The synthesis of pyrido(2,3,4-,kl)acridine unit of some marine alkaloids

Article abstract of DOI:10.1139/v00-119

A simple and convenient synthesis of pyrido(2,3,4-kl)acridine (1), the main skeleton of some marine alkaloids, via cyclization and intramolecular nitrene insertion, is described. The importance of the planarity of the molecule during the nitrene insertion

Full text of DOI:10.1139/v00-119

1158
The synthesis of pyrido(2,3,4-kl)acridine unit of
some marine alkaloids
Turan Ozturk and Alexander McKillop
Abstract: A simple and convenient synthesis of pyrido(2,3,4-kl)acridine (1), the main skeleton of some marine alka-
loids, via cyclization and intramolecular nitrene insertion, is described. The importance of the planarity of the molecule
during the nitrene insertion is explained.
Key words: pyridoacridine, marine alkaloids, nitrene insertion, quinoline, quinolinone.
Résumé : On décrit une synthèse simple et pratique de la pyrido(2,3,4-kl)acridine (1), le squelette fondamental de
quelques alcaloïdes marins; elle implique une cyclisation et une insertion intramoléculaire de nitrène. On explique
l’importance de la planéité de la molécule au cours de l’insertion du nitrène.
Mots clés : pyridoacridine, alcaloïdes marins, insertion de nitrène, quinoléine, quinoléinone.
[Traduit par la Rédaction] Ozturk and McKillop 1164
Introduction
Recently, many polycyclic fused-ring alkaloids containing
pyrido(2,3,4-kl)acridine (1) skeleton have been isolated from
a variety of marine sources such as sponges, molluscs, and
tunicates, most of which have been reported to have cyto-
toxic, antitumor, and antiviral activities (1). Calliactine (2),
2-bromoleptoclinidinone (3), ascididemin (4), cystodytins A,
B, and C (5), petrosamine (6), diplamine (7), varamines (8),
dercitin (9), cyclodercitin (10), segolines A (11, 12) and B
(12), isosegoline
A (11, 12), norsegoline (11, 12),
shermilamines A (12), B (13, 14), C (5b), D and E (15),
styelsamine A, B, C, and D (16), arnoamine A and B (17),
kuanoniamine A, B, C, and D (13, 5b), eilatin (12),
amphimedine (18), neoamphimedine (19), pantherinine (20),
lissoclin A and B (21), are among this type of alkaloid. Al-
though elegant synthetic methodologies for most of these al-
kaloids have been developed and total synthesis of many of
these natural products have been achieved, such alkaloids
are still continuing to be the focus of many synthetic groups
(1, 22). This is due to their interesting biological activities
and challenging structures. It seems that any contribution to-
ward the synthesis of pyridoacridine units is worthwhile
since most of the strategies involve the synthesis of such
units. The route we present here involves two important key
steps, cyclization to form the quinolinone moiety and intra-
molecular nitrene insertion to build a tetracyclic system.
This approach may also be utilized as an easy access for the
synthesis of ring B-modified analogues of this type of alka-
loid.
Results and discussion
The synthesis of this important pyridoacridine intermedi-
ate 21 has been achieved in 10 steps with overall 13.5%
yield. Our synthesis started with the condensation of the
commercially available reagents 2-methoxy-5-nitroaniline
(2) and ethyl benzoylacetate (3) in toluene, which led to the
formation of the amide 4 in 75% yield (Scheme 1) (22c).
Hydrogenation of the nitro and keto groups of 4, over palla-
dium on charcoal at room temperature in ethanol, took place
at the same time with a 90% yield. Acetylation of the amino
group of 5 with acetyl chloride was followed by the
cyclization of the corresponding product 6 with 80% H2SO4,
which smoothly yielded the quinolinone 7 in 92% yield. Un-
fortunately, our other cyclization attempts with various
amides such as 8, 9, 10, and 11 to obtain such an important
intermediate were not successful. Although these attempts
were carried out in various reagents, conc. H2SO4, H3PO4,
poly.H3PO4, POCl3, HCl, and 80% H2SO4, in almost all re-
actions, intractable products or starting materials were ob-
tained, except 8 and 9 which gave hydrolysis of the amide
Received March 22, 2000. Published on the NRC Research
Press website on August 18, 2000.
T. Ozturk.1 TUBITAK Marmara Research Center, Chemistry
Department, Gebze-Kocaeli, Turkey.
e-mail: turan@mom.gov.tr
A. McKillop. The University of East Anglia, School of
Chemical Sciences, Norwich, U.K.
1Author to whom correspondence may be addressed.
University of Waterloo, Chemistry Department, Waterloo,
ON N2L 3G1 Canada. e-mail: turan@muskie.uwaterloo.ca
Can. J. Chem. 78: 1158–1164 (2000)
© 2000 NRC Canada

Ozturk and McKillop
1159
Scheme 1. (a) Toluene, reflux, 75%; (b) Pd/C, H2, ethanol, rt, 90%; (c) AcCl, pyridine, 75%; (d) H2SO4 (80%), 92%.
when treated with HCl or 80% H2SO4, and dehydration with
80% H2SO4, respectively.
the amine 12. Further confirmation that 12 had been
obtained, was provided by oxidative demethylation with
manganese dioxide, which gave the trione 15 in 78% yield,
and the analytical and spectroscopic data for 15 were fully
consistent with the assigned structure.
In this attempted cyclization of 13 to 14 via the nitrene in-
sertion, which was carried out in xylene, both in the pres-
ence and absence of a nitrogen atmosphere, it was assumed
that conversion of the nitrene 13 to the aniline 12 was the re-
sult of hydrogen abstraction from the solvent. In an attempt
to circumvent this, the azide 13 was carefully melted and the
liquid azide was stirred under nitrogen in the absence of sol-
vent. After 30 min, NMR and TLC examination of the crude
product showed the same result as previously, that is, forma-
tion of the amine 12. Hydrogen abstraction in this case could
involve the benzylic hydrogen atom at the 4-position of the
dihydroquinolinone ring. Moreover, the stereochemical situ-
ation in 13 is probably less than ideal as far as the intended
intramolecular cyclisation is concerned. The phenyl group is
not on the same plane with the azide, and this is obviously
one of the driving forces in such cyclizations (22g, j, k, 23).
To circumvent the problem encountered during intra-
molecular nitrene insertion, it was decided to introduce a
double bond to the system to bring the phenyl group to the
same plane with the azide. Then, employment of the one of
the most common dehydrogenation reagents DDQ (2,3-
dichloro-5,6-dicyanobenzoquinone), unfortunately, did not
give any result, only starting material was recovered. This is
perhaps not too surprising in view of the large steric bulk of
the reagent and the relative steric shielding of the hydrogen
atoms at the 3- and 4-positions of the dihydroquinolinone by
the 4-phenyl substituent. Then, the conventional method,
palladium on charcoal in diphenyl ether, yielded the
quinolinone 16 in 65% yield together with 20% of the start-
ing material (Scheme 3). Hydrolysis of the amide group us-
ing 45% sulphuric acid proceeded smoothly to give the
aminoquinolinone 17 in 96% yield, and conversion of the
After constructing the quinolinone ring successfully, we
concentrated on building the last ring, utilizing the
intramolecular nitrene insertion methodology. Initially,
deacetylation of 7 was performed, and after some explor-
atory work, it was found that deacetylation of 7 to 12 best
took place in hot 45% sulphuric acid, and 12 was obtained
in a very satisfactory, 88% yield (Scheme 2). Conversion of
12 to the corresponding azide 13 was then carried out by the
classical nitrous acid followed by sodium azide combination
of reactions. With the azide 13 available, conversion to the
tetracyclic system 14 was attempted. Thus, 13 was heated in
refluxing xylene until no starting material remained in the
reaction mixture, as shown by TLC. Examination of the
NMR spectrum of the product, however, showed that it was
© 2000 NRC Canada

1160
Can. J. Chem. Vol. 78, 2000
Scheme 2. (a) H2SO4 (45%), reflux, 2 h, 88%; (b) (i) NaNO2, 0–5°C; (ii) NaN3, 0–5°C, 86%; (c) xylene, reflux; (d) MnO2, H2SO4
(35%), 78%.
amino to the azide group, as usual, presented no difficulties.
The crude azide 18, which showed only one spot on TLC,
was obtained in 93% yield. It proved to be sensitive to both
heat and light and hence no attempt to obtain an analytical
sample was made.
The next step in the synthesis was the key intramolecular
nitrene insertion reaction. Azide 18 was heated under reflux
in xylene for 1.5 h. In contrast to the complete failure to
achieve cyclization with the dihydro derivative 13, the azide
18 reacted quite smoothly to give the required tetracyclic
material 19 in 78% yield. Use of the azidoquinolinone rather
than the dihydroquinolinone had proved successful, there-
fore, and would seem to imply that the controlling feature in
the reaction as far as nitrene insertion is concerned is
sterochemistry.
mental analyzer. Infrared spectra were recorded on Perkin–
Elmer 257, 297 grating infrared spectrophotometers using
the standard Nujol mull or liquid film techniques between
sodium chloride plates. Proton NMR spectra were recorded
on JEOL PMX 60 MHz and JEOL GX-400 MHz spectrome-
ters. The 13C NMR spectra were recorded on a JEOL EX-
90Q 24 MHz spectrometer. Tetramethylsilane (TMS) was
used as the internal standard in all NMR spectra run in
CDCl3, DMSO-d6. Mass spectra were recorded on a Kratos
MS-25 mass spectrometer with an ionization potential of
70 eV at 200°C. All column chromatography was performed
on silica gel (Merck, Kieselgel 60H, Art 7736) and Merck
aluminum oxide 60 PF24k
.
N-(2-Methoxy-5-nitrophenyl)-3-oxo-3-
The synthesis of the tetracyclic compound 19 constitutes
achievement of one of the major objectives, namely the syn-
thesis of an advanced tetracyclic intermediate in which the B
ring is functionalized. Analogues of natural products con-
taining pyridoacridine units could be available from it by
manipulation of the quinolinone ring.
The key compound 21 was then easily prepared from 19
by conversion to the chloroquinoline 20 in 83% yield by
reaction with hot phosphorus oxychloride, followed by reductive
removal of the chlorine on charcoal in triethylamine in 79%
yield.
phenylpropanamide (4)
2-Methoxy-5-nitroaniline (2) (15 g, 90 mmol) and ethyl
benzoylacetate (3) (17.29 g, 90 mmol) were condensed in to-
luene (400 mL) using a Dean and Stark’s apparatus for 6 h,
and the mixture was then left overnight at room temperature.
The solid, which separated, was collected by filtration and
recrystallized from ethanol. Yield: 21.9 g, 75%. Light yellow
crystals, mp 183–185°C. MS: m/z 314 (M+). 1H NMR
(CDCl3) δ: 4.02 (s, 3H), 4.08 (s, 2H), 6.86 (d, J = 8.4 Hz,
1H), 7.60 (s, 5H), 8.0 (m, 2H). Anal. calcd. for C16H14N2O5:
C 61.14, H 4.46, N 8.91; found: C 61.12, H 4.15, N 8.91.
N-(5-Amino-2-methoxyphenyl)-3-hydroxy-3-
phenylpropanamide (5)
Experimental
Melting points were determined on a Kofler hotstage mi-
croscope melting point apparatus and are uncorrected.
Microanalysis were performed with a Carlo Erba 1106 ele-
Compound 4 (6 g, 19 mmol) and C/Pd (0.21 g, 5%) were
hydrogenated in ethanol (100 mL) at room temperature until
the disappearance of the starting material (TLC). The
© 2000 NRC Canada

Ozturk and McKillop
1161
Scheme 3. (a) Pd/C, diphenyl ether, reflux, 65%, 20% (starting material); (b) H2SO4 (45%), reflux, 96%; (c) (i) NaNO2; (ii) NaN3,
93%; (d) xylene, reflux, 78%; (e) POCl3, reflux, 83%; (f) Pd/C, H2, Et3N, 79%.
catalyst was filtered off through kieselguhr under suction
and the kieselguhr was washed with acetone. After evapora-
tion of the solvent, the crude solid was recrystallized from
toluene. Yield: 4.89 g, 90%. Light yellow needles, mp 155–
158°C. MS: m/z 286 (M+). IR (Nujol) (cm–1): 3420, 3360,
m/z 328 (M+). IR (Nujol) (cm–1): 3110–3400, 1630–1680.
1H NMR (CDCl3) δ: 2.04 (s, 3H), 2.68 (d, J = 3.0 Hz, 2H),
3.00 (s, 3H), 4.04 (s, 1H), 5.08 (t, J = 3.0 Hz, 1H), 6.66 (d,
J = 10.0 Hz, 1H), 7.24 (s, 5H), 7.44 (dd, J = 10.0, 1.1 Hz,
1H), 8.20 (d, J = 1.0 Hz, 1H), 8.25 (s, 1H). Anal. calcd. for
C18H20N2O4: C 65.85, H 6.09, N 8.53; found: C 65.24, H
6.18, N 8.21.
1
3100–3480, 1654. H NMR (CDCl3) δ: 2.68 (d, J = 2.9 Hz,
2H), 3.28 (s, 2H), 3.68 (s, 3H), 5.08 (t, J = 2.9 Hz, 1H), 6.26
(dd, J = 10.1, 1.2 Hz, 1H), 6.64 (d, J = 9.7 Hz, 1H), 7.26 (s,
5H), 7.82 (d, J = 1.2 Hz, 1H), 8.06 (s, 1H). Anal. calcd. for
C16H18N2O3: C 67.43, H 6.29, N 9.79; found: C 67.43, H
6.40, N 9.58.
5-Acetamido-3,4-dihydro-8-methoxy-4-phenylquinolin-
2(1H)-one (7)
Compound 6 (0.50 g) was stirred in H2SO4 (80%,
100 mL) at 80°C for 1 h. The reaction mixture was cooled to
room temperature and poured into ice water. The resulting
solution was then neutralized with Na2CO3 and the Na2SO4
which separated was removed by filtration and washed with
CH2Cl2 (3 × 40 mL) and the combined extracts were dried
(Mg2SO4) and the solvent was evaporated under reduced
pressure. The crude product was recrystallized from toluene.
Yield: 0.42 g, 92%. Colorless crystalline solid, mp 218–
220°C. MS: m/z 310 (M+), 311. IR (Nujol) (cm–1): 3200–
3440, 1656, 1650. 1H NMR (CDCl3) δ: 1.91 (s, 3H), 2.63 (d,
J = 15.7 Hz, 1H), 2.89 (dd, J = 16.1, 6.9 Hz, 1H), 3.80
N-(5-Acetamido-2-methoxyphenyl)-3-hydroxy-3-
phenylpropanamide (6)
To compound 5 (3 g, 10 mmol), dissolved in pyridine
(25 mL) and cooled in an ice bath, was added dropwise
freshly distilled acetyl chloride (0.80 mL, 110 mmol). The
mixture was stirred for 2 h at room temperature and then
poured into water (50 mL). The resulting mixture was ex-
tracted with CH2Cl2 (3 × 40 mL), dried over Mg2SO4. The
solvent was evaporated under reduced pressure. Yield:
2.46 g, 75%. Colorless crystalline solid, mp 79–82°C. MS:
© 2000 NRC Canada

1162
Can. J. Chem. Vol. 78, 2000
(s, 3H), 4.53 (d, J = 5.9 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H),
6.98 (d, J = 8.8 Hz, 1H), 7.02–7.29 (m, 5H), 9.21 (s, 1H),
9.25 (s,1H). Anal. calcd. for C18H18N2O3: C 69.67, H 5.80,
N 9.03; found: C 69.73, H 5.92, N 8.93.
NMR and TLC of the crude product showed that the product
is 12.
3,4-Dihydro-4-phenylquinolin-2(1H),5,8-trione (15)
To a stirred solution of the product obtained from at-
tempted insertion reaction of 13 (0.38 g, 1.4 mmol) dis-
solved in H2SO4 (59 mL, 35%) was added activated MnO2
(0.46 g) portionwise at 0°C. Stirring was carried out 1 h lon-
ger, then the mixture was diluted with CH2Cl2 (30 mL), neu-
tralized with Na2CO3, and filtered. The filtrate was washed
with water and the CH2Cl2 phase was separated, dried over
Mg2SO4, filtered, and the solvent was evaporated under re-
duced pressure. The crude product was crystallized from to-
luene. Yield: 0.27 g, 78%. Red needles, mp 154–156°C. MS:
m/z 253 (M+). IR (Nujol) (cm–1): 3340, 1740, 1654, 1640.
1H NMR (CDCl3) δ: 2.88 (m, 2H), 4.44 (m, 1H), 6.66 (s,
2H), 7.22 (s, 5H), 8.22 (s, 1H). Anal. calcd. for C15H11NO3:
C 71.14, H 4.34, N 5.53; found: C 70.90, H 4.04, N 5.30.
5-Amino-3,4-dihydro-8-methoxy-4-phenylquinolin-2(1H)-
one (12)
Compound 7 (0.5 g, 1.6 mmol) was refluxed in H2SO4
(25 mL, 45%) for 2 h. The mixture was cooled down to
room temperature and poured into water (50 mL). The re-
sulting solution was then neutralized with Na2CO3, and the
aqueous mixture was extracted with CH2Cl2 (3 × 40 mL).
The organic extracts were dried over Mg2SO4, filtered, and
the solvent was evaporated under reduced pressure. The
crude solid was recrystallized from ethanol. Yield: 0.41 g,
88%. Colorless crystalline solid, mp 225–228°C. MS: m/z
1
268 (M+). IR (Nujol) (cm–1): 3460, 3380, 1700. H NMR
(DMSO-d6) δ: 2.49 (d, J = 15.7 Hz, 1H), 2.87 (dd, J = 16.1,
6.9 Hz, 1H), 3.71 (s, 3H), 4.40 (d, J = 6.2 Hz, 1H), 4.57 (s,
2H), 6.21 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H),
7.09–7.25 (m, 5H), 9.85 (s, 1H). 13C NMR (DMSO-d6) δ:
35.7, 38.4, 55.7, 102.8, 109.7, 109.8, 126.4, 127.0, 128.3,
132.1, 134.7, 142.1, 142.4, 168.0. Anal. calcd. for
C16H16N2O2: C 71.64, H 5.97, N 10.44; found: C 71.45,
H 6.05, N 10.15.
5-Acetamido-8-methoxy-4-phenylquinolin-2(1H)-one (16)
A mixture of compound 7 (0.30 g, 1 mmol) and Pd/C
(10%, 53 mg) in diphenyl ether (30 mL) was refluxed for
48 h. The reaction mixture was cooled to room temperature,
filtered through kiselguhr under suction, and the kiselguhr
washed with CH2Cl2 (50 mL). The dichloromethane solution
was evaporated under reduced pressure and the resulting di-
phenyl ether solution was poured into petroleum ether
(bp 40–60°C, 100 mL). The solid, which separated, was
collected by filtration and washed with petroleum ether
(25 mL). The crude solid was chromatographed on silica,
using ethyl acetate as the first eluent to remove starting ma-
terial (20%) and then ethanol–ethyl acetate (1:6) to obtain
the product. Yield: 0.2 g, 65%. Colorless crystalline solid,
mp 193–196°C. MS: m/z 308 (M+). IR (Nujol) (cm–1):
5-Azido-3,4-dihydro-8-methoxy-4-phenylquinolin-2(1H)-
one (13)
To concentrated H2SO4 (1.72 mL) dissolved in water
(5.7 mL) was added 12 (1.90 g, 7 mmol). The mixture was
stirred for 10 min at room temperature, then more water
(3 mL) was added and the mixture was cooled to 0–5°C in
an ice water bath. A solution of sodium nitrite (0.63 g,
10 mmol) in water (5 mL) was carefully added dropwise and
the mixture was stirred for 45 min. With strong stirring, a
solution of sodium azide (0.7 g, 10 mmol) in water (5 mL)
was then added dropwise and stirring was continued for a
further 40 min. The light yellow solid, which separated, was
collected by filtration and washed with plenty of water. The
crystalline solid was dried under vacuum, mp 134–137°C.
Yield: 1.80 g, 86%. MS: m/z 294 (M+). IR (Nujol) (cm–1):
1
1615–1654. H NMR (DMSO-d6) δ: 1.12 (s, 3H), 3.93 (s,
3H), 6.22 (s, 1H), 6.84 (d, 1H, J = 8.2 Hz, 1H), 7.18 (d, J =
8.2 Hz, 1H), 7.21–7.41 (m, 5H), 8.81 (s, 1H), 10.88 (s, 1H).
13C NMR (DMSO-d6) δ: 21.8, 56.4, 110.9, 115.1, 121.6,
124.3, 127.1, 127.3, 127.5, 127.7, 129.9, 139.4, 144.2,
151.1, 159.9, 168.1. Anal. calcd. for C18H16N2O3: C 70.12,
H 5.19, N 9.09; found: C 70.50, H 5.41, N 8.96.
1
2120, 1656. H NMR (DMSO-d6) δ: 2.60 (d, J = 16.2 Hz,
1H), 2.96 (dd, J = 16.2, 7.3 Hz, 1H), 3.82 (s, 3H), 4.43 (d,
J = 6.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 7.05 (d, J =
8.5 Hz, 1H), 7.08–7.26 (m, 5H), 9.44 (s, 1H). 13C NMR
(DMSO-d6) δ: 36.2, 36.8, 56.0, 111.4, 112.3, 117.7, 126.7,
128.4, 128.6, 129.5, 141.6, 143.0, 143.8, 168.1. Anal. calcd.
for C16H14N4O2: C 65.30, H 4.76, N 19.04; found: C 65.07,
H 4.72, N 18.76.
Compound 13 was dissolved in xylene (750 mL) and
refluxed for 4 h until the disappearance of the starting mate-
rial (TLC). Then the reaction mixture was left in the refrig-
erator for overnight and the formed deep brown solid was
filtered and washed with petroleum ether (bp 49–60°C). The
crude material was chromatographed using ethyl acetate as
an eluent and a brown crystalline solid was then obtained.
Its TLC, NMR, and mass analysis showed that the product
was indeed 5-amino-3,4-dihydro-8-methoxy-4-phenylquinolin-
2(1H)-one (12).
5-Amino-8-methoxy-4-phenylquinolin-2(1H)-one (17)
The same reaction conditions and work-up were applied
as in the preparation of 12 for the deacetylation of 16 to ob-
tain 17. The crude product was recrystallized from toluene.
Yield: 96%. Yellow needles, mp 216–218°C. MS: m/z 266
(M+). IR (nujol) (cm–1): 3480, 3440,1650. 1H NMR (DMSO-
d6) δ: 3.80 (s, 3H), 4.12 (s, 2H), 6.05 (s, 1H), 6.30 (d, J =
8.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 7.38–7.51 (m, 5H),
10.39 (s, 1H). 13C NMR DMSO-d6 δ: 56.9, 105.4, 107.1,
114.7, 121.0, 127.5, 128.4, 128.6, 130.1, 137.0,139.4, 139.7,
151.2, 159.9. Anal. calcd. for C16H14N2O2: C 72.14, H 5.26,
N 10.52; found: C 72.14, H 5.19, N 10.29.
5-Azido-8-methoxy-4-phenylquinolin-2(1H)-one (18)
Using the same reaction conditions as in the preparation
of 13, compound 17 was converted to the azide 18. Instead
of filtering the precipitate, which formed after the addition
of NaN3, the reaction mixture was poured into water
(30 mL), and the resulting solution neutralized with Na2CO3
Compound 13 (1 g) was melted and kept stirring at 150°C
under nitrogen atmosphere for 30 min. Examination of the
© 2000 NRC Canada

Ozturk and McKillop
1163
and extracted with CH2Cl2 (3 × 40 mL). The organic ex-
tracts were dried (Mg2SO4), filtered, and the solvent was
evaporated under reduced pressure. The yellow crystalline
solid, which was obtained in 93% yield, was used directly
for the next insertion step. IR (Nujol) (cm–1): 2120, 1640. 1H
NMR (CDCl3) δ: 4.0 (s, 3H), 6.44 (s, 1H), 6.84 (s, 1H), 6.86
(s, 1H), 7.12–7.24 (m, 5H), 9.16 (s, 1H).
References
1. (a) M.H.G. Munro, R.T. Luibrand, and J.W. Blunt. In Bio-
organic marine chemistry. Vol. 1. Edited by P.J. Scheuer.
Springer, New York. 1987; (b) T. Ozturk. In The alkaloids.
Vol. 49. Edited by G.A. Cordell. Academic Press, New York.
1997; (c) C.J. Moody and R. Thomas. Adv. Heterocycl. Nat.
Prod. Synth. 2, 377 (1992); (d) T.F. Molinski. Chem. Rev. 93,
1825 (1993).
2. E. Lederer, G. Tessier, and C. Huttrer. Bull. Soc. Chim. Fr. 7,
608 (1940).
3. (a) S.J. Bloor and F.J. Schmitz. J. Am. Chem. Soc. 109, 6134
(1987); (b) F.S. de Guzman and F.J. Schmitz. Tetrahedron Lett.
30, 1069 (1989).
4. J. Kobayashi, J. Cheng, H. Nakamura, Y. Ohizumi, Y. Hirata,
T. Sasaki, T. Ohta, and S. Nozoe. Tetrahedron Lett. 29, 1177
(1988).
5. (a) J. Kobayashi, J. Cheng, M.R. Walchli, H. Nakamura, Y.
Hirata, T. Sasaki, and Y. Ohizumi. J. Org. Chem. 53, 1800,
(1988); (b) L.A. McDonald, G.S. Eldredge, L.R Barrows, and
C.M. Ireland. J. Med. Chem. 37, 3819 (1994).
6. T.F. Molinski, E. Fahy, D.J. Faulkner, G.D. Van Duyne, and J.
Clardy. J. Org. Chem. 53, 1340 (1988).
7. G.A. Charyulu, T.C. McKee, and C.M. Ireland. Tetrahedron
Lett. 30, 4201 (1989).
8. T.F. Molinski and C.M. Ireland. J. Org. Chem. 54, 4256
(1989).
9. G.P. Gunawardana, S. Kohmoto, S.P. Gunasekara, O.J.
McConnell, and F.E. Koehn. J. Am. Chem. Soc. 110, 4856
(1988).
10. G.P. Gunawardana, S. Kohmoto, and N.S. Barres. Tetrahedron
Lett. 30, 4359 (1989).
11. A. Rudi, Y. Benayahu, I. Goldberg, and Y. Kashman. Tetrahe-
dron Lett. 29, 3861 (1988).
12. A. Rudi and Y. Kashman. J. Org. Chem. 54, 5331 (1989).
13 (a) A.R. Carroll and P.J. Scheuer. J. Org. Chem. 55, 4426
(1990); (b) C. Eder, P. Schupp, P. Proksch, V. Wray, K. Steube,
C.E. Müller, W. Frobenius, M. Herderich, and R.W.M. van
Soest. J. Nat. Prod. 61, 301 (1998).
3,7-Dihydro-4-methoxy-2-oxo-pyrido(2,3,4-kl)acridine
(19)
Compound 18 (0.60 g, 2 mmol) was refluxed in xylene
(750 mL) for 1.5 h. The reaction mixture was cooled to
room temperature and left overnight. The solid, which sepa-
rated, was collected by filtration and washed with petroleum
ether (bp 40–60°C, 25 mL). This crude product was
chromatographed on silica using ethyl acetate–ethanol (4:2)
as eluent. Yield: 0.41 g, 78%. Brown crystalline solid, mp
270°C (decomp.). MS: m/z 264 (M+). IR (Nujol) (cm–1):
1
1610–1650. H NMR (DMSO-d6) δ: 3.83 (s, 3H), 6.44 (s,
1H), 6.56 (d, J = 8.7 Hz, 1H), 6.97 (t, J = 7.1 Hz, 1H), 7.07
(d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.41 (t, J =
7.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 10.01 (s, 1H), 10.42
(s, 1H). 13C NMR (DMSO-d6) δ: 56.7, 101.8, 102.6, 108.2,
114.1, 115.8, 115.9, 120.1, 124.4, 129.6, 131.6, 131.7,
137.5, 139.2, 142.3, 162.4. Anal. calcd. for C16H12N2O2:
C 72.72, H 4.54, N 10.60; found: C 72.39, H 4.56, N 10.34.
2-Chloro-4-methoxy-7H-pyrido(2,3,4-kl)acridine (20)
Compound 19 (0.20 g, 0.75 mmol) was refluxed in POCl3
(30 mL) for 1 h. The reaction mixture was cooled to room
temperature and poured into water (50 mL). The resulting
solution was neutralized with Na2CO3 and the solid, which
separated, was collected by filtration. This gave 0.17 g
(83%) of crude red crystalline solid which showed one spot
on the TLC and was used directly for the next step. A sam-
ple was crystallized from toluene for the analysis, mp 202°C
1
(decomp.). MS: m/z 282 (M+). H NMR (DMSO-d6) δ: 3.85
(s, 3H), 6.69 (d, J = 8.4 Hz, 1H), 6.92–7.41 (m, 5H), 7.99
(d, J = 8.0 Hz, 1H), 10.57 (s, 1H). 13C NMR (DMSO-d6) δ:
56.1, 113.6, 114.3, 115.6, 117.9, 120.2, 124.6, 128.1, 128.8,
131.9, 132.4, 139.8, 140.1, 143.7, 144.8, 151.8, 1H. Anal.
calcd. for C16H11ClN2O: C 67.97, H 3.92, N 9.91, Cl 12.54;
found: C 67.84, H 4.05, N 9.66, Cl 12.20.
14. A.R. Carroll, N.M. Cooray, A. Pointer, and P.J. Scheuer. J.
Org. Chem. 54, 4231 (1989).
15. G.K.-Goldhldshlager, M. Aknin, E.M. Gaydou, and Y.
Kashman. J. Org. Chem. 63, 4601 (1998).
16. B.R. Copp, J. Jompa, A. Tahir, and C.M. Ireland. J. Org.
Chem. 63, 8024 (1998).
17. A. Plubrukarn and B.S. Davidson. J. Org. Chem. 63, 1657
(1998).
18. F.J. Schmitz, S.K. Agarwal, S.P. Gunasekera, P.G. Schmidt,
and J.N. Shoolery. J. Am. Chem. Soc. 105, 4835 (1983).
19. F.S. de Guzman, B. Carte, N. Troupe, D.J. Faulkner, M.K.
Harper, G.P. Concepcion, G.C. Mangalindan, S.S.
Matsumoto, L.R. Barrows, and C.M. Ireland. J. Org. Chem.
64, 1400 (1999).
4-Methoxy-7H-pyrido(2,3,4-kl)acridine (21)
Compound 20 (0.50 g, 2 mmol) was catalytically hydro-
genated with 10% Pd/C (50 mg) in ethyl alcohol (40 mL) in
the presence of triethylamine (0.25 g, 2.7 mmol) for 6 h at
room temperature. The catalyst was filtered off through kie-
selguhr under suction, and then the solvent was evaporated
under reduced pressure. This gave 0.34 g (79%) of red crys-
talline product, which showed one spot on TLC, mp 224°C
20. J. Kim. E.O. Pordesimo, S.I. Toth, F.J. Schmitz, and I. Van
Altena. J. Nat. Prod. 56, 1813 (1993).
1
(decomp.). MS: m/z 248 (M+). H NMR (DMSO-d6) δ: 3.84
21. P.A. Searle and T.F. Molinski. J. Org. Chem. 59, 6600 (1994).
22. (a) A. Echavarren and J.K. Stille. J. Am. Chem. Soc. 110,
4051 (1988); (b) R.H. Prager and C. Tsopelas. Heterocycles,
29, 847 (1989); (c) A. Kubo and S. Nakahara. Heterocycles,
27, 2095 (1988); (d) F. Bracher. Liebigs Ann. Chem. 205
(1990); (e) C.J. Moody, C.W. Rees, and R. Thomas. Tetrahe-
dron Lett. 31, 4375 (1990); (f) F. Bracher. Heterocycles, 29,
2093 (1989); (g) C.V. Labarca, A.R. McKenzie, C.J. Moody,
C.W. Rees, and J. Vaquero. J. Chem. Soc. Perkin Trans. 1, 927
(s, 3H), 6.58 (d, J = 8.9 Hz, 1H), 6.90 (t, J = 8.3 Hz, 1H),
6.95 (d, J = 8.3 Hz, 1H), 7.1 (d, J = 8.3 Hz, 1H), 7.33 (t, J =
7.6 Hz, 1H), 7.41 (d, J = 4.9 Hz, 1H), 7.93 (d, J = 7.3 Hz,
1H), 8.48 (d, J = 4.9 Hz, 1H), 10.30 (s, 1H). 13C NMR
(DMSO-d6) δ: 56.2, 101.5, 107.1, 112.3, 115.1, 119.2,
119.8, 124.0, 130.8, 131.7, 132.1, 139.6, 140.2, 141.1,
145.7, 150.7. Anal. calcd. for C16H12N2O: C 77.42, H 4.48,
N 11.29; found: C 77.21, H 4.84, N 11.24.
© 2000 NRC Canada

1164
(1987); (h) C. Subramanyam, M. Noguchi, and S.M. Weinreb.
Can. J. Chem. Vol. 78, 2000
Bracher. Tetrahedron, 53, 1743 (1997); (p) S. Nakahara, J.
Matsui, and A. Kubo. Tetrahedron Lett. 39, 5521 (1998); (s)
Y. Kitahara, F. Tamura, M. Nishimura, and A. Kubo. Tetrahe-
dron, 54, 8421 (1998); (t) D. Zhang, I. Llorente, and L.S.
Liebeskind. J. Org. Chem. 62, 4330 (1997); (v) M. Alvarez, L.
Feliu, W. Ajana, J.A. Joule, and J.L.F.-Puentes. Eur. J. Org.
Chem. 849 (2000).
J. Org. Chem. 54, 5580 (1989); (i) M.A. Ciufolini and N.E.
Byrne. Tetrahedron Lett. 30, 5559 (1989); (j) N.M. Ali, S.K.
Chattopadhyay, A. McKillop, R.M.P.-Gentil, T. Ozturk, and
R.A. Rebelo. J. Chem. Soc. Chem. Commun. 1453 (1992); (k)
S.H. Dunn and A. McKillop. J. Chem. Soc. Perkin Trans. 1,
879 (1993); (l) M. Alvarez and J.A. Joule. Heterocycles, 34,
2385 (1992); (m) G. Gellerman, A. Rudi, and Y. Kashman.
Tetrahedron, 50, 12959 (1994); (n) B.S. Lindsay, A.N. Pearce,
and B.R. Copp. Synth. Commun. 27, 2587 (1997); (o) N.
Bontemps, E. Delfourne, J. Bastide, C. Francisco, and F.
23. (a) M.A. Ciufolini and M.J. Bishop. J. Chem. Soc. Chem.
Commun. 1463 (1993); (b) M.A. Ciufolini and N.E. Byrne. J.
Am. Chem. Soc. 113, 8016 (1991).
© 2000 NRC Canada