Synthesis of 2,4-disubstituted quinolines by reactions of o-isocyano-β-methoxystyrene derivatives with organolithiums

Article abstract of DOI:10.1246/cl.2003.76

Alkyl(or aryl)lithiums reacted efficiently with o-isocyano-β-methoxystyrene derivatives, prepared in three steps from o-aminophenyl ketones, to afford the corresponding 2,4-disubstituted quinolines in satisfactory yields.

Full text of DOI:10.1246/cl.2003.76

76
Chemistry Letters Vol.32, No.1 (2003)
Synthesis of 2,4-Disubstituted Quinolines
by Reactions of o-Isocyano-ꢀ-methoxystyrene Derivatives with Organolithiums
Kazuhiro Kobayashi,ꢀ Keiichi Yoneda, Masaaki Mano, Osamu Morikawa, and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552
(Received October 7, 2002; CL-020858)
Alkyl(or aryl)lithiums reacted efficiently with o-isocyano-b-
methoxystyrene derivatives, prepared in three steps from o-
aminophenyl ketones, to afford the corresponding 2,4-disubsti-
tuted quinolines in satisfactory yields.
Scheme 2.
Quinolines are important because of their occurrence in
nature,1 their biological properties,2 and their utilities as inter-
mediates for the design of biologically active compounds.3
Especially 2-alkylated derivatives have been reported to exhibit
notable biological activities.4 Thus, a large number of general
methods for the preparation of substituted quinolines have
recently been reported.5;6 In this paper we wish to describe the
results of our investigation, which offer a simple and general
method for preparing 2,4-disubstituted quinolines by reactions of
o-isocyano-b-methoxystyrene derivatives with alkyl(or aryl)-
lithiums.
o-Isocyano-b-methoxystyrene derivatives 1 were prepared in
three steps from o-aminophenyl ketones as shown in Scheme 1.
Thus, formylation of o-aminophenyl ketones with formic acid
afforded the corresponding formamides which were dehydrated
by treatment with phosphoryl chloride/triethylamine to afford o-
isocyanophenyl ketones. Wittig reaction of these isocyano
ketones with (methoxymethyl)triphenylphosphonium ylide gave
o-isocyano-b-methoxystyrene derivatives 1, as a mixture of
stereoisomers in each case.7
Table 1. Preparation of 2,4-disubstituted quinolines 2 according
to Scheme 2
Entry
1
R3 in R3Li
2 (Yield/%)a
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
n-Bu
sec-Bu
tert-Bu
Ph
p-Tol
2-thienyl
2-furyl
tert-Bu
Ph
2a (79)
2b (84)
2c (89)
2db (91)
2ec (88)
2fd (74)
2gd (75)
2h (87)
2ie (85)
2jf (58)
2kg (55)
tert-Bu
Ph
11
aIsolated yields after purification by preparative TLCon silica
gel. bRef. 8. cRef. 9. dRef. 10. eRef. 11. fRef. 12. gRef. 13.
THF, rather diminished yields of the desired products were
obtained. This is probably attributable to the lability of THF to
alkyl(or aryl)lithiums.
A typical procedure is illustrated by the preparation of 2-
butyl-4-phenylquinoline (2a). To a stirred solution of isocyano-
styrene 1a (0.12 g, 0.51 mmol) in 1,2-dimethoxyethane (2.5 mL)
at ꢁ78 ꢂC under argon was added dropwise butyllithium
(0.77 mmol; 1.6 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 diethyl ether three times (15 mL
each). The combined extracts were washed with brine, dried over
anhydrous sodium sulfate, and evaporated. The residue was
purified by preparative TLCon silica gel ( 1 : 3 EtOAc–hexane) to
give 2a (0.11 g, 79%) as a pale-yellow viscous oil.14
The pathway to quinoline derivatives 2 is outlined in Scheme
3. The a-addition of a nucleophile to the isocyano carbon of 1
resulted in formation of the imidoyl anion intermediate 3. This
anion attacks to the a-carbon atom of the methoxyvinyl moiety of
3 to afford the benzyl anion intermediate 4, which, after a loss of
methoxide, provides 2.
Scheme 1.
o-Isocyano-b-methoxystyrene derivatives 1 were treated
with alkyl(or aryl)lithiums (1.5 eq) at ꢁ78 ꢂC in 1,2-dimethoxy-
ethane (DME) and the mixtures were allowed to warm to room
temperature. Usual aqueous workup, followed by purification
using preparative TLCon silica gel, gave 2,4-disubstituted
quinoline derivatives 2. The results summarized in Table 1
demonstrate that the good yields of the desired products were
obtained in general (entries 1–9), though somewhat poorer results
were obtained by using o-isocyano-b-methoxy-a-methylstyrene
(1c) (entries 10 and 11). When the reactions were conducted in
In conclusion, we have demonstrated that the reactions of o-
isocyano-b-methoxystyrene derivatives with alkyl(or aryl)-
lithiums provide a new method to prepare 2,4-disubstituted
Copyright ꢀ 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.1 (2003)
77
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6
7
The quinoline synthesis initiated by the addition of nuleophiles to
the isocyanide carbon of (o-isocyanophenyl)acetylenes has been
reported: M. Suginome, T. Fukuda, and Y. Ito, Org. Lett., 1, 1977
(1999).
1a: a pale-yellow viscous oil; Rf 0.66 (1 : 3 EtOAc–hexane); IR
(neat) 2123, 1636 cmꢁ1; 1H NMR (270 MHz, CDCl3) ꢀ 3.81 (1.5H,
s), 3.83 (1.5H, s), 6.38 (0.5H, s), 6.69 (0.5H, s), 7.05–7.5 (9H, m);
MS m=z 235 (Mþ, 97) 165 (100). 1b: a pale-yellow viscous oil; Rf
0.61 (1 : 3 EtOAc–hexane); IR (neat) 2123, 1636 cmꢁ1; 1H NMR
(270 MHz, CDCl3) ꢀ 3.82 (1.5H, s), 3.84 (1.5H, s), 6.40 (0.5H, s),
6.69 (0.5H, s), 7.10 (1H, dd, J ¼ 7:9, 1.6 Hz), 7.2–7.4 (7H, m); MS
m=z 269 (Mþ, 100). 1c: a pale-yellow oil; Rf 0.31 (1 : 10 EtOAc–
hexane); IR (neat) 2124, 1666 cmꢁ1; 1H NMR (270 MHz, CDCl3) ꢀ
1.91 (2.1H, d, J ¼ 1:3 Hz), 2.00 (0.9H, d, J ¼ 1:3 Hz), 3.63 (2.1H,
s), 3.73 (0.9H, s), 6.13 (0.7H, q, J ¼ 1:3 Hz), 6.23 (0.3H, q,
J ¼ 1:3 Hz), 7.15–7.4 (4H, m); MS m=z 173 (Mþ, 60), 130 (100).
W. Borsche and F. Sinn, Liebigs Ann. Chem., 538, 283 (1939); T.
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Scheme 3.
quinolines. This method is useful because of its efficiency, the
ready availability of the starting materials and the ease of
operation. Work on investigating the reactions using other
nucleophiles for preparing 2-functionalized quinolines is cur-
rently progress in our laboratory.
We wish to express our appreciation to Mrs. Miyuki
Tanmatsu of this Department for her support in determining the
MS spectra and performing combustion analyses.
8
9
References and Notes
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1
2a; Rf 0.67; IR (neat) 1592 cmꢁ1; H NMR (270 MHz, CDCl3) ꢀ
0.97 (3H, t, J ¼ 7:3 Hz), 1.47 (2H, sextet, J ¼ 7:3 Hz), 1.75–1.9
(2H, m), 3.01 (2H, t, J ¼ 7:9 Hz), 7.24 (1H, s), 7.43 (1H, td,
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1592 cmꢁ1; 1H NMR (270 MHz, CDCl3) ꢀ0.93 (3H, t, J ¼ 7:3 Hz),
1.40 (3H, d, J ¼ 6:9 Hz), 1.65–2.0 (2H, m), 2.95–3.15 (1H, m), 7.23
(1H, s), 7.43 (1H, td, J ¼ 8:2, 1.3 Hz), 7.5–7.55 (5H, m), 7.68 (1H,
td, J ¼ 8:2, 1.3 Hz), 7.86 (1H, dd, J ¼ 8:2, 1.3 Hz), 8.12 (1H, dd,
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dd, J ¼ 8:2, 1.3 Hz); MS m=z 261 (Mþ, 43), 246 (100). Found: C,
87.48; H, 7.09; N, 5.27. Calcd for C19H19N: C, 87.31; H, 7.33; N,
5.36. 2h: a pale-yellow viscous oil; Rf 0.81 (1 : 3 hexane-AcOEt);
IR (neat) 1590 cmꢁ1; 1H NMR (270 MHz, CDCl3) ꢀ 1.48 (9H, s),
7.4–7.6 (6H, m including s at ꢀ7.45), 7.60 (1H, dd, J ¼ 8:9, 2.3 Hz),
7.80 (1H, J ¼ 2:3 Hz), 8.05 (1H, d, J ¼ 8:9 Hz); MS m=z 295 (Mþ,
37), 280 (100). Found: C, 76.96; H, 5.95; N, 4.55. Calcd for
C19H18NCl: C, 77.15; H, 6.13; N, 4.74.
3
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5