An efficient access to the synthesis of novel 12-phenylbenzo[6,7]oxepino[3, 4-b]quinolin- 13(6H)-one derivatives

Article abstract of DOI:10.3762/bjoc.8.213

An efficient access to the tetracyclic-fused quinoline systems, 12-phenylbenzo[6,7]oxepino[3,4-b]quinolin-13(6H)-one derivatives 4a-l, is described, involving the intramolecular Friedel-Crafts acylation reaction of 2-(phenoxymethyl)-4-phenylquinoline-3- c

Full text of DOI:10.3762/bjoc.8.213

An efficient access to the synthesis of novel
12-phenylbenzo[6,7]oxepino[3,4-b]quinolin-
13(6H)-one derivatives
Wentao Gao*, Guihai Lin, Yang Li, Xiyue Tao, Rui Liu and Lianjie Sun
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1849–1857.
Institute of Superfine Chemicals, Bohai University, Jinzhou 121000,
China
doi:10.3762/bjoc.8.213
Received: 20 July 2012
Email:
Accepted: 20 September 2012
Published: 30 October 2012
Wentao Gao* - bhuzh@163.com
* Corresponding author
Associate Editor: T. J. J. Müller
Keywords:
© 2012 Gao et al; licensee Beilstein-Institut.
License and terms: see end of document.
Eaton’s reagent; Friedel–Crafts acylation; Friedländer reaction;
one-pot; PPA; quinoline; tetracyclic-fused
Abstract
An efficient access to the tetracyclic-fused quinoline systems, 12-phenylbenzo[6,7]oxepino[3,4-b]quinolin-13(6H)-one derivatives
4a–l, is described, involving the intramolecular Friedel–Crafts acylation reaction of 2-(phenoxymethyl)-4-phenylquinoline-3-
carboxylic acid derivatives 3a–l aided by the treatment with PPA (polyphosphoric acid) or Eaton’s reagent. The required starting
compound (2) was obtained by Friedländer reaction of 2-aminobenzophenone (1) with 4-chloroethylacetoacetate by using CAN
(cerium ammonium nitrate, 10 mol %) as catalyst at room temperature. The substrates 3a–l were prepared through one-pot reaction
of ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate (2) and substituted phenols. Our developed strategy, involving a three-
step route, offers easy access to tetracyclic-fused quinoline systems in short reaction times, and the products are obtained in
moderate to good yields.
Introduction
Polycyclic heterocycle-fused quinoline systems as important new families of such quinoline systems still attracts much
group compounds can be found in many biologically active interest from both medicinal and synthetic organic chemists
natural products as well as in pharmacologically significant [11-14]. Most reports in the literature contain a common five-
molecules, and have wide applications in medicinal chemistry or six-membered heterocycle fused to a quinoline ring, such as
[1-4]. It has been well-established that planar heterocycle-fused pyrazolo [15], pyrano [16], indolo [12,17], benzofuro [18],
tri- or tetracyclic quinoline systems on privileged templates benzothienoquinolines [19], and synthetic analogues thereof.
have significant biological properties, such as antitumoral [5,6], However, to the best of our knowledge, there are very few
anti-inflammatory [7], antimalarial [8], antituberculosis [9], and reports in which a medium-sized seven-membered benzoxepin
antiplasmodial [10] activities. Accordingly, the synthesis of ring is fused to a quinoline unit. In this context, Bera et al. [20]
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described a one-pot method for the synthesis of 6,7-dihy-
drobenzo[2,3]oxepino[4,5-b]quinolin-12-ols. However, the
report is of episodic character and no efforts have been made to
develop a general synthetic approach. Furthermore, the reported
approach features a major restriction in the use of the expen-
sive and unavailable 5-chloro-2,3-dihydrobenzo[b]oxepine-4-
carbaldehyde as a reactant. Thus, a facile synthesis of such
compounds by using inexpensive and readily available ma-
terials represents a challenging area for exploration.
Scheme 1: Synthesis of ethyl 2-(chloromethyl)-4-phenylquinoline-3-
carboxylate (2).
On the other hand, the seven-membered benzoxepine nucleus [38] reported the preparation of ethyl 2-(chloromethyl)-4-(3,4-
can be found in many medicinally relevant natural products and dimethoxyphenyl)-6,7-dimethoxy quinoline-3-carboxylate by
synthetic compounds and represents one of the most profiled the reaction of ethyl 4-chloroacetoacetate with 2-amino-
chemotypes in modern drug discovery, owing to several 3’,4,4’,5-tetramethoxybenzophenone hydrochloride in ethanol.
pronounced biological activities, such as antitumor and anti- However, in our case the reaction of 2-aminobenzophenone (1)
inflammatory properties, attributed to the presence of the with ethyl 4-chloroacetoacetate did not take place, and a
benzoxepine unit [21-24]. Last but not least, the benzoxepine gummy mass was obtained as product. In this context, Muscia
nucleus has been of increasing relevance as a synthetic building et al. [39] described the synthesis of ethyl 6-chloro-2-
block for the synthesis of manifold biologically and pharmaceu- (chloromethyl)-4-phenylquinoline-3-carboxylate by the
tically important compounds [25,26]. As a consequence, the Friedländer reaction employing microwave irradiation (MW) in
remarkable bioactivity surrounding the benzoxepine moiety has the presence of a catalytic amount of hydrochloric acid. Subse-
elicited a significant amount of interest as demonstrated by syn- quently, we reported a similar reaction under ultrasound irradi-
thetic work already published [27-30].
ation conditions by using KHSO4 as catalyst [36]. Although the
two methodologies are elegant and impressive, our attempts to
In light of the above findings as well as the combination princi- follow both routes to synthesize 2 were frustrated by very low
ples for drug design [31], we were intrigued to explore the yields. In this regard, Bose et al. [40] reported the preparation of
incorporation of a quinoline ring fused together with a benzox- ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxy-
epine nucleus, which would be much more attractive and valu- late by the treatment of 2-amino-5-chlorobenzophenone with
able for medicinal chemistry and drug discovery. In recent 4-(chloroethyl)acetoacetate in MeOH by using 10 mol % CAN
years, our research team has been interested in the development as catalyst at room temperature. To our delight, under similar
of efficient synthesis for the quinoline-based bioactive mole- reaction conditions, we were able to obtain 2 from 2-aminoben-
cules [32-37]. Thus, in connection with our continuing interest zophenone (1) and 4-(chloroethyl)acetoacetate in a good yield
in the synthesis of highly valuable quinoline compounds, we are of 84% (Scheme 1). Moreover, the obtained product was very
actively involved in diversifying our work on the synthesis of pure, and a chromatographic purification was unnecessary.
hetero-fused quinoline systems that are of interest for medical
research. Thus, the aim of the present work is to present the Next, the resulting 2-(chloromethyl)quinoline 2 was subjected
synthesis of novel compounds combining these two bioactive to the Williamson reaction with a variety of phenols with
components in a molecular frame work as fused forms.
varying substituents in the presence of K2CO3 as base in MeCN
under reflux as shown in Scheme 2.
Results and Discussion
The synthetic methodology developed in our laboratory for the
synthesis of a new class of benzoxepino-fused quinoline com-
pounds was achieved in a three-step procedure, commencing
with the preparation of ethyl 2-(chloromethyl)-4-phenylquino-
line-3-carboxylate (2) as shown in Scheme 1.
In fact, from the beginning, we were well aware that the prepar-
ation of ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxy-
late (2) is very interesting because such compounds are viewed
as ideal starting materials for the flexible synthesis of a large
range of quinoline derivatives [38-40]. Recently, Mizuno et al.
Scheme 2: Synthesis of 2-(phenoxymethyl)-4-phenylquinoline-3-
carboxylic acid derivatives 3a–l.
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Beilstein J. Org. Chem. 2012, 8, 1849–1857.
In this reaction, we adopted MeCN as the solvent of choice gation are listed in Table 1 together with yields and melting
simply because of its low boiling point, bringing much conve- points.
nience to the workup procedure. Thus, upon the completion of
the Williamson reaction as observed on TLC, MeCN was As shown in Table 1, high yields of 3 were achieved irrespec-
simply evaporated to dryness, 80% ethanolic potassium tive of the electronic nature or positions of the substituents,
hydroxide solution (15 mL) was directly added to the residue, except for in the cases of 3i and 3k (Table 1, entries 9 and 11).
and the resulting reaction mixture was stirred under reflux. The relatively lower yields of 3i and 3k may be ascribed to the
When the reactions were completed (usually within four sterically hindered nature of the bulky tert-butyl group at the
hours) the quinoline-3-carboxylic acid ether compounds o-position of aryl.
were obtained in high yields (80–93%) after simple
recrystallization from ethanol. The structures assigned Thus, the resulting substrates, quinoline-3-carboxylic acids
to these compounds are confirmed by spectral data and 3a–l, further served as active synthons for the intramolecular
elemental analysis, which were fully consistent with the Friedel–Crafts acylation reaction to construct the desired tetra-
assigned molecular structure as depicted in Supporting Informa- cyclic benzoxepino-fused quinoline systems. Of the commonly
tion File 1. The beauty of this reaction is that two chemical available cyclization agents screened for the intramolecular
transformations, i.e., Williamson ether synthesis and subse- Friedel–Crafts acylation reaction (e.g., AlCl3, H2SO4, p-TsOH,
quent ester hydrolysis take place in one-pot, thereby providing TiCl4, P2O5), the use of inexpensive and readily available
the acids in good yields of 66–93% with operational and experi- polyphosphoric acid (PPA), requiring no additional solvent, was
mental simplicity. Moreover, the presence of sterically hindered found to be very suitable for such a reaction in terms of good
tert-butyl groups is not problematic although slightly lower yield, short reaction time and simple workup [37,41]. Upon use
yields were obtained when the aryl-ring was substituted in of PPA as the cyclization agent, we found that the cyclization
o-position by a tert-butyl group. The scope and generality of the reaction of 3a–h could be performed smoothly at 150 °C as
newly synthesized compounds 3a–l during the present investi- shown in Scheme 3.
Table 1: Yields and melting points of compounds 3a–l.
Entry
Product
Yield (%)a
Mp (°C)
1
83
191–192
3a
2
3
4
91
88
93
209–210
212–213
207–208
3b
3c
3d
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Table 1: Yields and melting points of compounds 3a–l. (continued)
5
86
83
88
82
71
85
66
197–198
167–168
165–166
196–197
192–194
188–190
230–232
3e
6
3f
7
3g
8
3h
9
3i
10
3j
11
3k
12
82
239–241
3l
aIsolated yield.
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Beilstein J. Org. Chem. 2012, 8, 1849–1857.
Scheme 3: Synthesis of 12-phenylbenzo[6,7]oxepino[3,4-b]quinolin-13(6H)-ones 4a–h.
After the reaction was completed (monitored by TLC), the reac- tory elemental and spectral data. The compounds 4a–h, newly
tion mixture was poured into cold water to induce precipitation, synthesized in the present investigation, are listed in Table 2.
followed by neutralization with NaHCO3 solution. Thus, the
cyclized products 4a–h were obtained in good yields, ranging As shown in Table 2, the cyclization reaction appears to be gen-
from 69–85% after recrystallization from ethanol, and their erally applicable, as most of the substrates 3 were consumed
identities were unequivocally ascertained from their satisfac- within 5–7 hours to give the corresponding cyclized products
Table 2: Structures and yields of the cyclized products 4a–h.
Entry
Product
Time (h)
Yield (%)a
Mp (°C)
1
6
77
197–198
4a
4b
4c
2
3
5
5
80
83
215–216
199–200
4
5
6
5
5
7
82
85
74
195–197
197–199
175–177
4d
4e
4f
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Beilstein J. Org. Chem. 2012, 8, 1849–1857.
Table 2: Structures and yields of the cyclized products 4a–h. (continued)
7
7
7
69
72
171–172
179–180
4g
8
4h
aIsolated yield.
with reasonable yields. However, the method was limited due to by Friedel–Crafts reaction at a high reaction temperature using
difficulties in tolerating the tert-butyl groups. For example, a high-boiling-point solvent [42], we presumed the occurrence
when substrate 3l was treated by PPA under the reaction condi- of debutylation reaction during the cyclization course probably
tions, the resulting product was assigned not to the expected 4l, due to the high reaction temperature.
but characterized as the de-tert-butylation product 4l′ as shown
in Scheme 4. The product was easily characterized from its 1H
NMR spectrum, which showed no signals attributable to the
carboxylic acid proton and tert-butyl protons of its precursor 3l,
along with the presence of a total count of twelve aromatic
protons between 7.15–8.20 ppm, perfectly matched with their
structures with additional support from its 13C NMR spectrum
and other analytical data.
Considering these results, an alternative route would be desir-
able. Recently, the Eaton’s reagent, a mixture of P2O5 and
MeSO3H [43], has gained wide application as an advantageous
medium for cyclization reactions [44], and we have also
reported the serendipitous discovery of its excellent perfor-
mance in these types of transformations [32,33,45]. Thus, we
resorted to the use of our reliable approach to conduct the
cyclization reaction. Under the same experimental conditions as
Similarly, in the present investigation the substrates 3i–k also in our previous methods, the ring closure of compounds 3i–l
showed the same reaction patterns and the obtained product was was achieved and the corresponding cyclized products retaining
identified as being the same structure as 4a. Obviously, the the tert-butyl moiety were afforded in satisfactory yields of
problem with this is the loss of the tert-butyl group during the 59–70%. The reaction results are summarized in Table 3.
cyclization reaction course. In addition, slow and gradual
warming to the reaction temperature was also tried, but this had As shown in Table 3, by the treatment with Eaton’s reagent, the
no effect on the outcome of the reaction. Thus, according to our tert-butyl-substituted quinoline-3-carboxylic acids 3i–l under-
previous experience [33], coupled with the fact that the tert- went the conversion smoothly and gave the corresponding
butyl substituent could be easily removed from aromatic nuclei cyclized products 4i–l as expected. Compounds 4i–l containing
Scheme 4: Cyclization and de-tert-butylation reaction of 3l by using PPA.
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Beilstein J. Org. Chem. 2012, 8, 1849–1857.
Table 3: Synthesis of tert-butyl-substituted compounds 4i–l.
Entry
1
Product
Time (h)
Yield (%)a
Mp (°C)
6
68
70
193–195
4i
4j
2
3
5
5
5
210–212
166–168
209–210
62
59
4k
4l
4
aIsolated yield.
tert-butyl groups are interesting candidates for medicinal appli- experimental operation, and satisfactory yields, which
cations since it was reported that the introduction of tert-butyl contribute to the usefulness of this method. These compounds
groups into organic molecules could increase the lipophilicity of belong to a new class of linearly fused tetracyclic heterocyclic
the molecule, which is very important for allowing passage quinoline systems, which could be potentially applied for the
through the extraordinarily thick and tight cell wall [46]. Alto- development of biologically and pharmaceutically important
gether, the strategy using Eaton’s reagent instead of PPA compounds. Access to such biologically intriguing structures
showed a satisfactory conversion and gave us easy access to should allow us to study their biological activities, and currently
mono- and di-tert-butyl-substituted tetracyclic-fused quinoline we are exploring this possibility.
systems. In addition, it is noteworthy that we also attempted
additional experiments by conducting the cyclization reaction of Experimental
3a–l under the given conditions (Eaton’s reagent, 70 °C). All chemicals (AR graded) were commercially available and
Although the cyclization reaction proceeded, the yields of the used without further purification. The melting points were
desired products were not as good as with PPA.
determined by using a WRS-1B melting-points apparatus and
were uncorrected. The IR spectra were obtained as KBr pellets
in the range of 400–4000 cm−1 on a Shimadzu FTIR-8400S
Conclusion
In conclusion, we have described the synthesis of a series of spectrophotometer (Shimadzu, Japan). 1H NMR and 13C NMR
structurally new 12-phenylbenzo[6,7]oxepino[3,4-b]quinolin- spectra were recorded on a Bruker AVANCE NMR spectrom-
13(6H)-ones 4a–l. The advantages of the current protocol eter with CDCl3 or DMSO-d6 as the solvent. The reported
include the ready availability of starting materials, ease of chemical shifts (δ values) are given in parts per million (ppm)
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downfield from tetramethylsilane (TMS) as the internal stan- derivatives (3i–l, 0.5 mmol) and Eaton’s reagent (5 mL) were
dard. Mass spectra were determined on a MSD VL ESI1 spec- added to a round flask (10 mL) and stirred at 70 °C for 5–6 h.
trometer. Elemental analysis was recorded on an Elementar The conversion was monitored by TLC. After the reaction was
vario EL-III element analyzer.
completed, the reaction mixture was poured slowly into cold
water under stirring to induce precipitation, followed by
Procedure for the preparation of 2-(chloromethyl)-4- neutralization with NaHCO3 solution. The crude products were
phenylquinoline-3-carboxylate (2) [40]. To a stirred solution obtained after filtration and washing with water.
of 2-aminobenzophenone (1, 1.97 g, 10 mmol) and ethyl The pure products 4i–l were obtained by recrystallization from
4-chloroacetoacetate (1.65 g, 10 mmol) in methanol (15 mL), ethanol. The yields are summarized in Table 3 and the spectra
was added CAN (0.55 g, 1 mmol, 10 mol %). The resulting and analytical data are given in Supporting Information File 1.
reaction mixture was stirred at room temperature for 2 h. After
the reaction was completed (monitored by TLC), the mixture
Supporting Information
was washed with water (15 mL), extracted with ethyl acetate
(30 × 2 mL), dried over Na2SO4, and concentrated under
Supporting Information File 1
reduced pressure. The resulting residue was purified by silica
gel column chromatography with petroleum ether/EtOAc (5:1)
as eluent to afford 2.74 g of the product 2 as yellow crystals in
84% yield. Mp 103–105 °C (lit. [47] mp 109–111 °C).
Characterization data of the title compounds and NMR and
HRMS spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-213-S1.pdf]
General procedure for the synthesis of 2-(phenoxymethyl)-
4-phenylquinoline-3-carboxylic acid derivatives 3a–l. A mix-
ture of ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate
(0.325 g, 1 mmol), substituted phenol (1 mmol) and K2CO3
(0.414 g, 3 mmol) was stirred in CH3CN (10 mL) under reflux.
After completion of the reaction (monitored by TLC), CH3CN
was evaporated to dryness. Then, a solution of KOH (2.8 g, 20
mmol) in 80% ethanol (15 mL) was added to the residue, and
the mixture was heated under reflux for 4 h, cooled, and acidi-
fied with 1 M hydrochloric acid solution. The resulting crude
product was recrystallized from ethanol to afford 3a–l. The
yields and melting points of all compounds are summarized in
Table 1 and the spectral and analytical data are given in
Supporting Information File 1.
Acknowledgements
The authors would like to thank the Natural Science Founda-
tion of Liaoning Province (Grant No. 201202001) for financial
support.
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