Efficient synthesis of novel six-member ring-fused quinoline derivatives via the Friedlaender reaction

Article abstract of DOI:10.1002/hc.20356

Novel quinolines fused with a six-member ring 5a-j were prepared in high yields (75-95%) via the Friedlaender reaction of dimethoxy-substituted o-aminobenzaldehydes of 3a or 3b with cyclic ketones 4, respectively. The structures of 5aj were determined by IR, ¹H NMR, MS, and elemental analysis.

Full text of DOI:10.1002/hc.20356

Heteroatom Chemistry
Volume 19, Number 3, 2008
Efficient Synthesis of Novel Six-Member
Ring-Fused Quinoline Derivatives via the
Friedlander Reaction
¨
Dingqiao Yang, Wei Guo, Yuepeng Cai, Lasheng Jiang,
Kailing Jiang, and Xiaobing Wu
School of Chemistry and Environment, South China Normal University, Guangzhou 510006,
People’s Republic of China
Received 27 March 2006; revised 15 November 2006
ticancer and antiplatelet [4], antiasthmatic [5], anti-
ABSTRACT: Novel quinolines fused with a six-
inflammatory [6], and antihypertensive [7] activities.
member ring 5a–j were prepared in high yields (75–
In addition, quinoline’s derivatives have been widely
95%) via the Friedla¨nder reaction of dimethoxy-
utilized as ligands for preparing metal complexes [8]
substituted o-aminobenzaldehydes of 3a or 3b with
and as useful materials for organic synthesis [9].
cyclic ketones 4, respectively. The structures of 5a–
Among these quinoline derivatives, we are par-
j were determined by IR, 1H NMR, MS, and ele-
ticularly interested in six-member ring-fused quino-
ꢀ
C
mental analysis.
2008 Wiley Periodicals, Inc. Het-
lines due to their promising antitumor activity [10].
One of the most widely used methods for prepar-
ing substituted quinolines is the Friedla¨nder reac-
tion [11], in which an aromatic o-aminoaldehyde
or an aromatic o-aminoketone is condensed with
an aldehyde or ketone containing an alpha active
methylene group (Scheme 1).
eroatom Chem 19:229–233, 2008; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20356
INTRODUCTION
In this paper, we report an efficient method for
the synthesis of novel quinoline derivatives fused
with a six-member ring via the Friedla¨nder reac-
tion, that is, the condensation reaction of dimethoxy-
substituted o-aminobenzaldehydes with cyclic ke-
tones in the presence of sodium ethoxide.
As a potential drug candidate, quinoline derivatives
have recently attracted increasing interest because of
their broad range of biological activities [1]. For ex-
ample, quinoline derivatives have been found to be
potent, selective, and orally bioavailable inhibitors
for the platelet-derived growth factor receptor [2a]
and an effective inhibitor for the replication of
the severe acute respiratory syndrome coronavirus
in vitro [2b]. Moreover, quinoline analogues were
reported to display promising antibacterial [3], an-
RESULTS AND DISCUSSION
The starting materials, dimethoxy-substituted o-
aminobenzaldehydes, 3a,b, were prepared in two
steps as outlined in Scheme 2.
Dimethoxy-substituted o-nitrobenzaldehydes of
2a and 2b were prepared by nitration of the
corresponding dimethoxy-substituted benzaldehy-
des 1a,b, respectively. Because of the electron-
withdrawing effects and less stability of the
Correspondence to: Dingqiao Yang; e-mail: yangdq@scnu.
edu.cn.
Contract grant sponsor: Natural Science Foundation of
Guangdong Province.
Contract grant number: 04010404.
2008 Wiley Periodicals, Inc.
c
ꢀ
229

230 Yang et al.
SCHEME 1
SCHEME 3
aldehdyde group in the strong acidic conditions,
compounds 1a,b were found to give the expected
products 2a,b in poor yields (less than 40%) at room
temperature by using 70% nitric acid, the classic ni-
tration method, as described in the literature [12].
We found that using nitric acid and acetic anhy-
dride as solvent the yields of compounds 2a,b were
remarkably improved (73–80%). The reaction of 1a
under this condition gave compound 2a (73%) as
yellow needles, whereas that of 1b gave a mixture
of 2,5-dimethoxy-4-nitrobenzaldehyde (14%) and
3,6-dimethoxy-2-nitrobenzaldehyde 2b [13] (80%),
which were separated and purified through a flash
silica gel chromatographic column using petroleum
ether/ethyl acetate (1:1, v/v) as solvent.
To selectively reduce the nitro group in 2a and
2b in the amino group, reagents, described in the
literature such as Na2S2O4 [14], and FeSO4·7H2O–
NH3·H2O [15], had been first attempted. How-
ever, we found that all reactions gave products in
poor yields. It is worth to point out that, when
FeSO4·7H2O–NH3·H2O was used, the reaction pro-
duced large amount of semisolid inorganic wastes
and made the filtration process very difficult. We
then attempted to use iron powder, which was able
to selectively reduce the nitro group of 2a and2b
to give the corresponding amino products 3a (62%)
and 3b (76%), respectively.
acterized by IR, 1H NMR, MS, and elemental analysis
(see the Experimental).
CONCLUSION
We have reported an efficient method for the syn-
thesis of novel quinoline derivatives 5a–j through
the condensation reaction of dimethoxy-substituted
aminoaldehydes 3a,b with cyclic ketones 4 via the
Friedla¨nder reaction. The experimental procedure is
very simple. Our protocol can be applied to a wide
range of substrates. These methods not only afford
significant improvements in the reaction rates and
yields but also present a more straightforward and
easy work-up procedure. The anticancer activities
of the new quinoline derivatives are currently under
evaluation.
EXPERIMENTAL
General
Melting points were determined on a microscopic
melting point apparatus (Kofler, Guangzhou, PRC)
and were uncorrected. The IR spectra were recorded
on a Perkin-Elmer 1730 FT-IR spectrometer using
1
KBr films. The H NMR spectra were recorded on
The condensation reaction of the dimethoxy-
substituted aminoaldehydes 3a,b with cyclic ketones
4 in anhydrous ethanol, in the presence of catalytic
amount of sodium ethoxide, yielded the expected
six-member ring-fused quinolines 5a–j in high yields
(Scheme 3; Table 1). Their structures were fully char-
a Varian Inova 500 MHz in CDCl3 solutions using
TMS as an internal standard. The mass spectra were
obtained on a Shimadzu Qp5050A spectrometer. El-
emental analysis was performed on an elemental
Varioel spectrometer. 3,4-Dimethoxybenzaldehyde,
2,5-dimethoxybenzaldehyde, cyclic ketones, and
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of Novel Six-Member Ring-Fused Quinoline Derivatives via the Friedla¨nder Reaction 231
TABLE 1 Physical Data of Compounds 5a–j
Compounds
Rꢁ
Rꢁꢁ
X
Time (h)
Melting Point (◦C)
Yield (%)
5a
5b
5c
5d
5e
5f
H
H
H
H
H
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
H
H
H
H
H
NCOOCH2CH3
NCH3
NCOC6H5
2
2
1.5
139–141
138–140
135–138
117–119
140–142
—
145–146
141–143
134–136
160–161
90
95
75
90
90
85
90
70
95
95
S
O
1.5
2
2
1.5
2
2
NCOOCH2CH3
NCH3
NCOC6H5
5g
5h
5i
S
O
5j
heterocyclic 6-member ring ketones were purchased
from Aldrich (Beijing, PRC).
Preparation of 3,6-Dimethoxy-2-aminobenz-
aldehyde (3b). Compound 3b was prepared by fol-
lowing the same experimental procedure described
for 3a. 3b was recrystallized from 95% ethanol, and
a yellow solid 3b (1.60 g, yield 76%, mp 67−68◦C
(Lit. 67–68◦C) [16]) was obtained. 1H NMR (500
MHz, CDCl3), δ (ppm) : 10.32 (s, 1H, CHO), 6.69 (d,
1H, J4,5 = 8.7 Hz, H4), 6.8–6.5 (br s, 2H, NH2), 5.90
(d, 1H, H5), 3.74 (s, 6H, OCH3).
Preparation of 4,5-Dimethoxy-2-nitrobenzal-
dehyde (2a). Nitric acid (4 mL; 89 mmol), acetic
anhydride (4 mL; 42 mmol), and 1a (2.0 g; 12 mmol)
were added at 0◦C with stirring, respectively. After
2 h stirring, the mixture was poured onto 10 mL
ice water. The resultant yellow solid was filtered,
washed with cold water and then cold ethanol, and
recrystallized from 95% ethanol; a yellow needle
compound 2a (1.85 g, yield 73%, mp 132−133◦C
(Lit. 132–133◦C) [13]) was obtained.
General Procedure for the Synthesis of Novel
Six-Member Ring-Fused Quinoline Derivatives
via the Friedla¨nder Reaction
To a solution of dimethoxy-substituted aminoalde-
hyde 3 (0.90 mmol) and heterocyclic six-member
ring ketone 4 (0.90 mmol) in anhydrous ethanol
(10 mL), sodium ethoxide (3 mL; prepared by 0.01 g
sodium and 3 mL anhydrous ethanol) was added.
The solution was stirred at reflux about 2 h. The
mixture was cooled to room temperature. The sol-
vent was removed under vacuum (30–40 mmHg).
The residue was purified through silica gel chro-
matographic column to get products 5.
Preparation of 3,6-Dimethoxy-2-nitrobenzal-
dehyde (2b). Compound 2b was prepared by fol-
lowing the same experimental procedure described
for 2a. 2b was recrystallized from 95% ethanol,
and a yellow, needle-shaped compound 2b (2.0 g,
yield 80%, mp 162–163◦C (Lit. 163–165◦C) [13]) was
obtained.
Preparation of 3,4-Dimethoxy-6-aminobenzal-
dehyde (3a) [16]. 4,5-Dimethoxy-2-nitrobenzal-
dehyde 2a (0.43 g; 2 mmol), iron powder (0.42 g; 74
mmol), and 0.01 mL of concentrated HCl were in-
troduced into a solution of EtOH (5.0 mL), AcCOOH
(5.0 mL ), and H2O (3.0 mL). The resultant mixture
was refluxed for 30 min with stirring prior to the
filtration. The filtrate was diluted with H2O (30 mL)
and was extracted with CH2Cl2 (3 × 15 mL). The
combined organic layer was washed with saturated
aqueous NaHCO3 (2 × 15 mL) and H2O (2 × 15 mL),
dried over anhydrous Na2SO4. After removing the
solvent under reduced pressure, the residue was
separated by column chromatography to get 3a
7,8-Dimethoxy-3,4-dihydro-1H-benzo[b][1,6]-
naphthyridine-2-carboxylic Acid Ethyl Ester (5a).
The compound was purified by flash silica gel
chromatographic column (ethyl acetate/petroleum
ether = 3:1, v/v) to give 5a as a white solid in yield of
90%. It has R 0.30 (ethyl acetate/petroleum ether =
f
3/1, v/v), and mp 139–141◦C. IR (KBr), ν (cm−1):
2958, 1695, 1500, 1434, 1395, 893, 850. 1H NMR
(500 MHz, CDCl3), δ (ppm): 1.21 (t, J = 7.0 Hz,
3H, CH3), 3.16 (t, J = 6.0 Hz, 2H, CH2), 3.87 (t,
J = 6.0 Hz, 2H, CH2), 4.00 (s, 3H, OCH3), 4.01 (s,
3H, OCH3), 4.22–4.60 (m, J = 7.0 Hz, 2H, CH2), 4.78
(s, 2H, CH2), 6.98 (s, 1H, H-6), 7.34 (s, 1H, H-3),
7.72 (s, 1H, H-10). MS (m/z, %): 316 (M+, 18), 287
(100), 243 (19).
1
(0.23 g, 62%) as an orange oil. H NMR (500 MHz,
CDCl3), δ (ppm) : 9.70 (s, 1H, CHO), 6.65 (s, 2H,
ArH), 6.10 (br s, 2H, NH2), 3.85 (s, 3H, OCH3), 3.79
(s, 3H, OCH3).
Heteroatom Chemistry DOI 10.1002/hc

232 Yang et al.
Anal. Calcd. for C17H20N2O4(316.14), C, 64.54; H,
6.37; N, 8.86. Found: C, 64.16; H, 6.51; N, 8.58.
ether = 1:1, v/v) to give 5e as a white solid in yield of
90%. It has Rf 0.34 (ethyl acetate/petroleum ether,
1:1, v/v). mp 140–142◦C. IR (KBr), ν (cm−1): 2933,
1622, 1504, 1393, 1249, 1155, 1013, 891, 851. 1H
NMR (500 MHz, CDCl3), δ (ppm): 3.08 (t, J = 6.0
Hz, 2H, CH2), 3.90 (3H, OCH3), 3.92 (3H, OCH3),
4.06 (t, J = 6.0 Hz, 2H, CH2), 4.82 (s, 2H, CH2), 6.86
(s, 1H, H-6), 7.26 (s, 1H, H-3), 7.49 (s, 1H, H-10).
MS (m/z, %): 246 (15), 245 (M+, 100), 244 (40), 217
(19), 115 (5), 77 (6).
7,8-Dimethoxy-2-methyl-1,2,3,4-tetrahydro-benzo-
[b][1,6]naphthyridine (5b). The compound was
purified by flash chromatographic column
(dichloromethane/ethanol = 4:1, v/v) to give 5b
as a white solid in yield of 95%. It has Rf 0.40
(dichloromethane/ethanol = 4:1, v/v) and mp 138–
140◦C. IR (KBr), ν (cm−1): 2938, 1624, 1503, 1464,
1395, 1251, 850. 1H NMR (500 MHz, CDCl3), δ
(ppm): 2.53 (s, 3H, CH3), 2.88 (t, J = 6.5 Hz, 2H,
CH2), 3.22 (t, J = 6.5 Hz, 2H, CH2), 3.74 (s, 2H, CH2),
4.00 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.96 (s, 1H,
H-6), 7.33 (s, 1H, H-3), 7.63 (s, 1H, H-10). MS (m/z,
%): 258 (M+, 60), 257 (100), 215 (44), 128 (23).
Anal. Calcd for C15H18N2O2(258.13). C, 69.74; H,
7.02; N, 10.84. Found: C, 69.69; H, 7.27; N, 10.70.
Anal. Calcd for C14H15NO3(245.11), C, 68.56; H,
6.16; N, 5.71. Found: C, 68.61; H, 6.44; N, 5.64.
6,9-Dimethoxy-3,4-dihydro-1H-benzo[b][1,6]-
naphthyridine-2-carboxylic Acid Ethyl Ester (5f).
The compound was purified by flash chromato-
graphic column (ethyl acetate/petroleum ether =
3:1, v/v) to give 5f as a yellow oil in yield of 85%.
It has Rf 0.39 (ethyl acetate/petroleum ether = 3:1,
v/v). IR (KBr), ν (cm−1): 2936, 1697,1479, 1435,
1262, 1097, 725. 1H NMR (500 MHz, CDCl3), δ
(ppm): 1.29 (t, J = 7.0 Hz, 3H, CH3), 3.28 (t, J = 6.0
Hz, 2H, CH2), 3.86 (t, J = 6.0 Hz, 2H, CH2), 3.96 (s,
3H, OCH3), 4.03 (s, 3H, OCH3), 4.21–4.60 (m, J = 7.0
Hz, 2H, CH2), 4.83 (s, 2H, CH2), 6.70 (d, J = 8.5 Hz,
1H, H-1), 6.87 (d, J = 8.5 Hz, 1H, H-2), 8.29 (s, 1H,
H-10). MS (m/z, %): 317 (29), 316 (M+, 89), 315 (27),
301 (100), 287 (62), 243 (20).
(7,8-Dimethoxy-3,4-dihydro-1H-benzo[b][1,6]-
naphthyridin-2-yl)-phenyl-methanone
(5c). The
compound was purified by flash chromatographic
column (ethyl acetate/petroleum ether = 3:1, v/v) to
give 5c as a white solid in yield of 75%. It has R
f
0.22 (ethyl acetate/petroleum ether = 3:1, v/v). mp
135–138◦C. IR (KBr), ν (cm−1): 2933, 1628, 1500,
1434, 1395, 1250, 1011, 877. H NMR (500 MHz,
CDCl3), δ (ppm): 3.21 (s, 2H, CH2), 3.81 (s, 2H, CH2),
4.00 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 5.02 (s, 2H,
CH2), 6.99 (s, 1H, H-6), 7.37 (s, 1H, H-3), 7.42–7.48
(m, 5H, C6H5), 7.81 (s, 1H, H-10). MS (m/z, %): 349
(25), 348 (M+, 100), 243 (36), 228 (34), 105 (80), 77
(56).
Anal. Calcd for C17H20N2O4(316.14), C, 64.54; H,
6.37; N, 8.86. Found: C, 64.53; H, 6.64; N, 8.56.
6,9-Dimethoxy-2-methyl-1,2,3,4-tetrahydro-benzo-
[b][1,6]naphthyridine (5g). The compound was
purified by flash chromatographic column
(dichloromethane/ethanol = 9:1, v/v) to give 5g
as a yellow solid in yield of 90%. It has Rf 0.55
(dichloromethane/ethano l = 9:1, v/v). mp 145–
146◦C. IR (KBr), ν (cm−1): 2946, 1607, 1480, 1389,
1258, 971, 812. 1H NMR (500 MHz, CDCl3), δ (ppm):
2.52 (s, 3H, CH3), 2.88 (t, J= 6.0 Hz, 2H, CH2), 3.34
(t, J = 6.0 Hz, 2H, CH2), 3.79 (s, 2H, CH2), 3.94 (s,
3H, OCH3), 4.02 (s, 3H, OCH3), 6.66 (d, J = 8.5 Hz,
1H, H-1), 6.83 (d, J = 8.5 Hz, 1H, H-2), 8.17 (s, 1H,
H-10). MS (m/z, %): 259 (16), 258 (M+, 100), 243
(53), 227 (33), 128 (26), 77 (6).
Anal. Calcd for C21H20N2O3(348.15), C, 72.40; H,
5.79; N, 8.04. Found: C, 72.35; H, 6.02; N, 7.98.
6,7-Dimethoxy-3,4-dihydro-1H-2-thia-10-aza-ant-
hracene (5d). The compound was purified by flash
chromatographic column (ethyl acetate/petroleum
ether = 1:1, v/v) to give 5d as a white solid in yield
of 90%. It has Rf 0.40 (ethyl acetate/petroleum ether
= 1:1, v/v). mp 117–119◦C. IR (KBr), ν (cm−1): 2928,
1
1621, 1500, 1390, 1252, 1154, 1010, 851. H NMR
(500 MHz, CDCl3), δ (ppm): 3.08 (t, J = 6.0 Hz, 2H,
CH2), 3.35 (t, J = 6.0 Hz, 2H, CH2), 3.90 (s, 2H,
CH2), 4.00 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.98
(s, 1H, H-6), 7.35 (s, 1H, H-3), 7.70 (s, 1H, H-10).
MS (m/z, %): 262 (16), 261 (M+,100), 260 (17), 246
(12), 230 (10), 228 (56), 215 (32), 77 (7).
Anal. Calcd for C15H18N2O2(258.13), C, 69.74; H,
7.02; N, 10.84. Found: C, 69.28; H, 7.35; N, 10.60.
(6,9-Dimethoxy-3,4-dihydro-1H-benzo[b][1,6]-
Anal. Calcd for C14H15NO2S (261.08), C, 64.34;
H, 5.79; N, 5.36. Found: C, 64.74; H, 6.00; N, 5.10.
naphthyridin-2-yl)-phenyl-methanone
(5h). The
compound was purified by flash chromatographic
column (ethyl acetate/petroleum ether = 3:1, v/v)
to give 5h as a yellow solid in the yield of 70%. It
has Rf 0.28 (ethyl acetate/petroleum ether = 3:1,
v/v). mp 141–143◦C. IR (KBr), ν (cm−1): 3055, 2936,
7,8-Dimethoxy-3,4-dihydro-1H-pyrano[4,3-b]qui-
noline (5e). The compound was purified by flash
chromatographic column (ethyl acetate/petroleum
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of Novel Six-Member Ring-Fused Quinoline Derivatives via the Friedla¨nder Reaction 233
1
[3] (a) Vaitilingam, B.; Nayyar, A.; Palde, P. B.; Monga,
V.; Jain, R.; Kaur, S.; Singh, P. P. Bioorg Med Chem
2004, 12, 4179–4188; (b) Chen, Y.-L.; Fang, K.-C.;
Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C. C. J Med Chem 2001,
44, 2374–2377.
[4] (a) Lee, B. D.; Li, Z.; French, K. J.; Zhuang, Y.; Xia,
Z.; Smith, C. D. J Med Chem 2004, 47, 1413–1422;
(b) Gopal, M.; Shenoy, S.; Doddamani, L. S. J Pho-
tochem Photobiol B 2003, 72, 69–78; (c) Tara, F.;
Hanna, I. P.; Walter, T. G.; Kurtis, C. B.; Stephen,
J. G.; Alexandra, M. Z. S.; Howard, D. B.; Christopher,
J. M. Bioorg Med Chem 2004, 12, 1667–1687; (d) Ko,
T.-C.; Hour, M.-J.; Lien, J.-C.; Teng, C.-M.; Lee, K.-H.;
Kuo, S.-C.; Huang, L.-J. Bioorg Med Chem Lett 2001,
11, 279–282.
[5] (a) Larsen, R. D.; Corley, E. G.; King, A. O.; Carrol,
J. D.; Davis, P.; Verhoeven, T. R.; Reider, P. J.; Labelle,
M.; Gauthier, J. Y.; Xiang, Y. B.; Zamboni, R. J. J
Org Chem 1996, 61, 3398–3405; (b) Zwaagstra, M.
E.; Timmerman, H.; Van De Stolpe, A. C.; De Kanter,
F. J.; Tamura, M.; Wada, Y.; Zhang, M. Q. J Med
Chem 1998, 41, 1428–1438; (c) Von Sprecher, A.;
Gerspacher, M.; Beck, A.; Kimmel, S.; Wiestner, H.;
Anderson, G. P.; Niederhauser, U.; Subramanian, N.;
Bray, M. A. Bioorg Med Chem Lett 1998, 8, 965–
970; (d) Doube`, D.; Blouin, M.; Brideau. C.; Chan, C.;
Desmarais, S.; Ethier, D.; Falgueyret, J. P.; Friesen,
R. W.; Girard, M.; Girard, Y.; Guay, J.; Tagari. P.;
Young, R. N. Bioorg Med Chem Lett 1998, 8, 1255–
1260.
[6] Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.;
Ghia, M. Eur J Med Chem 2000, 35, 1021–1035.
[7] (a) Morizawa, Y.; Okazoe, T.; Wang, S.-Z.; Sasaki,
J.; Ebisu, H.; Nishikawa, M.; Shinyama, H. J Flu
Chem 2001, 109, 83–86; (b) Ferrarini, P. L.; Mori, C.;
Badawneh, M.; Calderonem, V.; Greco, R.; Manera,
C.; Martinelli, A.; Nieri, P.; Saccomanni, G. Eur J Med
Chem 2000, 35, 815–826.
1622, 1479, 1435, 1264, 1077, 725. H NMR (500
MHz, CDCl3), δ (ppm): 3.33 (s, 2H, CH2), 3.95 (s,
2H, CH2), 4.03 (s, 6H, 2OCH3), 5.09 (s, 2H, CH2),
6.72 (d, J = 8.5 Hz, 1H, H-1), 6.90 (d, J = 8.5 Hz, 1H,
H-2) 7.44–7.47 (m, 5H, C6H5), 8.20 (s, 1H, H-10).
MS (m/z, %): 349 (11), 348 (M+, 49), 333 (53), 213
(23), 200 (13), 105 (79), 77 (100).
Anal. Calcd for C21H20N2O3(348.15), C, 72.40; H,
5.79; N, 8.04. Found: C, 72.19; H, 6.05; N, 7.96.
5,8-Dimethoxy-3,4-dihydro-1H-2-thia-10-aza-an-
thracene (5i). The compound was purified by flash
chromatographic column (ethyl acetate/petroleum
ether = 1:1, v/v) to give 5i as a yellow solid in yield
of 95%. It has Rf 0.35 (ethyl acetate/petroleum ether
= 1/1, v/v). mp 134–136◦C. IR (KBr), ν (cm−1): 3080,
2952, 1620, 1477, 1385, 1266, 1163, 1097, 973, 813.
1H NMR (500 MHz, CDCl3), δ (ppm): 3.08 (t, J = 6.0
Hz, 2H, CH2), 3.47 (t, J = 6.0 Hz, 2H, CH2), 3.95 (s,
2H, CH2), 3.95 (s, 3H, OCH3), 4.03 (s, 3H, OCH3),
6.72 (d, J = 8.5 Hz, 1H, H-1), 6.88 (d, J = 8.5 Hz,
1H, H-2), 8.26 (s, 1H, H-10). MS (m/z, %): 262 (11),
261 (M+, 55), 246 (100), 232 (26), 200 (31), 186 (6),
115 (17), 77 (7).
Anal. Calcd for C14H15NO2S (261.08), C, 64.34;
H, 5.79; N, 5.36. Found: C, 64.46; H, 6.12; N, 5.18.
6,9-Dimethoxy-3,4-dihydro-1H-pyrano[4,3-b]qui-
noline (5j). The compound was purified by flash
chromatographic column (ethyl acetate/petroleum
ether = 1:1, v/v) to give 5j as a yellow solid in a yield
of 95%. It has Rf 0.28 (ethyl acetate/petroleum ether
= 1:1, v/v. mp 160–161◦C. IR (KBr), ν (cm−1): 2962,
[8] (a) Hu, Y. Z.; Zhang, G.; Randolph, P. T. Org Lett
2003, 5, 2251–2253; (b) Ohashi, A.; Tsuguchi, A.;
Imura, H.; Ohashi, K. Anal Sci 2004, 20, 1091–1093;
(c) Wang, H.; Liu, Z.; Liu, C.; Zhang, D.; Lu, Z.; Geng,
H.; Shuai, Z.; Zhu, D. Inorg Chem 2004, 43, 4091–
4098.
[9] (a) Chiang, C.-L.; Shu, C.-F. Chem Mater 2002, 14,
682–686; (b) Nakatani, K.; Sando, S.; Saito, I. Bioorg
Med Chem 2001, 9, 2381–2385; (c) Nakatani, K.;
Sando, S.; Saito, I. J Am Chem Soc 2000, 122, 2172–
2177; (d) Nguyen, C. H.; Marchand, C.; Delane, S.;
Sun, J.-S.; Garestier, H.; Bisagni, E. J Am Chem Soc
1998, 120, 2501–2507.
1
1621, 1606, 1482, 1391, 1180, 1076, 812. H NMR
(500 MHz, CDCl3), δ (ppm): 3.30 (t, J = 6.0 Hz, 2H,
CH2), 3.94 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 4.15
(t, J = 6.0 Hz, 2H, CH2), 4.96 (s, 2H, CH2), 6.68 (d,
J = 8.5 Hz, 1H, H-1), 6.86 (d, J = 8.5 Hz, 1H, H-2),
8.16 (s, 1H, H-10). MS (m/z, %): 246 (4), 245 (M+,
28), 244 (14), 230 (100), 216(19), 200 (35), 186 (11),
115 (6), 77 (8).
Anal. Calcd for C14H15NO3 (245.11), C, 68.56; H,
6.16; N, 5.71. Found: C, 68.37; H, 6.36; N, 5.55.
[10] Sugimori, M.; Ejima. A.; Qhsuki. S.; Uoto. K.; Mitsui.
I.; Kawato, Y. J Med Chem 1998, 41, 2308–2318.
[11] Brian, R, M.; Benjamin, L, M. Org Lett 2003, 5, 4257–
4259.
[12] Sandeep, K.; Ellen, J. W.; Ehud, K. J Org Chem 1993,
58, 3821–3827.
[13] Randolph, P. T.; Sara, C.; Christophe, H.; Jean-Lue,
L.; Tie-Lin, W. J Org Chem 1993, 58, 1666–1671.
[14] Christiane, V.; Jean-Luc, V.; Georges, D. Tetrahedron
2001, 57, 3087–3098.
[15] Yang, D.-Q.; Zeng, H.-P.; Liu, C.-Y. J South China
Normal Uni 2000, 4, 44–46.
[16] Guo, W.; Jiang, Q.-J.; Lu¨, F.; Yang, D.-Q. Chin J Synth
Chem 2004, 12, 12–14.
REFERENCES
[1] Chauhan, P. M. S.; Srivastav, S. K. Curr Med Chem
2001, 8, 1535–1542.
[2] (a) Heath, J. A.; Mehrotra, M. M.; Chi, S.; Yu, J. C.;
Hutchaleelaha, A.; Hollenbach, S. J.; Giese, N. A.;
Scarborough, R. M.; Pandey, A. Bioorg Med Chem
Lett 2004, 14, 4867–4872; (b) Keyaerts, E.; Vijgen, L.;
Maes, P.; Neyts. J.; Ranst, M. V. Biochem Biophys
Res Commun 2004, 323, 264–268.
Heteroatom Chemistry DOI 10.1002/hc