An efficient synthesis of the new benzo[c]pyrido[2,3,4-kl]acridine skeleton

Article abstract of DOI:10.1021/jo011057m

A series of molecules of therapeutic interest, possessing the new skeleton of 1H-benzo[c]pyrido[2,3,4-kl]-acridine with acyl or aminoacyl and methoxy or aminoalkoxy substituents on the aromatic homocycles were synthesized by means of a Friedlaender-type r

Full text of DOI:10.1021/jo011057m

3502
J . Org. Chem. 2002, 67, 3502-3505
Sch em e 1
An Efficien t Syn th esis of th e New
Ben zo[c]p yr id o[2,3,4-kl]a cr id in e Sk eleton
Sarah Chackal, Raymond Houssin, and
J ean-Pierre He´nichart*
Institut de Chimie Pharmaceutique Albert Lespagnol,
Universite´ de Lille 2, EA 2692, rue du Professeur Laguesse,
BP 83, 59006 Lille, France
henicha@phare.univ-lille2.fr
Received November 6, 2001
Abstr a ct: A series of molecules of therapeutic interest,
possessing the new skeleton of 1H-benzo[c]pyrido[2,3,4-kl]-
acridine with acyl or aminoacyl and methoxy or aminoalkoxy
substituents on the aromatic homocycles were synthesized
by means of a Friedla¨nder-type reaction. The requisite
5-aminodihydroquinoline-4-ones 1, whose preparation is
described, were reacted with the appropriate R-tetralones 2
using an acidic catalyst (PPTS) under azeotropic conditions.
Optimized reaction time and yield depend on temperature,
which must not be below 90 °C.
condensed with an aldehyde or ketone containing at least
one methylene group R to the carbonyl. An extension of
this reaction was envisaged to elaborate the 1H-benzo-
[c]pyrido[2,3,4-kl]acridine skeleton, which was chosen
from the structural analysis of natural topoisomerase
inhibitors such as DHDMC12 (or 5,6-dihydro-8-desmeth-
ylcoralyne), an isoquino[3,2-a]isoquinoline, and shermi-
lamin,13 a pyrido[4,3,2-de]quinoline. In this case, the
prerequisite aminoketone is a 5-amino-7,8-dimethoxy-2,3-
dihydro-1H-quinolin-4-one 1 that can be opposed to an
R-tetralone 2 (Scheme 1).
This paper describes the synthesis of the 5-amino-
2,3-dihydro-1H-quinolin-4-ones 1a and 1b and their
subsequent use in the Friedla¨nder-type synthesis of
the 2,3,12,13-tetrahydro-1H-benzo[c]pyrido[2,3,4-kl]acri-
dines 3 and 4.
The synthesis of 1a (Scheme 2) began with the conver-
sion of 2,3-dimethoxybenzoic acid into 2,3-dimethoxy-
aniline 6 (95% yield) via urethane 5, prepared as de-
scribed by White14 using Yamada’s modification15 of the
Curtius rearrangement16 and hydrolyzed under basic
conditions. The anilinopropionic acid 7 was obtained by
a regioselective nucleophilic attack on carbon 3 of â-pro-
piolactone17,18 in acetonitrile. Cyclization into dihydro-
quinolinone 8 was completed with PPA before acetylation
of the amino group to suppress the susceptibility of the
amine to oxidative conditions during nitration (10a ) and
to allow for the spontaneous cyclodehydration of the
DNA topoisomerases I and II are nuclear enzymes able
to break and religate the sugar-phosphate bonds of DNA
and adjust the topological states of the DNA helix during
cellular processes. Mammalian topoisomerase poisons
and topoisomerase inhibitors have been recognized as
effective cancer chemotherapeutics. They have recently
received considerable attention,1-7 particularly with re-
gard to the biological activity of camptothecin, a specific
inhibitor of topoisomerase I. This natural compound and
other topoisomerase-interacting drugs exhibit common
structural elements that have been considered as es-
sential for their activity, particularly quinoline-based
heterocyclic systems. Herein, we report the synthesis of
the new fused pentacyclic skeleton named 2,3,12,13-
tetrahydro-1H-benzo[c]pyrido[2,3,4-kl]acridine, contain-
ing quinoline, as a potential topoisomerase ligand.
One of the most generally used methods for preparing
substituted quinolines is the Friedla¨nder synthesis,8-11
in which an aromatic o-aminoaldehyde or ketone is
* To whom correspondence should be addressed. Tel: + 33-3-2096-
4374. Fax: + 33-3-2096-4361.
(1) Tewey, P. M.; Chen, G. L.; Nelson, E. M.; Liu, L. F. J . Biol. Chem.
1984, 259, 9182.
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R. Nucleic Acids Res. 1987, 15, 6713.
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J ardillier, J .-C.; Riou, J .-F. Biochem. Pharmacol. 1993, 46, 1403.
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Bull. 1991, 39, 1446.
(12) Makhey, D.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J . Bioorg.
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(13) Ding, Q.; Chichak, K.; Lown, J . W. Current Med. Chem. 1999,
6, 1.
(14) White, J . D.; Yager, K. M.; Yakura, T. J . Am. Chem. Soc. 1994,
116, 1831.
(7) Kingsbury, W. D.; Boehm, J . C.; J akas, D. R.; Holden, K. G.;
Hecht, S. M.; Gallagher, G.; Caranfa, M. J .; McCabe, F. L.; Faucette,
L. F.; J ohnson, R. K.; Hertsberg, R. P. J . Med. Chem. 1991, 34, 98.
(8) Friedla¨nder, P. Ber. Deutsch. Chem. Ges. 1882, 15, 272.
(9) Eldelfield, R. C. In The Chemistry of Heterocyclic Compounds;
Eldelfield, R. c., Ed.; Wiley: New York, 1952; Vol. 4, p 45.
(10) J ones, G. In The Chemistry of Heterocyclic Compounds, Quino-
lines; J ones, G., Ed.; Wiley: New York, 1977; Part 1, p 181.
(11) Cheng, C.-C.; Yan, S.-J . Org. React. 1982, 28, 37.
(15) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203.
(16) Smith, P. A. S. Org. React. 1946, 3, 337.
(17) Sugimori, M.; Ejima, A.; Ohsuki, S.; Uoto, K.; Mitsui, I.;
Matsumoto, K.; Kawato, Y.; Yasuoko, M.; Sato, K.; Tagawa, H.;
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10.1021/jo011057m CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/23/2002

Notes
J . Org. Chem., Vol. 67, No. 10, 2002 3503
Ta ble 1. P r ep a r a tion of 3a -e a n d 4a -c,e u n d er Acid ic
Sch em e 2
Ca ta lysis
time
(h)
yield
(%)
mp (°C)
(solvent)
1
a
2
a
3 or 4 conda
3a
3b
3c
3d
3e
4a
4b
4c
4e
A
C
A
C
A
C
A
C
B
C
C
24
4
58
67
62
81
65
79
54
85
60
48
75
204 (water)
a
a
a
a
b
b
b
b
b
c
d
e
a
b
c
e
24
5.5
24
3.5
24
5
120
2
12
210 (ethanol)
210 (ethanol)
246 (ethanol)
214 (ethanol-ether)
230-232
(methanol-ether)
C
C
C
12
12
24
72
75
78
227
(methanol-ether)
222-225
(methanol-ether)
>250 (ethanol-ether)
a
Method A: azeotropic distillation; solvent, toluene; catalyst,
PPTS. Method B: azeotropic distillation; solvent, toluene/ethanol
(2:1); catalyst, PPTS. Method C: azeotropic distillation; solvent,
butan-1-ol; catalyst, PPTS.
Chemical shifts are reported in ppm downfield from TMS.
Splitting patterns are designated as follows: s, singlet; d,
doublet; t, triplet; p, pentet; m, multiplet; b, broad. Coupling
constants are given in hertz. Elemental analyses were performed
by the Service Central d’Analyse-De´partement Analyse Ele´men-
taire, CNRS, F-69390 Vernaison. Dimethylformamide was dis-
tilled from CaH2 and stored over 3 Å molecular sieves. Tetrahy-
drofuran was distilled over sodium benzophenone before use.
Ma ter ia ls. The preparation of N-(ethoxycarbonyl)-3,4-dimeth-
oxyaniline14 5 and 2,3-dimethoxyaniline14 6 have been described
previously.
condensation product during the Friedla¨nder reaction.17
The regioselectivity of nitration was ascertained by 2D
ROESY NMR. Reduction to the corresponding amine 1a
was carried out with iron powder.19,20 Aminoquinolinone
1b was obtained using the same strategy (Scheme 2):
amidification of 8 followed by nucleophilic substitution
with 4-methylpiperazine provided dihydroquinolinone
10b, whose nitration and subsequent reduction yielded
dihydroquinolinone 1b.
3-(2,3-Dim eth oxyp h en yla m in o)p r op ion ic Acid (7). A so-
lution of 6 (5.4 g, 35.3 mmol) in acetonitrile (10 mL) was heated
to reflux, and â-propiolactone (2.21 mL, 35.3 mmol) was then
added. The mixture was refluxed for 24 h. After concentration
of the solution, the residue was dissolved in 10% aqueous
potassium carbonate. The resulting brown solution was washed
with ether. The aqueous fraction was acidified up to pH 4 (6 N
HCl) and extracted several times with ethyl acetate. The organic
layers were washed with saturated aqueous sodium chloride and
dried over magnesium sulfate. After removal of the solvent, the
crude product was recrystallized from cyclohexane to yield 3.78
g (70%) of 7 as a beige solid: mp 88 °C; IR (KBr) 3406, 1713,
The cyclization reaction between 1a ,b and substituted
tetralones 2a -e was carried out in acid-catalyzed me-
dium, excluding extreme conditions (absence of solvent,
temperature ranging from 150 to 220 °C) and classical
basic catalysis (KOH; NaOEt; Triton B; piperidine),
which appeared unsuccessful here. However, using acetic
acid as solvent and catalyst in the reaction of the
enolizable ketone 2a with 1a led to acetylation of the
5-NH2 of this latter compound (amide 12) rather than to
the Schiff base intermediate. The preparation of penta-
cyclic compounds 3a -d was conveniently carried out
using toluene as solvent and pyridinium p-toluene-
sulfonate (PPTS) with azeotropic distillation of water
(method A). In the case of 3e, a toluene/ethanol (2:1)
mixture was used (method B) due to the insolubility of
ketone 2e in toluene; under these conditions, reaction
took place in 5 days instead of 24 h due to the lower
temperature of the ternary azeotrope (68 °C vs 84 °C).
The reaction for 4a -c,e (method C) was completed in 4
h by using butan-1-ol (azeotropic temperature: 93 °C).
These conditions were used to prepare compounds
3a -e and proved that this method gave a significantly
higher yield at a temperature about 90 °C and a lower
reaction time than classically found (Table 1).
1608, 1514, 1477, 1452 cm-1 1H NMR (CDCl3) δ 2.68 (t, J )
;
6.5, 2H), 3.49 (t, J ) 6.4, 2H), 3.79 (s, 3H), 3.83 (s, 3H), 6.35 (d,
J ) 8.3, 2H), 6.55 (bs, 2H), 6.94 (t, J ) 8.3, 1H). Anal. Calcd for
C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C, 58.62; H, 6.66;
N, 6.34.
7,8-Dim eth oxy-2,3-d ih yd r o-1H-qu in olin -4-on e (8). Com-
pound 7 (5 g, 22.2 mmol) was added portionwise to stirred PPA
(100 g) at 90 °C. After being stirred for 20 min, the dark brown
mixture was poured into ice. The resulting red solution was
extracted several times with ethyl acetate. The organic layers
were washed with 10% aqueous potassium carbonate and
saturated aqueous sodium chloride and then dried over mag-
nesium sulfate. The concentrate was purified by chromatography
(silica gel, 50% ethyl acetate-heptane) and recrystallized from
cyclohexane to give 4 g (80%) of 8 as beige crystals: mp 92 °C;
IR (KBr) 3376, 1667, 1608, 1519, 1484, 1459 cm-1 1H NMR
;
(CDCl3) δ 2.67 (t, J ) 6.9, 2H), 3.57 (t, J ) 6.9, 2H), 3.83 (s,
3H), 3.90 (s, 3H), 4.93 (bs, 1H), 6.39 (d, J ) 8.8, 1H), 7.64 (d,
J ) 9.0, 1H). Anal. Calcd for C11H13NO3 (0.25 H2O): C, 62.40;
H, 6.43; N, 6.62. Found: C, 62.41; H, 6.32; N, 6.65.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined with a
1-Acet yl-7,8-d im et h oxy-2,3-d ih yd r o-1H -q u in olin -4-on e
(9a ). Acetyl chloride (3.6 mL, 49.7 mmol) was added dropwise
to a solution of 8 (3.43 g, 16.5 mmol) in toluene (10 mL) and
pyridine (4.33 mL, 53.8 mmol). After being stirred overnight at
room temperature, the mixture was partitioned between ethyl
acetate and water. The organic layer was washed with 1 N HCl,
water, and saturated aqueous sodium chloride and was dried
1
capillary melting point apparatus and are uncorrected. H and
13C NMR spectra were recorded at 300 and 75 MHz respectively.
(19) Thummel, R. P.; Chirayil, S.; Hery, C.; Lim, J . L.; Wang, T. L.
J . Org. Chem. 1993, 58, 1666.
(20) Guay, V.; Brassard, P. J . Heterocycl. Chem. 1987, 24, 1649.

3504 J . Org. Chem., Vol. 67, No. 10, 2002
Notes
over magnesium sulfate. After removal of the solvent, the crude
product was recrystallized from cyclohexane to yield 2.4 g (70%)
of 9a as a pale yellow solid: mp 107 °C; IR (KBr) 1687, 1663
cm-1; 1H NMR (CDCl3) δ 2.14 (s, 3H), 2.83 (m, 2H), 3.41 (t, J )
11.1, 1H), 3.75 (s, 3H), 3.97 (s, 3H), 5.06 (d, J ) 11.1, 1H), 6.90
gave the crude product, which was recrystallized from 2-pro-
panol-ether (1a ) or toluene (1b).
1-Acetyl-5-a m in o-7,8-d im eth oxy-2,3-d ih yd r o-1H-qu in o-
lin -4-on e (1a ): yield 82%; yellowish solid; mp 173 °C; IR (KBr)
1
3415, 3303, 1651, 1629, 1610, 1549, 1494, 1471, 1455 cm-1; H
(d, J ) 8.8, 1H), 7.77 (d, J ) 8.8, 1H). Anal. Calcd for C13H15
-
NMR (CDCl3) δ 2.11 (s, 3H), 2.51 (dd, J ) 18.1; 2.1, 1H), 2.81
(m, 1H), 3.26 (td, J ) 13.1, 3.6, 1H), 3.62 (s, 3H), 3.88 (s, 3H),
4.99 (dd, J ) 12.2, 5.0, 1H), 6.00 (s, 1H), 6.57 (bs, 2H). Anal.
Calcd for C13H16N2O4 (0.5 H2O): C, 57.13; H, 6.27; N, 10.25.
Found: C, 57.16; H, 6.32; N, 10.11.
NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.71; H, 6.05; N,
5.51.
1-(2-Ch lor oa cetyl)-7,8-d im eth oxy-2,3-d ih yd r o-1H-qu in o-
lin -4-on e (9b). Chloroacetyl chloride (14.8 mL, 185 mmol) was
added dropwise to a suspension of 8 (6.04 g, 29 mmol) and
cesium carbonate (16.63 g, 51 mmol) in toluene (60 mL). After
being stirred overnight at room temperature, the mixture was
diluted with ethyl acetate and washed with water, 1 N HCl, and
saturated aqueous sodium chloride. The organic layer was dried
over magnesium sulfate. Removal of the solvent gave an oily
product, which precipitated in diisopropyl ether. After washing
of the crude product with diisopropyl ether, recrystallization
from toluene yielded 5 g (60%) of 9b as a white solid: mp 166-
5-Am in o-7,8-d im et h oxy-1-[2-(4-m et h ylp ip er a zin -1-yl)-
a cetyl]-2,3-d ih yd r o-1H-qu in olin -4-on e (1b): yield 87%; beige
solid; mp 198 °C; IR (KBr) 3385, 3383, 1671, 1623, 1547, 1494,
1455 cm-1 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.30-2.75 (m,
;
10H), 3.15 (d, J ) 15.6, 1H), 3.30 (bs, 1H), 3.39 (d, J ) 15.6,
1H), 3.57 (s, 3H), 3.84 (s, 3H), 4.92 (m, 1H), 5.97 (s, 1H), 6.58
(bs, 2H). Anal. Calcd for C18H26N4O4 (0.5 H2O): C, 58.21; H, 7.33;
N, 15.08. Found: C, 58.33; H, 7.28; N, 15.01.
1-Acet yl-5-a cet yla m in o-7,8-d im et h oxy-2,3-d ih yd r o-1H -
qu in olin -4-on e (12). R-Tetralone 2e (0.33 g, 2.2 mmol) diluted
in acetic acid (5 mL) was added to a refluxing solution of 1a
(0.5 g, 1.9 mmol) in glacial acetic acid (5 mL). The mixture was
stirred at reflux for 5 h. Removal of the solvent gave the crude
product, which was subjected to chromatography (silica gel, 20%
acetone-30% toluene-cyclohexane). The concentrate was re-
crystallized from ethanol to yield 230 mg (40%) of 12 as a beige
solid: mp 180 °C; IR (KBr) 1699, 1673, 1650, 1608, 1580, 1508,
168 °C; IR (KBr) 1686, 1661, 1590, 1496, 1460, 1440 cm-1 1H
;
NMR (CDCl3) δ 2.76 (m, 2H), 3.49 (m, 1H), 3.75 (s, 3H), 3.98 (s,
3H), 4.22 (s, 1H), 4.24 (s, 1H), 5.04 (m, 1H), 6.92 (d, J ) 8.9,
1H), 7.81 (d, J ) 8.6, 1H). Anal. Calcd for C13H14ClNO4: C, 55.04;
H, 4.97; N, 4.94. Found: C, 55.04; H, 5.00; N, 4.85.
1-[2-(4-Meth ylp ip er a zin -1-yl)a cetyl]-7,8-d im eth oxy-2,3-
d ih yd r o-1H-qu in olin -4-on e (10b). 4-Methylpiperazine (8.5
mL, 76 mmol) was added to a solution of 9b (9.80 g, 34.5 mmol)
in dry DMF (50 mL), and the mixture was stirred overnight at
80 °C. The mixture was diluted with 1 N HCl and extracted
several times with ethyl acetate. The aqueous layer was made
basic using potassium carbonate and extracted several times
with ethyl acetate. The organic layers were washed with
saturated aqueous sodium chloride and dried over magnesium
sulfate. Concentration yielded an oily product that precipitated
in a mixture of ether-petroleum ether. Recrystallization from
cyclohexane-diisopropyl ether gave 9.60 g (80%) of 10b as white
crystals: mp 156-157 °C; IR (KBr) 1668, 1667, 1592, 1496, 1455
cm-1; 1H NMR (CDCl3) δ 2.18 (s, 3H), 2.18-2.70 (m, 10H), 3.31
(s, 1H), 3.33 (s, 1H), 3.50 (m, 1H), 3.73 (s, 3H), 3.94 (s, 3H), 4.92
(m, 1H), 6.87 (d, J ) 9.0, 1H), 7.76 (d, J ) 8.0, 1H). Anal. Calcd
for C18H25N3O4 (0.5 H2O): C, 60.66; H, 7.35; N, 11.79. Found:
C, 60.87; H, 7.36; N, 11.76.
Gen er a l P r oced u r e for Nitr a tion . Compound 9a or 10b
(n mmol) was gradually added to a well-cooled (-30 °C) mixture
of nitric acid (d ) 1.41) (30.n mmol) and sulfuric acid (16.n
mmol). After being warmed to -10 °C, the solution was poured
into ice and diluted with ethyl acetate. The layers were
separated, and the yellow organic layer was washed with 10%
aqueous potassium carbonate, water, and saturated aqueous
sodium chloride and dried over magnesium sulfate before
removal of the solvent.
1
1466, 1449 cm-1; H NMR (CDCl3) δ 2.11 (s, 3H), 2.24 (s, 3H),
2.62 (m, 1H), 2.81-2.94 (m, 1H), 3.30-3.37 (m, 1H), 3.69 (s, 3H),
3.98 (s, 3H), 4.98-5.05 (m, 1H), 8.40 (s, 1H), 12.05 (s, 1H); MS
(EI) m/e 306 (M+, 42), 275 (18), 249 (35), 207 (100). Anal. Calcd
for C15H18N2O5: C, 58.82; H, 5.92; N, 9.15. Found: C, 58.97; H,
5.60; N, 9.06.
6-[3-(4-Met h ylp ip er a zin -1-yl)p r op oxy]-3,4-d ih yd r o-2H -
n a p h th a len -1-on e (2e). Potassium carbonate (3.4 g, 24 mmol)
was added to a solution of 6-hydroxytetralone (1 g, 6.1 mmol) in
dry DMF (10 mL), and the mixture was stirred for 30 min at
room temperature. Then 1-(3-chloropropyl)-4-methylpiperazine
dihydrochloride (1.23 g, 4.9 mmol) was added. The mixture was
stirred overnight at 80 °C, diluted with water, and extracted
several times with ethyl acetate. The organic layers were washed
with saturated aqueous sodium chloride and dried over mag-
nesium sulfate. Concentration followed by chromatography
(silica gel, 15% methanol-5% ammoniacal dichloromethane)
gave 0.75 g (75%) of 2e as a brown oil: IR (KBr) 1675, 1599,
1569, 1493, 1459 cm-1; 1H NMR (CDCl3) δ 1.90 (p, J ) 6.4, 2H),
2.01 (p, J ) 6.4, 2H), 2.21 (s, 3H), 2.41-2.53 (m, 12H), 2.82 (t,
J ) 6.0, 2H), 3.98 (t, J ) 6.4, 2H), 6.61 (d, J ) 2.6, 1H), 6.72
(dd, J ) 8.7, 2.6, 1H), 7.90 (d, J ) 8.6, 1H). Anal. Calcd for
C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.49; H, 8.66;
N, 9.28.
Syn th esis of Qu in olin es 3a -d . Meth od A. A solution of
1a (0.5 g, 1.89 mmol), PPTS (0.47 g, 1.89 mmol), and the
appropriate tetralone 2a -d (2.84 mmol) in toluene (10 mL) was
heated under reflux using a Dean-Stark trap. The precipitate
obtained after cooling was collected by filtration and washed
successively with toluene and ether.
Syn th esis of Qu in olin es 3a -d . Meth od C. A solution of
1a (0.5 g, 1.89 mmol), PPTS (0.70 g, 2.84 mmol), and the
appropriate tetralone 2a -d (5.67 mmol) in butan-1-ol (10 mL)
was heated under reflux using a Dean-Stark trap. After cooling,
the solvent was evaporated and the residue was triturated with
ether. After the precipitate was washed with ether, the crude
product was subjected to chromatography (silica gel, 2% metha-
nol-dichloromethane-TFA (5 drops)). Solids were additionally
recrystallized.
1-Acetyl-7,8-d im eth oxy-5-n itr o-2,3-d ih yd r o-1H-qu in olin -
4-on e (10a ): yield 76%; yellow solid mp 203 °C (ethanol); IR
1
(KBr) 1694, 1671, 1589, 1542, 1500, 1461, 1348 cm-1; H NMR
(CDCl3) δ 2.15 (s, 3H), 2.81 (m, 2H), 3.55 (bs, 1H), 3.84 (s, 3H),
4.00 (s, 3H), 4.96 (bs, 1H), 6.98 (s, 1H). Anal. Calcd for
C13H14N2O6: C, 53.06; H, 4.80; N, 9.52. Found: C, 53.12; H, 4.75;
N, 9.59.
7,8-Dim eth oxy-1-[2-(4-m eth ylp ip er a zin -1-yl)a cetyl]-5-n i-
tr o-2,3-d ih yd r o-1H-qu in olin -4-on e (11b). The crude oily prod-
uct was precipitated in diisopropyl ether: yield 77%; yellow solid;
mp 147-149 °C (toluene-diisopropyl ether); IR (KBr) 1693,
1
1668, 1592, 1537, 1498, 1375 cm-1; H NMR (CDCl3) δ 2.24 (s,
3H), 2.20-2.60 (m, 8H), 2.77 (t, J ) 6.3, 2H), 3.25-3.41 (m, 2H),
3.69 (bs, 1H), 3.82 (s, 3H), 3.98 (s, 3H), 4.81 (bs, 1H), 6.96 (s,
1H). Anal. Calcd for C18H24N4O6: C, 55.09; H, 6.16; N, 14.28.
Found: C, 54.98; H, 5.91; N, 14.03.
3-Acetyl-4,5-d im eth oxy-2,3,12,13-tetr a h yd r o-1H-ben zo-
[c]p yr id o[2,3,4-kl]a cr id in e (3a ): yellow solid; IR (KBr) 1673,
1641, 1594, 1487 cm-1; 1H NMR (CDCl3) δ 2.14 (s, 3H), 2.99 (s,
4H), 3.12 (m, 3H), 3.87 (s, 3H), 4.10 (s, 3H), 5.23 (bs, 1H), 7.28
(d, J ) 6.7, 1H); 7.42 (p, J ) 7.3, 1.3, 2H), 7.58 (s, 1H), 8.52 (dd,
J ) 7.0, 2.0, 1H); 13C NMR (CDCl3) δ 171.43, 156.61, 149.98,
142.93, 142.07, 140.13, 131.32, 130.54, 128.01, 127.96, 127.78,
126.99, 126.24, 116.55, 103.01, 61.05, 56.60, 41.94, 27.48, 23.54,
22.02; MS (EI) m/e 374 (M+, 62), 331 (27), 316 (100). Anal. Calcd
for C23H22N2O3 (0.5 TFA, 0.5 H2O): C, 65.47; H, 5.38; N, 6.36.
Found: C, 65.55; H, 5.11; N, 6.60.
Gen er a l P r oced u r e for Red u ction . A mixture of 10a or
11b (n mmol), iron powder (8.n mmol) and 37% HCl (0.15.n
mmol) in a mixture of acetic acid/ethanol/water (2:2:1) (20 mL)
was refluxed for 15 min. The warmed solution was filtered
through Celite and washed with water. The filtrate was ex-
tracted with chloroform, and the layers were separated. The dark
green organic layer was washed with saturated aqueous sodium
bicarbonate and saturated aqueous sodium chloride and dried
over magnesium sulfate. Filtration and removal of the solvent

Notes
3-Acetyl-4,5,10-tr im eth oxy-2,3,12,13-tetr a h yd r o-1H-ben -
J . Org. Chem., Vol. 67, No. 10, 2002 3505
160.05, 157.50, 155.04, 150.52, 142.08, 140.98, 139.97, 127.55,
126.04, 125.05, 115.65, 114.90, 113.63, 113.46, 104.90, 65.24,
60.43, 56.14, 53.19, 53.05, 50.62, 49.15, 48.77, 48.15, 42.20, 39.28,
26.81, 26.00, 24.51, 23.21, 21.97; MS (EI) m/e 530 (M+, 56), 460
(57), 391 (100). Anal. Calcd for C31H38N4O4‚2HCl (0.5 H2O,
TFA): C, 54.54; H, 5.83; N, 7.71; Cl, 9.76. Found: C, 54.76; H,
5.55; N, 7.43; Cl, 9.46.
Syn th esis of Qu in olin es 4a -c,e. Meth od C. A solution of
1b (0.5 g, 1.38 mmol), PPTS (0.52 g, 2.07 mmol), and the
appropriate tetralone 2a -c,e (4.14 mmol) in butan-1-ol (10 mL)
was heated under reflux using a Dean-Stark trap. The mixture
was cooled to room temperature, made basic using 10% aqueous
potassium carbonate, and diluted with ethyl acetate, and the
layers were separated. The dark red organic layer was washed
with saturated aqueous sodium chloride and dried over mag-
nesium sulfate. Removal of the solvent gave an oily product that
precipitated in ether. After filtration and washing with ether,
the crude product was subjected to chromatography (silica gel,
5% methanol-dichloromethane (4a -c), 30% methanol-dichlo-
romethane to 50% methanol-1% ammoniacal dichloromethane
(4e)). Evaporation of the appropriate fraction gave quinolines
as bases. Dichloromethane saturated with HCl was added to a
solution of these bases in dichloromethane to yield quinolines 4
as hydrochlorides.
zo[c]p yr id o[2,3,4-kl]a cr id in e (3b): bright yellow solid; IR
1
(KBr) 1681, 1641, 1599, 1576, 1508, 1487, 1456 cm-1; H NMR
(CDCl3) δ 2.17 (s, 3H), 2.99 (s, 4H), 3.18 (m, 3H), 3.88 (s, 3H),
3.90 (s, 3H), 4.12 (s, 3H), 5.22 (bs, 1H), 6.84 (d, J ) 2.3, 1H),
7.03 (dd, J ) 9.1, 2.6, 1H), 8.16 (s, 1H), 8.7 (d, J ) 12.1, 1H);
13C NMR (CDCl3) δ 171.37, 163.61, 158.28, 153.5, 148.22, 146.85,
142.53, 136.45, 130.41, 128.35, 125.96, 119.68, 116.06, 114.29,
113.53, 99.97, 61.21, 57.10, 55.63, 41.90, 28.02, 27.67, 23.37,
22.07; MS (EI) m/e 404 (M+, 51), 361 (17), 346 (100). Anal. Calcd
for C24H24N2O4 (TFA): C, 60.23; H, 4.86; N, 5.40. Found: C,
60.25; H, 4.85; N, 5.49.
3-Acetyl-4,5,9-tr im eth oxy-2,3,12,13-tetr a h yd r o-1H-ben -
zo[c]p yr id o[2,3,4-kl]a cr id in e (3c): beige solid; IR (KBr) 1661,
1
1617, 1587, 1504, 1482, 1429 cm-1; H NMR (CDCl3) δ 2.14 (s,
3H), 2.94 (s, 4H), 3.14 (m, 3H), 3.86 (s, 3H), 3.96 (s, 3H), 4.10 (s,
3H), 5.24 (bs, 1H), 6.94 (dd, J ) 8.5, 2.8, 1H), 7.20 (d, J ) 8.2,
1H), 7.42 (s, 1H), 8.10 (d, J ) 2.8, 1H); 13C NMR (CDCl3) δ
171.85, 159.03, 154.63, 152.31, 144.10, 141.21, 138.00, 135.65,
131.25, 128.82, 127.93, 125.90, 116.72, 116.36, 109.73, 106.57,
61.04, 56.14, 55.56, 42.23, 27.07, 27.02, 24.19, 22.18; MS (EI)
m/e 404 (M+, 56), 361 (26), 346 (100). Anal. Calcd for C24H24N2-
O4: C, 71.27; H, 5.98; N, 6.92. Found: C, 71.05; H, 5.96; N, 6.98.
3-Acetyl-4,5,9,10,-tetr a m eth oxy-2,3,12,13-tetr a h yd r o-1H-
ben zo[c]p yr id o[2,3,4-kl]a cr id in e (3d ): pale yellow solid; IR
(KBr) 1662, 1618, 1583, 1511, 1487, 1462 cm-1; 1H NMR (CDCl3)
δ 2.14 (s, 3H), 2.96-3.17 (m, 7H), 3.85 (s, 3H), 3.96 (s, 3H), 4.07
3-[2-(4-Meth ylp ip er a zin -1-yl)a cetyl]-4,5-d im eth oxy-2,3,-
12,13-tetr a h yd r o-1H-ben zo[c]p yr id o[2,3,4-kl]a cr id in e h y-
d r och lor id e (4a ): yellow solid; IR (KBr) 1687, 1634, 1595,
(s, 6H), 5.23 (bs, 1H), 6.77 (s, 1H), 7.40 (s, 1H), 8.07 (s, 1H); 13
C
1519, 1484, 1415 cm-1 1H NMR (DMSO-d6, 60 °C) δ 2.82 (s,
;
NMR (CDCl3) δ 171.87, 154.57, 152.38, 150.41, 148.36, 144.12,
140.88, 137.70, 132.17, 128.01, 127.35, 125.10, 115.91, 110.44,
108.58, 106.42, 61.05, 56.14, 56.11, 55.98, 42.26, 27.48, 27.04,
24.18, 22.20; MS (EI) m/e 434 (M+, 82), 391 (13), 376 (100). Anal.
Calcd for C25H26N2O5 (0.5 H2O): C, 67.70; H, 6.14; N, 6.32.
Found: C, 67.87; H, 5.97; N, 6.42.
Syn th esis of Qu in olin e 3e. Meth od B. A solution of 1a (2
g, 7.57 mmol), PPTS (0.95 g, 3.79 mmol), and tetralone 2e (1.14
g, 3.79 mmol) in 15 mL of a mixture of toluene/ethanol (2:1) was
heated under reflux using a Dean-Stark trap. The precipitate
formed after cooling to room temperature was collected by
filtration and washed successively with toluene and ether. The
crude product was subjected first to chromatography (silica gel,
10% methanol-dichloromethane) and then to preparative HPLC
(C18, 4.6 × 150 mm, 5 µm, 100 Å MeOH 34%-H2O 66%-TFA
0.1%). Evaporation of the appropriate fraction (tR ) 14.87 min)
afforded 3e as a beige solid. Saturated methanol with HCl was
added to a solution of this solid in methanol to yield 3e as the
hydrochloride.
Syn th esis of Qu in olin e 3e. Meth od C. A solution of 1a (0.7
g, 2.65 mmol), PPTS (0.33 g, 1.3 mmol) and tetralone 2e (0.4 g,
1.3 mmol) in butan-1-ol (10 mL) was heated under reflux using
a Dean-Stark trap. After being cooled to room temperature, the
mixture was diluted with 1 N HCl and extracted several times
with ethyl acetate. The aqueous layer was made basic using
potassium carbonate and extracted several times with ethyl
acetate. The organic layers were washed with saturated aqueous
sodium chloride and dried over magnesium sulfate. Removal of
the solvent gave the crude product, which was subjected to
chromatography (silica gel, 10% methanol-dichloromethane).
3-Acet yl-4,5-d im et h oxy-10-[3-(4-m et h ylp ip er a zin -1-yl)-
p r op oxy]-2,3,12,13-tetr a h yd r o-1H-ben zo[c]p yr id o[2,3,4-kl]-
a cr id in e h yd r och lor id e (3e): IR (KBr) 1673, 1651, 1610, 1585,
1484, 1462 cm-1; 1H NMR (DMSO-d6) δ 2.02 (s, 3H), 2.80-3.07
(m, 17H), 3.37-3.42 (m, 5H), 3.77 (s, 3H), 4.00 (s, 3H), 4.12 (t,
J ) 5.6, 2H), 4.73 (bs, 1H), 6.94 (s, 1H), 6.98 (d, J ) 8.9, 1H),
7.37 (s, 1H), 8.33 (d, J ) 8.6, 1H); 13C NMR (DMSO-d6) δ 170.07,
3H), 3.07 (s, 4H), 3.34-3.51 (m, 11H), 3.92 (s, 3H), 4.11 (s, 3H),
4.22 (m, 3H), 7.52 (m, 3H), 8.03 (s, 1H), 8.70 (d, J ) 6.7, 1H);
MS (CI) m/e 473 (M + 1), 501 (M + 29). Anal. Calcd for
C
28H32N4O3‚3HCl (2 H2O): C, 54.41; H, 6.36; N, 9.06; Cl, 17.21.
Found: C, 54.74; H, 6.20; N, 9.09; Cl, 17.21.
3-[2-(4-Meth ylp ip er a zin -1-yl)a cetyl]-4,5,10-tr im eth oxy-
2,3,12,13-t et r a h yd r o-1H -b en zo[c]p yr id o[2,3,4-k l]a cr id in e
h yd r och lor id e (4b): yellow solid; IR (KBr) 1687, 1635, 1611,
1574, 1512, 1486, 1456 cm-1; 1H NMR (DMSO-d6, 60 °C) δ 2.80
(s, 3H), 3.06 (s, 4H), 3.20-3.55 (m, 11H), 3.91 (s, 3H), 3.95 (s,
3H), 4.11 (s, 3H), 4.22 (m, 3H), 7.11 (m, 2H), 8.15 (s, 1H), 8.73
(s, 1H); MS (CI) m/e 503 (M + 1), 531 (M + 29). Anal. Calcd for
C29H34N4O4‚3HCl (2.5 H2O): C, 53.01; H, 6.44; N, 8.52; Cl, 16.18.
Found: C, 53.74; H, 6.21; N, 8.64; Cl, 16.39.
3-[2-(4-Met h ylp ip er a zin -1-yl)a cet yl]-4,5,9-t r im et h oxy-
2,3,12,13-t et r a h yd r o-1H -b en zo[c]p yr id o[2,3,4-k l]a cr id in e
h yd r och lor id e (4c): yellow solid; IR (KBr) 1682, 1634, 1591,
1573, 1523, 1487, 1462 cm-1; 1H NMR (DMSO-d6, 60 °C) δ 2.83
(s, 3H), 3.01-3.06 (m, 4H), 3.35-3.60 (m, 10H), 3.93 (s, 3H),
4.00 (s, 3H), 4.12 (s, 3H), 4.30 (m, 3H), 7.17 (d, J ) 8.2, 1H),
7.41 (d, J ) 8.2, 1H), 8.29 (s, 1H), 8.36 (s, 1H); MS (CI) m/e 503
(M + 1), 531 (M + 29). Anal. Calcd for C29H34N4O4‚2.5HCl (4.5
H2O): C, 51.61; H, 6.79; N, 8.30; Cl, 13.13. Found: C, 51.40; H,
6.01; N, 8.35; Cl, 12.85.
3-[2-(4-Met h ylp ip er a zin -1-yl)a cet yl]-4,5-d im et h oxy-10-
[3-(4-m eth ylp ip er a zin -1-yl)p r op oxy]-2,3,12,13-tetr a h yd r o-
1H-ben zo[c]p yr id o[2,3,4-kl]a cr id in e h yd r och lor id e (4e):
yellow solid; IR (KBr) 1687, 1635, 1612, 1575, 1512, 1488, 1456
cm-1; MS (CI) m/e 629 (M + 1), 657 (M + 29). Anal. Calcd for
C
36H48N6O4‚5HCl (3.5 H2O): C, 49.46; H, 6.91; N, 9.61; Cl, 20.27.
Found: C, 49.47; H, 6.69; N, 9.67; Cl, 20.33.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
7, 8, 9a ,b, 10a ,b, 11b, 1a ,b, and 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O011057M