New synthesis of 2,4-dimethylfuro[3,2-c]quinolines

Article abstract of DOI:10.1007/s11178-005-0018-0

Thermal cyclization of ethyl α-(2-chloro-2-propenyl)-β- arylaminocrotonates in mineral oil afforded the corresponding substituted 2,4-dimethylfuro[3,2-c]quinolines instead of the expected 4-hydroxy-2-methyl-3- (2-chloro-2-propenyl)quinolines.

Full text of DOI:10.1007/s11178-005-0018-0

Russian Journal of Organic Chemistry, Vol. 40, No. 9, 2004, pp. 1351–1352. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 9, 2004,
pp. 1397–1398.
Original Russian Text Copyright © 2004 by Avetisyan, Aleksanyan, Pivazyan.
New Synthesis of 2,4-Dimethylfuro[3,2-c]quinolines
A. A. Avetisyan, I. L. Aleksanyan, and A. A. Pivazyan
Erevan State University, ul. A. Manukyana 1, Erevan, 375025 Armenia
e-mail: organkim@sun.ysu.am
Received August 5, 2003
Abstract—Thermal cyclization of ethyl α-(2-chloro-2-propenyl)-β-arylaminocrotonates in mineral oil afforded
the corresponding substituted 2,4-dimethylfuro[3,2-c]quinolines instead of the expected 4-hydroxy-2-methyl-3-
(2-chloro-2-propenyl)quinolines.
Development of the quinoline chemistry has been
stimulated mainly by the isolation and studying of
furoquinoline alkaloids. These compounds attract
interest from both theoretical and practical viewpoints
due to wide spectrum of their biological activity [1, 2].
Among the most widely known furoquinoline alka-
loids, dictamnine (4-methoxyfuro[2,3-b]quinoline),
fagarine (8-methoxydictamnine), and skimmianine
(7,8-dimethoxydictamnine) [1, 2] should be noted.
cyclization of α-allyl-, α-(3,3-dichloroallyl)-, and
α-(3-chloro-2-butenyl)-β-arylaminocrotonic acids
afforded the corresponding 3-allyl-, 3-(3,3-dichloro-
allyl)-, and 3-(3-chloro-2-butenyl)-4-hydroxy-2-methyl-
quinolines [4, 5]. The unusual reaction path leading to
substituted furoquinolines III (which were identical to
those reported in [4]) may be interpreted as follows.
The primary thermal cyclization products are likely to
be 4-hydroxy-3-(2-chloro-2-propenyl)-2-methylquino-
lines A which are then converted into the correspond-
ing 2-chloro-2,4-dimethyl-2,3-dihydrofuro[3,2-c]-
quinolines B, and the subsequent aromatization of
the latter via elimination of hydrogen chloride yields
2,4-dimethylfuro[3,2-c]quinolines IIIa–IIIf as shown
in Scheme 1. The proposed scheme is supported by
the fact that treatment of 4-hydroxyquinolines having
an allyl group in position 3 with pyridine hydro-
The present communication reports on a new con-
venient method for the synthesis of 2,4-dimethylfuro-
[3,2-c]quinolines IIIa–IIIf by thermal cyclization of
ethyl 2-[1-(arylamino)ethylidene]-4-chloro-4-penten-
oates IIa–IIf. The latter were prepared by reaction of
ethyl 2-acetyl-4-chloro-4-pentenoate (I) [3] with sub-
stituted anilines and were subjected to cyclization on
heating to 250°C in mineral oil. Previously, the
Scheme 1.
O
O
Me
R
CH2
EtOH
RC6H4NH2
Me
OEt
CH2
N
H
MeCOCH2COOEt
+
ClCH2C(Cl) CH2
Cl
OEt
O
Cl
I
IIa–IIf
Cl
Me
Me
Me
OH
O
O
H
CH2
250°C
H
R
R
R
Cl
N
Me
N
Me
N
A
B
IIIa–IIIf
R = H (a), 6-CH3 (b), 8-CH3 (c), 6-OCH3 (d), 8-OCH3 (e), 6-Cl (f).
1070-4280/04/4009-1351 © 2004 MAIK “Nauka/Interperiodica”

AVETISYAN et al.
1352
4-H), 7.37–7.78 m (4H, Harom). Found, %: C 79.10;
H 5.70; N 7.16. C13H11NO. Calculated, %: C 79.19;
H 5.58; N 7.10.
chloride on heating or with sulfuric acid or bromine
at room temperature leads to formation of the corre-
sponding furoquinolines [6–8]. It was also found that
furoquinolines containing a halogen atom in the
α-position of the furan ring readily undergo aromatiza-
tion as a result of elimination of hydrogen halide even
by the action of a weak base [6].
2,4,6-Trimethylfuro[3,2-c]quinoline (IIIb). Yield
74%, mp 72–73°C, Rf 0.67. Found, %: C 79.49;
H 6.33; N 6.76. C14H13NO. Calculated, %: C 79.62;
H 6.16; N 6.64.
2,4,8-Trimethylfuro[3,2-c]quinoline (IIIc). Yield
75%, mp 80–81°C, Rf 0.60. Found, %: C 79.75;
H 6.20; N 6.51. C14H13NO. Calculated, %: C 79.62;
H 6.16; N 6.64.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Mercury-300 spectrometer (300 MHz) from solutions
in DMSO-d6. The purity of the products was checked
by thin-layer chromatography on Silufol UV-254
plates using chloroform–hexane (1:2) as eluent and
iodine vapor as developer.
6-Methoxy-2,4-dimethylfuro[3,2-c]quinoline
1
(IIId). Yield 76%, mp 115°C, Rf 0.59. H NMR spec-
trum, δ, ppm: 2.30 s (3H, CH3), 2.67 s (3H, NCCH3),
3.9 s (3H, OCH3), 6.62 s (1H, 4-H), 7.40–7.80 m
(4H, Harom). Found, %: C 73.80; H 5.90; N 6.10.
C14H13NO2. Calculated, %: C 73.99; H 5.77; N 6.17.
Ethyl 2-acetyl-4-chloro-4-pentenoate (I) was syn-
thesized by the procedure described in [3] from ethyl
acetoacetate and 2,3-dichloropropene. Yield 153.4 g
(71%), bp 84–86°C (5 mm) , nD20 = 1.4625.
8-Methoxy-2,4-dimethylfuro[3,2-c]quinoline
(IIIe). Yield 79%, mp 95–96°C, Rf 0.54. Found, %:
C 74.06; H 5.86; N 6.21. C14H13NO2. Calculated, %:
C 73.99; H 5.77; N 6.17.
Ethyl 2-(1-arylaminoethylidene)-4-chloro-4-pen-
tenoates IIa–IIf (general procedure). A mixture of
20.45 g (0.1 mol) of compound I, 0.1 mol of the cor-
responding substituted aniline, and 2–3 drops of hydro-
chloric acid in 200 ml of benzene was heated at the
boiling point with simultaneous removal of water as
azeotrope with benzene. When the required amount of
water separated (1.8 ml), the solvent was distilled off,
and the residue was subjected to heterocyclization
without additional purification.
6-Chloro-2,4-dimethylfuro[3,2-c]quinoline (IIIf).
Yield 68%, mp 118°C, Rf 0.64. Found, %: C 67.48;
H 4.20; Cl 15.19; N 6.17. C13H10ClNO. Calculated,%:
C 67.36; H 4.32; Cl 15.33; N 6.05.
REFERENCES
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Heterocycles, 1976, no. 5, p. 565.
2. Michael, J.P., Nat. Prod. Rep., 1997, vol. 14, p. 11.
2,4-Dimethylfuro[3,2-c]quinolines IIIa–IIIf (gen-
eral procedure). Compound IIa–IIf, was added in
a stream of nitrogen under vigorous stirring to 300 ml
of mineral oil heated to 250°C. The mixture was
cooled, the precipitate was filtered off and dissolved in
5% hydrochloric acid, the solution was treated with
charcoal and filtered, and the filtrate was made
alkaline (pH 8–8.5) by adding a solution of sodium
hydroxide. The precipitate was filtered off and recrys-
tallized from aqueous alcohol (1:1).
3. Organikum. Organisch-chemisches Grundpraktikum,
Berlin: Wissenschaften, 1976, 15th edn. Translated under
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Erevan, 1985.
7. Gyul’budagyan, L.V. and Sagatelyan, Sh.A., Khim.
Geterotsikl. Soedin., 1973, p. 84.
2,4-Dimethylfuro[3,2-c]quinoline (IIIa). Yield
1
78%, mp 63°C, Rf 0.62. H NMR spectrum, δ, ppm:
8. Gyul’budagyan, L.V. and Aleksanyan, I.L., Arm. Khim.
Zh., 1989, vol. 42, p. 407.
2.20 s (3H, CH3), 2.52 s (3H, NCCH3), 6.65 s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 9 2004