 247 (100). Calcd for C19H20N2: C, 82.57;
H, 7.29; N, 10.14. Found: C, 82.55; H, 7.49; N, 10.13.
2.4.6. 4-Phenyl-2-(2-thienyl)quinoline (3f).13a A pale-
yellow solid; mp 89–92 8C (hexane–Et2O) (lit.,13b 83–
85 8C); IR (KBr disk) 3065, 1590, 1548, 1489, 1428, 828,
772, 761, 712, 700 cmK1; 1H NMR d 7.15 (1H, dd, JZ5.0,
3.6 Hz), 7.35–7.6 (7H, m), 7.65–7.75 (3H, m), 7.83 (1H, dd,
JZ8.2, 1.3 Hz), 8.15 (1H, d, JZ8.2 Hz); MS m/z 287 (MC,
100).
2-Aminoquinoline derivatives 5b–k were prepared accord-
ing to the procedure described above, excepting that 2.0 mol
amounts each of lithium diisopropylamide (for 5b and 5j)

K. Kobayashi et al. / Tetrahedron 60 (2004) 11639–11645
11643
and lithium dicyclohexylamide (for 5c) were used and that
the preparation of 5h and 5i were conducted at K78–0 8C.
IR (KBr disk) 3068, 2852, 1605, 1543, 1471, 1438, 1413,
1
1347, 1072, 965, 858, 705 cmK1; H NMR d 2.0–2.1 (4H,
m), 3.6–3.65 (4H, m), 6.65 (1H, s), 7.4–7.55 (7H, m), 7.68
(1H, d, JZ8.9 Hz); MS m/z 308 (MC, 45), 279 (100). Calcd
for C19H17ClN2: C, 73.90; H, 5.55; N, 9.07. Found: C,
74.11; H, 5.53; N, 8.85.
2.5.2. 2-Diisopropylamino-4-phenylquinoline (5b). A
pale-yellow solid; mp 104–105 8C (hexane); IR (KBr disk)
3056, 2928, 1607, 1593, 1544, 1491, 1478, 1373, 1350,
1244, 771, 706 cmK1; 1H NMR d 1.41 (12H, d, JZ6.9 Hz),
4.42 (2H, septet, JZ6.9 Hz), 6.81 (1H, s), 7.07 (1H, ddd,
JZ8.2, 6.9, 1.3 Hz), 7.4–7.6 (7H, m), 7.72 (1H, dd, JZ8.6,
1.3 Hz); MS m/z 304 (MC, 29), 261 (100). Calcd for
C21H24N2: C, 82.85; H, 7.95; N, 9.20. Found: C, 82.59; H,
8.12; N, 9.39.
2.5.9. 6-Chloro-4-phenyl-2-(piperidin-1-yl)quinoline
(5i). A pale-yellow solid; mp 136–139 8C (hexane–Et2O);
IR (KBr disk) 3060, 2925, 2846, 1595, 1543, 1483, 1413,
1
1223, 953, 778, 708 cmK1; H NMR d 1.65–1.7 (6H, m),
3.7–3.8 (4H, m), 6.91 (1H, s), 7.4–7.55 (7H, m), 7.66 (1H, d,
JZ8.9 Hz); MS m/z 322 (MC, 100). Calcd for C20H19ClN2:
C, 74.41; H, 5.93; N, 8.68. Found: C, 74.40; H, 6.02; N,
8.66.
2.5.3. 2-Dicyclohexylamino-4-phenylquinoline (5c). A
pale-yellow solid; mp 167–169 8C (hexane–Et2O); IR
(KBr disk) 3062, 2927, 2846, 1608, 1597, 1545, 1493,
1
1473, 1376, 1216, 758, 704 cmK1; H NMR d 1.15–1.50
2.5.10. 2-Diisopropylamino-4-methylquinoline (5j). A
pale-yellow solid; mp 60–62 8C (hexane); IR (KBr disk)
3059, 2966, 1606, 1552, 1493, 1469, 1428, 1353, 1238,
1150, 753 cmK1; 1H NMR d 1.39 (12H, d, JZ6.9 Hz), 2.57
(3H, s), 4.38 (2H, septet, JZ6.9 Hz), 6.74 (1H, s), 7.15 (1H,
ddd, JZ8.2, 6.9, 1.3 Hz), 7.46 (1H, ddd, JZ8.2, 6.9,
1.3 Hz), 7.63 (1H, dd, JZ8.2, 1.3 Hz), 7.72 (1H, dd, JZ8.2,
1.3 Hz); MS m/z 242 (MC, 10), 199 (100). Calcd for
C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.15; H,
9.16; N, 11.54.
(6H, m), 1.65–1.9 (10H, m), 2.0–2.2 (4H, m), 3.75–3.9 (2H,
m), 6.84 (1H, m), 7.06 (1H, ddd, JZ8.2, 6.9, 1.3 Hz), 7.4–
7.6 (7H, m), 7.70 (1H, dd, JZ8.2, 1.3 Hz); MS m/z 384
(MC, 25), 301 (100). Calcd for C27H32N2: C, 84.33; H, 8.39;
N, 7.28. Found: C, 84.28; H, 8.60; N, 7.23.
2.5.4. 4-Phenyl-2-(pyrrolidin-1-yl)quinoline (5d). A pale-
yellow solid; mp 145–148 8C (hexane–Et2O) (lit.,18 mp
139.5 8C); IR (KBr disk) 3051, 2967, 2861, 1604, 1593,
1
1547, 1500, 1427, 1342, 785, 759, 713 cmK1; H NMR d
2.0–2.1 (4H, m), 3.65–3.7 (4H, m), 6.65 (1H, s), 7.10 (1H,
ddd, JZ8.2, 6.9, 1.3 Hz), 7.4–7.55 (6H, m), 7.59 (1H, dd,
JZ8.2, 1.0 Hz), 7.77 (1H, d, JZ8.6 Hz); MS m/z 274 (MC,
39), 245 (100).
2.5.11. 4-Methyl-2-(piperidin-1-yl)quinoline (5k).20
A
pale-yellow solid; mp 119–120 8C (hexane–AcOEt) (lit.,21
mp 119–121 8C); the spectral data for this compound were
identical to those reported previously.21
2.5.5. 4-Phenyl-2-(piperidin-1-yl)quinoline (5e). A pale-
yellow solid; mp 121–123 8C (hexane–Et2O); IR (KBr disk)
3050, 2929, 2825, 1610, 1596, 1547, 1492, 1429, 1230, 778,
761, 710 cmK1; 1H NMR d 1.69 (6H, br s), 3.7–3.8 (4H, m),
6.90 (1H, s), 7.13 (1H, ddd, JZ8.2, 6.9, 1.3 Hz), 7.4–7.55
(6H, m), 7.59 (1H, dd, JZ8.2, 1.3 Hz), 7.74 (1H, d, JZ
8.2 Hz); MS m/z 288 (MC, 96), 259 (100). Calcd for
C20H20N2: C, 83.30; H, 6.99; N, 9.71. Found: C, 83.19; H,
7.08; N, 9.39.
2.6. 4-Phenyl-2-(phenylthio)quinoline (6)
To a stirred solution of benzenethiol (86 mg, 0.55 mmol) in
THF (1.5 mL) at K78 8C under argon was added butyl-
lithium (0.55 mmol; 1.6 M in hexanes). After stirring for
15 min, isocyanostyrene 1a (0.10 g, 0.43 mmol) was added
and the mixture was allowed to warm to room temperature,
then it was heated at reflux temperature for 7.5 h. After
similar workup as described for the above typical procedure,
followed by separation by preparative TLC on silica gel to
give 6 (43 mg, 32%) as a pale-yellow solid; mp 99–101 8C
(hexane–Et2O); IR (KBr disk) 3062, 1609, 1578, 1540, 773,
2.5.6. 2-(Morpholin-1-yl)-4-phenylquinoline (5f). A pale-
yellow solid; mp 124–126 8C (hexane–Et2O); IR (KBr disk)
3060, 2965, 1605, 1594, 1548, 1491, 1425, 1229, 1125,
1
762 cmK1; H NMR d 3.72–3.78 (4H, m), 3.82–3.88 (4H,
m), 6.88 (1H, s), 7.19 (1H, ddd, JZ8.2, 6.9, 1.3 Hz), 7.45–
7.60 (6H, m), 7.64 (1H, dd, JZ8.2, 1.3 Hz), 7.78 (1H, d, JZ
8.2 Hz); MS m/z 290 (MC, 58), 259 (100). Calcd for
C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.48; H,
6.34; N, 9.66.
1
745, 702, 690 cmK1; H NMR (270 MHz, CDCl3) d 6.96
(1H, s), 7.35–7.5 (9H, m), 7.6–7.7 (3H, m), 7.76 (1H, dd,
JZ8.4, 1.1 Hz), 8.00 (1H, dd, JZ8.4, 0.7 Hz); MS m/z 313
(MC, 100). Calcd for C21H15NS: C, 80.48; H, 4.82; N, 4.47;
S, 10.23. Found: C, 80.50; H, 4.65; N, 4.37; S, 10.21.
2.5.7. 2-(4-Methylpiperazin-1-yl)-4-phenylquinoline
(5g). A pale-yellow solid; mp 124–126 8C (hexane–Et2O)
(lit.,19 mp 123–129 8C); IR (KBr disk) 3057, 2832, 2847,
1609, 1595, 1547, 1492, 1424, 1424, 1231, 772, 699 cmK1
;
Acknowledgements
1H NMR d 2.36 (3H, s), 2.56 (4H, t, JZ5.1 Hz), 3.80 (4H, t,
JZ5.1 Hz), 6.90 (1H, s), 7.16 (1H, ddd, JZ8.2, 6.9,
1.3 Hz), 7.4–7.6 (6H. m), 7.61 (1H, dd, JZ8.2, 1.3 Hz), 7.76
(1H, dd, JZ8.2, 1.3 Hz); MS m/z 303 (MC, 5.3), 233 (100).
We wish to express our appreciation to Mrs. Miyuki
Tanmatsu of this Department for her support in determining
MS spectra and performing combustion analyses. This work
was partially supported by a Grant-in-Aid for Scientific
Research (C) No. 15550092 from Japan Society for the
Promotion of Science.
2.5.8. 6-Chloro-4-phenyl-2-(pyrrolidin-1-yl)quinoline
(5h). A pale-yellow solid; mp 158–160 8C (hexane–Et2O);

11644
K. Kobayashi et al. / Tetrahedron 60 (2004) 11639–11645
Varlet, D.; Fourmaintraux, E.; Depreux, P.; Lesieur, D.
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