A novel construction of quino-fused tropone skeleton: First synthesis of 12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one derivatives

Article abstract of DOI:10.1016/j.tet.2014.01.049

In the present investigation, the incorporation of both quinoline moiety and tropone ring in a molecule frame work in fused form leading to a series of structurally novel and biologically intriguing quinoline/tropone hybrids 12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one derivatives has been first achieved through a simple, and economical two-step procedure, involving the one-pot synthesis of (E)-2-(arylvinyl)quinoline-3-carboxylic acids followed by intramolecular Friedel-Crafts acylation reaction using polyphosphoric acid (PPA).

Full text of DOI:10.1016/j.tet.2014.01.049

Tetrahedron 70 (2014) 2180e2189
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel construction of quino-fused tropone skeleton: first synthesis
of 12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one derivatives
*
Wentao Gao , Xueda Xing, Yang Li, Shuai Lan
Institute of Superfine Chemicals, Bohai University, Jinzhou 121000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present investigation, the incorporation of both quinoline moiety and tropone ring in a molecule
frame work in fused form leading to a series of structurally novel and biologically intriguing quinoline/
tropone hybrids 12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one derivatives has been first achieved
through a simple, and economical two-step procedure, involving the one-pot synthesis of (E)-2-(ar-
ylvinyl)quinoline-3-carboxylic acids followed by intramolecular FriedeleCrafts acylation reaction using
polyphosphoric acid (PPA).
Received 29 September 2013
Received in revised form 21 January 2014
Accepted 23 January 2014
Available online 11 February 2014
Keywords:
Quinoline
Ó 2014 Elsevier Ltd. All rights reserved.
Tropone
Polyphosphoric acid
Intramolecular FriedeleCrafts acylation
One-pot synthesis
1. Introduction
Tintamine (III, Fig. 1),7 and Pareitropone (IV, Fig. 1).8 Recent stud-
ies have suggested that some heterocycles with the combination of
The cyclohepta-2,4,6-trienone, better known under the com-
mon name tropone, is a pharmaceutically important structural unit.
Compounds bearing this moiety possess a broad spectrum of bi-
ological activities.1e3 Especially, some tropones fused to aromatic or
heteroaromatic rings are an important class of compounds, which
represent privileged moieties in medicinal chemistry,4 and are
ubiquitous sub-structure associated with biologically active natural
products, such as Colchicine (I, Fig. 1),5 Caulersine (II, Fig. 1),6
a tropone ring could increase their biological activities or create
new medicinal properties due to the different electronic distribu-
tion and the additional basic character of the tropone ring.9,10 In
addition, the tropone moiety also plays an important role in mo-
lecular assemblies for a faster and efficient lead generation towards
the new drug discovery.11e13 Despite featuring only seven ring
carbon atoms and no stereocentres, the synthesis of structurally
novel ring-fused is still a considerable synthetic challenge as tro-
pone derivatives are scarce in nature,14 occurring only in lower
plants and fungi,15 and limited information is available on these
compounds. On account of these facts, extensive synthetic efforts
have been devoted surrounding the tropone ring to design and
synthesize novel ring-fused tropone systemes.16e19
On the other hand, it has been well-established that planar
polycyclic-fused quinoline system, especially tri- or tetracyclic-
fused frame work could intercalate into base pairs of DNA as an
intercalator to induce topoisomerase II dependent DNA cleav-
age,20,21 thereby exhibiting significant biological properties, such as
antitumoral, anti-cancer,22 anti-inflammatory,23 antituberculosis,24
and antiplasmodial activities.25 For example, tetracyclic inden-
oquinoline derivatives (V, Fig. 1) were reported to show potent
antiproliferative activities against breast (MCF-7), lung epithelial
(A-549), and cervical (HeLa) adenocarcinoma cells.26 As a conse-
quence, the remarkable bioactivities along with the unique struc-
tural arrays displayed by these tetracyclic-fused quinoline systems
have made them a particularly appealing target for the synthetic
efforts.27e30
Fig. 1. Examples of hetero-fused tropones (IeVI).
* Corresponding author. Tel./fax: þ86 416 3400266; e-mail address: bhuzh@163.
com (W. Gao).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.049

W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
2181
Considering the above valid points, and in view of structural
diversity playing a prominent role in medicinal and combinatorial
chemistry,31 we conceived that the incorporation of the tropone
nucleus into the planar tetracyclic-fused quinoline systems leading
to new prototypes, as possible drug-like candidates for pharma-
cological studies, would be of synthetic importance. Therefore, in
the context of our ongoing studies concerning the synthesis of
potential biologically active hybrid molecules,32e38 we wish to re-
port, herein, a facile and inexpensive procedure for the preparation
of planar linearly tetracyclic-fused benzotroponoquinoline sys-
tems, wherein the tropone ring is fused at its 2,3-position to the b-
position of quinoline ring to give a compact structure like the
compounds VI in Fig. 1. To the best of our knowledge, this type of
polycyclic-fused structure is still unprecedented.
whereas an incomplete reaction was observed when using EtONa
as base. The use of t-BuOK gave an intractable complex mixture that
we could not separate any desired product in appreciable yield. To
our delight, we discovered that 1.1 equiv of NaH were suitable to
promote the reaction, which was completed within 2 h as TLC in-
dicated the absence of intermediate A. Since the newly-formed
olefination product B did not interfere with further ester hydroly-
sis reaction, purification at this stage was unnecessary. Accordingly,
we simply added 5% aqueous NaOH solution directly to the reaction
mixture and continued to reflux for 2 h. After the reaction was
completed followed by an acidic work-up, the corresponding free
carboxylic acid 3a was obtained in a good overall yield of 76%. The
stereochemistry of 3a was established as an E-stereoisomer on the
basis of its 1H NMR spectrum, which showed the mutual coupling
constant value J¼15.6 Hz of the two arising vinylic protons CH]CH
at 8.08 and 8.17 ppm, respectively.
2. Results and discussion
It is well known that the intramolecular FriedeleCrafts acylation
reaction of some appropriate aryl- or heteroarylcarboxylic acids has
been particularly useful in synthetic organic chemistry,39e41 since
this reaction could result in the construction of an extra ring by
generation of a new CeC bond, including seven-membered ring
construction.42,43 For example, Karcher and co-worker reported
the intramolecular FriedeleCrafts acylation reaction of 2-
styrylnicotinic acid for the synthesis of benzotroponopyridine de-
rivatives.9 In this regard, we recently reported the intramolecular
FriedeleCrafts acylation reaction of 2-aryloxymethylquinoline-3-
carboxylic acids for the construction of polycyclic-fused benzo
[6,7]oxepino[3,4-b]quinolin-13(6H)-ones.32,38 Taking these obser-
vations into account, we reasoned that if we could achieve the facile
synthesis of suitably 2-styrylquinoline-3-carboxylic acid derivatives
(3) as the tetracyclic precursors, it might be possible to convert
them into the desired tetracyclic quino-fused tropone systems 4 via
the intramolecular cyclization strategy as shown in Scheme 1.
Scheme 2. One-pot synthesis of 2-styrylquinoline-3-carboxylic acid (3a).
Thereafter, various aromatic aldehydes 2ber with differing
electronic properties were subjected to the one-pot sequence un-
der the same reaction conditions for the synthesis of a series of 2-
styrylquinoline-3-carboxylic acid derivatives (3ber). The reaction
results were listed in Table 1.
Table 1
Synthesis of differently substituted (E)-2-(arylvinyl) quinoline-3-carboxylic acids
(3aer)
Entry
Product
3aer
Yielda (%)
Scheme 1. Possible construction of quino-fused tropone systems via FriedeleCrafts
cyclization reaction.
1
3a
76
Thus, the key to implement our strategy was the realization of
the facile preparation of the key substrates 3. Prior to the current
investigation, a few related examples involving the synthesis of 2-
styrylpyridine3-carboxylic acids, structurally analogous to 3, have
been reported.9,17 Although the two methodologies are elegant and
impressive, our attempts to follow both routes to synthesize our 2-
styrylquinoline-3-carboxylic acid derivatives were unfruitful, and
no promising result was obtained. Therefore, we felt that there was
a real need for the development of a direct and concise method to
synthesize the required substrates 3. To this end, we postulated an
efficient and attractive one-pot reaction procedure. As outlined in
Scheme 2, ethyl 2-(bromomethyl)quinoline-3-carboxylate (1) was
first subjected to the Arbuzov reaction with triethyl phosphate at
160 ꢀC. After the complete conversion of the starting material to the
corresponding intermediate A (TLC), triethyl phosphate was evap-
orated to dryness under reduced pressure. Subsequently, we con-
2
3
4
5
6
3b
3c
3d
3e
3f
75
83
71
74
80
ducted the HornereEmmons olefination reaction of
A with
benzaldehyde (2a) by adding directly a solution of 1.1 equiv of 2a in
DMF to the residue at 90 ꢀC. We examined this reaction by using
different bases (NaOH, K2CO3, Et3N, EtONa, t-BuOK, NaH) and
varying their equivalents, from one to three, separately. We found
that the reaction could not occur upon using NaOH, K2CO3 or Et3N,
(continued on next page)

2182
W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
Table 1 (continued )
bases, were well tolerated in the one-pot process without any ex-
Yielda (%)
perimental difficulties.
Entry
Product
3aer
Due to the simplicity and efficiency of the one-pot synthesis, we
decided to further extend its scope to the preparation of 2-(hetar-
ylvinyl)quinoline-3-carboxylic acids. To this purpose, an analogous
series of reactions were performed using some heteroaromatic al-
dehydes viz., thiophene-2-carbaldehyde (2s), furan-2-carbaldehyde
(2t), and pyridine aldehydes (2uew) in place of aromatic aldehydes
under similar reaction conditions (only varying the reaction time
according to TLC monitoring). As shown in Table 2, all these het-
eroaromatic aldehydes were equally amenable to the one-pot re-
action sequence, furnishing the expected E-configuration 2-
(hetarylvinyl)quinoline-3-carboxylic acids (3sew), albeit in slightly
low yields of 52e61%.
7
8
9
3g
73
3h
3i
76
70
Table 2
One-pot synthesis of (E)-2-(hetarylvinyl)quinoline-3-carboxylic acids (3sew)
10
3j
79
Entry
1
Product
3sew
Yielda (%)
54
11
12
13
14
3k
3l
74
81
79
68
3s
2
3
4
3t
61
3m
3n
3u
3v
55
56
52
15
16
17
3o
3p
3q
72
73
70
5
3w
a
Yield of isolated product.
Encouraged by these results, we also attempted the reaction of 1
with 1-naphthaldehydes (2x) and 2-naphthaldehydes (2y) under
similar reaction conditions with the aim of diversifying our work on
the synthesis of novel precursor compounds of quino-fused tro-
pones. As expected, this one-pot reaction proceeded smoothly, and
gave the corresponding (E)-2-(2-(naphthalen-1-yl)vinyl) quino-
line-3-carboxylic acid (3x) and (E)-2-(2-(naphthalen-2-yl)vinyl)
quinoline-3-carboxylic acid (3y) in 72% and 76% yields, respectively
(Scheme 3).
18
3r
74
a
Yield of isolated product.
As shown in Table 1, various substituted 2-styrylquinoline-3-
carboxylic acids (3ber) were successfully synthesized with over-
all yields ranging from 68% to 83%. The nature and site of sub-
stituent present in the aromatic aldehydes did not seem to affect
the one-pot reaction significantly, neither in product yield nor in
reaction rate. In addition, it was worthy to mention that the halo-
gen (F, Cl, Br), cyanogen, and nitro groups, which were sensitive to
Scheme 3. One-pot synthesis of (E)-2-(2-(naphthalenyl)vinyl)quinoline-3-carboxylic
acids (3x and 3y).

W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
2183
From these results, it may be concluded that the novel one-pot
method provides an efficient, straightforward, and general access to
the construction of a wide variety of novel (E)-2-((aryl/hetaryl) vinyl)
quinoline-3-carboxylic acids (3aey) with good yields. The beauty of
this one-pot reaction procedure is that three chemical trans-
formations [i.e., Arbuzov reaction, HornereWadswortheEmmons
reaction, and ester hydrolysis] take place in one-pot procedure,
thereby simplifying reaction handling and product purification, im-
proving synthetic efficiency, and reducing solvent consumption and
disposal.
12H-areno[4,5]cyclohepta[1,2-b]quinolin-12-ones (4a, b, eem) in
good yields, ranging from 65 to 80% as shown in Table 3. Their
structures were confirmed via spectroscopic data and elemental
analyses with the results being in full agreement with the proposed
structures. As an example, in the IR spectrum of 4a, the disap-
pearance of OH and C]O stretching peaks of its carboxyl group at
3421 cmꢁ1 and 1716 cmꢁ1, and the appearance of the tropone C]O
stretching frequency at a decreased wave number of 1650 cmꢁ1
Table 3
Having in hand a series of the newly synthesized substrates
3aey, our attention was transferred to their intramolecular Frie-
deleCrafts acylation reaction for building the desired tetracyclic
quino-fused tropone systems. At this stage, we first investigated the
intramolecular FriedeleCrafts reaction of the representative 2-
styrylquinoline-3-carboxylic acid (3a) using Eaton’s reagent as
the cyclizing agent. Our recent work has proved that the use of
Eaton’s reagent is very efficient for the construction of polycyclic-
fused quinoline systems.44,45 However, in the present case, we
found that it failed to promote the reaction efficiently and the
corresponding cyclized product 12H-benzo[4,5]cyclohepta[1,2-b]
quinolin-12-one (4a) was obtained in a very low yield (15%). Other
attempts by varying the reaction temperature and the amount of
Eaton’s reagent used also failed. Additionally, we also attempted to
use other cyclization reagents, such as sulfuric acid, hydrogen
fluoride, trifluoroacetic anhydride, methanesulfonic acid,
PPAeP2O5, and TFAeTfOH, but they produced either low yielding
mixtures or no identifiable products. Upon using PPE (poly-
phosphate ester), no formation of product was observed and the
starting material was recovered unchanged. The reaction using
POCl3 as cyclization reagent was also investigated according to the
method reported recently by Meesala et al.46 Unfortunately, the 1H
HMR spectrum of the reaction mixture showed that 4a was not
formed even in a trace amount. After these fruitless attempts, we
decided to focus on the use of PPA (polyphosphoric acid) as the
cycling agent. To our delight, we found that the cyclization reaction
of 3a could be performed smoothly at 150 ꢀC as shown in Scheme 4.
After the reaction was complete within 4 h, the reaction mixture
was poured into cold water followed by neutralization with
NaHCO3 solution. TLC examination of the crude reaction mixture
revealed the presence of a fast running major component con-
taminated with dark base line material, thereby rendering the
purification of the resulting product by flash chromatography easy.
Thus, the cyclized product 4a was obtained in a good yield of 78%. In
this reaction, the reaction temperature highly affected the product
yield, and the yield significantly decreased when the reaction
temperature was below 150 ꢀC. Although the higher reaction
temperature shortened the reaction time from 4 h to 1 h, tarry
byproducts were formed, which significantly reduced the yield of
the desired products. As far as the amount to PPA was concerned,
the use of 15 g PPA to 1 mmol of 3a was found most suitable to
provide maximum yield and there was no further improvement in
the yield with increasing the amount of PPA.
Synthesis of 12H-areno[4,5]cyclohepta[1,2-b]quinolin-12-ones (4a, b, eem)
Entry
Product
4a, b, eem
Yielda (%)
1
4a
78
2
3
4b
4e
80
66
4
5
6
4f
78
76
72
4g
4h
7
8
4i
4j
65
76
9
4k
4l
70
79
10
Scheme 4. Synthesis of 12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one (4a).
11
4m
74
Encouraged by the successful synthesis of compound 4a, we
tested this protocol for the intramolecular cyclization of other
substrates 3bey in a similar fashion. The substrates 3a, b, eem
could be smoothly transformed to the desired cyclized products
a
Yield of isolated product.

2184
W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
were clear evidences for the intramolecular cyclization occurring.
The main feature of its 1H NMR spectrum was the appearance of
two aromatic protons representing the peaks at 7.28 and 7.48 ppm,
respectively, as ortho coupled doublets with a coupling constant
J¼12.5 Hz, which was characteristic of ortho-proton coupling of
tropone ring protons. The other synthesized compounds exhibited
similar spectral characteristics. Herein, it is worthy to mention that
most of these newly synthesized quino-fused tropone systems
contain one or two halogen substituents, which make them par-
ticularly appealing, since these functional groups could provide
ample opportunities for further synthetic manipulation by cross
coupling reactions to obtain more complex ring-fused systems.
An example that is particularly relevant to the present discussion
is described in the literature,12 where the structural analogs of
Although we have not yet established the mechanism for for-
mation of the lactone structure and the detailed experimental ev-
idences are still elusive at the current stage, taking into
consideration the entire outcome, this might be explained by the
assumption that these substrates may be protonated at the carbon
position of the olefinic group under the action of PPA. Importantly,
the formation of this type of protonation of the styryl group has
been already reported by Klumpp et al.49e51 Thus, a tentative hy-
pothesis is depicted in Scheme 5 using ethyl substrate 3d as an
example. The reaction presumably involves the protonation of 3d at
the olefinic group to form the carbocation C. It has been reported
intramolecular acylation methods that directly use carboxylic acids
as the electrophile often suffered from the poor leaving group
ability of the eOH moiety.52 Thus, the carbocation C might be
trapped through intramolecular attack of the eOH oxygen leading
to efficient cyclization to D. Subsequently, the elimination of hy-
drogen ion from D afforded the product 4d.
tricyclic
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyr-
idin-5-one could be served as valuable synthetic intermediate for
the synthesis of MK-8033, a specific c-Met/Ron dual kinase
inhibitor.12
However, to our surprise, the substrates 3c, 3d, 3o and 3p dis-
played a different reactivity pattern, where the predicted tetracyclic
quino-fused tropone products were not observed and instead, un-
expected lactones 4c, 4d, 4o and 4p were formed as the main
component in this intramolecular FriedeleCrafts reaction as shown
in Table 4. Their structures were easily deduced from their 1H NMR
spectra. For example, the 1H NMR spectrum of 4c revealed the
presence of two unequivalent methylene protons at 3.42 and 3.80
coupled with each other with
a geminal coupling constant
J¼16.8 Hz, and in turn with the vicinal methine proton at 5.88 ppm,
along with the signals for 9 aromatic protons exactly matching its
structure in the range of aromatic region. The spectral pattern in
our case was very similar to some structurally analogous
lactones.47,48
Scheme 5. A tentative hypothesis to formation of the lactone 4d.
But the question about why protonation of these substrates is
positioned at the styryl group still remains unclear and elusive at
the current stage. Given our present state of knowledge, the re-
action results are difficult to guess prior to performing the actual
experiments. It was pertinent to note that there was a similar report
where the intramolecular FriedeleCrafts reaction of (E)-2-(4-
bromostyryl)-5-chloronicotinic acid (I) by the treatment with PPA
at 210 ꢀC also resulted in the formation of a lactone II (Scheme 6).17
But in this literature no detailed mechanistic studies have been
carried out, and there is no consensus of opinion regarding the
formation of the structure of lactone. Further research to explore its
reaction mechanism represents an intriguing goal that we are
currently contemplating.
Table 4
An unexpected synthesis of 3-phenyl-3,4-dihydro-1H-pyrano[4,3-b]quinolin-1-
ones
Entry
1
Product
Yielda (%)
71
2
3
69
66
Scheme 6. Formation of the lactone II from the intramolecular FriedeleCrafts acylation
reaction.
Unfortunately, our similar endeavors to cyclize the substrates 3n
and 3qey did not meet any success. TLC and 1H NMR spectroscopy
of the reaction mixture showed a combination of starting materials
and an intractable mixture of products, from which neither the
desired quino-fused tropones nor the cyclized lactones could be
isolated. Furthermore, our attempts to increase the amount of PPA
or use other cyclization reagents were also unsatisfactory. Work is
currently ongoing to extend the scope of intramolecular Friedele-
Crafts acylation reaction, and more studies toward screening cat-
alysts and additives etc. will be part of our future efforts.
4
62
a
Yield of isolated product.

W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
2185
3. Conclusions
QuinoeH), 8.36 (d, J¼8.1 Hz, 1H, QuinoeH), 8.23 (d, J¼8.1 Hz, 1H,
QuinoeH), 8.14 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.08 (d, J¼15.6 Hz,
1H, eCH]CHe), 8.01 (t, J¼8.1 Hz, 1H, QuinoeH), 7.75 (t, J¼8.1 Hz,
1H, QuinoeH), 7.62 (d, J¼8.1 Hz, 2H, PheH), 7.30 (d, J¼8.1 Hz, 2H,
PheH), 2.37 (s, 3H, Me); MS (FAB) m/z: 290.1 ([MþH]þ, 100). Anal.
Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84%. Found: C, 78.58; H,
5.12; N, 4.78%.
In conclusion, we have succeeded in achieving the first con-
struction of structurally novel and biologically intriguing
tetracyclic-fused quinolineetropone systems 2H-areno[4,5]cyclo-
hepta[1,2-b]quinolin-12-ones by the intramolecular FriedeleCrafts
acylation reaction of (E)-2-(arylvinyl)quinoline-3-carboxylic acids,
albeit there is still a demand for expanding the scope of the acyl-
ation reaction. In view of the synergism of both the medium-sized
seven-membered tropone ring and quinoline unit in a molecular
frame work, the newly synthesized compounds would likely pos-
sess significant biological activities and be potentially applied for
the development of biologically and pharmaceutically important
drugs. Our further work focusing on intramolecular FriedeleCrafts
acylation reaction in the synthesis of quino-fused tropones is cur-
rently ongoing, and more studies toward screening catalysts and
additives etc. is being actively pursued in our laboratory.
4.2.3. (E)-2-(4-Methoxystyryl)quinoline-3-carboxylic acid (3c). Pale
yellow needles, mp 170e171 ꢀC; FT-IR (KBr) nmax: 3421, 1716, 1625,
1585, 1453, 1385, 1346, 1264, 1202, 1066, 964 cmꢁ1 1H NMR
;
(DMSO-d6, 600 MHz):
d 13.49 (s, br, 1H, COOH), 8.88 (s, 1H,
QuinoeH), 8.07e8.09 (m, 2H, QuinoeH), 8.05 (d, J¼15.6 Hz, 1H,
eCH]CHe), 7.97 (d, J¼15.6 Hz, 1H, eCH]CHe), 7.86 (t, J¼7.8 Hz,
1H, QuinoeH), 7.64 (d, J¼8.4 Hz, 2H, PheH), 7.61 (t, J¼7.8 Hz, 1H,
QuinoeH), 7.02 (d, J¼8.4 Hz, 2H, PheH), 3.82 (s, 3H, OMe); MS (FAB)
m/z: 306.1 ([MþH]þ, 100). Anal. Calcd for C19H15NO3: C, 74.74; H,
4.95; N, 4.59%. Found: C, 74.95; H, 5.09; N, 4.44%.
4. Experimental section
4.1. General
4.2.4. (E)-2-(4-Ethylstyryl)quinoline-3-carboxylic acid (3d). Pale
yellow prisms, mp 208e210 ꢀC; FT-IR (KBr) nmax: 3421, 1716, 1624,
1587, 1489, 1453, 1416, 1385, 1347, 1222, 1197, 1065, 980 cmꢁ1 1H
;
The chemical used in this work was obtained from Fluka and
were used without purification. Melting points (uncorrected) were
determined by using WRS-1B melting points apparatus. 1H NMR
spectra were recorded on a Brucker AVANCE NMR spectrometer
using CDCl3 or DMSO-d6 as the solvent. The reported chemical
NMR (DMSO-d6, 300 MHz) d: 13.50 (s, br, 1H, COOH), 9.24 (s, 1H,
QuinoeH), 8.46 (d, J¼8.4 Hz, 1H, QuinoeH), 8.27 (d, J¼8.1 Hz, 1H,
QuinoeH), 8.20 (d, J¼15.9 Hz, 1H, eCH]CHe), 8.00e8.06 (m, 2H,
ArH and eCH]CHe), 7.77 (t, J¼8.1 Hz, 1H, QuinoeH), 7.67 (d,
J¼8.4 Hz, 2H, PheH), 7.04 (d, J¼8.4 Hz, 2H, PheH), 4.10 (q, J¼6.9 Hz,
2H, eCH2CH3), 1.36 (t, J¼6.9 Hz, 3H, eCH2CH3); MS (FAB) m/z: 304.1
([MþH]þ, 100). Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65; N,
4.62%. Found: C, 79.48; H, 5.45; N, 4.51%.
shifts (d values) are given in parts per million downfield from tet-
ramethylsilane (TMS) as the internal standard. The progress of re-
actions was monitored by thin-layer chromatography (TLC) on
silica gel GF254 using Ethyl acetate/petroleum ether (1:3) as eluent.
4.2.5. (E)-2-(4-Fluorostyryl)quinoline-3-carboxylic acid (3e). Pale
yellow needles, mp 161e163 ꢀC; FT-IR (KBr) nmax: 3440, 1737, 1632,
1598,1554,1508,1422,1379,1230,1159, 972 cmꢁ1; 1H NMR (DMSO-
4.2. General procedure for synthesis of (E)-2-((aryl/hetaryl)vinyl)
quinoline-3-carboxylic acids (3aey)
d6, 300 MHz):
d 13.62 (s, br, 1H, COOH), 8.95 (s, 1H, QuinoeH), 8.15
Ethyl 2-bromomethylquinoline-3-carboxylate (1) (0.294 g,
1 mmol) was dissolved in triethyl phosphate (4 mL). The resulting
reaction mixture was stirred at 160 ꢀC for about 1 h. The conversion
was monitored by TLC. After the reaction was complete, the ex-
cessive triethyl phosphate was removed in vacuo, and a solution of
aromatic or heteroaromatic aldehyde 2aey (1.1 mmol) in DMF
(5 mL) and NaH (0.026 g, 1.1 mmol) were added to the residue,
respectively. The mixture was stirred for about 1 h at room tem-
perature and stirred further at 90 ꢀC for 1 h. After completion (TLC),
5% aqueous solution of sodium hydroxide (5 mL) was added to the
reaction mixture and continued to stir at the temperature for 2 h.
The mixture was cooled to room temperature followed by acidifi-
cation with 1 mol/L HCl. The resulting crude product was purified
by recrystallization from ethanol to give 3 with yields ranging from
in 52e83%.
(d, J¼15.7 Hz, 1H, eCH]CHe), 8.08e8.12 (m, 2H, ArH), 7.97 (d,
J¼15.7 Hz, 1H, eCH]CHe), 7.90 (t, J¼7.4 Hz, 1H, ArH), 7.71e7.78 (m,
2H, ArH), 7.65 (t, J¼7.6 Hz, 1H, ArH), 7.26e7.32 (m, 2H, ArH); MS
(FAB) m/z: 294.1 ([MþH]þ, 100). Anal. Calcd for C18H12FNO2: C,
73.71; H, 4.12; N, 4.78%. Found: C, 73.94; H, 4.37; N, 4.63%.
4.2.6. (E)-2-(2-Chlorostyryl)quinoline-3-carboxylic acid (3f). Pale
yellow needles, mp 231e232 ꢀC; FT-IR (KBr) nmax: 3373, 1715, 1630,
1491, 1471, 1429, 1247, 1197, 1135, 1058, 973 cmꢁ1; 1H NMR (DMSO-
d6, 300 MHz): d 13.59 (s, br, 1H, COOH), 8.95 (s, 1H, QuinoeH), 8.30
(d, J¼15.6 Hz, 1H, eCH]CHe), 8.23 (d, J¼15.7 Hz, 1H, eCH]CHe),
8.14 (d, J¼8.0 Hz,1H, ArH), 8.09 (d, J¼8.6 Hz,1H, ArH), 7.87e7.93 (m,
2H, ArH and eCH]CHe), 7.66 (t, J¼7.8 Hz, 1H, ArH), 7.56 (dd, J¼7.5,
7.6 Hz, 1H, ArH), 7.38e7.49 (m, 2H, ArH); MS (FAB) m/z: 310.1
([MþH]þ, 100), 312.1 (35). Anal. Calcd for C18H12ClNO2: C, 69.80; H,
3.90; N, 4.52%. Found: C, 69.49; H, 3.96; N, 4.22%.
4.2.1. (E)-2-Styrylquinoline-3-carboxylic acid (3a). Pale yellow
needles, mp 190e191 ꢀC; FT-IR (KBr) nmax: 3421, 1716, 1625, 1586,
4.2.7. (E)-2-(3-Chlorostyryl)quinoline-3-carboxylic acid (3g). Pale
yellow needles, mp 205e206 ꢀC; FT-IR (KBr) nmax: 3443, 1698, 1617,
1561, 1491, 1455, 1379, 1232, 1199, 1138, 957 cmꢁ1; 1H NMR (DMSO-
1488, 1453, 1384, 1264, 1202, 1066, 963 cmꢁ1 1H NMR (DMSO-d6,
;
300 MHz):
d 13.51 (s, br, 1H, COOH), 9.13 (s, 1H, ArH), 8.32 (d,
J¼8.1 Hz, 1H, ArH), 8.22 (d, J¼8.1 Hz, 1H, QuinoeH), 8.17 (d,
J¼15.6 Hz,1H, eCH]CHe), 8.08 (d, J¼15.6 Hz,1H, eCH]CHe), 7.99
(t, J¼8.1 Hz, 1H, ArH), 7.73 (t, J¼8.1 Hz, 3H, ArH), 7.39e7.50 (m, 3H,
ArH); MS (FAB) m/z: 276.1 ([MþH]þ, 100). Anal. Calcd for
d6, 300 MHz): d 13.55 (s, br, 1H, COOH), 8.93 (s, 1H, QuinoeH), 8.12
(d, J¼7.9 Hz, 1H, ArH), 8.08 (t, J¼8.1 Hz, 1H, ArH), 8.22 (d, J¼15.7 Hz,
1H, eCH]CHe), 7.93 (d, J¼15.7 Hz, 1H, eCH]CHe), 7.86e7.91 (m,
1H, ArH), 7.75 (s, 1H, PheH), 7.63e7.68 (m, 2H, ArH), 7.48 (t,
J¼7.5 Hz, 1H, ArH), 7.42 (d, J¼8.1 Hz, 1H, ArH); MS (FAB) m/z: 310.0
([MþH]þ, 100), 312.0 (32). Anal. Calcd for C18H12ClNO2: C, 69.80; H,
3.90; N, 4.52%. Found: C, 69.97; H, 3.76; N, 4.75%.
C
18H13NO2: C, 78.53; H, 4.76; N, 5.09%. Found: C, 78.71; H, 4.94; N,
5.02%.
4.2.2. (E)-2-(4-Methylstyryl)quinoline-3-carboxylic acid (3b). Pale
yellow needles, mp 232e234 ꢀC; FT-IR (KBr) nmax: 3421, 1716, 1624,
4.2.8. (E)-2-(4-Chlorostyryl)quinoline-3-carboxylic acid (3h). Pale
yellow needles, mp 189e190 ꢀC; FT-IR (KBr) nmax: 3400, 1625, 1624,
1587, 1488, 1453, 1415, 1384, 1346, 1262, 1197, 1065, 979 cmꢁ1 1H
;
NMR (DMSO-d6, 300 MHz):
d
13.56 (s, br, 1H, COOH), 9.17 (s, 1H,
1584, 1491, 1411, 1379, 1269, 1220, 1090, 1012, 973 cmꢁ1 1H NMR
;

2186
W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
(DMSO-d6, 300 MHz)
d: 13.57 (s, br, 1H, COOH), 9.01 (s, 1H,
860 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
; d 13.60 (s, 1H, COOH),
QuinoeH), 8.20 (d, J¼15.8 Hz, 1H, eCH]CHe), 8.13e8.16 (m, 2H,
QuinoeH), 7.98 (d, J¼15.7 Hz, 1H, eCH]CHe), 7.91 (d, J¼8.0 Hz, 1H,
QuinoeH), 7.72 (d, J¼8.4 Hz, 2H, PheH), 7.69 (d, J¼8.1 Hz, 1H,
QuinoeH), 7.52 (d, J¼8.4 Hz, 2H, PheH); MS (FAB) m/z: 310.0
([MþH]þ, 100), 312.0 (38). Anal. Calcd for C18H12ClNO2: C, 69.80; H,
3.90; N, 4.52%. Found: C, 69.51; H, 3.68; N, 4.31%.
8.97 (s, 1H, QuinoeH), 8.26 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.18 (d,
J¼15.9 Hz, 1H, eCH]CHe), 8.15 (d, J¼7.8 Hz, 1H, eCH]CHe), 8.07
(d, J¼8.1 Hz, 2H, eCH]CHe), 7.97 (d, J¼7.5 Hz, 1H, ArH), 7.90 (t,
J¼7.5 Hz, 1H, ArH), 7.82 (t, J¼7.5 Hz, 1H, ArH), 7.61e7.69 (m, 2H,
ArH); MS (FAB) m/z: 321.0 ([MþH]þ, 100). Anal. Calcd for
C
18H12N2O4: C, 67.50; H, 3.78; N, 8.75%. Found: C, 67.62; H, 3.71; N,
8.79%.
4.2.9. (E)-2-(2,3-Dichlorostyryl)quinoline-3-carboxylic acid (3i). Pale
yellow needles, mp 251e252 ꢀC; FT-IR (KBr) nmax: 3412, 1696, 1615,
4.2.15. (E)-2-(3-Nitrostyryl)quinoline-3-carboxylic acid (3o). Pale
yellow powder, mp 228e229 ꢀC; FT-IR (KBr) nmax: 3441, 1702, 1645,
1616, 1589, 1560, 1534, 1491, 1456, 1416, 1352, 1203, 1139, 1064, 993,
1564, 1491, 1449, 1406, 1380, 1249, 1188, 1142, 1061, 964 cmꢁ1 1H
;
NMR (DMSO-d6, 300 MHz):
d 13.60 (s, br, 1H, COOH), 8.97 (s, 1H,
QuinoeH), 8.25 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.21 (d, J¼15.7 Hz,
1H, eCH]CHe), 8.14 (d, J¼8.0 Hz, 1H, ArH), 8.11 (d, J¼8.4 Hz, 1H,
ArH), 7.84e7.93 (m, 2H, ArH), 7.65e7.70 (m, 2H, ArH), 7.47 (t,
J¼7.9 Hz, 1H, ArH); MS (FAB) m/z: 344.1 ([MþH]þ, 100), 346.0 (72),
348.0 (12). Anal. Calcd for C18H11Cl2NO2: C, 62.81; H, 3.22; N, 4.07%.
Found: C, 62.53; H, 3.33; N, 3.78%.
860 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d 13.60 (s, br, 1H, COOH),
8.95 (s, 1H, QuinoeH), 8.50 (s, 1H, PheH), 8.36 (d, J¼15.7 Hz, 1H,
eCH]CHe), 8.20 (d, J¼8.0 Hz, 1H, ArH), 8.12e8.18 (m, 2H, ArH),
8.09 (d, J¼8.1 Hz, 1H, ArH), 8.06 (d, J¼15.7 Hz, 1H, eCH]CHe), 7.74
(t, J¼8.0 Hz, 1H, ArH), 7.67 (t, J¼7.5 Hz, 1H, ArH), 7.91 (dd, J¼7.4,
8.0 Hz, 1H, ArH); MS (FAB) m/z: 276.1 (9), 321.1 ([MþH]þ, 100). Anal.
Calcd for C18H12N2O4: C, 67.50; H, 3.78; N, 8.75%. Found: C, 67.64; H,
3.81; N, 8.57%.
4.2.10. (E)-2-(3,5-Dichlorostyryl)quinoline-3-carboxylic acid (3j). Pale
yellow prisms, mp 243e244 ꢀC; FT-IR (KBr) nmax: 3410, 1719, 1615,
1584, 1561, 1488, 1414, 1320, 1274, 1203, 1131, 1068, 969 cmꢁ1
;
1H
4.2.16. (E)-2-(4-Nitrostyryl)quinoline-3-carboxylic acid (3p). Pale
yellow solid, mp 248e249 ꢀC; FT-IR (KBr) nmax: 3446, 1731, 1650,
1604, 1573, 1515, 1496, 1396, 1329, 1267, 1213, 1158, 1064, 993,
NMR (DMSO-d6, 300 MHz):
d 13.56 (s, br, 1H, COOH), 8.94 (s, 1H,
QuinoeH), 8.24 (d, J¼15.7 Hz, 1H, eCH]CHe), 8.13 (d, J¼8.0 Hz, 1H,
QuinoeH), 8.06 (d, J¼8.4 Hz, 1H, QuinoeH), 7.85e7.93 (m, 2H,
QuinoeH), 7.76 (s,1H, PheH), 7.75 (s,1H, PheH), 7.66 (t, J¼7.5 Hz,1H,
QuinoeH), 7.59 (s, 1H, PheH); MS (FAB) m/z: 306.1 (54), 344.0
([MþH]þ, 100), 346.0 (66), 348.0 (12). Anal. Calcd for C18H11Cl2NO2:
C, 62.81; H, 3.22; N, 4.07%. Found: C, 62.46; H, 3.47; N, 3.75%.
840 cmꢁ1 1H NMR (DMSO-d6, 300 MHz):
; d 13.57 (s, 1H, COOH),
8.99 (s, 1H, QuinoeH), 8.39 (d, J¼15.9 Hz, 1H, eCH]CHe), 8.29 (d,
J¼8.4 Hz, 2H, PheH), 8.11e8.17 (m, 2H, ArH), 8.05 (d, J¼15.9 Hz, 1H,
eCH]CHe), 7.90e7.97 (m, 3H, ArH), 7.69 (t, J¼7.5 Hz, 1H, ArH); MS
(FAB) m/z: 321.1 ([MþH]þ, 100). Anal. Calcd for C18H12N2O4: C,
67.50; H, 3.78; N, 8.75%. Found: C, 67.66; H, 3.74; N, 9.04%.
4.2.11. (E)-2-(2-Bromostyryl)quinoline-3-carboxylic acid (3k). Pale
yellow powder, mp 244e245 ꢀC; FT-IR (KBr) nmax: 3446, 1716, 1616,
4.2.17. (E)-2-(3-Cyanostyryl)quinoline-3-carboxylic acid (3q). Yellow
needles, mp 241e242 ꢀC; FT-IR (KBr) nmax: 3251, 1698, 1638, 1616,
1590, 1561, 1490, 1451, 1431, 1380, 1270, 1227, 1198, 1138, 1064, 957,
1558, 1558, 1490, 1466, 1426, 1378, 1247, 1197, 1134, 1056, 972 cmꢁ1
;
1H NMR (DMSO-d6, 300 MHz):
d 13.59 (s, br, 1H, COOH), 8.96 (s, 1H,
QuinoeH), 8.26 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.08e8.16 (m, 3H,
ArH and eCH]CHe), 7.86e7.93 (m, 2H, ArH), 7.74 (d, J¼8.1 Hz, 1H,
ArH), 7.67 (dd, J¼7.8, 7.5 Hz, 1H, ArH), 7.50 (t, J¼7.5 Hz, 1H, ArH),
7.33 (t, J¼7.8 Hz,1H, ArH); MS (FAB) m/z: 200.1 (27), 354.0 ([MþH]þ,
100), 356.0 (90). Anal. Calcd for C18H12BrNO2: C, 61.04; H, 3.41; N,
3.95%. Found: C, 60.70; H, 3.11; N, 3.58%.
922 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d 13.56 (s, br, 1H, COOH),
8.27 (d, J¼15.9 Hz, 1H, eCH]CHe), 8.12 (d, J¼8.1 Hz, 1H, ArH),
8.05e8.14 (m, 2H, ArH), 7.97 (s, 1H, PheH), 7.86e7.92 (m, 3H, ArH),
7.81 (d, J¼7.8 Hz, 1H, ArH), 7.64 (t, J¼7.8 Hz, 2H, ArH); MS (FAB) m/z:
301.0 ([MþH]þ, 100). Anal. Calcd for C19H12N2O2: C, 75.99; H, 4.03;
N, 9.33%. Found: C, 76.15; H, 4.10; N, 9.12%.
4.2.12. (E)-2-(3-Bromostyryl)quinoline-3-carboxylic acid (3l). Pale
yellow powder, mp 219e220 ꢀC; FT-IR (KBr) nmax: 3447, 1703, 1615,
1552,1487,1426,1400,1210,1130,1058, 980 cmꢁ1; 1H NMR (DMSO-
4.2.18. (E)-2-(4-Cyanostyryl)quinoline-3-carboxylic acid (3r). Pale
yellow plates, mp 246e247 ꢀC; FT-IR (KBr) nmax: 3243, 1724, 1615,
1603, 1554, 1488, 1458, 1422, 1357, 1245, 1192, 1126, 1052, 972,
d6, 300 MHz):
d
13.55 (s, br, 1H, COOH), 8.93 (s, 1H, QuinoeH), 8.22
933 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d 13.86 (s, br, 1H, COOH),
(d, J¼15.7 Hz, 1H, eCH]CHe), 8.12 (d, J¼7.8 Hz, 1H, ArH), 8.07 (d,
J¼8.4 Hz, 1H, ArH), 7.87e7.94 (m, 3H, ArH and eCH]CHe),
7.63e7.72 (m, 2H, ArH), 7.56 (d, J¼7.9 Hz, 1H, ArH), 7.42 (t, J¼7.8 Hz,
1H, ArH); MS (FAB) m/z: 200.1 (38), 354.0 ([MþH]þ, 88), 356.0 (92).
Anal. Calcd for C18H12BrNO2: C, 61.04; H, 3.41; N, 3.95%. Found: C,
60.89; H, 3.37; N, 3.87%.
8.95 (s, 1H, QuinoeH), 8.34 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.13 (d,
J¼8.1 Hz,1H, ArH), 8.08 (d, J¼8.4 Hz,1H, ArH), 7.99 (d, J¼15.6 Hz,1H,
eCH]CHe), 7.84e7.92 (m, 5H, ArH), 7.66 (t, J¼7.8 Hz, 1H, ArH); MS
(FAB) m/z: 301.0 ([MþH]þ, 100). Anal. Calcd for C19H12N2O2: C,
75.99; H, 4.03; N, 9.33%. Found: C, 75.74; H, 3.96; N, 9.05%.
4.2.19. (E)-2-(2-(Thiophen-2-yl)vinyl)quinoline-3-carboxylic acid (3s).
Yellow solid, mp 245e246 ꢀC; FT-IR (KBr) nmax: 3421, 1717, 1614, 1586,
4.2.13. (E)-2-(4-Bromostyryl)quinoline-3-carboxylic acid (3m). Pale
yellow needles, mp 217e218 ꢀC; FT-IR (KBr) nmax: 3446, 1698, 1616,
1488, 1425, 1385, 1342, 1264, 1231, 1199, 1062, 969 cmꢁ1 1H NMR
;
1590, 1562, 1491, 1472, 1379, 1258, 1200, 1140, 1066, 957 cmꢁ1
;
1H
(DMSO-d6, 300 MHz) d: 12.51 (s, br,1H, COOH), 9.07 (s,1H, QuinoeH),
NMR (DMSO-d6, 300 MHz)
d
: 13.55 (s, br, 1H, COOH), 8.93 (s, 1H,
8.29 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.17e8.24 (m, 2H, ArH), 7.98 (d,
J¼15.5 Hz, 1H, eCH]CHe), 7.93e7.97 (m,1H, ArH), 7.67e7.72 (m, 2H,
ArH), 7.49 (d, J¼3.4 Hz, 1H, ArH), 7.16e7.19 (m, 1H, ArH); MS (FAB) m/
z: 282.0 ([MþH]þ, 100). Anal. Calcd for C16H11NO2S: C, 68.31; H, 3.94;
N, 4.98%. Found: C, 68.15; H, 3.80; N, 4.82%.
QuinoeH), 8.22 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.12 (d, J¼8.1 Hz, 1H,
ArH), 8.07 (d, J¼8.4 Hz, 1H, ArH), 7.87e7.95 (m, 3H, ArH), 7.63e7.72
(m, 2H, ArH), 7.56 (d, J¼7.8 Hz, 1H, ArH), 7.42 (t, J¼7.8 Hz, 1H,
QuinoeH); MS (FAB) m/z: 200.1 (28), 354.0 ([MþH]þ, 100), 356.0
(90). Anal. Calcd for C18H12BrNO2: C, 61.04; H, 3.41; N, 3.95%. Found:
C, 61.25; H, 3.48; N, 3.89%.
4.2.20. (E)-2-(2-(Furan-2-yl)vinyl)quinoline-3-carboxylic acid (3t).
Yellow plates, mp 241e242 ꢀC; FT-IR (KBr) nmax: 3313, 1699, 1609,
1586, 1489, 1450, 1373, 1345, 1319, 1276, 1221, 1154, 1067, 1017, 967,
4.2.14. (E)-2-(2-Nitrostyryl)quinoline-3-carboxylic acid (3n). Pale
yellow solid, mp 214e216 ꢀC; FT-IR (KBr) nmax: 3441, 1708, 1627,
1605, 1560, 1526, 1451, 1439, 1339, 1249, 1197, 1135, 1060, 966,
928 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d
13.54 (s, br, 1H, COOH),
8.98 (s, 1H, QuinoeH), 8.09e8.15 (m, 2H, ArH), 8.02 (d, J¼15.6 Hz,

W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
2187
1H, eCH]CHe), 7.89e7.93 (m, 2H, ArH and eCH]CHe), 7.85 (d,
J¼8.4 Hz, 1H, ArH), 7.66 (t, J¼7.6 Hz, 1H, ArH), 6.86 (d, J¼3.3 Hz, 1H,
FuraneH), 6.64e6.66 (m, 1H, ArH); MS (FAB) m/z: 266.0 ([MþH]þ,
100). Anal. Calcd for C16H11NO3: C, 72.45; H, 4.18; N, 5.28%. Found:
C, 72.30; H, 4.23; N, 5.12%.
the reaction mixture was poured slowly into cold saturated sodium
hydrogen carbonate solution. The crude products were obtained
after filtration, and purified by flash chromatography (petroleum
ether/EtOAc, 1:1).
4.3.1. 12H-Benzo[4,5]cyclohepta[1,2-b]quinolin-12-one (4a). White
solid, mp 204e205 ꢀC; FT-IR (KBr) nmax: 1650, 1616, 1594, 1572,
1488, 1463, 1431, 1403, 1382, 1338, 1284, 1232, 1118, 1089, 944,
4.2.21. (E)-2-(2-(Pyridin-2-yl)vinyl)quinoline-3-carboxylic acid (3u).
Yellow solid, mp 208e210 ꢀC; FT-IR (KBr) nmax: 3410, 1696, 1615,
1591, 1563, 1486, 1430, 1377, 1322, 1288, 1149, 1056, 1013, 986,
889 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 9.05 (s, 1H, QuinoeH), 8.26
934 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d
13.60 (s, br, 1H, COOH),
(d, J¼8.4 Hz, 1H, ArH), 8.16 (d, J¼8.4 Hz, 1H, ArH), 8.02 (d, J¼8.1 Hz,
1H, ArH), 7.86 (ddd, J¼8.4, 7.0, 1.2 Hz, 1H, ArH), 7.64e7.71 (m, 2H,
ArH), 7.57e7.62 (m, 2H, ArH), 7.48 (d, J¼12.5 Hz, 1H, TroponeeH),
7.28 (d, J¼12.5 Hz, 1H, TroponeeH); MS (FAB) m/z: 113.0 (100),
258.0 ([MþH]þ, 70). Anal. Calcd for C18H11NO: C, 84.03; H, 4.31;
N, 5.44%. Found: C, 83.81; H, 4.63; N, 5.37%.
8.93 (s, 1H, QuinoeH), 8.68 (d, J¼4.0 Hz, 1H, PyeH), 8.65 (d,
J¼15.3 Hz, 1H, eCH]CHe), 8.12 (t, J¼8.7 Hz, 2H, ArH), 8.02 (d,
J¼15.3 Hz, 1H, eCH]CHe), 7.84e7.93 (m, 2H, ArH), 7.64e7.70 (m,
2H, ArH), 7.36 (dd, J¼6.6, 4.8 Hz, 1H, ArH); MS (FAB) m/z: 277.0
([MþH]þ, 100). Anal. Calcd for C17H12N2O2: C, 73.90; H, 4.38; N,
10.14%. Found: C, 73.67; H, 4.33; N, 10.03%.
4.3.2. 10-Methyl-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
(4b). White solid, mp 179e181 ꢀC; FT-IR (KBr) nmax: 1631, 1606,
1570, 1552, 1487, 1430, 1381, 1330, 1304, 1271, 1192, 1128, 1045, 937,
4.2.22. (E)-2-(2-(Pyridin-3-yl)vinyl)quinoline-3-carboxylic acid (3v).
Yellow prisms, mp 258e259 ꢀC; FT-IR (KBr) nmax: 3411, 1699, 1636,
1616, 1583, 1554, 1485, 1420, 1400, 1326, 1253, 1206, 1122, 1047,
850 cmꢁ1 1H NMR (CDCl3, 300 MHz):
; d 9.06 (s, 1H, ArH), 8.26 (d,
968 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d
13.59 (s, br, 1H, COOH),
J¼8.6 Hz, 1H, ArH), 8.17 (d, J¼8.5 Hz, 1H, ArH), 8.03 (d, J¼8.3 Hz, 1H,
ArH), 7.84e7.90 (m, 1H, ArH), 7.65e7.70 (m, 1H, ArH), 7.57e7.62 (m,
2H, ArH), 7.48 (d, J¼12.5 Hz, 1H, TroponeeH), 7.28 (d, J¼12.5 Hz, 1H,
TroponeeH), 1.59 (s, 3H, Me); MS (FAB) m/z: 272.1 ([MþH]þ, 100).
Anal. Calcd for C19H13NO: C, 84.11; H, 4.83; N, 5.16%. Found: C,
84.27; H, 4.99; N, 5.34%.
8.94 (s, 1H, QuinoeH), 8.88 (d, J¼1.5 Hz, 1H, PyeH), 8.55 (dd, J¼4.2,
1.1 Hz, 1H, PyeH), 8.29 (d, J¼15.8 Hz,1H, eCH]CHe), 8.07e8.14 (m,
3H, ArH), 7.98 (d, J¼15.8 Hz, 1H, eCH]CHe), 7.87e7.92 (m, 1H,
ArH), 7.66 (t, J¼7.6 Hz, 1H, ArH), 7.48 (dd, J¼7.8, 7.8 Hz, 1H, ArH); MS
(FAB) m/z: 277.0 ([MþH]þ,100). Anal. Calcd for C17H12N2O2: C, 73.90;
H, 4.38; N, 10.14%. Found: C, 74.09; H, 4.29; N, 9.88%.
4.3.3. 3-(4-Methoxyphenyl)-3,4-dihydro-1H-pyrano[4,3-b]quinolin-
4.2.23. (E)-2-(2-(Pyridin-4-yl)vinyl)quinoline-3-carboxylic acid (3w).
Yellow prisms, mp 219e220 ꢀC; FT-IR (KBr) nmax: 3412, 1716, 1609,
1557, 1506, 1451, 1419, 1378, 1275, 1206, 1128, 1056, 1028, 976,
1-one (4c). Pale yellow solid, mp 189e191 ꢀC; FT-IR (KBr) nmax
:
3062, 3016, 2972,1732,1617,1566,1516,1417,1377,1304,1253,1213,
1130,1062,1033, 847 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d
9.08 (s,
958 cmꢁ1; 1H NMR (DMSO-d6, 300 MHz):
d
13.60 (s, br, 1H, COOH),
1H, QuinoeH), 8.24 (d, J¼7.8 Hz, 1H, QuinoeH), 8.07 (d, J¼8.4 Hz,
1H, QuinoeH), 7.94 (t, J¼8.4 Hz, 1H, QuinoeH), 7.70 (dd, J¼8.4,
7.8 Hz,1H, QuinoeH), 7.50 (d, J¼8.7 Hz, 2H, PheH), 7.01 (d, J¼8.7 Hz,
2H, PheH), 5.88 (dd, J¼11.4, 3.0 Hz, 1H, CH), 3.80 (dd, J¼16.8, 3.0 Hz,
1H, CH2), 3.78 (s, 3H, Me), 3.42 (dd, J¼16.8, 3.0 Hz, 1H, CH2); MS
(FAB) m/z: 306.1 ([MþH]þ, 100). Anal. Calcd for C19H15NO3: C, 74.74;
H, 4.95; N, 4.59%. Found: C, 74.54; H, 5.01; N, 4.72%.
8.96 (s, 1H, QuinoeH), 8.63 (d, J¼4.2 Hz, 2H, PyeH), 8.42 (d,
J¼15.7 Hz, 1H, eCH]CHe), 8.14 (d, J¼8.1 Hz, 1H, ArH), 8.09 (d,
J¼8.5 Hz,1H, ArH), 7.90 (d, J¼15.7 Hz, 1H, eCH]CHe), 7.65e7.70 (m,
2H, ArH), 7.64 (d, J¼4.4 Hz, 2H, PyeH); MS (FAB) m/z: 277.0 ([MþH]þ,
100). Anal. Calcd for C17H12N2O2: C, 73.90; H, 4.38; N, 10.14%. Found:
C, 73.72; H, 4.32; N, 9.92%.
4.2.24. (E)-2-(2-(Naphthalen-1-yl)vinyl)quinoline-3-carboxylic acid
4.3.4. 3-(4-Ethylphenyl)-3,4-dihydro-1H-pyrano[4,3-b]quinolin-1-
one (4d). White solid, mp 171e173 ꢀC; FT-IR (KBr) nmax: 2966, 2931,
1724,1619,1567,1498,1417,1379,1216,1194,1053, 986, 834 cmꢁ1; 1H
(3x). Yellow needles, mp 211e213 ꢀC; FT-IR (KBr) nmax: 3442, 1707,
1616, 1588, 1559, 1489, 1396, 1346, 1253, 1187, 1133, 1060, 963 cmꢁ1
;
1H NMR (DMSO-d6, 300 MHz):
d
13.57 (s, br, 1H, COOH), 8.95 (s, 1H,
NMR (DMSO-d6, 300 MHz):
d
9.06 (s,1H, QuinoeH), 8.22 (d, J¼8.1 Hz,
QuinoeH), 8.77 (d, J¼15.3 Hz,1H, eCH]CHe), 8.36 (d, J¼8.4 Hz,1H,
ArH), 8.26 (d, J¼15.6 Hz, 1H, eCH]CHe), 8.13e8.17 (m, 2H, ArH),
8.00 (t, J¼8.1 Hz, 2H, ArH), 7.88e7.94 (m, 2H, ArH), 7.58e7.68 (m, 4H,
ArH); MS (FAB) m/z: 326.1 ([MþH]þ,100). Anal. Calcd for C22H15NO2:
C, 81.21; H, 4.65; N, 4.30%. Found: C, 81.37; H, 4.59; N, 4.06%.
1H, QuinoeH), 8.05 (d, J¼8.4 Hz, 1H, QuinoeH), 7.92 (t, J¼7.8 Hz,1H,
QuinoeH), 7.68 (t, J¼8.1 Hz, 1H, QuinoeH), 7.46 (d, J¼7.8 Hz, 2H,
PheH), 7.28 (d, J¼8.1 Hz, 2H, PheH), 5.91 (dd, J¼11.4, 3.0 Hz,1H, CH),
3.75 (dd, J¼16.5, 3.0 Hz, 1H, CH2), 3.43 (dd, J¼16.5, 3.0 Hz, 1H, CH2),
2.62 (q, J¼7.8 Hz, 2H, CH2CH3), 1.80 (t, J¼7.8 Hz, 3H, CH2CH3); MS
(FAB) m/z: 304.1 ([MþH]þ, 100). Anal. Calcd for C20H17NO2: C, 79.19;
H, 5.65; N, 4.62%. Found: C, 79.41; H, 5.74; N, 4.54%.
4.2.25. (E)-2-(2-(Naphthalen-2-yl)vinyl)quinoline-3-carboxylic acid
(3y). Yellow powder, mp 239e241 ꢀC; FT-IR (KBr) nmax: 3441, 1712,
1616, 1558, 1492, 1453, 1436, 1379, 1248, 1186, 1135, 1057, 969, 819,
4.3.5. 10-Fluoro-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
749 cmꢁ1; 1H NMR (DMSO-d6, 400 MHz)
d
: 13.15 (s, br, 1H, COOH),
(4e). White solid, mp 186e188 ꢀC; FT-IR (KBr) nmax: 1650, 1604,
8.97 (s, 1H, QuinoeH), 8.33 (d, J¼16.0 Hz, 1H, eCH]CHe), 8.16 (d,
J¼15.6 Hz, 1H, eCH]CHe), 8.12e8.15 (m, 2H, ArH), 8.10 (s, 1H,
ArH), 8.00 (d, J¼8.4 Hz, 2H, ArH), 7.88e7.96 (m, 3H, ArH), 7.67 (t,
J¼8.0 Hz, 1H, ArH), 7.53e7.58 (m, 2H, ArH); MS (FAB) m/z: 326.1
([MþH]þ, 100). Anal. Calcd for C22H15NO2: C, 81.21; H, 4.65; N,
4.30%. Found: C, 80.99; H, 4.74; N, 4.33%.
1573, 1515, 1496, 1395, 1329, 1227, 1213, 1158, 1064, 993, 840 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
d 9.08 (s, 1H, QuinoeH), 8.17 (d,
J¼8.6 Hz, 1H, ArH), 7.96e8.01 (m, 2H, ArH), 7.85e7.90 (m, 1H, ArH),
7.57e7.66 (m, 2H, ArH), 7.45 (d, J¼12.6 Hz, 1H, TroponeeH),
7.38e7.41 (m, 1H, ArH), 7.24 (d, J¼12.6 Hz, 1H, TroponeeH); MS
(FAB) m/z: 276.0 ([MþH]þ, 100). Anal. Calcd for C18H10FNO: C,
78.54; H, 3.66; N, 5.09%. Found: C, 78.75; H, 3.73; N, 4.84%.
4.3. General procedure for synthesis of the cyclized products
4aen
4.3.6. 8-Chloro-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
(4f). Pale yellow solid, mp 218e219 ꢀC; FT-IR (KBr) nmax: 1655, 1616,
1584, 1557, 1488, 1464, 1425, 1382, 1337, 1299, 1268, 1191, 1133,
(E)-2-Arylvinylquinoline-3-carboxylic acid (0.5 mmol) and PPA
(83% P2O5, 7.5 g) were added to round flask (25 mL) and stirred at
150 ꢀC for about 4 h. The conversion was monitored by TLC. Then
1098, 964, 936, 866, 830 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d: 8.87 (s,
1H, QuinoeH), 8.17 (d, J¼8.5 Hz, 1H, ArH), 7.87 (ddd, J¼8.5, 6.9,

2188
W. Gao et al. / Tetrahedron 70 (2014) 2180e2189
1.2 Hz, 1H, ArH), 7.99e8.03 (m, 2H, ArH), 7.73 (dd, J¼7.9, 1.1 Hz, 1H,
ArH), 7.79 (d, J¼12.9 Hz, 1H, TroponeeH), 7.62 (t, J¼7.2 Hz, 1H, ArH),
7.54 (d, J¼12.9 Hz, 1H, TroponeeH), 7.47 (t, J¼7.9 Hz, 1H, ArH); MS
(FAB) m/z: 113.0 (16), 292.0 ([MþH]þ, 100), 294.0 (37). Anal. Calcd
for C18H10ClNO: C, 74.11; H, 3.46; N, 4.80%. Found: C, 73.95; H, 3.60;
N, 4.93%.
1580, 1551, 1486, 1430, 1372, 1319, 1282, 1226, 1129, 1100, 943, 894,
817 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
9.05 (s, 1H, QuinoeH), 8.17
d
(d, J¼8.7 Hz, 1H, ArH), 8.12 (d, J¼8.5 Hz, 1H, ArH), 8.02 (d, J¼8.2 Hz,
1H, ArH), 7.88 (ddd, J¼8.5, 6.9, 1.4 Hz, 1H, ArH), 7.73 (d, J¼1.8 Hz, 1H,
PheH), 7.68 (dd, J¼8.6, 1.9 Hz, 1H, PheH), 7.61e7.66 (m, 1H, ArH),
7.50 (d, J¼12.5 Hz, 1H, TroponeeH), 7.15 (d, J¼12.6 Hz, 1H,
TroponeeH); MS (FAB) m/z: 336.0 ([MþH]þ, 100), 338.0 (95). Anal.
Calcd for C18H10BrNO: C, 64.31; H, 3.00; N, 4.17%. Found: C, 64.41; H,
3.07; N, 4.06%.
4.3.7. 9-Chloro-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
(4g). Yellow solid, mp 221e222 ꢀC; FT-IR (KBr) nmax: 1645, 1618,
1585, 1553, 1487, 1377, 1321, 1281, 1221, 1171, 1111, 944, 893,
821 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
d
9.07 (s, 1H, ArH), 8.22 (d,
4.3.13. 10-Bromo-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
(4m). White solid, mp 213e214 ꢀC; FT-IR (KBr) nmax: 1655, 1616,
1576, 1557, 1488, 1431, 1382, 1306, 1261, 1125, 1094, 964, 900,
J¼8.4 Hz, 1H, ArH), 8.17 (d, J¼8.6 Hz, 1H, ArH), 8.03 (d, J¼8.0 Hz, 1H,
ArH), 7.88 (ddd, J¼8.4, 6.9, 1.3 Hz, 1H, ArH), 7.64 (dd, J¼7.9, 7.1 Hz,
1H, ArH), 7.52e7.57 (m, 2H, ArH and TroponeeH), 7.50 (d, J¼6.9 Hz,
1H, ArH), 7.17 (d, J¼12.6 Hz, 1H, TroponeeH); MS (FAB) m/z: 200.1
(8), 292.0 ([MþH]þ, 100), 294.0 (35). Anal. Calcd for C18H10ClNO: C,
74.11; H, 3.46; N, 4.80%. Found: C, 73.89; H, 3.63; N, 4.98%.
836 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d: 9.05 (s, 1H, QuinoeH), 8.40
(d, J¼1.8 Hz,1H, PheH), 8.17 (d, J¼8.5 Hz,1H, ArH), 8.03 (d, J¼8.2 Hz,
1H, ArH), 7.88 (dd, J¼8.1, 7.2 Hz, 1H, ArH), 7.78 (dd, J¼8.3, 2.0 Hz, 1H,
PheH), 7.64 (t, J¼7.4 Hz, 1H, ArH), 7.50 (d, J¼12.5 Hz, 1H,
TroponeeH), 7.45 (d, J¼8.3 Hz, 1H, ArH), 7.21 (d, J¼12.5 Hz, 1H,
TroponeeH); MS (FAB) m/z: 335.9 ([MþH]þ, 100), 338.0 (94). Anal.
Calcd for C18H10BrNO: C, 64.31; H, 3.00; N, 4.17%. Found: C, 64.43; H,
3.08; N, 4.02%.
4.3.8. 10-Chloro-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
(4h). Pale yellow solid, mp 209e210 ꢀC; FT-IR (KBr) nmax: 1655,
1617,1577,1551, 1482, 1432,1384,1306, 1304,1260,1228,1213,1127,
967, 837 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 9.06 (s, 1H, QuinoeH),
8.25 (d, J¼2.2 Hz, 1H, PheH), 8.17 (d, J¼8.5 Hz, 1H, ArH), 8.04 (d,
J¼8.1 Hz, 1H, ArH), 7.88 (ddd, J¼8.4, 7.0, 1.4 Hz, 1H, ArH), 7.62e7.67
(m, 2H, ArH), 7.53 (d, J¼8.4 Hz, 1H, ArH), 7.49 (d, J¼12.6 Hz, 1H,
TroponeeH), 7.23 (d, J¼12.6 Hz, 1H, TroponeeH); MS (FAB) m/z:
292.0 ([MþH]þ, 100), 294.0 (32). Anal. Calcd for C18H10ClNO: C,
74.11; H, 3.46; N, 4.80%. Found: C, 74.29; H, 3.31; N, 4.92%.
4.3.14. 3-(3-Nitrophenyl)-3,4-dihydro-1H-pyrano[4,3-b]quinolin-1-
one (4o). Yellow solid, mp 184e185 ꢀC; FT-IR (KBr) nmax: 1722, 1619,
1599, 1489, 1447, 1405, 1349, 1258, 1225, 1153, 1102, 1035, 924; 1H
NMR (DMSO-d6, 300 MHz) d: 9.12 (s, 1H, QuinoeH), 8.48 (s, 1H,
PheH), 8.22e8.29 (m, 3H, ArH), 7.91e7.97 (m, 2H, ArH), 7.79 (t,
J¼8.0 Hz, 1H, ArH), 7.71 (t, J¼8.1 Hz, 1H, ArH), 6.15 (dd, J¼11.8,
2.8 Hz, 1H, CH), 3.82 (dd, J¼16.4, 3.0 Hz, 1H, CH2), 3.56 (dd, J¼16.4,
3.0 Hz, 1H, CH2); MS (FAB) m/z: 321.0 ([MþH]þ, 100). Anal. Calcd for
4.3.9. 8,9-Dichloro-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
(4i). White solid, mp 241e242 ꢀC; FT-IR (KBr) nmax: 1652, 1617,
1575, 1549, 1488, 1457, 1431, 1382, 1355, 1332, 1294, 1265, 1225,
C18H12N2O4: C, 67.50; H, 3.78; N, 8.75%. Found: C, 67.75; H, 4.08; N,
8.83%.
1169, 1099, 961, 812 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 8.86 (s, 1H,
QuinoeH), 8.17 (d, J¼8.6 Hz, 1H, ArH), 8.01 (d, J¼8.1 Hz, 1H, ArH),
7.95 (d, J¼8.6 Hz, 1H, ArH), 7.85e7.90 (m, 1H, ArH), 7.80 (d,
J¼12.9 Hz, 1H, TroponeeH), 7.62e7.66 (m, 2H, ArH), 7.56 (d,
J¼12.9 Hz, 1H, TroponeeH); MS (FAB) m/z: 113.0 (15), 326.0
([MþH]þ, 100), 327.9 (75), 330.0 (15). Anal. Calcd for C18H9Cl2NO: C,
66.28; H, 2.78; N, 4.29%. Found: C, 66.07; H, 2.89; N, 4.38%.
4.3.15. 3-(4-Nitrophenyl)-3,4-dihydro-1H-pyrano[4,3-b]quinolin-1-
one (4p). Yellow solid, mp 192e193 ꢀC; FT-IR (KBr) nmax: 1730, 1617,
1567, 1525, 1494, 1464, 1413, 1377, 1347, 1320, 1292, 1262, 1195,
1064, 1003, 964, 937, 844 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d: 9.03
(s, 1H, QuinoeH), 8.32 (d, J¼8.8 Hz, 2H, PheH), 8.12 (d, J¼8.4 Hz, 1H,
QuinoeH), 8.01 (d, J¼8.3 Hz, 1H, QuinoeH), 7.89e7.94 (m, 1H,
QuinoeH), 7.74 (d, J¼8.7 Hz, 2H, PheH), 7.67 (dd, J¼8.0, 7.3 Hz, 1H,
QuinoeH), 5.87 (dd, J¼10.1, 4.8 Hz,1H, CH), 3.62e3.66 (m, 2H, CH2);
MS (FAB) m/z: 294.1 (10), 321.1 ([MþH]þ, 100). Anal. Calcd for
4.3.10. 9,11-Dichloro-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-
one (4j). White solid, mp 225e226 ꢀC; FT-IR (KBr) nmax: 1673, 1616,
1577, 1542, 1488, 1458, 1369, 1328, 1226, 1248, 1164, 1118, 958, 929,
C18H12N2O4: C, 67.50; H, 3.78; N, 8.75%. Found: C, 67.77; H, 3.61; N,
891, 862, 836 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
d
8.66 (s, 1H,
8.94%.
QuinoeH), 8.16 (d, J¼8.7 Hz, 1H, QuinoeH), 8.01 (d, J¼8.1 Hz, 1H,
QuinoeH), 7.84e7.89 (m, 1H, QuinoeH), 7.62e7.67 (m, 1H,
QuinoeH), 7.58 (d, J¼1.9 Hz, 1H, PheH), 7.45 (d, J¼12.6 Hz, 1H,
TroponeeH), 7.43 (d, J¼1.5 Hz, 1H, PheH), 7.14 (d, J¼12.5 Hz, 1H,
TroponeeH); MS (FAB) m/z: 326.0 ([MþH]þ, 100), 328.0 (65), 330.0
(10). Anal. Calcd for C18H9Cl2NO: C, 66.28; H, 2.78; N, 4.29%. Found:
C, 66.47; H, 2.83; N, 4.11%.
Acknowledgements
This work was financially supported by the Natural Science
Foundation of Liaoning Province (Grant No. 201202001), and the
Scientific Research Foundation of the Education Department of
Liaoning Province (Grant No. L2013428).
4.3.11. 8-Bromo-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one
(4k). White solid, mp 210e211 ꢀC; FT-IR (KBr) nmax: 1656, 1616,
1581, 1558, 1489, 1463, 1382, 1338, 1298, 1267, 1191, 1127, 1093, 961,
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.01.049.
863, 828 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 8.85 (s, 1H, QuinoeH),
8.17 (d, J¼8.5 Hz, 1H, ArH), 8.04 (d, J¼7.8 Hz, 1H, ArH), 8.00 (d,
J¼8.3 Hz, 1H, ArH), 7.94 (d, J¼7.8 Hz, 1H, ArH), 7.87 (dd, J¼8.0,
7.2 Hz, 1H, ArH), 7.75 (d, J¼12.9 Hz, 1H, TroponeeH), 7.63 (t,
J¼7.4 Hz, 1H, ArH), 7.52 (d, J¼12.9 Hz, 1H, TroponeeH), 7.39 (t,
J¼7.9 Hz, 1H, ArH); MS (FAB) m/z: 116.1 (20), 149.1 (18), 336.0
([MþH]þ, 100), 338.0 (93). Anal. Calcd for C18H10BrNO: C, 64.31; H,
3.00; N, 4.17%. Found: C, 64.16; H, 2.90; N, 4.31%.
References and notes
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