Synthesis of 3-methoxyquinolines via cyclization of 1-isocyano-2-(2-lithio-2-methoxyethenyl)benzenes

Article abstract of DOI:10.1016/S0040-4039(03)01040-2

2-(2-Isocyanophenyl)acetaldehyde dimethyl acetals were treated with excess LDA to generate 1-isocyano-2-(2-lithio-2-methoxyethenyl)benzenes, which cyclized intramolecularly to afford 3-methoxyquinolines in good to excellent yields.

Full text of DOI:10.1016/S0040-4039(03)01040-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4733–4736
Synthesis of 3-methoxyquinolines via cyclization of
1-isocyano-2-(2-lithio-2-methoxyethenyl)benzenes
Kazuhiro Kobayashi,* Keiichi Yoneda, Tatsuya Mizumoto, Hironobu Umakoshi, Osamu Morikawa
and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552, Japan
Received 3 March 2003; revised 7 April 2003; accepted 18 April 2003
Abstract—2-(2-Isocyanophenyl)acetaldehyde dimethyl acetals were treated with excess LDA to generate 1-isocyano-2-(2-lithio-2-
methoxyethenyl)benzenes, which cyclized intramolecularly to afford 3-methoxyquinolines in good to excellent yields. © 2003
Elsevier Science Ltd. All rights reserved.
There is a large number of general preparative methods
of quinolines available in the literature1 because of their
useful biological properties.2 However, few reports on
the general synthesis of 3-methoxyquinolines have been
reported3 in spite of their potential importance in
organic and medicinal chemistries, though Akula et
al.3a synthesized 3-methoxy-2-methylquinoline using the
Friedlander quinoline synthesis and, more recently,
Cherng synthesized 3-methoxyquinoline by nucleophilic
substitution of 3-bromoquinoline with sodium methox-
Scheme 1.
Keywords: isocyanides; lithiation; quinolines.
* Corresponding author. Tel./fax: +81 857 31 5263; e-mail: kkoba@chem.tottori-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01040-2

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K. Kobayashi et al. / Tetrahedron Letters 44 (2003) 4733–4736
Table 1. Preparation of 3-methoxyquinoline derivatives 9 from 2-nitrotoluenes 1
Entry
1
2 (Yield/%)a
3 (Yield/%)a
4 (Yield/%)a
5 (Yield/%)a
9 (Yield/%)a
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
2a (74)b
2b (73)
2c (53)
2d (72)
2e (60)
2f (75)
3a (97)b
3b (82)
3c (88)
3d (93)
3e (91)
3f (91)
4a (94)
4b (82)
4c (99)
4d (86)
4e (87)
4f (68)c
5a (97)
5b (93)
5c (90)
5d (94)
5e (96)
5f (82)
9ad (79)
9b (72)
9c (63)
9d (71)
9e (47)
9e (97)
a Isolated yields.
b See Ref. 4.
c Hexyl formate was used.
d Refs. 3b and 3c.
ide.3b We decided to investigate the possibility of devel-
oping an efficient general method for preparing 3-
methoxyquinoline derivatives from readily available
starting materials. We found that 2-(2-isocyano-
phenyl)acetaldehyde dimethyl acetals 5 were treated
with excess LDA to give 3-methoxyquinolines 9 via
cyclization of 1-isocyano-2-(2-lithio-2-methoxyethenyl)-
benzenes 7. In this letter, the results of our preliminary
investigation, which offer the first general construction
of the 3-methoxyquinoline system, are reported.
A representative experimental procedure for the prepa-
ration of 3-methoxyquinoline derivatives 9 from 2-(2-
isocyanophenyl)acetaldehyde dimethyl acetals
5 is
illustrated for the preparation of 3-methoxyquinoline
(9a). To a stirred solution of LDA (14 mmol; generated
from diisopropylamine and butyllithium by the stan-
dard method) in diglyme (8.0 mL) at −78°C under
argon was added dropwise isocyano acetal 5a (0.65 g,
3.4 mmol). After stirring for 1 h at the same tempera-
ture, the reaction was quenched by adding aqueous
saturated NH4Cl, and the mixture was extracted with
Et2O twice (20 mL each). The combined extracts were
washed with water three times and with brine once, and
dried over anhydrous K2CO3. After evaporation of the
solvent the residue was purified by preparative TLC on
silica gel (EtOAc–hexane 1:3) to give 9a3b,c (0.43 g,
79%).5
2-(2-Isocyanophenyl)acetaldehyde dimethyl acetals 5
were prepared from commercially available o-nitro-
toluene derivatives by a five-step sequence as shown in
Scheme
1.
Thus,
2-(2-nitrophenyl)acetaldehyde
dimethyl acetals 2 were synthesized according to the
procedure reported by Fukuyama et al.4 These nitro
compounds 2 were hydrogenated (1 atm) over 10% Pd
on activated carbon. The resulting amino compounds 3
were then formylated with butyl formate (or hexyl
formate for 3f) at reflux temperature to form for-
mamides 4, dehydration of which by treatment with
POCl3/Et3N afforded the isocyano acetals 5.5 These
results are summarized in Table 1.
In summary, we have demonstrated that the present
reaction sequence provides the first general preparative
method of 3-methoxyquinolines. Studies on the synthe-
sis of methoxypyridine-fused heterocyclic compounds,
such as naphthyridine and azaindole derivatives, utiliz-
ing the present procedure are now under way in our
laboratory.
The preparation of 3-methoxyquinolines 9 from 2-(2-
isocyanophenyl)acetaldehyde dimethyl acetals 5 is also
illustrated in Scheme 1 and the yields are summarized
in Table 1 as well. Isocyano acetals 5 were treated with
4 equiv. of LDA in diglyme at −78°C. The action of
LDA upon 5 generated the corresponding benzylan-
ions, from which elimination of methoxide gave o-iso-
cyano-b-methoxystyrenes 6. These isocyano styrenes 6
were lithiated with additional molar(s) of LDA to
Acknowledgements
The authors thank Mrs. Miyuki Tanmatsu of this
department for obtaining the mass spectra and per-
forming combustion analyses.
generate
1-isocyano-2-(2-lithio-2-methoxyethenyl)-
benzenes 7, which underwent an intramolecular cycliza-
tion to provide 3-methoxyquinolines 9. The use of less
than 4 equiv. of LDA in the reaction with 2-(2-iso-
cyanophenyl)acetaldehyde dimethyl acetals (5a)
resulted in decrease of the yield of the desired 3-
methoxyquinoline (9a), and 1-isocyano-2-(E)-(2-
methoxyethenyl)benzene (6a) were obtained. 2-(1-Iso-
cyanonaphthalen-2-yl)acetaldehyde dimethyl acetal (5f),
derived similarly from 2-methyl-1-nitronaphthalene,
was allowed to react with LDA under the same condi-
tions to give the corresponding desired product, 3-
methoxybenzo[h]quinoline (9f), in excellent yield (entry
6).
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K. Kobayashi et al. / Tetrahedron Letters 44 (2003) 4733–4736
4735
1
1:3); IR (neat) 2120 cm−1; H NMR (270 MHz, CDCl3) l
3.08 (2H, d, J=5.6 Hz), 3.38 (6H, s), 4.60 (1H, t, J=5.6
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Rf 0.62 (EtOAc–hexane, 1:3); IR (neat) 2119 cm−1 1H
;
NMR (270 MHz, CDCl3) l 2.33 (3H, s), 3.02 (2H, d,
J=5.3 Hz), 3.37 (6H, s), 4.57 (1H, t, J=5.3 Hz), 7.14 (1H,
d, J=8.2 Hz), 7.17 (1H, s), 7.23 (1H, d, J=8.2 Hz); MS
m/z 205 (M+, 0.90), 204 (1.1), 174 (59), 130 (81), 103 (100).
Calcd for C12H15NO2: M, 205.1103. Found: m/z 205.1086.
5c: a pale yellow liquid; Rf 0.60 (EtOAc–hexane, 1:3); IR
(neat) 2118 cm−1; 1H NMR (270 MHz, CDCl3) l 2.35 (3H,
s), 3.03 (2H, d, J=5.6 Hz), 3.37 (6H, s), 4.60 (1H, t, J=5.6
Hz), 7.05 (1H, dd, J=7.9, 1.3 Hz), 7.14 (1H, s), 7.24 (1H,
d, J=7.9 Hz); MS m/z 205 (M+, 1.0), 204 (1.4), 174 (75),
130 (100). Calcd for C12H15NO2: M, 205.1103. Found: m/z
205.1125. 5d: a pale yellow liquid; Rf 0.62 (EtOAc–hexane,
1
1:3); IR (neat) 2119 cm−1; H NMR (270 MHz, CDCl3) l
1.24 (6H, d, J=7.0 Hz), 2.88 (1H, septet, J=7.0 Hz), 3.03
(2H, d, J=5.5 Hz), 3.37 (6H, s), 4.59 (1H, t, J=5.5 Hz),
7.19 (1H, dd, J=7.7, 1.6 Hz), 7.21 (1H, s), 7.26 (1H, d,
J=7.7 Hz); MS m/z 233 (M+, 0.72), 232 (2.5), 202 (100).
Calcd for C14H19NO2: M, 233.1416. Found: m/z 233.1398.
5e: a pale yellow liquid; Rf 0.53 (EtOAc–hexane, 1:2); IR
(neat) 2118 cm−1; 1H NMR (270 MHz, CDCl3) l 3.03 (2H,
d, J=5.3 Hz), 3.38 (6H, s), 3.81 (3H, s), 4.59 (1H, t, J=5.3
Hz), 6.75 (1H, dd, J=8.6, 1.6 Hz), 6.85 (1H, d, J=1.6
Hz), 7.29 (1H, d, J=8.6 Hz); MS m/z 221 (M+, 8.7), 205
(100). Calcd for C12H15NO3: M, 221.1052. Found: m/z
221.1053. 5f: a pale yellow solid; mp 71–72°C (hexane–
Et2O); IR (KBr disk) 2113 cm−1 1H NMR (270 MHz,
;
CDCl3) l 3.28 (2H, d, J=5.3 Hz), 3.40 (6H, s), 4.68 (1H,
t, J=5.3 Hz), 7.45 (1H, d, J=8.3 Hz), 7.56 (1H, ddd,
J=8.2, 7.3, 1.0 Hz), 7.66 (1H, ddd, J=8.2, 7.3, 1.3 Hz),
7.83 (1H, d, J=8.3 Hz), 7.86 (1H, J=8.2 Hz), 8.17 (1H,
dd, J=8.2, 1.0 Hz); MS m/z 241 (M+, 9.9), 210 (100).
Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found:
C, 74.44; H, 6.40; N, 5.90. 9b: colorless crystals; mp
2. (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic
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8, 965–970; (d) Doube´, D.; Blouin, M.; Brideau, C.; Chen,
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82–85°C (hexane–CH2Cl2); IR (KBr disk) 1608 cm−1 1H
;
NMR (270 MHz, CDCl3) l 2.54 (3H, s), 3.94 (3H, s),
7.3–7.4 (2H, m), 7.63 (1H, d, J=8.6 Hz), 7.82 (1H, s), 8.63
(1H, d, J=3.0 Hz); MS m/z 173 (M+, 99), 130 (100). Calcd
for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.27; H, 6.46; N, 8.34. 9c: a pale yellow liquid; Rf 0.37
(EtOAc–hexane, 1:3); IR (neat) 1608 cm−1; H NMR (270
1
MHz, CDCl3) l 2.52 (3H, s), 3.94 (3H, s), 7.29 (1H, d,
J=3.0 Hz), 7.38 (1H, dd, J=8.6, 2.0 Hz), 7.49 (1H, s),
7.92 (1H, d, J=8.6 Hz), 8.60 (1H, d, J=3.0 Hz); MS m/z
173 (M+, 60), 130 (100). Calcd for C11H11NO: C, 76.28; H,
6.40; N, 8.09. Found: C, 76.40; H, 6.70; N, 7.88. 9d: a pale
yellow liquid; Rf 0.62 (EtOAc–hexane, 1:3); IR (neat) 1607
cm−1; H NMR (270 MHz, CDCl3) l 1.35 (6H, d, J=6.9
1
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E.; Dacrema, L. M. J. Chem. Soc., Perkin Trans. 1 1980,
2738–2742.
Hz), 3.09 (1H, septet, J=6.9 Hz), 3.93 (3H, s), 7.35 (1H, d,
J=3.0 Hz), 7.42 (1H, dd, J=8.2, 1.6 Hz), 7.66 (1H, d,
J=8.2 Hz), 7.87 (1H, s), 8.64 (1H, d, J=3.0 Hz); MS m/z
201 (M+, 44), 186 (100). Calcd for C13H15NO: C, 77.58; H,
7.51; N, 6.96. Found: C, 77.79; H, 7.69; N, 7.09. 9e: a pale
yellow solid; mp 85–86°C (hexane); IR (KBr disk) 1625
4. Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 71–74.
cm−1 1H NMR (270 MHz, CDCl3) l 3.92 (3H, s), 3.94
;
5. All new compounds gave satisfactory spectral and analyti-
cal data. 5a: a pale yellow liquid; Rf 0.57 (EtOAc–hexane
(3H, s), 7.01 (1H, d, J=2.6 Hz), 7.20 (1H, dd, J=9.2, 1.3
Hz), 7.30 (1H, d, J=3.0 Hz), 7.92 (1H, d, J=9.2 Hz), 8.51

4736
K. Kobayashi et al. / Tetrahedron Letters 44 (2003) 4733–4736
(1H, d, J=3.0 Hz); MS m/z 189 (M+, 100). Calcd for
C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.69;
7.55–7.75 (3H, m), 7.80 (1H, d, J=8.6 Hz), 7.88 (1H, dd,
J=7.6, 1.3 Hz), 8.75 (1H, d, J=2.6 Hz), 9.17 (1H, dd,
J=8.2, 1.0 Hz); MS m/z 209 (M+, 100). Calcd for
C14H11NO: C, 80.36; H, 5.30; N, 6.69. Found: C, 80.51;
H, 5.22; N, 6.48.
H, 5.84; N, 7.11. 9f: a white solid; mp 149–150°C (hex-
ane–Et2O); IR (KBr disk) 1596 cm−1 1H NMR (270
;
MHz, CDCl3) l 3.99 (3H, s), 7.49 (1H, d, J=3.0 Hz),