Synthesis of novel oxepine-containing polycyclic-fused quinoline systems

Article abstract of DOI:10.1515/hc-2013-0227

In the present investigation, the incorporation of the oxepine ring into a polycyclic-fused quinoline system leading to a series of structurally novel hybrids benzo[h] areno[6,7]oxepino[3,4-b]quinolin-8(14H)-ones has been achieved through a simple, and economical two-step procedure that involves the one-pot synthesis of 2-(aryloxymethyl) benzo[h]quinoline-3-carboxylic acids followed by intramolecular Friedel-Crafts acylation reaction using Eaton's reagent.

Full text of DOI:10.1515/hc-2013-0227

Heterocycl. Commun. 2014; 20(3): 161–166
Wentao Gao*, Chengming Nie, Liangyu Xu, Binbin Zhao and Yang Li
Synthesis of novel oxepine-containing
polycyclic-fused quinoline systems
Abstract: In the present investigation, the incorporation of benzofuran [14], and benzothienoquinoline [15], fused
the oxepine ring into a polycyclic-fused quinoline system to a quinoline system, and synthetic analogs thereof.
leading to a series of structurally novel hybrids benzo[h] However, to the best of our knowledge, there are very few
areno[6,7]oxepino[3,4-b]quinolin-8(14H)-ones has been reports on a medium-sized seven-membered oxepin ring
achieved through a simple, and economical two-step pro- fused to a quinoline unit [16].
cedure that involves the one-pot synthesis of 2-(aryloxy-
The seven-membered oxepine system is a pharmaceu-
methyl)benzo[h]quinoline-3-carboxylic acids followed tically important structural unit of some natural products
by intramolecular Friedel-Crafts acylation reaction using such as tournefolic acid B (4, Figure 1) [17] and bauhini-
Eaton’s reagent.
astatin 1 (5, Figure 1) [18], and has found wide application
in the design and discovery of novel bioactive molecules
Keywords: intramolecular Friedel-Crafts acylation; one- and drugs. Some compounds with the oxepine ring have
pot synthesis; oxepine; polycyclic-fused; quinoline.
been reported to exhibit potent biological activities such
as antifungal [19], anxiolytic [20], cyclooxygenase inhibi-
tory [21], and aminopeptidase N (APN) inhibitory activities
[22]. Given the importance of the oxepine core as a phar-
macophore, extensive synthetic efforts have been devoted
to the design and synthesis of oxepine-containing hetero-
cycles [23–26]. A recent review concerning the synthesis of
oxepines has been reported [27].
DOI 10.1515/hc-2013-0227
Received December 10, 2013; accepted March 31, 2014
Introduction
It is well known that the development of hybrid com-
pounds through the combination of different chromo-
phores or pharmacophores in a molecular framework
is an important goal of synthetic organic chemistry and
plays a prominent role in modern drug discovery [28]. In
light of these findings, it would be of synthetic importance
to incorporate the oxepine nucleus into planar polycyclic-
fused quinoline systems leading to new prototypes, as
possible drug candidates for pharmacological studies.
Thus, in the context of our ongoing work on the synthe-
sis of fused quinolines [29–32], we would like to report
herein the synthesis of novel oxepine-containing polycy-
clic-fused quinoline systems, wherein the oxepine ring is
fused at its 2,3-position to the b-position of the quinoline
system to give a compact structure exemplified by com-
pounds 6 shown in Figure 1. To the best of our knowledge,
this simple polycyclic-fused system has never been previ-
ously described in the literature.
Polycyclic-fused quinolines are an important group of
compounds in medicinal chemistry [1–3] and are ubiq-
uitous substructures associated with biologically active
natural products such as Luotomins (1, Figure 1) [4] and
Calothrixin B (2, Figure 1) [5]. Studies have shown that
planar polycyclic-fused quinoline systems can cleave DNA
[6] and exhibit significant biological properties such as
antitumoral [7], anti-cancer [8], anti-inflammatory [9],
antibacterial, and antituberculosis activities [10]. For
example, owing to their aromatic character and planar
structure, indenoquinoline derivatives (3, Figure 1) show
potent antiproliferative activities against breast (MCF-
7), lung epithelial (A-549), and cervical (HeLa) adeno-
carcinoma cells [3]. Accordingly, attention has been
increasingly focused on the construction of various
polycyclic-fused quinoline systems. Most reports in the
literature describe a common heteroaromatic system,
such as indene [3], pyrazole [11], pyran [12], indole [13],
*Corresponding author: Wentao Gao, Institute of Superfine
Chemicals, Bohai University, Keji Street, Jinzhou 121000, P.R. China,
e-mail: bhuzh@163.com
Results and discussion
Chengming Nie, Liangyu Xu, Binbin Zhao and Yang Li: Institute of
Superfine Chemicals, Bohai University, Keji Street, Jinzhou 121000,
P.R. China
Recently, we have reported a direct and efficient synthesis
of ethyl 2-(chloromethyl)benzo[h]quinoline-3-carboxylate
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ꢀW. Gao et al.: Oxepine-containing polycyclic-fused quinoline systems
R
O
O
MeO2C
O
OR
H
N
N
OMe
OMe
N
N
N
N
O
Luotomins (1)
Calothrixin B (2)
Indeno[1,2-b]quinolines (3)
OH
O
O
O
Me
OMe
O
OH
OH
N
R
O
HO
O
HO2C
Tournefolic acid B (4)
Bauhiniastatin 1 (5)
Targeted compounds (6)
Figure 1ꢂStructures of natural products and synthetic compounds 1–6.
(8 in Scheme 1) and its application in the one-pot syn- afford intermediates 7. Subsequently, the intramolecular
thesis of 2-(benzofuran-2-yl)benzo[h]quinoline-3-carbox- Friedel-Crafts acylation reaction of 7 would result in the
ylic acid derivatives [29]. The inspiring results obtained formation of the oxepine ring by the generation of a new
prompted us to further study the synthetic application of C-C bond.
8 associated with the construction of a polycyclic-fused
Ethyl 2-(chloromethyl)benzo[h]quinoline-3-carboxy-
oxepine-containing quinoline system. Our synthetic late (8) was first subjected to the Williamson reaction with
plan, as shown in Scheme 1, was to use the 2-chlorome- substituted phenols in the presence of NaOEt as base in
thyl group of 8 to generate the aryloxymethyl moiety via refluxing anhydrous EtOH. In this reaction, the NaOEt/
the Williamson reaction with substituted phenols fol- EtOH base system was selected because the formation
lowed by the transformation of the ethyl ester at its 3-posi- of a precipitate provided a convenient visual indicator of
tion into corresponding quinoline-3-carboxylic acids to the reaction progress. Because the formed aryloxymethyl
ether from the Williamson reaction did not interfere with
further ester hydrolysis reaction, purification at this stage
was unnecessary. Thus, we simply added 80% ethanolic
OH
COOH
O
CO2Et
CH2Cl
potassium hydroxide solution to the reaction mixture and
continued the reflux for an additional 2 h. After the reac-
tion was complete followed by an acidic workup, the cor-
responding free quinoline-3-carboxylic acids 7a–f were
obtained in good overall yields of 78–85%. Owing to the
simplicity and efficiency of the one-pot synthesis, we
further attempted the reaction of 8 with 1-naphthol and
2-naphthol. Interestingly, these substrates were equally
amenable to the one-pot reaction sequence and gave
rise to the corresponding 2-[(naphthalen-1-yloxy)methyl]
benzo[h]quinoline-3-carboxylic acid (7g) and 2-[(naphtha-
len-2-yloxy)methyl]benzo[h]quinoline-3-carboxylic acid
(7h) in 75% and 77% yields, respectively. Products 7a–h
are new compounds and their structures were confirmed
by both spectral data and elemental analyses.
R
N
N
1
2
1) NaOEt, EtOH
2) 80% KOH
3) 1 M HCl
R
8
7a-h
O
1 2
Eaton's reagent
80°C
R
O
N
6a-h
7e, 6e: R = 4-Cl
7f, 6f
7a, 6a: R = H
7b, 6b: R = 2-Me
: R = 4-NO2
7g, 6g: R = benzo[2,3- ]
b
7c, 6c: R = OMe
7h, 6h: R = benzo[3,4-b]
t
7d, 6d
: R = 4- Bu
Scheme 1ꢂSynthetic route to benzo[h]areno[6,7]oxepino[3,4-b]
quinolin-8(14H)-ones 6a–h.
4
O
O
COOH
1
3
4
1
4
O
1
N
O
N
O
N
3
6h'
7h
6h
Scheme 2ꢂPossible intramolecular cyclization reactions of 7h.
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Having in hand a series of the newly synthesized A similar observation was also reported by Wang et al. for
intermediates 7a–h, our attention was transferred to their the intramolecular cyclization reaction of 2-naphthyl-sub-
intramolecular Friedel-Crafts acylation reaction for build- stituted benzoic acid [34].
ing the desired oxepino-fused quinoline systems. At this
stage, we investigated the reaction using POCl3 according
to the method recently reported by Meesala and Nagara-
jan [33]. However, in the present case, these conditions
Conclusions
failed to efficiently promote the reaction and none of the
A series of structurally new oxepine-containing poly-
expected products were detected. We also attempted to
cyclic-fused quinoline systems, benzo[h]areno[6,7]
conduct the reaction using polyphosphoric acid (PPA) as
oxepino[3,4-b] quinolin-8(14H)-ones, via the intramolecu-
the cyclization agent [30, 31]. Unfortunately, the reaction
lar Friedel-Crafts acylation reaction of 2-(aryloxymethyl)
did not occur at temperatures lower than 150°C even after
benzo[h]quinoline-3-carboxylic acids was synthesized.
12 h. At the temperature above 150°C, black tarry byprod-
Biological activities of the newly synthesized compounds
ucts were formed, which significantly reduced the yield of
are currently being studied.
the desired products. Despite numerous trials under dif-
ferent conditions, the yield of this reaction could not be
optimized. After these fruitless attempts, it was decided to
focus on the use of Eaton’s reagent (phosphorus pentox- Experimental
ide in methanesulfonic acid) [31, 32]. To our delight, with
The chemicals used in this work were obtained from Fluka and were
Eaton’s reagent the intramolecular cyclization reaction of
used without purification. Melting points (uncorrected) were deter-
7a proceeded smoothly at 80°C with advantages in ease
mined by using WRS-1B melting points apparatus. 1H NMR (600 MHz)
of handling, low reaction temperature, and good yield
(76%). The ease of isolation of the product was notable.
After simple aqueous workup and crystallization from
ethanol, the corresponding product was isolated in an
analytically pure form.
and 13C NMR (150 MHz) spectra were recorded on a Brucker AVANCE
NMR spectrometer. Elemental analyses were performed for C, H, and
N using an Elementar Vario EL-III element analyzer. The progress
of reactions was monitored by thin layer chromatography (TLC) on
silica gel GF254 using ethyl acetate/petroleum ether (1:6) as eluent.
Anhydrous ethanol was used in the synthesis work.
Encouraged by the successful synthesis of 7a, we
tested this protocol to the preparation of other substrates
7b–h. With the exception of 7f, good yields of the remain-
ing products in the range of 69–80% were obtained.
The intramolecular Friedel-Crafts acylation reaction of
7f failed to give the desired cyclized product, even after
raising the reaction temperature and prolonging the reac-
tion time. This negative result can be explained in terms
of the presence of the strongly electron-withdrawing NO2
group, which renders the benzene ring highly electron-
deficient, thereby retarding the cyclization process.
We would also like to comment on the transforma-
tion of 7h to the cyclized product 6h. In principle, the
General procedure for the synthesis
of 2-(aryloxymethyl)benzo[h]quinoline-
3-carboxylic acids 7a–h
To a suspension of ethyl 2-(chloromethyl)benzo[h]quinoline-3-car-
boxylate (8) (0.3 g, 1 mmol) in sodium ethoxide solution [prepared
by adding elemental sodium (0.025 g, 1.1 mmol) to absolute ethanol
(8 mL)] was added the corresponding phenol (1 mmol). The resulting
mixture was heated under reflux for 2 h, during which time a white
precipitate was formed. Afer the reaction was complete as monitored
by TLC, a solution of KOH (0.56 g, 10 mmol) in 80% ethanol (10 mL)
was added and the mixture was heated under reflux for an additional
intramolecular cyclization reaction of 7h might produce 2 h, then cooled and acidified with 1 M HCl solution to pH 4–5. The
resultant precipitate was collected by filtration and then washed
two possible structural isomers 6h and 6h′ because of the
with 25% NH4OH solution and water. The crude product was crystal-
existence of two vacant ortho sites, the positions 1- and
ized from ethanol to afford compound 7a–h.
3-, as indicated in Scheme 2. However, the cyclization is
regioselective occurring at the more electron-rich position
2-(Phenoxymethyl)benzo[h]quinoline-3-carboxylic acid (7a)
Colorless crystals; reaction time 2 h; yield 83%; mp 189–190°C; H
1
1 to give 6h as the sole product as evidenced by analysis of
1
NMR (CDCl3): δ 13.44 (s, 1H), 9.24 (d, 1H, 8.8 Hz), 8.75 (s, 1H), 7.90 (d,
1H, J ꢀ= ꢀ 8.8 Hz), 7.82 (d, 1H, J ꢀ= ꢀ 8.4 Hz), 7.71–7.74 (m, 3H), 7.23–7.30 (m,
3H), 7.09 (d, 1H, J ꢀ= ꢀ 8.4 Hz), 6.92 (t, 1H, J ꢀ= ꢀ 7.2 Hz), 5.84 (s, 2H); 13C NMR
(DMSO-d6): δ 168.7, 159.1, 154.4, 144.8, 138.1, 137.6, 134.7, 133.8, 130.4,
129.4, 128.7, 128.1, 127.9, 127.2, 125.6, 124.9, 124.2, 121.3, 120.4, 114.8, 69.9.
Anal. Calcd for C21H15NO3: C, 76.58; H, 4.59; N, 4.25. Found: C, 76.88;
the H NMR spectrum. In particular, the signal of the H-4
proton is a doublet at 8.52 ppm with a coupling constant
J ꢀ= ꢀ 8.4 Hz, which is a typical value for ortho-protons cou-
pling. If the cyclization reaction occurred at the 3-position
affording the corresponding product 6h′, the H-4 proton
signal in the 1H NMR spectrum should have been a singlet. H, 4.76; N, 4.51.
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2-((o-Tolyloxy)methyl)benzo[h]quinoline-3-carboxylic acid (7b) 2-[(Naphthalen-2-yloxy)methyl]benzo[h]quinoline-3-carboxylic
1
Yellow solid; reaction time 2 h; yield 79%; mp 172–173°C; H NMR acid (7h) White solid; reaction time 2 h; yield 77%; mp 232–233°C;
(DMSO-d6): δ 13.49 (s, 1H), 9.07 (d, 1H, J ꢀ= ꢀ 8.4 Hz), 8.96 (s, 1H), 8.08 (d, 1H NMR (DMSO-d6): δ 13.52 (s, 1H), 9.09 (d, 1H, J ꢀ= ꢀ 7.8 Hz), 8.98 (s,
1H, J ꢀ= ꢀ 7.8 Hz), 7.98–8.03 (m, 2H), 7.81 (t, 1H, J ꢀ= ꢀ 7.4 Hz), 7.76 (t, 1H, J ꢀ= ꢀ 7.4 1H), 8.07 (d, 1H, J ꢀ= ꢀ 7.8 Hz), 8.01–8.05 (m, 2H), 7.82–7.86 (m, 2H), 7.79
Hz), 7.12 (d, 1H, J ꢀ= ꢀ 7.8), 7.00 (d, 1H, J ꢀ= ꢀ 7.8), 6.89 (d, 1H, J ꢀ= ꢀ 7.7 Hz), 6.85 (t, 2H, J ꢀ= ꢀ 8.3 Hz), 7.73 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.52 (d, 1H, J ꢀ= ꢀ 7.6 Hz), 7.44 (t,
(d, 1H, J ꢀ= ꢀ 7.7 Hz), 5.75 (s, 2H), 2.44 (s, 3H); 13C NMR (DMSO-d6): δ 1 6 7.4 , 1H, J ꢀ= ꢀ 7.0 Hz), 7.33 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.29 (m, 1H), 5.89 (s, 2H); 13C NMR
158.9, 154.5, 145.7, 139.2, 138.9, 134.2, 130.2, 129.3, 129.2, 128.5, 128.2, (DMSO-d6): δ 167.3, 156.8, 154.3, 145.7, 139.3, 139.1, 134.3, 134.2, 130.1,
127.5, 125.5, 125.4, 124.8, 124.4, 121.5, 115.5, 111.7, 70.2, 21.2. Anal. Calcd 129.4, 129.3, 128.7, 128.5, 128.2, 127.5, 127.5, 126.7, 126.4, 125.5, 124.8,
for C22H17NO3: C, 76.95; H, 4.99; N, 4.08. Found: C, 76.72; H, 5.14; N, 4.32. 124.3, 123.6, 118.7, 107.4, 70.3. Anal. Calcd for C25H17NO3: C, 79.14; H,
4.52; N, 3.69. Found: C, 78.97; H, 4.79; N, 3.55.
2-((2-Methoxyphenoxy)methyl)benzo[h]quinoline-3-carboxylic
acid (7c) White solid; reaction time 2 h; yield 85%; mp 192–193°C; 1H
NMR (DMSO-d6): δ 13.49 (s, 1H), 9.07 (d, 1H, J ꢀ= ꢀ 7.6 Hz), 8.96 (s, 1H),
General procedure for the synthesis of
8.08 (d, 1H, J ꢀ= ꢀ 8.2 Hz), 7.81 (t, 1H, J ꢀ= ꢀ 7.5 Hz), 7.76 (t, 1H, J ꢀ= ꢀ 7.5 Hz),
benzo[h]areno[6,7]oxepino[3,4-b]quinolin-
7.12 (d, 2H, J ꢀ= ꢀ 7.8 Hz), 7.00 (d, 2H, J ꢀ= ꢀ 7.8 Hz), 6.89 (t, 1H, J ꢀ= ꢀ 7.8 Hz),
6.78 (d, 1H, J ꢀ= ꢀ 8.2 Hz, 1H), 5.75 (s, 2H), 3.77 (s, 3H); 13C NMR (150 MHz,
8(14H)-ones 6a–h
DMSO-d6): δ 167.3, 154.6, 149.2, 148.5, 145.8, 139.4, 134.2, 130.2, 129.3,
128.5, 128.2, 127.5, 125.5, 125.2, 124.8, 124.4, 121.1, 120.8, 113.8, 112.6,
70.8, 55.7. Anal. Calcd for C22H17NO4: C, 73.53; H, 4.77; N, 3.90. Found:
C, 73.78; H, 4.85; N, 4.13.
2-(Aryloxymethyl)benzo[h]quinoline-3-carboxylic acid 7a–h (0.5 mmol)
and Eaton’s reagent (5 mL) were added to round flask (10 mL) and the
mixture was stirred at 80°C for 2–4 h. The conversion was monitored
by TLC. Afer the reaction was complete, the mixture was poured
slowly with stirring into cold water to induce precipitation followed
by neutralization with NaHCO3 solution. The crude product 6a–h
obtained afer filtration and washing with water was crystallized
from ethanol.
2-((4-(tert-Butyl)phenoxy)methyl)benzo[h]quinoline-3-carbox-
ylic acid (7d) White crystals; reaction time 2 h; yield 82%; mp 186–
1
188°C; H NMR (CDCl3): δ 13.46 (s, 1H), 9.23 (d, 1H, J ꢀ= ꢀ 8.7 Hz), 8.87
(s, 1H), 7.93 (d, 1H, J ꢀ= ꢀ 7.3 Hz), 7.88 (d, 1H, J ꢀ= ꢀ 8.7 Hz), 7.80–7.67 (m,
3H), 7.31 (d, 2H, J ꢀ= ꢀ 8.8 Hz), 7.04 (d, 2H, J ꢀ= ꢀ 8.8 Hz), 5.82 (s, 2H), 1.29
(s, 9H); 13C NMR (CDCl3): δ 163.4, 161.4, 156.7, 155.1, 153.9, 148.2, 147.5,
143.7, 140.3, 134.7, 131.0, 129.4, 129.0, 127.9, 127.5, 126.2, 125.4, 125.0,
124.8, 114.5, 71.1, 34.1, 31.5. Anal. Calcd for C25H23NO3: C, 77.90; H, 6.01;
N, 3.63. Found: C, 78.06; H, 5.82; N, 3.71.
Benzo[h]benzo[6,7]oxepino[3,4-b]quinolin-8(14H)-one (6a)
White solid from 7a; reaction time 2.5 h; yield 76%; mp 197–198°C; 1H
NMR (DMSO-d6): δ 9.26 (d, 1H, J ꢀ= ꢀ 9.0 Hz), 8.97 (s, 1H), 8.23 (d, 1H, J ꢀ= ꢀ
8.0 Hz), 8.13–8.10 (m, 1H), 8.08 (q, 2H, J ꢀ= ꢀ 9.0 Hz), 7.87–7.84 (m, 2H),
7.68 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.30 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.24 (d, 1H, J ꢀ= ꢀ 8.0 Hz),
5.68 (s, 2H). 13C NMR (CDCl3): δ 188.6, 161.5, 153.6, 148.0, 138.8, 135.7,
134.7, 133.8, 132.8, 132.1, 130.9, 129.4, 128.9, 128.0, 127.5, 126.0, 125.5,
125.3, 122.8, 121.1, 76.7. Anal. Calcd for C21H13NO2: C, 81.01; H, 4.21; N,
4.50. Found: C, 81.14; H, 4.39; N, 4.27.
2-((4-Chlorophenoxy)methyl)benzo[h]quinoline-3-carboxylic
acid (7e) White solid; reaction time 2 h; yield 80%; mp 172–173°C;
1H NMR (DMSO-d6): δ 13.52 (s, 1H), 9.02 (s, 1H), 8.83 (d, 1H, J ꢀ= ꢀ 8.2
Hz), 8.22 (d, 2H, J ꢀ= ꢀ 9.2 Hz), 8.10–7.97 (m, 3H), 7.78 (t, 1H, J ꢀ= ꢀ 7.6 Hz),
7.68 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.30 (d, 2H, J ꢀ= ꢀ 9.2 Hz), 5.99 (s, 2H); 13C NMR
(DMSO-d6): δ 167.3, 166.1, 158.9, 157.8, 154.2, 149.4, 145.8, 139.4, 134.2,
130.1, 129.4, 129.2, 128.5, 128.2, 127.5, 125.5, 124.9, 124.7, 124.3, 116.6,
70.4. Anal. Calcd for C21H14ClNO3: C, 69.33; H, 3.88; N, 3.85. Found: C,
69.14; H, 4.02; N, 4.01.
12-Methylbenzo[h]benzo[6,7]oxepino[3,4-b]quinolin-8(14H)-
one (6b) White solid from 7b; reaction time 2 h; yield 72%; mp 218–
219°C; 1H NMR (CDCl3): δ 9.37 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 8.82 (s, 1H), 8.17 (d,
1H, J ꢀ= ꢀ 8.0 Hz), 7.94 (m, 1H), 7.87 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.82–7.74 (m, 3H),
7.44 (d, 1H, J ꢀ= ꢀ 7.6 Hz), 7.10 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 5.65 (s, 2H), 2.36 (s, 3H);
13C NMR (CDCl3): δ 189.1, 159.8, 153.8, 148.0, 138.7, 136.7, 134.6, 132.9,
131.0, 130.0, 129.9, 129.4, 128.8, 128.0, 127.4, 126.1, 126.0, 125.5, 125.2,
122.3, 76.8, 16.6. Anal. Calcd for C22H15NO2: C, 81.21; H, 4.65; N, 4.30.
Found: C, 81.32; H, 4.79; N, 4.54.
2-((4-Nitrophenoxy)methyl)benzo[h]quinoline-3-carboxylic
acid (7f) Yellow solid; reaction time 2 h; yield 78%; mp 196–197°C;
1H NMR (DMSO-d6): δ 13.62 (s, 1H), 9.02 (s, 1H), 8.83 (d, 1H, J ꢀ= ꢀ 8.4 Hz),
8.22 (d, 2H, J ꢀ= ꢀ 9.2 Hz), 8.06 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 8.02 (d, 2H, J ꢀ= ꢀ 9.2 Hz),
7.78 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.68 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.58–7.62 (m, 2H), 5.99 (s,
2H); 13C NMR (DMSO-d6): δ 167.1, 164.5, 153.6, 151.4, 145.8, 141.2, 140.8,
139.8, 134.3, 130.1, 129.4, 128.6, 128.2, 127.5, 125.8, 125.5, 124.7, 124.3,
124.2, 115.5, 70.5. Anal. Calcd for C21H14N2O5: C, 67.38; H, 3.77; N, 7.48.
Found: C, 67.15; H, 3.57; N, 7.25.
10-Methoxybenzo[h]benzo[6,7]oxepino[3,4-b]quinolin-8(14H)-
one (6c) Yellow solid from 7c; reaction time 2 h; yield 80%; mp 197–
198°C; 1H NMR (CDCl3): δ 9.37 (d, 1H, J ꢀ= ꢀ 9.3 Hz), 8.83 (s, 1H), 7.95 (m,
1H), 7.91 (dd, 1H, J ꢀ= ꢀ 7.0 and 2.8 Hz), 7.88 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.82 (s, 1H),
7.79 (m, 2H), 7.16 (m, 2H), 5.72 (s, 2H), 3.96 (s, 3H); 13C NMR (DMSO-d6):
δ 188.8, 153.4, 151.6, 151.1, 148.1, 138.7, 134.6, 132.6, 131.0, 129.4, 128.8,
128.0, 127.5, 127.3, 125.9, 125.5, 125.3, 123.0, 122.3, 116.8, 76.8, 56.6. Anal.
Calcd for C22H15NO3: C, 77.41; H, 4.43; N, 4.10. Found: C, 77.24; H, 4.21;
N, 4.22.
2-[(Naphthalen-1-yloxy)methyl]benzo[h]quinoline-3-carboxylic
acid (7g) White solid; reaction time 2 h; yield 75%; mp 216–217°C; 1H
NMR (DMSO-d6): δ 13.44 (s, 1H), 9.36 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 9.04 (d, 1H,
J ꢀ= ꢀ 8.1 Hz), 8.98 (s, 1H), 8.94 (s, 1H), 8.27 (d, 1H, J ꢀ= ꢀ 8.1 Hz), 7.90 (d,
1H, J ꢀ= ꢀ 8.1 Hz), 7.85–7.76 (m, 4H), 7.43 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.18 (d, 1H, J ꢀ= ꢀ
7.6 Hz), 5.97 (s, 2H), 5.18 (s, 2H); 13C NMR (CDCl3): δ 169.0, 154.8, 152.7,
145.9, 144.2, 137.1, 134.2, 131.6, 130.5, 130.1, 129.4, 128.9, 128.3, 127.6,
127.0, 126.8, 126.2, 125.4, 125.0, 124.5, 124.0, 123.6, 112.4, 107.7, 70.3.
Anal. Calcd for C25H17NO3: C, 79.14; H, 4.52; N, 3.69. Found: C, 79.28;
H, 4.79; N, 3.85.
10-(tert-Butyl)benzo[h]benzo[6,7]oxepino[3,4-b]quinolin-
8(14H)-one (6d) Yellow solid from 7c; reaction time 3 h; yield 71%;
mp 197–198°C; 1H NMR (CDCl3): δ 9.26 (d, 1H, J ꢀ= ꢀ 9.0 Hz), 8.97 (s, 1H),
8.23 (d, 1H, J ꢀ= ꢀ 7.8 Hz), 8.10 (m, 2H), 8.06 (d, 1H, J ꢀ= ꢀ 9.0 Hz), 7.86
(m, 1H), 7.68 (t, 1H, J ꢀ= ꢀ 7.8 Hz), 7.29 (d, 1H, J ꢀ= ꢀ 7.8 Hz), 7.24 (d, 1H, J ꢀ= ꢀ
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8.4 Hz), 5.68 (s, 2H), 1.35 (s, 9H); 13C NMR (DMSO-d6): δ 189.1, 159.8,
157.4, 149.7, 148.2, 147.5, 144.6, 144.4, 143.6, 142.5, 140.0, 139.6, 138.7,
137.4, 135.7, 135.3, 134.7, 124.3, 124.2, 115.5, 76.7, 34.6, 31.7. Anal. Calcd
for C25H21NO2: C, 81.72; H, 5.76; N, 3.81. Found: C, 81.64; H, 5.91; N, 3.62.
[4] Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Two new
pyrroloquinazolinoquinoline alkaloids from Peganum
nigellastrum. Heterocycles 1997, 46, 541–546.
[5] Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N.
M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Calothrixins A
and B, novel pentacyclic metabolites from Calothrix cyanobac-
teria with potent activity against malaria parasites and human
cancer cells. Tetrahedron 1999, 55, 13513–13520.
[6] Gatto, B.; Capranico, G.; Palumbo, M. Drugs acting on DNA
topoisomerases: recent advances and future perspectives.
Curr. Pharm. Design 1999, 5, 195–215.
10-Chlorobenzo[h]benzo[6,7]oxepino[3,4-b]quinolin-8(14H)-
one (6e) Yellow solid from 7c; reaction time 4 h; yield 74%; mp
225–226°C; 1H NMR (DMSO-d6): δ 9.84 (s, 1H), 9.11 (d, 1H, J ꢀ= ꢀ 8.4 Hz),
8.31 (d, 1H, J ꢀ= ꢀ 7.8 Hz), 8.21 (m, 2H), 8.13 (t, 1H, J ꢀ= ꢀ 7.8 Hz), 7.74 (d, 1H,
J ꢀ= ꢀ 8.4 Hz), 7.31 (d, 1H, J ꢀ= ꢀ 8.4 Hz), 6.06 (s, 2H); 13C NMR (150 MHz,
DMSO-d6): δ 189.1, 162.1, 151.5, 140.6, 139.4, 136.4, 133.4, 132.5, 131.3,
126.3, 125.1, 124.5, 123.7, 120.7, 119.5, 117.6, 116.1, 115.7, 114.2, 113.9, 72.7.
Anal. Calcd for C21H12ClNO2: C, 72.94; H, 3.50; N, 4.05. Found: C, 73.13;
H, 3.31; N, 4.22.
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evaluation and DNA-binding study of novel tetrahydroquino-
lines and some derived tricyclic and tetracyclic ring systems.
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[8] Beauchard, A.; Jaunet, A.; Murillo, L.; Baldeyrou, B.;
Lansiaux, A.; Chérouvrier, J. R.; Domon, L.; Picot, L.; Bailly, C.;
Besson, T.; et al. Synthesis and antitumoral activity of novel
thiazolobenzotriazole, thiazoloindolo[3,2-c]quinoline and
quinolinoquinoline derivatives. Eur. J. Med. Chem. 2009, 44,
3858–3865.
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Wang, J. P. Synthesis and anti-inflammatory evaluation of
4-anilinofuro[2,3-b]quinoline and 4-phenoxyfuro[2,3-b]
quinoline derivatives. Part 3. Bioorg. Med. Chem. 2004, 12,
387–392.
Benzo[h]naphtho[2′,1′:6,7]oxepino[3,4-b]quinolin-8(16H)-one
(6g) Yellow solid from 7g; reaction time 3.5 h; yield 69%; mp 231–
232°C; 1H NMR (CDCl3): δ 9.40 (d, 1H, J ꢀ= ꢀ 7.6 Hz), 8.83 (s, 1H), 8.52 (d,
1H, J ꢀ= ꢀ 8.4 Hz), 8.33 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.93 (d, 1H, J ꢀ= ꢀ 7.6 Hz), 7.87
(d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.84–7.76 (m, 4H), 7.64 (t, 1H, J ꢀ= ꢀ 7.6 Hz), 7.55–7.59
(m, 2H), 5.84 (s, 2H); 13C NMR (150 MHz, CDCl3): δ 188.4, 160.0, 158.3,
152.9, 148.0, 138.7, 137.4, 134.6, 133.2, 130.9, 129.7, 129.4, 128.9, 128.0,
127.5, 126.9, 126.5, 126.3, 126.2, 125.5, 125.2, 124.2, 122.3, 120.3, 76.8.
Anal. Calcd for C25H15NO2: C, 83.09; H, 4.18; N, 3.88. Found: C, 82.94;
H, 4.09; N, 3.73.
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Benzo[h]naphtho[1′,2′:6,7]oxepino[3,4-b]quinolin-17(8H)-one
(6h) Yellow solid from 7h; reaction time 3.5 h; yield 71%; mp 199–
201°C; 1H NMR (CDCl3): δ 9.23 (m, 1H), 8.91 (s, 1H), 8.52 (d, 1H, J ꢀ= ꢀ 8.4
Hz), 7.93 (d, 1H, J ꢀ= ꢀ 8.4 Hz), 7.86 (m, 1H), 7.79 (d, 1H, J ꢀ= ꢀ 8.4 Hz), 7.77
(d, 1H, J ꢀ= ꢀ 8.4 Hz), 7.75 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.68 (m, 2H), 7.54 (m, 1H,
J ꢀ= ꢀ 7.8 Hz), 7.42 (t, 1H, J ꢀ= ꢀ 7.2 Hz), 7.30 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 5.64 (s, 2H);
13C NMR (DMSO-d6): δ 191.7, 159.1, 157.7, 155.5, 147.8, 138.6, 135.3, 134.7,
132.6, 132.0, 131.3, 130.7, 129.4, 128.6, 128.5, 128.4, 128.0, 127.4, 125.8,
125.6, 125.5, 125.4, 125.2, 120.9, 76.7. Anal. Calcd for C25H15NO2: C, 83.09;
H, 4.18; N, 3.88. Found: C, 83.28; H, 4.33; N, 4.05.
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M. H.; Tzeng, C. C. Identification of benzofuro[2,3-b]quinoline
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Acknowledgments: The authors would like to thank the
financial support from the Scientific Research Foundation
of the Education Department of Liaoning Province (Grant
No. L2013428).
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1-benzoxepinpterulone. Tetrahedron 2001, 57, 7181–7184.
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