A novel approach to ring A analogues of the marine pyridoacridine alkaloid ascididemin

Article abstract of DOI:10.1016/j.tet.2013.08.085

A novel approach to ring A analogues of the marine pyridoacridine alkaloid ascididemin starting from readily available 4-bromobenzo[c][2,7]naphthyridine (10) comprises a high-yield Minisci-type homolytic methoxycarbonylation at C-5, followed by introduction of the ring A scaffold via Suzuki cross-coupling reaction, and a trifluoromethanesulfonic acid-aided Friedel-Crafts-type intramolecular acylation. This protocol allows for the introduction of various electron-rich carbocyclic and heterocyclic ring A substitutes.

Full text of DOI:10.1016/j.tet.2013.08.085

Tetrahedron 69 (2013) 9857e9864
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel approach to ring A analogues of the marine pyridoacridine
alkaloid ascididemin
*
Alois Plodek, Stephan Raeder, Franz Bracher
€
€
€
€
Department fur PharmaziedZentrum fur Pharmaforschung, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, D-81377 Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2013
Received in revised form 29 August 2013
Accepted 30 August 2013
Available online 11 September 2013
A novel approach to ring A analogues of the marine pyridoacridine alkaloid ascididemin starting from
readily available 4-bromobenzo[c][2,7]naphthyridine (10) comprises a high-yield Minisci-type homolytic
methoxycarbonylation at C-5, followed by introduction of the ring A scaffold via Suzuki cross-coupling
reaction, and a trifluoromethanesulfonic acid-aided FriedeleCrafts-type intramolecular acylation. This
protocol allows for the introduction of various electron-rich carbocyclic and heterocyclic ring A
substitutes.
Keywords:
Alkaloids
Ó 2013 Elsevier Ltd. All rights reserved.
Pyridoacridines
Homolytic acylation
FriedeleCrafts acylation
Cyclization
Trifluoromethanesulfonic acid
1. Introduction
been investigated thoroughly in the last two decades, since several
approaches have been worked out for their total synthesis in the
Pyridoacridines are a unique class of alkaloids isolated from
sessile marine organisms like ascidians (tunicates), sponges and
bryozoa, and meanwhile more than 50 of these polycyclic hetero-
aromatic alkaloids have been isolated,1e3 and based on biosynthetic
considerations, a number of ‘undiscovered’ alkaloids of this family
have been predicted.4 Most of these alkaloids show high cytotox-
icity accompanied with their DNA-binding activities, but individual,
structurally even closely related pyridoacridines can vary dramat-
ically in their molecular mechanism of cell killing.3 Among the
predominant effects are inhibition of topoisomerase II and the
formation of reactive oxygen species,2,5 in addition, induction of
apoptosis has been demonstrated for ascididemin (1).6 Further-
more, antibacterial, antifungal, antiviral, and insecticidal,3 as well
as antiparasitic activities against Plasmodium, Leishmania, and
Trypanosoma species have been demonstrated.7
past (Fig. 2).
The most prominent subclass of pyridoacridine alkaloids are
pentacyclic compounds derived from ascididemin (1; 1,8,13-
triazabenzo[fg]naphthacen-9-one; different numberings of the
ring system are used, e.g., in Ref. 3) (Fig. 1), which was isolated from
the Okinawan tunicate Didemnum sp.8 Though these alkaloids are
available from natural sources only in trace amounts, they have
Fig. 1. Marine pyridoacridine alkaloids ascididemin (1), bromoleptoclinidinone (2),
neocalliactine acetate (3), and kuanoniamine A (5), as well as the bioactive synthetic
deaza-analogue 4.
The first total synthesis of ascididemin (1) utilizing an oxidative
amination of quinoline-5,8-dione, followed by acid-catalyzed cy-
clization and finally annulation of ring E, was worked out by one of
us.9 This methodology has later been applied to total syntheses of
the related alkaloids bromoleptoclinidinone (2), neocalliactine
* Corresponding author. Tel.: þ49 89 2180 77301; fax: þ49 89 2180 77802; e-mail
address: Franz.Bracher@cup.uni-muenchen.de (F. Bracher).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.085

9858
A. Plodek et al. / Tetrahedron 69 (2013) 9857e9864
14
Fig. 2. Previous approaches to the alkaloid ascididemin (1) reported by Echavarren,13 Bracher,9 Kashman,12 Alvarez, Moody,16 and Kristensen.17
ꢀ
acetate (3), and kuanoniamine A (5),10 as well as a number of
synthetic analogues11 by us and others. Mechanistically related
approaches, starting from the same quinone, were worked out by
Kashman12 and Echavarren.13 Another synthetic approach by
The observed changes in bioactivity associated with structural
modifications in ring A of ascididemin (1) made it desirable to work
out an alternative approach to ascididemin-type pyridoacridines
that allows for flexible modifications in this ring by using readily
available monocyclic building blocks for the introduction of this
ring. The classical approach9 is very straightforward and provides
the pentacyclic ring system in four steps starting from an (aza)
naphthoquinone as a ring AþB building block. However, this ap-
proach is less practical if the required bicyclic quinone has to be
prepared in multistep procedures,11d or gives mixtures of isomers
in the oxidative amination step.
14
ꢀ
Alvarez et al. starts from an acridone, and performs the final an-
nulation of ring A in a hetero-DielseAlder cycloaddition, similar to
the key step performed by us earlier in the synthesis of the
Annonaceae alkaloid cleistopholine.15 Moody’s total synthesis goes
through a quinoneimine derived from 1,10-phenanthroline epox-
ide,16 and recently, Kristensen17 published a novel approach to 1 via
anionic cascade ring closure of a phenylbipyridyl. Ciufolini et al.18
described an approach to related alkaloids with sulfur-containing
ring A by means of photochemically induced nitrene insertion re-
actions. Additionally, several unsuccessful approaches to
ascididemin-type pyridoacridine alkaloids have been published.19
Significant effort has been undertaken in investigating modifi-
cations in the A ring of ascididemin (1) and the resulting bio-
activities,11d,14,20 and a QSAR study21 confirmed the importance of
ring A for antitumor activity. The 13-deaza derivative 410,14 of 1
(also named AK37) shows reduced cytotoxicity, but in contrast to
the topoisomerase II inhibitor 1 is an inhibitor of topoisomerase I,
stabilizes the DNA-topoisomerase I cleavable complex, but does
obviously not act through generation of reactive oxygen species.22
Ring A analogues of 1 containing furan and thiophene rings
showed significant anti-tuberculosis activity, but were not in-
vestigated further due to the complicated synthetic routes.11d
Recently, weworkedoutanovelapproachto13-deazaascididemin
(4),utilizingbenzaldehydeastheringAbuildingblock, buttheyieldof
the final step (radical-induced cyclization to build up the C-13a,C-13b
bond) was very poor.23
In this communication we report on the development of a novel
approach to the pyridoacridine ring system in which readily
available areneboronic acids serve as the source of ring A. The
synthetic plan (Fig. 3) envisaged to start from 5-ethoxycarbonyl-4-
bromobenzo[c][2,7]naphythyridine (6), which is readily available
by regioselective homolytic ethoxycarbonylation of 4-bromobenzo
[c][2,7]naphythyridine (10).24a Suzuki cross-coupling with (het)
areneboronic acids should permit the introduction of various ring A
equivalents, and finally, the pentacyclic (or even larger) ring system
was to be constructed by intramolecular FriedeleCrafts-type acyl-
ation of the previously introduced aromatic ring.
Fig. 3. New strategy for the synthesis of pyridoacridines with high variability in ring A.

A. Plodek et al. / Tetrahedron 69 (2013) 9857e9864
9859
2. Results and discussion
4-chlorophenyl (8) and the 4-(2-furyl) analogue (9) were selected
for first investigations, since they differ in the electron density of
the arene ring that had to be acylated in the final step. Both in-
termediates were obtained by Suzuki cross-coupling without dif-
ficulty, albeit in poor yields (40 and 37%). To our disappointment,
both cyclization reactions failed to give the desired products.
Whereas the 4-chlorophenyl derivative was recovered unchanged,
the furyl analogue decomposed almost completely during the re-
action. Comparable instability of furans was observed in attempts
to perform related cyclizations under strongly acidic conditions.33
Hoping to get a practicable approach to pyridoacridines anyway,
we decided to modify the ester moiety in the intermediates. The
ethyl ester group was to be replaced by the sterically less de-
manding methyl ester, expecting that this would lead to more ef-
fective cyclization reactions. To our pleasure, the hitherto unknown
methyl ester 11 was obtained by homolytic methoxycarbonylation
of 4-bromobenzo[c][2,7]naphythyridine (10) with methyl pyruvate
under Fenton-like conditions24 in very good yield (93%; the corre-
sponding ethyl ester is obtained in <30% yield). This is in contrast to
observations of Regan et al.34 who obtained better yields for the
ethoxycarbonyl derivatives in the homolytic alkoxycarbonylation of
pyrimidines. In the same manner as observed in our previous
ethoxycarbonylation reactions leading to 6,24a the reaction gave
a mixture of fully aromatic ester 11 and its 5,6-dihydro analogue. No
efforts were made to separate the air-sensitive dihydro compound,
instead, oxidation of the crude reaction product with MnO2 under
microwave irradiation gave the fully aromatic product in very good
yield. Fortunately, Suzuki cross-coupling reactions with methyl
ester 11 proceeded with significantly higher yields compared to the
ethyl ester 6 as well.35 This enabled us to prepare a broad variety of
4-(hetero)aryl-5-methoxycarbonylbenzo[c][2,7]naphythyridines
(12aej) in good yields. The aromatic rings introduced this way
range from (substituted) phenyl over naphthyl to variously
substituted thienyl and benzothienyl, thereby comprising electron-
rich as well as electron poor moieties. Furan and pyrrole rings were
not further investigated due to their instability to strongly acidic
conditions.33
For working out the methodology, we selected 13-
deazaascididemin (4) as target compound, since we had an au-
thentic sample of this compound in hand from previous in-
vestigations.23 A first attempt for Suzuki cross-coupling of 5-
ethoxycarbonyl-4-bromobenzo[c][2,7]naphythyridine (6)24a with
phenylboronic acid was undertaken following reaction conditions
(Pd(Ph3P)4, K2CO3, DMF) that had previously been applied by Janin
et al.25 to the arylation of alkoxycarbonyl 1-bromoisoquinolines,
but the coupling product 7a was obtained in only 30% yield. A
significantly better yield (60%) was obtained by using a THF-water
mixture as solvent.26 The final step, the intramolecular Friedele-
Crafts-type acylation of the phenyl ring, should be conducted di-
rectly with the ester group as acylating agent. In literature, various
acids have been used successfully for comparable purposes, namely
polyphosphoric acid (PPA),27 polyphosphoric acid silylester
(PPSE),28 and concentrated sulfuric acid.29 Unfortunately, neither of
these reagents led to the desired cyclization to give 13-
deazaascididemin (4). Both PPA and sulfuric acid did not convert
the starting material at low temperatures (room temperature up to
90 ꢀC), but at higher temperature, only gave 4-phenylbenzo[c][2,7]
naphythyridine (7b) under desethoxycarbonylation. With PPSE at
100 ꢀC no conversion was observed. In a modified approach we
intended to hydrolyze the ester group and then perform the cy-
clization with the free carboxylic acid following methods from lit-
erature.30 Unfortunately, alkaline hydrolysis of ester 7a led
exclusively to the decarboxylated product 7b. This parallels
former observations from other31 and our24 groups that 5-
formylbenzo[c][2,7]naphythyridines readily undergo decarbon-
ylation reactions. This led us to a reinvestigation of the direct cy-
clization starting from the ester 7a, and the application of
a superacid was considered. Hwang et al.32 reported on in-
termolecular acylations of arenes by methyl benzoate, activated by
the superacid trifluoromethanesulfonic acid (pKa about ꢁ15).
Treating ester 7a with this superacid under the conditions de-
scribed by Hwang (85 ꢀC, open vessel) did not result in appreciable
conversion, but upon heating in a closed microwave vessel (under
nitrogen atmosphere, 150 W, maximum temperature of 110 ꢀC)
gave the desired pentacyclus 13-deazaascididemin (4) in 42% yield
(Scheme 1). More drastic conditions did not improve the yield. In
order to investigate the scope of this new reaction we investigated
the cyclization of other 4-arylbenzo[c][2,7]naphythyridines. The
Cyclization experiments under the optimized conditions de-
scribed above gave rise to an appreciable number of new penta-
and hexacyclic target compounds (Scheme 2). As hoped for, the
phenyl-substituted methyl ester 12a gave a significantly higher
yield of 4 than the corresponding ethyl ester (63% vs 42%). Also
other intermediates containing electron-rich aromatic rings at C-4
(2-naphthyl, 2-thienyl, 5-methyl-2-thienyl, 3-thienyl, benzothien-
2-yl) were cyclized to the products 13d/e11e/f/i/j in good to very
good yields (63e92%). Complete regioselectivity was observed for
the cyclizations of the 2-naphthyl (giving 13d via acylation at C-
3) and 3-thienyl intermediates (giving 13i via acylation at C-2), as
evidenced by NMR experiments.
Unfortunately, attempted cyclizations failed with substrates
bearing electron-deficient arenes (5-chlorothien-2-yl, 5-
acetylthien-2-yl, 2-bromophenyl). The reaction of the 2-
bromophenyl intermediate 12b did not give the desired pentacy-
clus, but the demethoxycarbonylation product 4-(2-bromophenyl)
benzo[c][2,7]naphthyridine (14) was isolated in 46% yield.36 Due to
the 2-bromo substituent the arylbenzo[c][2,7]naphthyridine (12b)
opened the opportunity to perform a Parham-type cyclization.
Bromo-metal exchange at low temperature, without affecting the
ester group, should be followed by spontaneous nucleophilic attack
of the organometallic species at the ester group, and give the
pentacyclic ketone 13-deazaascididemin (4). Following our pre-
viously reported synthesis of the azafluorenone alkaloid 6-
methyoxyonychine,30a,37 bromoester 12b was treated with n-
butyllithium at ꢁ100 ꢀC and then warmed up, but not even traces of
4 could be detected. The same disappointing results were obtained
when tert-butyllithium, isopropylmagnesium chloride,38 and
Scheme 1. Reagents and conditions: (a) phenylboronic acid, Pd(Ph3P)4 (cat.), K2CO3,
THF, H2O, 12 h, reflux (60%); (b) CF3eSO3H, 110 ꢀC, microwave irradiation (150 W), 1 h
(42%); (c) PPA, 130 ꢀC, 5 h (22%).

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A. Plodek et al. / Tetrahedron 69 (2013) 9857e9864
Scheme 2. Reagents and conditions: (a) methyl pyruvate, H2O2, FeSO4, H2SO4, acetic acid, 0 ꢀC, 2 h, then MnO2, CH2Cl2, microwave irradiation (150 W), 100 ꢀC, 30 min (93%); (b)
(het)areneboronic acid, Pd(Ph3P)4 (cat.), K2CO3, THF, H2O, 12 h, reflux; products and yields: 12a: Ar¼phenyl (63%), 12b: Ar¼2-bromophenyl (75%), 12c: Ar¼4-methoxyphenyl (74%),
12d: Ar¼2-naphthyl (61%), 12e: Ar¼2-thienyl (56%), 12f: Ar¼5-methyl-2-thienyl (64%), 12g: Ar¼5-chloro-2-thienyl (41%), 12h: Ar¼5-acetyl-2-thienyl (55%), 12i : Ar¼3-thienyl
(81%), 12j: Ar¼benzothien-2-yl (65%); (c) CF3eSO3H, 110 ꢀC, microwave irradiation (150 W), 1 h; products and yields: 4: (from 12a) 63%, 13d: 79%,13e: 91%, 13f: 68%, 13i: 65%,
13j: 92%. For details concerning the compounds 12b, 12c, 14, and 15, see text.
isopropylmagnesium chlorideelithium chloride39 were applied for
the desired bromo-metal exchange. Analysis of the resulting com-
plex mixtures of products indicated that the organometallic re-
agents underwent addition reactions to the starting material. This
3. Experimental section
3.1. General
is in accordance with reports of Queguiner31b,40 about nucleophilic
All solvents used were of HPLC grade or p.a. grade and/or pu-
rified according to standard procedures. Chemical reagents were
purchased from Sigma Aldrich (Schnelldorf, Germany), ABCR
(Karlsruhe, Germany) and Acros (Geel, Belgium). IR measurements
were performed with a Perkin Elmer FTIR Paragon 1000 spec-
trometer. All melting points were determined by open tube capil-
ꢀ
additions of organometallic reagents to benzo[c][2,7]naphthyr-
idines. As bis[2-(N,N-dimethylamino)ethyl] ether has been de-
scribed to suppress nucleophilic addition of isopropylmagnesium
chloride to pyrimidines,41 we investigated this additive, too, but
once again ended up with a complex mixture of products.
Surprisingly, the precursor 12c bearing an electron-rich 4-
methoxyphenyl residue did not give the expected methoxy-
substituted 13-deazaascididemin upon treatment with tri-
fluoromethanesulfonic acid, but we isolated the uncyclized 4-
hydroxy product 15. We assume that in this case acid-mediated
cleavage of the methyl ether occurs faster than the cyclization re-
action. The product 15 should be protonated at N-3 under the
strongly acidic conditions, and the so generated positive charge can
be delocalized to the hydroxyl group in this merocyanine-like salt,
thus rendering the phenyl ring less nucleophilic for the desired
acylation.
In conclusion, we have worked out a novel approach to ring A-
modified analogues of ascididemin-type marine pyridoacridine
alkaloids. This protocol enables us to perform structural variations
at a critical edge of the pentacyclic ring system in a very effective
manner, since the ring whose variation is of special interest (ring
A)20,21 can be introduced using commercially available arenebor-
onic acids in the next-to-last step of the synthesis. The final step is
a superacid- and microwave-assisted intramolecular acylation,
which works well with electron-rich aromatic residues. Work is in
progress to determine the biological activities of the new alkaloid
analogues.
€
lary method on a Buchi melting point B-450 apparatus and are
uncorrected. NMR spectra were recorded on Jeol JNMR-GX 400
(400 MHz) and Jeol JNMR-GX 500 (500 MHz) spectrometers with
tetramethylsilane as internal standard. NMR-Spectra were recorded
in deuterated solvents and chemical shifts are reported in parts per
million (ppm). J values are given in Hertz. Multiplicities are ab-
breviated as follows: s¼singlet, d¼doublet, t¼triplet, m¼multiplet.
Signal assignments were carried out based on 1H, 13C, HMBC,
HMQC, and COSY spectra. Mass spectra (MS) were run by atmo-
spheric pressure chemical ionization (APCI) on an AB Sciex API
2000 LC/MS/MS system or by chemical impact (CI) using a Hewlett
Packard 5989A mass spectrometer with 59980B Particle Beam LC/
MS Interface. HRMS were performed by electron impact (EI) at
70 eV on a Jeol GCmate II or on a Finnigan MAT 95 spectrometer.
Microwave-promoted syntheses were performed on a single-mode
microwave reactor (Discover) equipped with an IR temperature
sensor from CEM (Kamp-Lintfort, Germany). All reactions were
monitored by thin-layer chromatography (TLC) using precoated
plastic sheets POLYGRAMÒ SIL G/UV254 from MachereyeNagel
€
(Duren, Germany). Compounds on TLC plates were detected under
UV light at 254 nm and 366 nm. Chromatographic purification of
products was performed by using flash column chromatography

A. Plodek et al. / Tetrahedron 69 (2013) 9857e9864
9861
(FCC) on Merck silica gel 60 as stationary phase. Solutions were
concentrated in vacuo on a Heidolph rotary evaporator. Purity of all
synthesized compounds was >95%, determined by HPLC on
a Merck Hitachi LaChrom HPLC system equipped with a Poroshell
120 EC-C18 column (3.0ꢂ100 mm), with acetonitrile/water/THF
(700:298:2) eluent and UV detection at 210 and 254 nm.
9-H), 7.66e7.68 (m, 2H, 20-, 60-H), 7.49e7.53 (m, 3H, 30-, 40-, 50-H),
3.64 (q, J¼7.0 Hz, 2H, OCH2), 1.15 (t, J¼7.0 Hz, 3H, CH3). 13C NMR
(CDCl3):
d
(ppm)¼166.5 (C]O), 160.9 (C-4), 152.6 (C-5), 147.5 (C-2),
143.6 (C-6a, C-10b), 140.1 (C-10), 131.3 (C-8), 130.8 (C-7), 129.8 (C-
30), 129.4 (C-50), 129.0 (C-9), 128.5 (C-20, -40, -60), 122.8 (C-10), 122.5
(C-10a), 116.0 (C-4a), 113.7 (C-1), 62.2 (OCH2), 13.7 (CH3). m/z
(APCI)¼329 [MþH]þ. HRMS (EI): calcd for C21H16N2O2: 328.1212,
found 328.1217.
3.2. General procedure A (Suzuki cross-coupling)
A argon-flushed 50 mL flask was charged with methyl 4-
bromobenzo[c][2,7]naphthyridine-5-carboxylate (11) (0.316 g,
1.00 mmol) or ethyl 4-bromobenzo[c][2,7]naphthyridine-5-
carboxylate (6)24a (0.330 g, 1.00 mmol), tetrakis(triphenylpho-
sphine)palladium(0) (0.110 g, 0.100 mmol), the particular (het)are-
neboronic acid (1.3 mmol), and K2CO3 (0.138 g, 1.00 mmol). The flask
was purged with argon and a degassed mixture of THF (12 mL) and
water (2 mL) was added. The mixture was refluxed for 12 h. After
cooling to room temperature, the mixture was poured into water
(50 mL) and extracted with dichloromethane (3ꢂ30 mL). The com-
bined organic phases were dried over MgSO4 and concentrated un-
der reduced pressure. The residue was further purified by FCC
(dichloromethane/ethyl acetate 6:1).
3.4.3. 4-Phenylbenzo[c][2,7]naphthyridine (7b). Ethyl 4-phenylbe-
nzo[c][2,7]naphthyridine-5-carboxylate (7a) (46 mg (0.13 mmol))
and polyphosphoric acid (1.2 g) were heated with stirring for 5 h at
130 ꢀC, then ice-cold water (30 mL) was added, and after stirring for
10 min, the mixture was neutralized carefully with K2CO3 and
extracted with dichloromethane (3ꢂ30 mL). The combined organic
phases were dried over MgSO4 and concentrated under vacuum.
The product was further purified by FCC (dichloromethane/ethyl
acetate 3:1) to yield 7b (8 mg; 22%) as a white solid. Mp 163 ꢀC. IR
~
(KBr):
n
(cmꢁ1)¼3432, 3051, 2924, 2361, 2345, 1745, 1596, 1553,
1518, 1427, 1361, 1226, 1178, 1135, 1069, 1029. 1H NMR (CDCl3):
d
(ppm)¼9.53 (s, 1H, 5-H), 9.01 (d, J¼5.6 Hz, 1H, 2-H), 8.62 (dd,
J¼8.2 Hz, 1.3 Hz, 1H, 7-H), 8.42 (d, J¼5.6 Hz, 1H, 1-H), 8.24 (dd,
J¼8.2 Hz, 1.3 Hz, 1H, 10-H), 7.92 (t, J¼7.1 Hz, 1H, 8-H), 7.80 (m, 3H, 9-
H, 10, 60-H), 7.64e7.59 (m, 3H, 30-H, 40-H, 50-H). 13C NMR (CDCl3):
3.3. General procedure B (ring closure with tri-
fluoromethanesulfonic acid)
d
(ppm)¼161.6 (C-4), 152.0 (C-5), 148.0 (C-2), 145.9 (C-6a), 138.6 (C-
11), 137.9 (C-10), 130.9 (C-60, 20), 130.4 (C-8), 130.2 (C-10), 129.4 (C-
40), 128.7 (C-30, -50), 127.8 (C-9), 122.9 (C-7), 122.1 (C-4a), 119.0 (C-
10a), 114.3 (C-1). m/z (APCI)¼257 ([MþH]þ). HRMS (EI): calcd for
0.5 mL Trifluoromethanesulfonic acid was added to the 4,5-
disubstituted benzo[c][2,7]naphthyridine (7a/8/9/11aej) in
a flame-dried argon-flushed microwave vessel. The reaction was
performed in a single-mode microwave reactor under nitrogen
atmosphere at a maximum output of 150 W, a maximum temper-
ature of 110 ꢀC, and a reaction time of 60 min. After cooling, the
reaction mixture was poured into water (30 mL), neutralized with
K2CO3 and extracted with dichloromethane (3ꢂ40 mL). The com-
bined organic phases were dried over MgSO4 and concentrated
under vacuum. The product was further purified by FCC
(dichloromethane/ethyl acetate 4:1).
C
18H12N2: 256.1001, found 256.1001.
3.4.4. Ethyl 4-(4-chlorophenyl)benzo[c][2,7]naphthyridine-5-
carboxylate (8). Prepared following general procedure A from es-
ter 6 and 4-chlorophenylboronic acid (0.203ꢀg; 1.30 mmol) to yield
~
0.145 g (40%) as a white solid. Mp 165e167 C. IR (KBr):
n
(cmꢁ1)¼
3432, 3051, 2361, 1745, 1596, 1553, 1518, 1427, 1226, 1029, 889, 701.
1H NMR (CDCl3):
d
(ppm)¼9.00 (d, J¼5.7 Hz, 1H, 2-H), 8.62 (dd,
J¼8.2, 1.3 Hz, 1H, 7-H), 8.42 (d, J¼5.7 Hz, 1H, 1-H), 8.31 (dd, J¼8.2,
1.3 Hz, 1H, 10-H), 7.92 (t, J¼7.1 Hz, 1H, 8-H), 7.83 (t, J¼7.1 Hz, 1H, 9-
H), 7.59e7.65 (m, 2H, 20-, 60-H), 7.46e7.51 (m, 2H, 30-, 50-H), 3.75 (q,
J¼7.2 Hz, 2H, OCH2), 1.19 (t, J¼7.2 Hz, 3H, ester CH3). 13C NMR
3.4. Synthetic products
3.4.1. 9H-Benzo[b]pyrido[4,3,2-mn]acridin-9-one (4). Prepared fol-
lowing general procedure B from 12a (0.078 g; 0.250 mmol) to yield
0.044 g (63%) as a yellow solid. Mp 256e258 ꢀC, lit.23: mp 254 ꢀC. IR
~
(CDCl3):
d
(ppm)¼166.4 (C]O), 159.5 (C-4), 152.2 (C-5), 147.5 (C-2),
143.6 (C-6a), 140.1 (C-10b), 139.1 (C-40), 135.7 (C-10), 131.5 (C-8),
131.0 (C-20, -60), 130.8 (C-7), 129.2 (C-9), 128.7 (C-30, -50), 122.8 (C-
10), 122.4 (C-10a), 115.9 (C-4a), 113.9 (C-1), 62.4 (OCH2), 13.7 (CH3).
m/z (CI)¼365 [MþH]þ (34), 363 [MþH]þ (100), 318 (4), 234 (6), 129
(4). HRMS (EI): calcd for C21H15N2O2Cl: 362.0822, found 362.0812.
(KBr):
n
(cmꢁ1)¼3441, 3058, 2345, 1677, 1593, 1571, 1515, 1422,
1392, 1262, 1229, 1054, 778, 735. 1H NMR (CDCl3):
d
(ppm)¼9.07 (d,
J¼5.7 Hz, 1H, 2-H), 8.89 (d, J¼7.9 Hz, 1H, 13-H), 8.65 (d, J¼8.1 Hz, 1H,
4-H), 8.62 (d, J¼8.1 Hz, 1H, 7-H), 8.50 (d, J¼7.9 Hz, 1H, 10-H), 8.41 (d,
J¼5.7 Hz,1H, 3-H), 7.99 (t, J¼7.7 Hz,1H, 6-H), 7.91 (t, J¼7.7 Hz,1H, 5-
H), 7.85 (t, J¼7.6 Hz, 1H, 12-H), 7.69 (t, J¼7.6 Hz, 1H, 11-H). 13C NMR
3.4.5. Ethyl 4-(furan-2-yl)benzo[c][2,7]naphthyridine-5-carboxylate
(9). Prepared following general procedure A from ester 6 and fu-
ran-2-boronic acid (0.146 g; 1.30 mmol) to yield 0.117 g (37%) as
(CDCl3):
d
(ppm)¼182.2 (C-9), 150.5 (C-13b), 148.9 (C-2), 146.8 (C-
8a), 145.8 (C-7a), 137.8 (C-3a), 136.1 (C-13a), 134.9 (C-12), 133.0 (C-
7), 132.4 (C-9a), 131.6 (C-6), 131.2 (C-11), 130.3 (C-5), 128.7 (C-10),
125.7 (C-13),123.4 (C-3b),122.8 (C-4), 116.9 (C-13c), 115.5 (C-3). m/z
(APCI)¼283 [MþH]þ. HRMS (EI): calcd for C19H10N2O: 282.0793,
found 282.0798.
(cmꢁ1)¼3429, 3136, 2975,
ꢀ
~
a white solid. Mp 156e158 C. IR (KBr):
n
1739, 1590, 1549, 1488, 1463, 1383, 1235, 1108, 1030, 749. 1H NMR
(CDCl3):
d
(ppm)¼8.94 (d, J¼5.5 Hz, 1H, 2-H), 8.57 (d, J¼8.3 Hz, 1H,
7-H), 8.31e8.34 (m, 2H, 1-, 10-H), 7.90 (dd, J¼8.3, 7.5 Hz, 1H, 8-H),
7.80 (dd, J¼8.3, 7.5 Hz, 1H, 9-H), 7.64 (d, J¼1.8 Hz, 1H, 30-H), 7.08 (d,
J¼3.4 Hz, 1H, 50-H), 6.63 (t, J¼3.4, 1.8 Hz, 1H, 40-H), 4.11 (q, J¼7.2 Hz,
2H, OCH2), 1.25 (t, J¼7.2 Hz, 3H, ester CH3). 13C NMR (CDCl3):
Reacting ethyl ester 7a under the same conditions, gave product
4 in 42% yield.
d
(ppm)¼166.3 (C]O),153.7 (C-5),151.7 (C-4),149.4 (C-10),147.5 (C-
3.4.2. Ethyl 4-phenylbenzo[c][2,7]naphthyridine-5-carboxylate
(7a). Prepared following general procedure A from ester 6 and
phenylboronic acid (0.158 g; 1.30 mmol) to yield 0.197 g (60%) as
~
2), 144.6 (C-30), 143.5 (C-6a), 140.2 (C-10b), 131.4 (C-8), 130.9 (C-7),
129.1 (C-9), 122.6 (C-10), 122.3 (C-10a), 114.9 (C-4a), 113.8 (C-1),
112.5 (C-40), 112.3 (C-50), 62.5 (OCH2), 13.9 (CH3). m/z (CI)¼319
[MþH]þ (100), 248 (4), 163 (2). HRMS (EI): calcd for C19H14N2O3:
318.1005, found 318.1006.
white crystals. Mp 172e174 ꢀC. IR (KBr):
n
(cmꢁ1)¼3443, 2995,
2938,1746,1588,1549,1515,1422,1377,1331,1284,1229,1180,1097,
1025, 771, 748. 1H NMR (CDCl3):
d
(ppm)¼9.01 (d, J¼6.1 Hz, 1H, 2-
H), 8.62 (d, J¼7.7 Hz, 1H, 7-H), 8.41 (d, J¼6.1 Hz, 1H, 1-H), 8.31 (d,
J¼7.7 Hz, 1H, 10-H), 7.91 (t, J¼7.7 Hz, 1H, 8-H), 7.82 (t, J¼7.7 Hz, 1H,
3.4.6. Methyl 4-bromobenzo[c][2,7]naphthyridine-5-carboxylate
(11). Solution A: H2O2 (30% solution; 0.340 g; 3.00 mmol) and

9862
A. Plodek et al. / Tetrahedron 69 (2013) 9857e9864
methyl pyruvate (0.459 g; 4.50 mmol) were mixed and stirred at
ꢁ10 ꢀC for 10 min. Solution B: A solution of FeSO4$7H2O (0.83 g;
3.00 mmol) in 5 mL water was stirred at ꢁ10 ꢀC for 10 min. Solu-
tions A and B were added simultaneously over 10 min to a vigor-
ously stirred, ice-cold solution of 4-bromobenzo[c][2,7]
naphthyridine24a (10; 0.258 mg; 1.00 mmol) in a mixture of sulfuric
acid (96%; 0.29 g; 3.00 mmol), 2.5 mL water and 7.5 mL glacial
acetic acid. The reaction mixture was stirred at 0 ꢀC for 2 h, then
poured on ice, neutralized with K2CO3 and extracted with
dichloromethane (3ꢂ30 mL). The combined organic phases were
dried over MgSO4 and concentrated under reduced pressure. The
resulting mixture of dihydro derivative and fully aromatic product
(about 9:1) and 10 equiv MnO2 in dichloromethane (10 mL per
mmol substrate) were placed in a microwave vessel. The vessel was
closed tightly and irradiated for 30 min (ramp time: 8 min; 150 W,
maximum temperature 100 ꢀC). After cooling, MnO2 was filtered off
over silica gel and the solution was concentrated under vacuum.
The product was purified by FCC (dichloromethane/ethyl acetate
4:1) to yield 11 (0.295 g; 93%) as a pale yellow solid. Mp 189e191 ꢀC.
~
(cmꢁ1)¼3422, 3066, 3012, 2950, 2834, 1723, 1609, 1585, 1550, 1514,
1463, 1437, 1427, 1383, 1302, 1177, 1091, 838, 767. 1H NMR (CDCl3):
d
(ppm)¼8.98 (d, J¼5.6 Hz, 1H, 2-H), 8.61 (d, J¼8.1 Hz,1H, 7-H), 8.36
(d, J¼5.7 Hz, 1H, 1-H), 8.30 (d, J¼8.1 Hz, 1H, 10-H), 7.91 (t, J¼7.6 Hz,
1H, 8-H), 7.82 (t, J¼7.6 Hz, 1H, 9-H), 7.62 (d, J¼8.8 Hz, 2H, 20-, 60-H),
7.05 (d, J¼8.8 Hz, 2H, 30-, 50-H), 3.90 (s, 3H, OCH3), 3.44 (s, 3H,
estereCH3). 13C NMR (CDCl3):
d
(ppm)¼166.8 (C]O), 160.6 (C-40),
160.5 (C-4), 152.5 (C-5), 147.6 (C-2), 143.6 (C-6a), 140.1 (C-10b),
133.4 (C-10), 131.3 (C-8), 131.1 (C-20, -60), 130.7 (C-7), 129.0 (C-9),
122.8 (C-10), 122.6 (C-10a), 115.9 (C-4a), 114.0 (C-30, -50), 113.2 (C-1),
55.5 (OCH3), 52.8 (estereCH3). m/z (APCI)¼345 [MþH]þ. HRMS (EI):
calcd for C21H16N2O3: 344.1161, found 344.1160.
3.4.10. Methyl 4-(naphthalen-2-yl)benzo[c][2,7]naphthyridine-5-
carboxylate (12d). Prepared following general procedure A from
ester 11 and 2-naphthylboronic acid (0.223 g; 1.30 mmol) to yield
ꢀ
~
0.222 g (61%) as white crystals. Mp 207e209 C. IR (KBr):
n
(cmꢁ1)¼
3434, 3051, 2947, 2847,1731,1585,1549,1433,1424,1381,1285,1236,
1173, 1094, 1020, 769, 756, 736. 1H NMR (CDCl3):
d
(ppm)¼9.04 (d,
IR (KBr):
n
(cmꢁ1)¼3432, 3016, 2947, 2361, 2343, 1744, 1586, 1546,
J¼5.6 Hz,1H, 2-H), 8.61 (d, J¼8.2 Hz,1H, 7-H), 8.40 (d, J¼5.6 Hz,1H,1-
H), 8.31 (d, J¼8.2 Hz, 1H, 10-H), 8.00e8.08 (m, 2H, 20-, 80-H),
7.86e7.95 (m, 4H, 8-, 30-, 60-, 70-H), 7.82 (ddd, J¼8.3, 7.1, 1.3, 1H, 9-H),
7.52e7.57 (m, 2H, 40-, 50-H), 2.97 (s, 3H, CH3). 13C NMR (CDCl3):
1439, 1394, 1232, 1183, 1174, 1014, 942, 874, 836, 795, 761, 628. 1H
NMR (CDCl3):
d
(ppm)¼8.66 (d, J¼5.6 Hz,1H, 2-H), 8.53 (d, J¼8.2 Hz,
1H, 7-H), 8.41 (d, J¼5.6 Hz, 1H, 1-H), 8.26 (d, J¼8.2 Hz, 1H, 10-H),
7.92 (ddd, J¼8.2, 7.2,1.2 Hz,1H, 8-H), 7.82 (ddd, J¼8.2, 7.2,1.2 Hz,1H,
d
(ppm)¼166.8 (C]O), 160.9 (C-4), 152.6 (C-5), 147.8 (C-2), 143.6 (C-
9-H), 4.15 (s, 3H, CH3). 13C NMR (CDCl3):
d
(ppm)¼167.1 (C]O),
6a),140.2 (C-10b),138.0 (C-10),133.5 (C-60a),132.6 (C-20a),131.5 (C-8),
130.8 (C-7), 130.1 (C-80), 129.2 (C-9), 129.0 (C-30), 128.6 (C-60), 127.9
(C-20), 127.2 (C-70), 126.9 (C-40), 126.7 (C-50), 122.9 (C-10), 122.6 (C-
10a), 116.5 (C-4a), 113.7 (C-1), 52.7 (CH3). m/z (APCI)¼365 [MþH]þ.
HRMS (EI): calcd for C24H16N2O2: 364.1212, found 364.1212.
151.8 (C-5), 147.8 (C-2), 143.7 (C-6a), 142.2 (C-10b), 141.4 (C-4), 132.1
(C-8), 130.7 (C-10), 129.4 (C-9), 122.9 (C-7), 121.8 (C-10a), 118.9 (C-
4a), 115.5 (C-1), 53.8 (CH3). m/z (APCI)¼319 [MþH]þ, 317 [MþH]þ.
HRMS (EI): calcd for C14H9BrN2O2: 315.9847, found 315.9846.
3.4.7. Methyl 4-phenylbenzo[c][2,7]naphthyridine-5-carboxylate
(12a). Prepared following general procedure A from ester 11 and
phenylboronic acid (0.158 g; 1.30 mmol) to yield 0.223 g (71%) as
3.4.11. Methyl 4-(thiophen-2-yl)benzo[c][2,7]naphthyridine-5-
carboxylate (12e). Prepared following general procedure A from
ester 11 and 2-thiopheneboronic acid (0.166ꢀg; 1.30 mmol) to yield
~
pale yellow crystals. Mp 183e185 C. IR (KBr):
n
(cmꢁ1)¼3423, 2923,
0.180 g (56%) as a white solid. Mp 231e233 C. IR (KBr):
n
(cmꢁ1)¼
ꢀ
~
2346,1967, 1722, 1585, 1437,1246, 1177, 1097, 1025, 767, 749, 706. 1H
3381, 2949, 2360, 2341, 1733, 1582, 1548, 1439, 1235, 1174, 1098,
NMR (CDCl3):
d
(ppm)¼8.99 (d, J¼5.4 Hz,1H, 2-H), 8.60 (d, J¼7.2 Hz,
1022, 855, 755. 1H NMR (CDCl3):
d
(ppm)¼8.92 (d, J¼5.6 Hz, 1H, 2-
1H, 7-H), 8.38 (d, J¼5.4 Hz,1H,1-H), 8.30 (d, J¼7.2 Hz,1H,10-H), 7.90
(m, 1H, 8-H), 7.81 (m, 1H, 9-H), 7.66 (d, J¼7.2 Hz, 2H, 20-, 60-H),
7.50e7.55 (m, 3H, 30-, 40-, 50-H), 3.35 (s, 3H, CH3). 13C NMR (CDCl3):
H), 8.56 (d, J¼7.8 Hz, 1H, 7-H), 8.30 (m, 2H, 1-, 10-H), 7.90 (t,
J¼7.6 Hz, 1H, 8-H), 7.80 (t, J¼7.6 Hz, 1H, 9-H), 7.59 (dd, J¼5.0, 1.0 Hz,
1H, 30-H), 7.21 (dd, J¼3.5, 0.9 Hz, 1H, 50-H), 7.14 (dd, J¼5.0, 3.6 Hz,
d
(ppm)¼166.6 (C]O), 160.9 (C-4), 152.3 (C-5), 147.6 (C-2), 143.6 (C-
1H, 40-H), 3.56 (s, 3H, CH3). 13C NMR (CDCl3):
d
(ppm)¼166.7 (C]O),
6a), 140.7 (C-10b), 140.0 (C-10), 131.4 (C-8), 130.7 (C-7), 129.7 (C-30,
-50), 129.3 (C-9), 129.1 (C-40), 128.6 (C-20, -60), 122.8 (C-10), 122.5 (C-
10a), 116.1 (C-4a), 113.7 (C-1), 52.6 (CH3). m/z (APCI)¼315 [MþH]þ.
HRMS (EI): calcd for C20H14N2O2: 314.1055, found 314.1043.
153.9 (C-5), 151.9 (C-4), 147.6 (C-2), 143.6 (C-6a), 143.4 (C-10), 140.2
(C-10b), 131.4 (C-8), 130.7 (C-7), 130.6 (C-50), 129.4 (C-9), 129.1 (C-
40), 127.3 (C-30), 122.8 (C-10), 122.3 (C-10a), 116.0 (C-4a), 113.6 (C-1),
52.8 (CH3). m/z (APCI)¼321 [MþH]þ. HRMS (EI): calcd for
C18H12N2O2S: 320.0619, found 320.0618.
3.4.8. Methyl 4-(2-bromophenyl)benzo[c][2,7]naphthyridine-5-
carboxylate (12b). Prepared following general procedure A from
ester 11 and 2-bromophenylboronic acid (0.261 g; 1.30 mmol) to
3.4.12. Methyl
4-(5-methylthiophen-2-yl)benzo[c][2,7]naphthyr-
idine-5-carboxylate (12f). Prepared following general procedure A
from ester 11 and 5-methylthiophene-2-boronic acid (0.185 g;
1.30 mmꢀol) to yield 0.214 g (64%) as a pale orange solid. Mp
~
ꢀ
~
yield 0.294 g (75%) as a yellow solid. Mp 145e147 C. IR (KBr):
n
(cmꢁ1)¼3434, 3047, 2951, 2846, 2222, 1743, 1588, 1434, 1420, 1289,
1233,1173,1094,1021, 912, 843, 768, 752, 724, 615. 1H NMR (CDCl3):
181e143 C. IR (KBr):
n
(cmꢁ1)¼3423, 3064, 2947, 2369, 1717, 1583,
d
(ppm)¼9.06 (d, J¼5.7 Hz,1H, 2-H), 8.65 (dd, J¼8.4,1.1 Hz,1H, 7-H),
1552, 1442, 1374, 1276, 1248, 1176, 1095, 1024, 829, 770, 757, 725. 1H
8.51 (d, J¼5.7 Hz, 1H, 1-H), 8.28 (dd, J¼8.3, 1.3 Hz, 1H, 10-H), 7.92
(ddd, J¼8.4, 7.1,1.4 Hz,1H, 8-H), 7.84 (ddd, J¼8.4, 7.1,1.3 Hz,1H, 9-H),
7.75 (m, 1H, 60-H), 7.45e7.47 (m, 2H, 30-, 50-H), 7.37 (ddd, 1H, 40-H),
NMR (CDCl3):
d
(ppm)¼8.90 (d, 5.6 Hz, 1H, 2-H), 8.56 (d, 8.2 Hz, 1H,
7-H), 8.30 (d, 8.2 Hz, 1H, 10-H), 8.27 (d, 5.7 Hz, 1H, 1-H), 7.89 (t,
J¼7.6 Hz, 1H, 8-H), 7.80 (t, J¼7.6 Hz, 1H, 9-H), 6.99 (d, J¼3.5 Hz, 1H,
50-H), 6.80 (dd, J¼3.5, 1.1 Hz, 1H, 40-H), 3.61 (s, 3H, estereCH3), 2.60
3.42 (s, 3H, CH3). 13C NMR (CDCl3):
d
(ppm)¼166.6 (C]O), 159.3 (C-
4), 152.1 (C-5), 147.8 (C-2), 143.6 (C-6a), 140.2 (C-10), 139.4 (C-10b),
133.0 (C-30), 132.2 (C-60), 131.5 (C-8), 130.7 (C-7), 130.5 (C-40), 129.1
(C-9), 127.1 (C-50), 123.7 (C-20), 122.8 (C-10), 122.5 (C-10a), 116.8 (C-
4a), 114.9 (C-1), 52.7 (CH3). m/z (APCI)¼395 [MþH]þ, 393 [MþH]þ.
HRMS (EI): calcd for C20H13N2O2Br: 392.0160, found 392.0156.
(s, 3H, thiopheneeCH3). 13C NMR (CDCl3):
d
(ppm)¼166.8 (C]O),
154.2 (C-5), 152.1 (C-4), 147.6 (C-2), 144.6 (C-6a), 143.6 (C-10), 141.0
(C-10b), 140.3 (C-30), 131.3 (C-8), 131.0 (C-7), 130.7 (C-50), 129.0 (C-
9), 125.8 (C-40), 122.8 (C-10), 122.4 (C-10a), 115.7 (C-4a), 113.1 (C-1),
52.8 (estereCH3), 15.6 (thiopheneeCH3). m/z (APCI)¼335 [MþH]þ.
HRMS (EI): calcd for C19H14N2O2S: 334.0776, found 334.0776.
3.4.9. Methyl 4-(4-methoxyphenyl)benzo[c][2,7]naphthyridine-5-
carboxylate (12c). Prepared following general procedure A from
ester 11 and 4-methoxyphenylboronic acid (0.198 g;ꢀ1.30 mmol) to
~
3.4.13. Methyl 4-(5-chlorothiophen-2-yl)benzo[c][2,7]naphthyridine-
5-carboxylate (12g). Prepared following general procedure A from
ester 11 and 5-chlorothiophene-2-boronic acid (0.211 g;
yield 0.255 g (74%) as a white solid. Mp 173e175 C. IR (KBr):
n

A. Plodek et al. / Tetrahedron 69 (2013) 9857e9864
9863
1.30 mmol) to yield 0.146 g (41%) as a yellow solid. Mp 201e203 ꢀC.
331e333 C. IR (KBr):
(cmꢁ1)¼3424, 3056, 2343, 1677, 1620, 1585,
ꢀ
~
n
~
n
IR (KBr):
(cmꢁ1)¼3426, 3074, 3044, 2368, 1724, 1582, 1549, 1447,
1516, 1469, 1418, 1297, 1264, 1175, 1054, 907, 780, 758, 593. 1H NMR
1415, 1385, 1274, 1245, 1176, 1097, 1009, 786, 769, 752, 737. 1H NMR
(CDCl3):
d
(ppm)¼9.31 (s, 1H, 15-H), 9.08 (d, J¼5.6 Hz, 1H, 2-H), 9.06
(CDCl3):
d
(ppm)¼8.88 (d, J¼4.8 Hz, 1H, 2-H), 8.55 (d, J¼7.7 Hz, 1H,
(s, 1H, 10-H), 8.62 (d, J¼8.5 Hz, 2H, 4-, 7-H), 8.38 (d, J¼5.6 Hz, 1H, 3-
H), 8.09 (d, J¼8.1 Hz, 1H, 11-H), 8.06 (d, J¼8.1 Hz, 1H, 14-H), 7.97 (t,
J¼7.5 Hz, 1H, 6-H), 7.88 (t, J¼7.5 Hz, 1H, 5-H), 7.66 (t, J¼6.8 Hz, 1H,
7-H), 8.29e8.31 (m, 2H, 1-, 10-H), 7.90 (dd, J¼9.7, 4.8 Hz, 1H, 8-H),
7.80 (dd, J¼9.7, 4.8 Hz, 1H, 9-H), 6.95e6.97 (ddd, J¼5.5, 3.6, 1.7 Hz,
2H, 40-, 50-H), 3.66 (s, 3H, CH3). 13C NMR (CDCl3):
d
(ppm)¼166.7
12-H), 7.62 (t, J¼6.8 Hz, 1H, 13-H). 13C NMR (CDCl3):
(ppm)¼182.3
d
(C]O),152.9 (C-5), 151.5 (C-4), 147.6 (C-2), 143.6 (C-6a),141.9 (C-10),
140.3 (C-11), 134.5 (C-30), 131.6 (C-8), 130.8 (C-7), 129.6 (C-40), 129.3
(C-9), 126.4 (C-50), 122.8 (C-10), 122.2 (C-10a), 115.5 (C-4a), 113.8 (C-
1), 53.0 (CH3). m/z (APCI)¼355 [MþH]þ. HRMS (EI): calcd for
(C-9), 151.1 (C-15b), 149.1 (C-2), 147.5 (C-8a), 145.8 (C-7a), 138.3 (C-
3a), 136.3 (C-15a), 133.9 (C-10a), 133.0 (C-11), 131.6 (C-7), 131.5 (C-
9a),131.5 (C-6),130.3 (C-13), 130.2 (C-5),129.7 (C-12),129.6 (C-14a),
129.4 (C-10), 128.3 (C-14), 126.4 (C-15), 123.4 (C-3b), 122.9 (C-4),
117.7 (C-15c),115.1 (C-3). m/z (APCI)¼333 [MþH]þ. HRMS (EI): calcd
for C23H12N2O: 332.0950, found 332.0946.
C
18H11ClN2O2S: 354.0230, found 354.0220.
3.4.14. Methyl 4-(5-acetylthiophen-2-yl)benzo[c][2,7]naphthyridine-
5-carboxylate (12h). Prepared following general procedure A from
ester 11 and 5-acetylthiophene-2-boronic acid (0.221 g; 1.30 mmol)
to yield 0.199 g (55%) as a pale yellow solid. Mp 194e196 ꢀC. IR (KBr):
~
3.4.18. 9H-Pyrido[4,3,2-mn]thieno[2,3-b]acridin-9-one
(13e). Prepared following general procedure B from 12e (0.080 g;
0.250 mmol) to yield 0.066 g (91%) as a yellow solid. Mp
~
n
(cmꢁ1)¼3423, 3065, 2376, 1720, 1660, 1582, 1414, 1385, 1275, 1247,
283e285 ꢀC, lit.11e: mpꢃ300 ꢀC. IR (KBr):
n
(cmꢁ1)¼3432, 3099,
1176, 1095, 1022, 789, 770, 608, 593. 1H NMR (CDCl3):
d
(ppm)¼8.96
1666, 1605, 1590, 1523, 1447, 1415, 1273, 1058, 1006, 894, 761, 735,
(d, J¼5.6 Hz, 1H, 2-H), 8.59 (d, J¼8.2 Hz, 1H, 7-H), 8.39 (d, J¼5.6 Hz,
1H, 1-H), 8.33 (d, J¼8.2 Hz, 1H, 10-H), 7.93 (t, J¼7.6 Hz, 1H, 8-H), 7.84
(t, J¼7.6 Hz, 1H, 9-H), 7.70 (d, J¼3.9 Hz, 1H, 40-H), 7.20 (d, J¼3.9 Hz,
1H, 50-H), 3.57 (s, 3H, estereCH3), 2.64 (s, 3H, acetyleCH3). 13C NMR
660. 1H NMR (CDCl3):
d
(ppm)¼8.89 (d, J¼5.8 Hz, 1H, 2-H), 8.58 (d,
J¼8.6 Hz, 2H, 4-, 7-H), 8.31 (d, J¼5.8 Hz, 1H, 3-H), 7.96 (m, 1H, 6-H),
7.89 (ddd, J¼8.1, 7.1, 1.2 Hz, 1H, 5-H), 7.83 (d, J¼5.2 Hz, 1H, 11-H),
7.52 (d, J¼5.1 Hz, 1H, 10-H). 13C NMR (CDCl3):
d
(ppm)¼177.4 (C-9),
(CDCl3):
d
(ppm)¼190.7 (C]O, acetyl) 166.6 (C]O, ester), 152.9 (C-
149.6 (C-12a), 149.0 (C-2), 148.4 (C-12b), 147.7 (C-7a), 145.9 (C-8a),
139.6 (C-3a), 137.4 (C-9a), 133.2 (C-7), 131.7 (C-6), 130.6 (C-5), 129.4
(C-11),127.5 (C-10),122.9 (C-3b),122.8 (C-4),115.9 (C-12c), 115.6 (C-
3). m/z (APCI)¼289 [MþH]þ. HRMS (EI): calcd for C17H8N2OS:
288.0357, found 288.0349.
5), 151.3 (C-4), 150.8 (C-10), 147.8 (C-2), 146.5 (C-6a), 143.7 (C-30),
140.3 (C-10b), 131.8 (C-40), 131.7 (C-50), 130.9 (C-8), 130.5 (C-7), 129.6
(C-9), 122.9 (C-10), 122.3 (C-10a), 116.0 (C-4a), 114.7 (C-1), 53.0
(estereCH3), 27.2 (acetyleCH3). m/z (APCI)¼[MþH]þ. HRMS (EI):
calcd for C20H14N2O3S: 362.0725, found 362.0720.
3.4.19. 11-Methyl-9H-pyrido[4,3,2-mn]thieno[2,3-b]acridin-9-one
(13f). Prepared following general procedure B from 12f (0.084 g;
0.250 mmol) to yield 0.051 g (68%) as an orange solid. Mp
3.4.15. Methyl 4-(thiophen-3-yl)benzo[c][2,7]naphthyridine-5-
carboxylate (12i). Prepared following general procedure A from
ester 11 and 3-thiopheneboronic acid (0.166ꢀg; 1.30 mmol) to yield
~
284e286 C. IR (KBr):
n
(cmꢁ1)¼3428, 2921, 1674, 1662, 1591, 1494,
ꢀ
~
0.259 g (81%) as a brown solid. Mp 212e214 C. IR (KBr):
n
(cmꢁ1)¼
1425, 1411, 1266, 1222, 1139, 1067, 883, 758, 745, 724, 697. 1H NMR
3409, 3102, 3065, 2948, 2363, 1717, 1584, 1553, 1441, 1374, 1248,
(CDCl3):
d
(ppm)¼8.84 (d, J¼5.8 Hz, 1H, 2-H), 8.56 (d, J¼8.6 Hz 2H,
1095, 1024, 840, 829, 770, 725, 668. 1H NMR (CDCl3):
d
(ppm)¼8.92
4-, 7-H), 8.25 (d, J¼5.8 Hz, 1H, 3-H), 7.95 (ddd, J¼8.3, 7.0, 1.4 Hz, 1H,
6-H), 7.87 (ddd, J¼8.4, 7.1, 1.3 Hz, 1H, 5-H), 7.48 (s, 1H, 10-H), 2.62 (s,
(d, J¼5.6 Hz, 1H, 2-H), 8.54 (d, J¼8.1 Hz, 1H, 7-H), 8.31 (d, J¼5.6 Hz,
1H, 1-H), 8.26 (d, J¼8.1 Hz, 1H, 10-H), 7.86 (ddd, J¼8.3, 7.1, 1.4, 1H, 8-
H), 7.77 (ddd, J¼8.3, 7.1, 1.3, 1H, 9-H), 7.55 (dd, J¼4.9, 1.4 Hz, 1H, 50-
H), 7.50e7.46 (m, 2H, 20-, 40-H), 3.54 (s, 3H, CH3). 13C NMR (CDCl3):
3H, CH3). 13C NMR (CDCl3):
d
(ppm)¼177.3 (C-9), 149.0 (C-2), 148.6
(C-12a), 147.9 (C-12b), 147.7 (C-7a), 145.9 (C-8a), 144.8 (C-11), 140.0
(C-3a), 137.3 (C-9a), 133.1 (C-7), 131.5 (C-6), 130.5 (C-5), 125.2 (C-
10), 123.0 (C-3b), 122.8 (C-4), 115.7 (C-12c), 115.1 (C-3), 15.9 (CH3).
m/z (APCI)¼303 [MþH]þ. HRMS (EI): calcd for C18H10N2OS:
302.0514, found 302.0528.
d
(ppm)¼166.8 (C]O), 155.9 (C-5), 152.3 (C-4), 147.8 (C-2), 143.6 (C-
6a), 142.1 (C-10b), 139.9 (C-10), 131.4 (C-8), 130.8 (C-7), 129.2 (C-9),
128.6 (C-50), 127.0 (C-40), 126.6 (C-20), 122.9 (C-10), 122.5 (C-10a),
116.5 (C-4a), 113.7 (C-1), 52.9 (CH3). m/z (APCI)¼321 [MþH]þ.
HRMS (EI): calcd for C18H12N2O2S: 320.0619, found 320.0610.
3.4.20. 9H-Pyrido[4,3,2-mn]thieno[3,2-b]acridin-9-one
(13i). Prepared following general procedure B from 12i (0.080 g;
0.250 mmol) to yield 0.047 g (65%) as a yellow solid. Mp
3.4.16. Methyl
4-(benzo[b]thiophen-2-yl)benzo[c][2,7]naphthyr-
ꢀ
~
299e301 C. IR (KBr):
n
idine-5-carboxylate (12j). Prepared following general procedure A
from ester 11 and 2-benzo[b]thiophene-2-boronic acid (0.231 g;
1.30 mmol) to yield 0.241 g (65%) as a yellow solid. Mp 214e216 ꢀC.
~
(cmꢁ1)¼3445, 3076, 2852, 1662, 1590, 1513,
1453, 1416, 1377, 1284, 1255, 1181, 1020, 909, 820, 743, 568. 1H NMR
(CDCl3):
d
(ppm)¼8.97 (d, J¼5.9 Hz, 1H, 2-H), 8.60 (d, J¼7.4 Hz, 2H,
IR (KBr):
n
(cmꢁ1)¼3418, 3053, 2952, 1720, 1583, 1550, 1457, 1417,
4-, 7-H), 8.36 (d, J¼5.9 Hz, 1H, 3-H), 8.05 (d, J¼5.1 Hz,1H, 11-H), 7.97
1384, 1272, 1245, 1175, 1097, 1023, 842, 779, 767, 750. 1H NMR
(t, J¼7.7 Hz, 1H, 6-H), 7.88e7.92 (m, 2H, 5-, 12-H). 13C NMR (CDCl3):
(CDCl3):
d
(ppm)¼8.99 (d, J¼5.6 Hz, 1H, 2-H), 8.60 (d, J¼8.2 Hz, 1H,
d
(ppm)¼176.3 (C-9), 149.0 (C-2), 148.9 (C-12a), 147.9 (C-12b), 146.1
7-H), 8.37 (d, J¼5.6 Hz, 1H, 1-H), 8.32 (d, J¼8.2 Hz, 1H, 10-H),
(C-7a),145.8 (C-8a),140.2 (C-3a),137.7 (C-9a),136.2 (C-11),133.1 (C-
7), 131.6 (C-6), 130.6 (C-5), 125.9 (C-12), 123.3 (C-3b), 122.8 (C-4),
116.6 (C-12c), 115.6 (C-3). m/z (APCI)¼289 [MþH]þ. HRMS (EI):
calcd for C17H8N2OS: 288.0357, found 288.0359.
7.91e7.95 (m, 2H, 8-, 30-H), 7.80e7.85 (m, 2H, 9-, 60-H), 7.38e7.44
(m, 3H, 40-, 50-, 70-H), 3.31 (s, 3H, CH3). 13C NMR (CDCl3):
d
(ppm)¼
166.6 (C]O), 154.3 (C-5), 151.9 (C-4), 147.7 (C-2), 143.7 (C-6a), 143.1
(C-10), 141.1 (C-60a), 140.3 (C-20a), 139.4 (C-10b), 131.6 (C-8), 130.8
(C-7), 129.3 (C-9), 127.7 (C-40), 125.8 (C-50), 124.8 (C-60), 124.4 (C-30),
122.8 (C-10), 122.6 (C-70), 122.3 (C-10a), 116.4 (C-4a), 114.1 (C-1),
52.9 (CH3). m/z (APCI)¼371 [MþH]þ. HRMS (EI): calcd for
3.4.21. 9H-Benzo[4,5]thieno[2,3-b]pyrido[4,3,2-mn]acridin-9-one
(13j). Prepared following general procedure B from 12j (0.092 g;
0.250 mmol) to yield 0.078 g (92%) as an orange solid. Mp
~
C
22H14N2O2S: 370.0776, found 370.0769.
336e337 ꢀC. IR (KBr):
n
(cmꢁ1)¼3433, 1661, 1591, 1461, 1418, 1382,
1153, 1121, 749, 722. 1H NMR (CDCl3):
d
(ppm)¼8.96e8.99 (m, 2H),
3.4.17. 9H-Naphtho[2,3-b]pyrido[4,3,2-mn]acridin-9-one
(13d). Prepared following general procedure B from 12d (0.091 g;
0.250 mmol) to yield 0.066 g (79%) as a yellow solid. Mp
8.61e8.62 (m, 2H), 8.39 (d, J¼5.8 Hz, 1H), 7.95e7.98 (m, 2H), 7.91
(ddd, J¼8.3, 5.5,1.3 Hz,1H), 7.61 (m, 1H), 7.53 (ddd, J¼8.3, 7.2,1.3 Hz,
1H). A 13C NMR spectrum could not be recorded due to the

9864
A. Plodek et al. / Tetrahedron 69 (2013) 9857e9864
7. Copp, B. R.; Kayser, O.; Brun, R.; Kiderlen, A. F. Planta Med. 2003, 69, 527e531.
8. Kobayashi, J.-F.; Cheng, H.; Nakamura, H.; Ohizumi, Y. Tetrahedron Lett. 1988, 29,
1177e1180.
extremely poor solubility of the compound. m/z (APCI)¼339
[MþH]þ. HRMS (EI): calcd for C21H10N2OS: 338.0514, found
338.0508.
9. Bracher, F. Heterocycles 1989, 29, 2093e2095.
10. (a) Bracher, F. Liebigs Ann. Chem. 1990, 205e206; (b) Bracher, F. Liebigs Ann.
Chem. 1992, 1205e1207; (c) Kitahara, Y.; Nakahara, S.; Yonezawa, T.; Nagatsu,
M.; Shibano, Y.; Kubo, A. Tetrahedron 1997, 53, 17029e17038.
11. (a) Peterson, J. R.; Zjawiony, J. K.; Liu, S.; Hufford, C. D.; Clark, A. M.; Rogers, R. D.
J. Med. Chem. 1992, 35, 4069e4077; (b) Lindsay, B. S.; Christiansen, H. C.; Copp,
B. R. Tetrahedron 2000, 56, 497e505; (c) Brahic, C.; Darro, F.; Belloir, M.; Bastide,
J.; Kiss, R.; Delfourne, E. Bioorg. Med. Chem. 2002, 10, 2845e2853; (d) Appleton,
D. R.; Pearce, A. N.; Copp, B. R. Tetrahedron 2010, 66, 4977e4986; (e) Hepburn,
S. A.; Jackson, Y. A. Heterocycles 2006, 68, 975e981.
3.4.22. 4-(2-Bromophenyl)benzo[c][2,7]naphthyridine
compound was obtained by treating 11b (0.098 g; 0.250 mmol)
under the reaction conditions of general procedure B, yield: 0.039 g
(14). This
(46%), brown solid. Mp 136e138 C. IR (KBr):
n
(cmꢁ1)¼3439, 3049,
ꢀ
~
2345,1602,1576,1557,1516,1425,1360,1248,1225,1954,1027,1014,
891, 844, 763, 748, 616. 1H NMR (CDCl3):
d
(ppm)¼9.09 (s, 1H, 5-H),
12. Koller, A.; Rudi, A.; Garcia, G. M.; Kashman, Y. Molecules 2001, 6, 300e322.
9.01 (d, J¼5.7 Hz, 1H, 2-H), 8.62 (dd, J¼8.3, 1.1 Hz, 1H, 7-H), 8.44 (d,
J¼5.7 Hz,1H,1-H), 8.23 (dd, J¼8.2,1.0 Hz,1H,10-H), 7.87 (ddd, J¼8.3,
7.1,1.4 Hz,1H, 8-H), 7.74e7.78 (m, 2H, 9-, 60-H), 7.52e7.53 (m, 2H, 30-,
ꢀ
13. Cuerva, J. M.; Cardenas, D. J.; Echavarren, A. M. J. Chem. Soc., Perkin Trans. 1 2002,
1360e1365.
14. Alvarez, M.; Feliu, L.; Ajana, W.; Joule, J. A.; Fernandez-Puentes, J. L. Eur. J. Org.
Chem. 2000, 849e855.
15. Bracher, F. Liebigs Ann. Chem. 1989, 87e88.
16. Moody, C. J.; Rees, C. W.; Thomas, R. Tetrahedron 1992, 48, 3589e3602.
17. Petersen, I. N.; Crestey, F.; Kristensen, J. L. Chem. Commun. 2012, 9092e9094.
18. Ciufolini, M. A.; Shen, Y.-C.; Bishop, M. J. J. Am. Chem. Soc. 1997, 117,
12460e12469.
19. (a) Bracher. J. Heterocycl. Chem. 1993, 30, 157e159; (b) Guillier, F.; Nivoliers, F.;
Godard, A.; Marsais, F.; Queguiner, G.; Siddiqui, M. A.; Snieckus, V. J. Org. Chem.
1995, 60, 292e296.
50-H), 7.40e7.44 (m, 1H, 40-H). 13C NMR (CDCl3):
d
(ppm)¼160.6 (C-
4), 151.8 (C-5), 147.9 (C-2), 145.4 (C-6a), 138.8 (C-10), 137.9 (C-10b),
133.0 (C-30), 131.4 (C-60), 131.0 (C-8), 130.6 (C-7), 130.4 (C-40), 127.8
(C-9), 127.6 (C-50), 123.0 (C-20), 122.9 (C-10), 122.1 (C-10a), 119.5 (C-
4a), 115.2 (C-1). m/z (APCI)¼337 [MþH]þ, 335 [MþH]þ. HRMS (EI):
calcd for C18H11N2Br: 335.1973, found 335.0027.
20. (a) Delfourne, E.; Kiss, R.; Le Corre, L.; Merza, J.; Bastide, J.; Frydman, A.; Darro,
F. Bioorg. Med. Chem. 2003, 11, 4351e4356; (b) Lindsay, B. S.; Barrows, L. R.;
Copp, B. R. Bioorg. Med. Chem. Lett. 1995, 5, 739e742.
3.4.23. Methyl 4-(4-hydroxyphenyl)benzo[c][2,7]naphthyridine-5-
carboxylate (15). This compound was obtained by treating 12c
(0.086 g; 0.250 mmol) under the reaction conditions of general
procedure B, yield: 0.033 g (39%), brown solid. Mp 221e223 ꢀC. IR
~
21. Debnath, B.; Gayen, S.; Bhattacharya, S.; Samanta, S.; Jha, T. Bioorg. Med. Chem.
2003, 11, 5493e5499.
22. Marshall, K. M.; Holden, J. A.; Koller, A.; Kashman, Y.; Copp, B. R.; Barrows, L. R.
Anticancer Drugs 2004, 15, 907e913.
(KBr):
n
(cmꢁ1)¼3425, 3052, 2948, 2345, 1719, 1612, 1581, 1548,
1517, 1438, 1426, 1384, 1353, 1285, 1242, 1200, 1180, 1170, 1095,
23. Raeder, S.; Bracher, F. Arch. Pharm. Chem. Life Sci. 2012, 345, 822e826.
24. (a) Plodek, A.; Raeder, S.; Bracher, F. Tetrahedron 2012, 68, 4693e4700; (b) For
an early example of homolytic ethoxycarbonylation, see: Bernardi, R.; Caronna,
T.; Galli, R.; Minisci, F.; Perchinunno, M. Tetrahedron Lett. 1973, 14, 645e648.
25. Janin, Y. L.; Roulland, E.; Berdeley-Thomas, A.; Decaudin, D.; Monneret, C.;
Poupon, M.-F. J. Chem. Soc., Perkin Trans. 1 2002, 529e532.
26. Baik, C.; Hudson, Z. M.; Amarne, H.; Wang, S. J. Am. Chem. Soc. 2009, 131,
14549e14559.
1024, 883, 771. 1H NMR (MeOD-d3/CDCl3¼¼3:1):
d
(ppm)¼8.90 (d,
J¼5.7 Hz, 1H, 2-H), 8.79 (d, J¼7.5 Hz, 1H, 7-H), 8.60 (d, J¼5.7 Hz, 1H,
1-H), 8.23 (d, J¼7.5 Hz, 1H, 10-H), 7.97 (ddd, J¼8.3, 7.2, 1.4 Hz, 1H, 8-
H), 7.89 (m, 1H, 9-H), 7.46 (d, J¼8.6 Hz, 2H, 20-, 60-H), 6.96 (d,
J¼8.6 Hz, 2H, 30-, 50-H), 5.43 (s, 1H, OH), 3.44 (s, 3H, CH3). 13C NMR
(MeOD-D3/CDCl3¼3:1):
d
(ppm)¼166.85 (C]O), 161.0 (C-40), 159.0
27. (a) Bracher, F. Arch. Pharm. (Weinheim, Ger.) 1989, 322, 293e294; (b) Mink, K.;
Bracher, F. Arch. Pharm. Chem. Life Sci. 2007, 340, 429e433.
(C-4), 152.6 (C-5), 147.1 (C-2), 143.4 (C-6a), 140.7 (C-10), 131.7 (C-8),
131.4 (C-10b), 131.3 (C-20, -60), 129.7 (C-7), 129.3 (C-9), 123.4 (C-10),
122.6 (C-10a), 116.1 (C-4a), 115.3 (C-30, -50), 114.0 (C-1), 52.2 (CH3).
m/z (APCI)¼331 [MþH]þ. HRMS (EI): calcd for C20H14N2O3:
330.1004, found 330.0995.
ꢀ
28. Bennasar, M.-L.; Vidal, B.; Lazaro, A.; Kumar, R.; Bosch, J. Tetrahedron Lett. 1996,
37, 3541e3544.
29. Riahi, A.; Shkoor, M.; Fatunsin, O.; Khera, R. A.; Fischer, C.; Langer, P. Org. Biomol.
Chem. 2009, 7, 4248e4251.
30. (a) Bracher, F. Arch. Pharm. (Weinheim, Ger.) 1994, 327, 371e375; (b) Heiskanen,
J. P.; Hormi, O. E. O. Tetrahedron 2009, 65, 518e524; (c) Krapcho, A. P.; Maresch,
M. J.; Helgason, A. L.; Rosner, K. E.; Hacker, M. P.; Spinelli, S.; Menta, E.; Oliva, A.
J. Heterocycl. Chem. 1993, 30, 1597e1606; (d) Watanabe, M.; Shinoda, E.; Shi-
mizu, Y.; Furukawa, S.; Iwao, M.; Kuraishi, T. Tetrahedron 1987, 43, 5281e5286.
Conflict of interest
ꢀ
31. (a) Guillier, F.; Nivoliers, F.; Cochennec, C.; Godard, A.; Marsais, F.; Queguiner, G.
The authors declare no conflict of interest.
Supplementary data
Synth. Commun. 1996, 26, 4421e4436; (b) Guillier, F.; Nivoliers, F.; Godard, A.;
ꢀ
Marsais, F.; Queguiner, G. J. Heterocycl. Chem. 1999, 36, 1157e1165.
32. Hwang, J. P.; Surya Prakash, G. K.; Olah, G. A. Tetrahedron 2000, 56, 7199e7203.
33. Beger, J.; Treibs, W. Liebigs Ann. 1962, 652, 204e211.
34. Regan, C. F.; Pierre, F.; Schwaebe, M. K.; Haddach, M.; Jung, M. E.; Ryckman, D.
M. Synlett 2012, 443e447.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.08.085.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
35. Compared to the ethyl ester 6, methyl ester 11 gave an enhancement in yields
of more than 30% for coupling reactions with 4-methoxyphenylboronic acid
and 2-thiopheneboronic acid (data for the resulting ethyl esters not shown)
36. The reluctance of 12b to undergo cyclization might also be due to the fact that
the bulky ortho-bromo substituent impedes a coplanar orientation of the ring
systems
References and notes
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40. Cochennec, C.; Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. J. Chem. Soc.,
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