One-pot synthesis of novel 2-(benzofuran-2-yl)-4-phenylquinoline-3-carboxylates

Article abstract of DOI:10.3184/174751917X14839766277170

A facile and efficient synthesis of novel ethyl 2-(benzofuran-2-yl)-4-phenylquinoline-3-carboxylates and the corresponding acids through the one-pot three-step reaction of ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate with a series of salicylalde

Full text of DOI:10.3184/174751917X14839766277170

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 JANUARY, 45–49
RESEARCH PAPER 45
One-pot synthesis of novel 2-(benzofuran-2-yl)-4-phenylquinoline-3-
carboxylates
Wentao Gao*, Xinbo Fu, Yanan Zhao and Dongfang Wang
Institute of Superfine Chemicals, Bohai University, Keji Street, Jinzhou, 121000, P.R. China
A facile and efficient synthesis of novel ethyl 2-(benzofuran-2-yl)-4-phenylquinoline-3-carboxylates and the corresponding acids through
the one-pot three-step reaction of ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate with a series of salicylaldehydes is described. It
allows an efficient and practical access to some 2-(benzofuran-2-yl)quinolines under transition-metal-free conditions.
Keywords: benzofuran, salicylaldehyde, 4-phenylquinoline, one-pot synthesis, 2-(benzofuran-2-yl)-4-phenylquinolines
Bi(heteroaryl) structures can be widely found in numerous
natural products and have been attracting considerable interest
due to the potential applications of this kind of compound in
medicinal chemistry.1–3 These compounds are known for their
various biological activities and there is extensive interest in their
synthesis. Benzofuran is a pharmaceutically significant scaffold,
present in numerous naturally occurring and synthetic biologically
active molecules.4–6 On the other hand, quinolines, particularly
4-phenylquinoline, are well-known in drug discovery, due to their
significant biological activities, as antidepressants5,7,8 and receptor
antagonists.5,9 Although extensive and enduring efforts have been
invested in accessing structurally diverse 4-phenylquinoline-
or benzofuran-containing heterocycles, very few reports have
involved the construction of the bi(heteroaryl), 2-(benzofuran-2-
yl)quinoline, scaffold. On the basis of an inspection of literature
methodologies, it was found that the common strategies for the
generation of benzo[b]furan mainly relied on palladium or nickel-
catalysed coupling reactions.10,11 Accordingly, the development of
facile and practical methods with easily accessible precursors for
the construction of 2-(benzofuran-2-yl)quinoline compounds is
highly desirable and valuable.
2-aminobenzophenone and 4-chloroethylacetoacetate, as well
as its further application with various substituted phenols for
the flexible synthesis of tetracyclic-fused quinoline systems.12
Building on this evolving expertise and in order to continue
our interest in the development of potentially biologically
interesting quinoline derivatives, our intention was to extend to
the reaction of 1 with various salicylaldehydes to obtain a series
of novel 2-(benzofuran-2-yl)-4-phenylquinolines.
For the construction of 2-substituted benzofurans, the most
widely used approach involves the general palladium-catalysed
heteroannulation of 2-halophenols with a terminal alkyne by
a tandem Sonogashira coupling-5-endo-dig-cyclisation,10,11,14
largely developed by Larock and co-workers. However,
this method requires an expensive catalyst and/or a multi-
step synthesis. Therefore, the development of a direct and
concise method to construct the benzofuran motif remains a
challenging area to explore in organic chemistry. Here we report
a facile one-pot procedure to synthesise 2-(benzofuran-2-yl)-
4-phenylquinoline-3-carboxylic acid derivatives 3a–l and 4a–l
from ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate
(1) and salicylaldehydes as shown in Scheme 1.
With this background in mind, our intention was to develop a
facile one-pot method for the preparation of 2-(benzofuran-2-
yl)-4-phenylquinolines from cheap and easily available starting
materials and reagents under transition-metal-free conditions.
Thus, in continuation of our interest in the synthesis of biologically
active quinoline-based heterocyclic compounds,12,13 we would
like to report the first synthesis of ethyl 2-(benzofuran-2-yl)-
4-phenylquinoline-3-carboxylates and the corresponding acids
through the reaction of ethyl 2-(chloromethyl)-4-phenylquinoline-
3-carboxylate with salicylaldehydes. Such hybrids may be valuable
for medicinal chemistry and drug discovery.
The procedure uses an inexpensive inorganic base as the
catalyst under mild reaction conditions for the straightforward
and easy attachment of the benzofuran core onto the quinoline
nucleus at the 2-position. In our experiment, the substrate 1
was first subjected to the Williamson reaction with various
salicylaldehydes 2a–l in the presence of K2CO3 as the base in
refluxing CH3CN. This solvent is employed because of its low
boiling point, which brings much convenience to the work-up
procedure. Thus, once the Williamson reaction was complete
as observed by thin layer chromatography (TLC), we simply
evaporated off the CH3CN. Ethanolic KOH solution (10
mL) and PEG-400 (5 drops) were added to this residue and
refluxing continued, the conversion being monitored by TLC.
After the reaction was completed, we found that two products
were indicated by TLC. The resulting mixture was subjected
to column chromatography over silica gel using hexane/ethyl
Results and discussion
Recently, our research group has reported an efficient method for
the preparation of ethyl 2-(chloromethyl)-4-phenylquinoline-
3-carboxylate (1) by a Friedländer condensation reaction of
R3
R2
H
H
C
O
COOH
1
K CO , MeCN
COOEt
)
2
3
COOEt
Cl
2) PEG-400, KOH, EtOH/H2O
R1
R1
O
O
O
3) 1 mol L–1 HCl
N
N
N
R1
R2
R2
2a-l
1
3a-l
R3
4a-l
R3
Scheme 1
* Correspondent. E-mail: bhuzh@163.com

46 JOURNAL OF CHEMICAL RESEARCH 2016
Table 1 Synthesis of 2-(benzofuran-2-yl)-4-phenylquinoline-3-carboxylic
acid derivatives 3a–l and 4a–la
In conclusion, we have described the one-pot synthesis of a
series of novel ethyl 2-(benzofuran-2-yl)-4-phenylquinoline-
3-carboxylates and the corresponding carboxylic acids. The
advantages of the current protocol include the ready availability
of starting materials, experimental simplicity, mild reaction
conditions and satisfactory yields, which contribute to the
usefulness of this method. The method not only allows for the
preparation in a single step but also is an example of a transition-
metal-free access to 2-(benzofuran-2-yl)-4-phenylquinolines.
3
4
Entry
R1 R2 R3
Yield/%b
47
36
43
40
52
40
39
44
45
54
45
45
M.p./°C
Yield/%b
42
46
39
43
32
29
42
42
34
35
40
41
M.p./°C
1
2
3
4
5
6
7
8
a H
b Me H
H
H
H
173.0–173.7
169.7–170.9
158.8–160.2
163.6–163.9
135.9–136.1
135.5–135.8
155.3–155.8
160.3–161.1
217.5–218.0
175.9–176.5
220.0–220.5
224.5–224.6
232.0–232.2
211.8–212.6
225.5–226.2
215.4–217.1
198.9–199.0
221.4–222.3
244.7–245.1
243.8–244.7
275.8–277.2
230.3–231.1
242.7–243.9
243.9–244.5
c H Me H
d H
e H
H
g H
h H
Br
F
k Cl
Br
H
H
H
H
H
H
H
H
H
Me
tert–Bu
OMe
Cl
Br
Br
tert–Bu
tert–Bu
tert–Bu
f
Experimental
The melting points were determined using a WRS-1B melting point
apparatus and were uncorrected. The IR spectra were obtained in
KBr pellets in the range 400–4000 cm–1 using a Scimitar 2000 FTIR
spectrometer (Anilent, USA). 1H and 13C NMR spectra were recorded
on a Bruker Avance NMR spectrometer (600 MHz) with CDCl3 or
DMSO-d6 as the solvent. The reported chemical shifts (δ values) are
given in parts per million (ppm) downfield from tetramethylsilane
(TMS) as the internal standard. HRMS was obtained on a Bruker
Apex III (7.0 T) FT-ICR spectrometer. The progress of the reactions
was monitored by TLC on silica gel GF254 using ethyl acetate as the
mobile phase. All reagents are commercially available as analytical or
chemical reagents.
9
i
j
10
11
12
l
ªAll reactions were performed at 1 mmol scale in 12 mL CH3CN.
bYield of isolated product.
acetate (5:1, v/v) and then ethyl acetate/acetic acid (10:1, v/v)
as eluents, successively, to give the two products identified as
3a–l and 4a–l by spectroscopic analysis with 36–54 and 29–
46% yields respectively. In this case, the ethyl ester could not
be hydrolysed completely during the progress of the reaction,
no matter what changed reaction conditions, such as type of
solvent or concentration of KOH solution, were used. However,
if the reaction was stirred under reflux for 5 days or more, the
hydrolysis reaction proceeded completely as monitored by TLC
to afford the compounds 4a–l as the sole products. The reaction
results are listed in Table 1.
It seems that the electronic nature of the substituents has no
significant effect on the reaction. All the salicylaldehydes with
electron-donating groups (Table 1, entries 2–6) and electron-
withdrawing groups (Table 1, entries 7–9) and the halo and tert-
butyl disubstituted compounds (Table 1, entries 10–12) worked
well and gave the corresponding two products in good total
yields of 69–89%.
Synthesis of ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate
(1)12
Ceric ammonium nitrate (0.55 g, 1 mmol, 10 mol%) was added to
a stirred solution of 2-aminobenzophenone (1.97 g, 10 mmol) and
ethyl 4-chloroacetoacetate (1.65 g, 10 mmol) in methanol (15 mL).
The resulting reaction mixture was stirred at room temperature
for 2 h. After the reaction was completed (monitored by TLC), the
mixture was washed with water (15 mL), extracted with ethyl acetate
(2 × 30 mL), dried over Na2SO4, and concentrated to dryness at 40 °C
under 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 1 as yellow crystals in 84% yield; m.p.
105–107 °C (lit.13 103–105 °C).
Synthesis of ethyl 2-(benzofuran-2-yl)-4-phenylquinoline-3-carboxylates
(3a–l) and the corresponding acids (4a–l); general procedure
The structures of compounds 3a–l and 4a–l were confirmed by
their spectroscopic data with the results being in full agreement
with the proposed structures. For example, the IR spectrum of
3j exhibited the presence of a tert-butyl group and a carbonyl
group of a carboxyl moiety at 2960 and 1739 cm–1 respectively.
Its structure was unequivocally proven by its 1H NMR spectrum.
The main feature of this was the appearance of the furan proton
at 7.65 ppm, the tert-butyl protons at 1.38 ppm and ester proton at
4.20 and 1.05 ppm respectively. Its 13C NMR spectrum was also
in good agreement with the assigned structure and revealed the
presence of the tert-butyl and ethyl ester carbons at 13.7, 31.7, 35.0,
61.7 and 167.7 ppm respectively. Further, the molecular formula
of compound 3j was deduced to be C30H26FNO3 from its HRMS,
which showed a pseudo-molecular-ion peak at m/z 468.1967 ([M
+ H]+; calcd for C30H27FNO3+: 468.1975), indicating the presence
of 18° of unsaturation.
A mixture of ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate
(1) (0.325 g, 1.0 mmol), the appropriate salicylaldehyde 2a–l (1.1 mmol)
and anhydrous K2CO3 (0.552 g, 4.0 mmol) was stirred in CH3CN (12 mL)
under reflux. After completion of the reaction (monitored by TLC),
CH3CN was evaporated to dryness. Then, a solution of KOH (1.00 g,
18 mmol) in 60% ethanol (10 mL) and PEG-400 (5 drops) was added to
the residue and the mixture was heated under reflux. The conversion was
monitored by TLC. After completion, the mixture was cooled to room
temperature and acidified with 1 mol L–1 HCl solution. The resulting
precipitate was filtered off, washed with H2O and separated by column
chromatography over silica gel using hexane/ethyl acetate (5:1, v/v) then
ethyl acetate/acetic acid (10:1, V) to afford successively 3a–l and 4a–l.
The yields and melting points of all compounds are summarised in Table 1
and the spectroscopic and analytical data are given below.
Ethyl 2-(benzofuran-2-yl)-4-phenylquinoline-3-carboxylate (3a):
White solid; yield 47%; m.p. 173.0–173.7 °C; IR (KBr): ν 2998, 2994,
1
2929, 1728, 771, 704 cm–1; H NMR (600 MHz, CDCl3): δ 8.23 (d,
Mechanistically, the reaction might proceed through a
one-pot procedure route, involving either the intermolecular
nucleophilic substitution of the active chloromethyl moiety
with the OH group of the salicylaldehyde 2 followed by
intramolecular cyclisation or a Darzens reaction and subsequent
internal cyclisation to the ester. At the current stage, we have
not yet established the actual mechanism and the exact details
of how the reaction proceeds remain unclear. Our further
investigations towards the detailed mechanistic studies by
capturing the key intermediate and providing adequate proof of
concept are being actively pursued in our laboratory.
J = 8.4 Hz, 1H, ArH), 7.77 (t, J = 7.8 Hz, 1H, ArH), 7.68 (d, J = 7.8 Hz,
1H, ArH), 7.61 (s, 1H, furan–H), 7.56 (d, J = 8.4 Hz, 1H, ArH),
7.49–7.53 (m, 4H, ArH), 7.47 (t, J = 7.8 Hz, 1H, ArH), 7.40–7.44 (m,
2H, ArH), 7.34 (t, J = 7.8 Hz, 1H, ArH), 7.27 (t, J = 7.8 Hz, 1H, ArH),
4.15 (q, J = 7.2 Hz, 2H, CH2), 1.04 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(CDCl3, 150 MHz): δ 167.8, 155.5, 154.2, 147.9, 147.3, 144.8, 135.0,
130.6, 129.8, 129.6, 128.6, 128.5, 128.2, 127.4, 126.6, 126.1, 125.5,
123.3, 121.9, 111.6, 107.9, 61.6, 13.8; HRMS calcd for C26H20NO3: [M +
H]+: 394.1443; found: 394.1436.
2-(Benzofuran-2-yl)-4-phenylquinoline-3-carboxylic acid (4a):
Yellow solid; yield 42%; m.p. 232.0–232.2 °C; IR (KBr): ν 3331, 3145,

JOURNAL OF CHEMICAL RESEARCH 2016 47
1
1704, 1569, 1372, 890, 740 cm–1; H NMR (600 MHz, DMSO-d6): δ
129.9, 129.3, 128.0, 127.2, 126.1, 125.8, 124.8, 121.6, 111.5, 108.5, 21.5;
HRMS calcd for C25H18NO3: [M + H]+: 380.1286; found: 380.1284.
Ethyl 2-(5-(tert-butyl)benzofuran-2-yl)-4-phenylquinoline-3-carboxy-
late (3e): White solid; yield 52%; m.p. 135.9–136.1 °C; IR (KBr): ν 3061,
13.60 (s, 1H, COOH), 8.20 (d, J = 8.4 Hz, 1H, ArH), 7.88 (t, J = 7.8 Hz,
1H, ArH), 7.81 (d, J = 7.8 Hz, 1H, ArH), 7.67 (d, J = 8.4 Hz, 2H, ArH),
7.61 (t, J = 7.8 Hz, 1H, ArH), 7.54–7.58 (m, 3H, ArH), 7.42–7.46 (m,
4H, ArH), 7.34 (t, J = 7.2 Hz, 1H, ArH); 13C NMR (DMSO-d6, 150
MHz): δ 168.6, 154.8, 153.6, 146.9, 143.8, 134.7, 131.0, 129.5, 129.4,
128.7, 128.3, 128.1, 126.2, 126.1, 125.7, 123.6, 122.3, 111.6, 108.0;
HRMS calcd for C24H16NO3: [M + H]+: 366.1130; found: 366.1119.
Ethyl 2-(7-methylbenzofuran-2-yl)-4-phenylquinoline-3-carboxylate
(3b): Orange solid; yield 36%; m.p. 169.7–170.9 °C; IR (KBr): ν 3058,
1
2956, 1737, 1567, 1396, 870, 758 cm–1; H NMR (600 MHz, CDCl3): δ
8.23 (d, J = 7.8 Hz, 1H, ArH), 7.76 (t, J = 7.8 Hz, 1H, ArH), 7.66 (s, 1H,
furan–H), 7.56 (s, 1H, ArH), 7.50–7.54 (m, 4H, ArH), 7.46 (t, J = 7.8 Hz,
1H, ArH), 7.40–7.44 (m, 4H, ArH), 4.15 (q, J = 7.2 Hz, 2H, CH2), 1.40 (s,
9H, tert-butyl), 1.04 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, CDCl3):
δ 167.9, 154.2, 153.8, 147.9, 147.2, 146.4, 144.9, 135.1, 130.6, 129.8, 129.6,
128.6, 128.2, 127.3, 126.5, 126.0, 125.5, 123.7, 118.0, 111.0, 108.2, 61.6,
34.8, 31.8, 13.8; HRMS calcd for C30H28NO3: [M + H]+: 450.2069; found:
450.2058.
1
2972, 1728, 1540, 829, 763 cm–1; H NMR (600 MHz, CDCl3): δ 8.19
(d, J = 8.4 Hz, 1H, ArH), 7.76 (td, J = 7.8, 1.2 Hz, 1H, ArH), 7.68 (s, 1H,
furan–H), 7.55 (d, J = 7.8 Hz, 1H, ArH), 7.50–7.53 (m, 4H, ArH), 7.46
(t, J = 7.2 Hz, 1H, ArH), 7.41–7.43 (m, 2H, ArH), 7.17 (t, J = 7.2 Hz, 1H,
ArH), 7.13 (d, J = 7.2 Hz, 1H, ArH), 4.15 (q, J = 7.2 Hz, 2H, CH2), 2.53
(s, 3H, CH3), 0.92 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, CDCl3):
δ 167.7, 154.7, 154.1, 147.9, 147.4, 144.9, 135.1, 130.6, 129.6, 128.6, 128.2,
128.0, 127.3, 126.6, 126.3, 126.1, 125.3, 123.4, 121.6, 119.4, 108.1, 61.4,
15.1, 13.6; HRMS calcd for C27H22NO3: [M + H]+: 408.1599; found:
408.1587.
2-(5-(tert-Butyl)benzofuran-2-yl)-4-phenylquinoline-3-carboxylic
acid (4e): Yellow solid; yield 32%; m.p. 198.9–199.0 °C; IR (KBr): ν
1
3309, 1708, 1574, 816, 753 cm–1; H NMR (600 MHz, DMSO-d6): δ
13.46 (s, 1H, COOH), 8.20 (d, J = 8.4 Hz, 1H, ArH), 7.88 (t, J = 7.8 Hz,
1H, ArH), 7.79 (s, 1H, furan–H), 7.65–7.55 (m, 6H, ArH), 7.51 (d,
J = 8.4 Hz, 1H, ArH), 7.42–7.46 (m, 3H, ArH), 1.37 (s, 9H, tert-butyl);
13C NMR (150 MHz, DMSO-d6): δ 168.5, 153.6, 153.1, 146.9, 146.3,
145.8, 143.9, 134.7, 131.0, 129.5, 129.4, 128.8, 128.4, 128.1, 127.8,
126.2, 125.6, 124.1, 118.2, 110.9, 108.2, 34.6, 31.6; HRMS: calcd for
C28H24NO3:[M + H]+: 422.1756; found: 422.1749.
2-(7-Methylbenzofuran-2-yl)-4-phenylquinoline-3-carboxylic acid
(4b): Yellow solid; yield 46%; m.p. 211.8–212.6 °C; IR (KBr): ν 3332,
1731, 1550, 815, 761 cm–1; H NMR (600 MHz, DMSO-d6): δ 8.14
1
(d, J = 8.4 Hz, 1H, ArH), 7.75–7.78 (m, 2H, ArH), 7.51– 7.54 (m, 2H,
ArH), 7.42–7.48 (m, 5H, ArH), 7.40 (d, J = 8.4 Hz, 1H, ArH), 7.18–7.20
(m, 2H, ArH), 2.55 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6): δ
169.2, 153.7, 146.2, 144.4, 135.7, 130.5, 129.9, 129.3, 128.1, 127.9, 127.4,
126.3, 126.2, 125.9, 123.4, 121.2, 119.5, 108.5, 14.9; HRMS calcd for
C25H18NO3: [M + H]+: 380.1286; found: 380.1282.
Ethyl 2-(5-methoxybenzofuran-2-yl)-4-phenylquinoline-3-carboxy-
late (3f): White solid; yield 40%; m.p. 135.5–135.8 °C; IR (KBr): ν
2990, 2957, 1736, 1541, 850, 763 cm–1; 1H NMR (CDCl3, 600 MHz): δ
8.22 (d, J = 8.4 Hz, 1H, ArH), 7.77 (t, J = 7.2 Hz, 1H, ArH), 7.50–7.56
(m, 5H, ArH), 7.47 (t, J = 7.8 Hz, 1H, ArH), 7.39–7.42 (m, 3H, ArH),
7.11 (s, 1H, furan–H), 6.96 (d, J = 8.4 Hz, 1H, ArH), 4.14 (q, J = 7.2 Hz,
2H, CH2), 3.87 (s, 3H, OCH3), 1.04 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(CDCl3, 150 MHz): δ 167.8, 156.3, 154.9, 150.6, 147.8, 147.3, 144.7,
135.0, 130.6, 129.8, 129.6, 129.0, 128.6, 128.2, 127.4, 126.6, 126.0,
125.4, 114.9, 112.2, 108.1, 103.6, 61.6, 55.9, 13.8; HRMS calcd for
C27H22NO4: [M + H]+: 424.1549; found: 424.1538.
Ethyl 2-(6-methylbenzofuran-2-yl)-4-phenylquinoline-3-carboxylate
(3c): White solid; yield 43%; m.p. 158.8–160.2 °C; IR (KBr): ν 3048,
1
2982, 1732, 1561, 1408, 868, 760 cm–1; H NMR (600 MHz, CDCl3):
δ 8.36 (d, J = 8.4 Hz, 1H, ArH), 7.81 (t, J = 7.8 Hz, 1H, ArH), 7.59 (d,
J = 8.0 Hz, 1H, ArH), 7.50–7.55 (m, 5H, ArH), 7.40–7.45 (m, 3H, ArH),
7.28 (d, J = 1.8 Hz, 1H, ArH), 7.19 (d, J = 8.0 Hz, 1H, ArH), 4.17 (q,
J = 7.2 Hz, 2H, CH2), 2.48 (s, 3H, CH3), 1.06 (t, J = 7.2 Hz, 3H, CH3);
13C NMR (CDCl3, 150 MHz): δ 169.2, 147.8, 140.4, 139.5, 138.1, 137.6,
135.1, 135.0, 134.3, 133.8, 133.1, 132.9, 132.2, 132.2, 127.4, 126.6, 116.7,
67.3, 27.0, 19.4; HRMS calcd for C27H22NO3: [M + H]+: 408.1599; found:
408.1594.
2-(5-Methoxybenzofuran-2-yl)-4-phenylquinoline-3-carboxylic
acid (4f): Orange solid; yield 29%; m.p. 221.4–222.3 °C; IR (KBr):
1
ν 3419, 1563, 848, 763 cm–1; H NMR (600 MHz, DMSO-d6): δ 8.12
(d, J = 8.4 Hz, 1H, ArH), 7.78 (s, 1H, ArH), 7.74 (t, J = 7.8 Hz, 1H,
ArH), 7.60 (d, J = 8.4 Hz, 1H, ArH), 7.45–7.52 (m, 4H, ArH), 7.44 (d,
J = 7.2 Hz, 2H, ArH), 7.38 (d, J = 8.4 Hz, 1H, ArH), 7.21 (s, 1H, ArH),
6.99 (dd, J = 8.4, 2.4 Hz, 1H, ArH), 3.81 (s, 3H, OCH3); 13C NMR (150
MHz, DMSO-d6): δ 169.4, 155.8, 154.6, 149.6, 144.2, 130.0, 129.3,
129.2, 128.0, 127.2, 126.3, 125.8, 114.5, 112.1, 108.8, 103.9, 55.7;
HRMS calcd for C25H18NO4: [M + H]+: 396.1236; found: 396.1233.
Ethyl 2-(5-chlorobenzofuran-2-yl)-4-phenylquinoline-3-carboxy-
late (3g): White solid; yield 39%; m.p. 155.3–155.8 °C; IR (KBr): ν
2-(6-Methylbenzofuran-2-yl)-4-phenylquinoline-3-carboxylic acid
(4c): Yellow solid; yield 39%; m.p. 225.5–226.2 °C; IR (KBr): ν 3335,
1
1706, 1574, 817, 762 cm–1; H NMR (600 MHz, DMSO-d6): δ 13.48
(s, 1H, COOH), 8.18 (t, J = 8.4 Hz, 1H, ArH), 7.88 (t, J = 7.8 Hz, 1H,
ArH), 7.62 (d, J = 7.8 Hz, 1H, ArH), 7.60–7.54 (m, 5H, ArH), 7.52 (d,
J = 8.4 Hz, 1H, ArH), 7.42–7.45 (m, 3H, ArH), 7.26 (t, J = 8.4 Hz, 1H,
ArH), 2.43 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6): δ 168.5,
153.7, 153.3, 146.9, 143.8, 134.7, 132.7, 131.0, 129.5, 129.4, 128.8, 128.4,
128.2, 127.4, 126.2, 125.6, 121.8, 111.2, 107.7, 21.0; HRMS calcd for
C25H18NO3: [M + H]+: 380.1286; found: 380.1281.
1
3061, 2971, 1733, 1541, 1400, 873, 733 cm–1; H NMR (600 MHz,
CDCl3): δ 8.22 (d, J = 8.4 Hz, 1H, ArH), 7.81 (s, 1H, ArH), 7.78
(t, J = 7.8 Hz, 1H, ArH), 7.57 (d, J = 8.4 Hz, 1H, ArH), 7.54 (s, 1H,
furan–H), 7.46–7.53 (m, 4H, ArH), 7.37–7.45 (m, 4H, ArH), 4.13 (q,
J = 7.2 Hz, 2H, CH2), 1.02 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (CDCl3,
150 MHz): δ 167.7, 155.4, 154.1, 147.8, 147.5, 144.2, 134.9, 130.8,
130.4, 129.8, 129.5, 128.7, 128.4, 128.2, 127.7, 126.6, 126.2, 125.5,
124.5, 116.4, 113.1, 107.1, 61.6, 13.8; HRMS calcd for C26H1935ClNO3,
C26H1937ClNO3: [M + H]+: 428.1053, 430.1024; found: 428.1044,
430.1021.
Ethyl 2-(5-methylbenzofuran-2-yl)-4-phenylquinoline-3-carboxylate
(3d): White solid; yield 40%; m.p. 163.6–163.9 °C; IR (KBr): ν 3054,
1
2982, 1732, 1541, 836, 764 cm–1; H NMR (600 MHz, CDCl3): δ 8.21
(d, J = 8.4 Hz, 1H, ArH), 7.76 (td, J = 7.8, 1.2 Hz, 1H, ArH), 7.54–7.58
(m, 3H, ArH), 7.48–7.52 (m, 3H, ArH), 7.46 (t, J = 7.8 Hz, 1H, ArH),
7.41–7.43 (m, 2H, ArH), 7.31–7.33 (m, 1H, ArH), 7.10 (d, J = 7.8 Hz, 1H,
ArH), 4.16 (q, J = 7.2 Hz, 2H, CH2), 2.49 (s, 3H, CH3), 1.04 (t, J = 7.2 Hz,
3H, CH3); 13C NMR (150 MHz, CDCl3): δ 167.8, 156.0, 153.6, 147.9,
147.2, 144.9, 136.0, 135.1, 130.6, 129.7, 129.6, 129.5, 128.6, 128.2, 127.3,
126.5, 126.0, 125.4, 124.9, 121.4, 111.7, 107.9, 61.5, 21.9, 13.8; HRMS
calcd for C27H22NO3: [M + H]+: 408.1599; found: 408.1590.
2-(5-Chlorobenzofuran-2-yl)-4-phenylquinoline-3-carboxylic acid
(4g): Yellow solid; yield 42%; m.p. 244.7–245.1 °C; IR (KBr): ν 3392,
1
1699, 1558, 1398, 759, 669 cm–1; H NMR (600 MHz, DMSO-d6): δ
13.56 (s, 1H, COOH), 8.20 (d, J = 8.4 Hz, 1H, ArH), 8.05 (s, 1H, ArH),
7.90 (t, J = 7.2 Hz, 1H, ArH), 7.62–7.67 (m, 3H, ArH), 7.55–7.59 (m,
4H, ArH), 7.43–7.47 (m, 3H, ArH); 13C NMR (DMSO-d6, 150 MHz):
δ 168.4, 154.8, 153.6, 146.9, 146.0, 143.3, 134.6, 131.2, 130.3, 129.5,
129.4, 128.8, 128.7, 128.4, 126.2, 125.8, 124.7, 116.0, 113.7, 107.4;
HRMS calcd for C24H1535ClNO3, C24H1537ClNO3: [M + H]+: 400.0740,
402.0711; found: 400.0733, 402.0705.
2-(5-Methylbenzofuran-2-yl)-4-phenylquinoline-3-carboxylic acid
(4d): White solid; yield 43%; m.p. 215.4–217.1 °C; IR (KBr): ν 3335,
1
1706, 1544, 831, 762 cm–1; H NMR (DMSO-d6, 600 MHz): δ 8.13
(d, J = 8.4 Hz, 1H, ArH), 7.74–7.77 (m, 2H, ArH), 7.61 (d, J = 7.8 Hz,
1H, ArH), 7.47–7.52 (m, 5H, ArH), 7.42–7.44 (m, 2H, ArH), 7.38 (d,
J = 8.4 Hz, 1H, ArH), 7.14 (d, J = 7.8 Hz, 1H, ArH), 2.50 (s, 3H, CH3);
13C NMR (150 MHz, DMSO-d6): δ 169.3, 155.0, 153.3, 144.3, 135.7,
Ethyl 2-(5-bromobenzofuran-2-yl)-4-phenylquinoline-3-carboxy-
late (3h): White solid; yield 44%; m.p. 160.2–161.1 °C; IR (KBr):

48 JOURNAL OF CHEMICAL RESEARCH 2016
1
1
ν 3065, 2973, 1731, 1560, 1400, 858, 764 cm–1; H NMR (600 MHz,
(KBr): ν 3065, 2961, 1732, 1550, 818, 768 cm–1; H NMR (600 MHz,
CDCl3): δ 8.22 (d, J = 8.4 Hz, 1H, ArH), 7.78 (t, J = 7.8 Hz, 1H, ArH),
7.66 (s, 1H, furan–H), 7.57 (d, J = 8.4 Hz, 1H, ArH), 7.55 (s, 1H, ArH),
7.48–7.52 (m, 4H, ArH), 7.41–7.44 (m, 3H, ArH), 7.30 (d, J = 8.4 Hz,
1H, ArH), 4.13 (q, J = 7.2 Hz, 2H, CH2), 1.03 (t, J = 7.2 Hz, 3H, CH3);
13C NMR (CDCl3, 150 MHz): δ 167.7, 155.5, 153.8, 147.8, 147.5,
144.3, 134.9, 130.8, 129.8, 129.5, 128.9, 128.7, 128.2, 127.7, 126.6,
126.2, 125.8, 125.5, 121.4, 112.6, 107.3, 61.6, 13.7; HRMS calcd for
C26H1979BrNO3, C26H1981BrNO3: [M + H]+: 472.0548, 474.0528; found:
472.0544, 474.0522.
CDCl3): δ 8.20 (d, J = 8.4 Hz, 1H, ArH), 7.77 (td, J = 7.2, 1.2 Hz, 1H,
ArH), 7.68 (s, 1H, furan–H), 7.56–7.58 (m, 2H, ArH), 7.50–7.55 (m,
3H, ArH), 7.48 (td, J = 7.2, 1.2 Hz, 1H, ArH), 7.42–7.44 (m, 2H, ArH),
7.39 (d, J = 1.2 Hz, 1H, ArH), 4.24 (q, J = 7.2 Hz, 2H, CH2), 1.38 (s, 9H,
tert-butyl), 0.97 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, CDCl3): δ
167.5, 155.4, 149.5, 148.0, 147.8, 147.3, 144.4, 130.6, 129.7, 129.6, 128.6,
128.2, 127.5, 126.6, 126.2, 125.5, 123.8, 116.6, 116.1, 108.3, 61.8, 34.9,
31.7, 13.7; HRMS calcd for C30H2735ClNO3, C30H2737ClNO3: [M + H]+:
484.1674, 486.1650, found: 484.1677, 485.1719.
2-(5-Bromobenzofuran-2-yl)-4-phenylquinoline-3-carboxylic acid
(4h): Yellow solid; yield 42%; m.p. 243.8–244.7 °C; IR (KBr): ν 3384,
2-(5-(tert-Butyl)-7-chlorobenzofuran-2-yl)-4-phenylquinoline-3-
carboxylic acid (4k): Yellow solid; yield 40%; m.p. 242.7–243.9 °C;
1
1701, 1402, 862, 760 cm–1; H NMR (600 MHz, DMSO-d6): δ 13.64
1
IR (KBr): ν 3311, 2964, 1701, 1544, 861, 756 cm–1; H NMR (600
(s, 1H, COOH), 8.26 (d, J = 8.4 Hz, 1H, ArH), 7.97 (s, 1H, ArH), 7.95
(d, J = 7.8 Hz, 1H, ArH), 7.76 (d, J = 8.4 Hz, 1H, ArH), 7.68–7.73 (m,
2H, ArH), 7.61–7.65 (m, 3H, ArH), 7.49–7.53 (m, 4H, ArH); 13C NMR
(DMSO-d6, 150 MHz): δ 168.4, 155.0, 153.2, 146.9, 143.3, 134.6, 131.1,
129.7, 129.5, 129.4, 128.8, 128.4, 128.0, 126.2, 126.0, 125.8, 121.7,
113.2, 107.5; HRMS calcd for C24H1579BrNO3, C24H1581BrNO3: [M +
H]+: 444.0235, 446.0215; found: 444.0225, 446.0208.
MHz, DMSO-d6): δ 13.61 (s, 1H, COOH), 8.21 (d, J = 8.4 Hz, 1H,
ArH), 7.88 (t, J = 7.8 Hz, 1H, ArH), 7.74 (s, 1H, ArH), 7.70 (s, 1H,
furan–H), 7.63 (t, J = 7.8 Hz, 1H, ArH), 7.54–7.57 (m, 4H, ArH),
7.43–7.47 (m, 3H, ArH), 1.36 (s, 9H, tert-butyl); 13C NMR (150 MHz,
DMSO-d6): δ 168.4, 154.5, 148.6, 148.1, 146.8, 143.6, 134.8, 130.9,
129.6, 129.5, 129.4, 128.7, 128.3, 126.2, 125.8, 123.7, 117.4, 115.1,
108.7, 34.9, 31.4; HRMS calcd for C28H2335ClNO3, C28H2337ClNO3: [M
+ H]+: 456.1366, 458.1337; found: 456.1359, 458.1330.
Ethyl 2-(5,7-dibromobenzofuran-2-yl)-4-phenylquinoline-3-carboxy-
late (3i): White solid; yield 45%; m.p. 217.5–218.0 °C; IR (KBr): ν 3067,
Ethyl 2-(5-(tert-butyl)-7-bromobenzofuran-2-yl)-4-phenylquinoline-
3-carboxylate (3l): White solid; yield 45%; m.p. 224.5–224.6 °C; IR
1
2975, 1732, 1563, 1396, 853, 761 cm–1; H NMR (600 MHz, CDCl3):
δ 8.19 (d, J = 8.4 Hz, 1H, ArH), 7.79 (d, J = 7.2 Hz, 1H, ArH), 7.77 (d,
J = 1.2 Hz, 1H, ArH), 7.69 (s, 1H, ArH), 7.62 (s, 1H, furan–H), 7.58 (d,
J = 8.4 Hz, 1H, ArH), 7.48–7.52 (m, 4H, ArH), 7.40–7.42 (m, 2H, ArH),
4.24 (q, J = 7.2 Hz, 2H, CH2), 0.93 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(CDCl3, 150 MHz): δ 167.3, 156.5, 151.7, 147.8, 147.7, 143.8, 134.9,
131.0, 130.8, 130.6, 129.8, 129.5, 128.7, 128.2, 127.8, 126.7, 126.4, 125.5,
123.6, 116.6, 107.5, 104.9, 62.0, 13.6; HRMS calcd for C26H1879Br2NO3,
C26H1879Br81BrNO3, C26H1881Br2NO3: [M + H]+: 549.9653, 551.9633,
553.9613; found: 549.9644, 551.9628, 553.9612.
1
(KBr): ν 3066, 2961, 1732, 1550, 817, 768 cm–1; H NMR (600 MHz,
CDCl3): δ 8.19 (d, J = 8.4 Hz, 1H, ArH), 7.77 (t, J = 7.8 Hz, 1H, ArH),
7.70 (s, 1H, ArH), 7.61 (s, 1H, furan–H), 7.56 (d, J = 8.4 Hz, 1H, ArH),
7.54 (s, 1H, ArH), 7.46–7.50 (m, 4H, ArH), 7.42 (d, J = 7.2 Hz, 2H,
ArH), 4.26 (q, J = 7.2 Hz, 2H, CH2), 1.38 (s, 9H, tert-butyl), 0.94 (t,
J = 7.0 Hz, 3H, CH3); 13C NMR (150 MHz, CDCl3): δ 167.4, 155.4, 151.0,
148.3, 147.8, 147.4, 144.4, 135.0, 130.6, 129.7, 129.6, 129.4, 128.6, 128.2,
127.5, 126.6, 126.6, 126.2, 125.5, 117.3, 108.4, 103.5, 61.9, 34.9, 31.7, 13.7;
HRMS calcd for C30H2779BrNO3, C30H2781BrNO3: [M + H]+: 528.1174,
530.1154; found: 528.1167, 530.1151.
2-(5,7-Dibromobenzofuran-2-yl)-4-phenylquinoline-3-carboxylic
acid (4i): Red solid; yield 34%; m.p. 275.8–277.2 °C; IR (KBr): ν 3419,
1626, 1558, 850, 757 cm–1; 1H NMR (600 MHz, DMSO-d6): δ 8.14 (d,
J = 8.4 Hz, 1H, ArH), 7.92 (d, J = 7.2 Hz, 2H, ArH), 7.80 (s, 1H, ArH),
7.75 (t, J = 7.2 Hz, 1H, ArH), 7.53 (t, J = 7.2 Hz, 1H, ArH), 7.45–7.50
(m, 5H, ArH), 7.41 (d, J = 8.4 Hz, 1H, ArH); 13C NMR (DMSO-d6,
150 MHz): δ 169.2, 155.8, 150.7, 143.5, 131.6, 130.0, 129.8, 129.5,
128.0, 127.6, 126.7, 125.8, 124.0, 115.7, 108.8, 104.4; HRMS calcd
for C24H1479Br2NO3, C24H1479Br81Br2NO3, C24H1481Br2NO3: [M + H]+:
521.9340, 523.9320, 525.9300; found: 521.9333, 523.9311, 525.9292.
Ethyl 2-(5-(tert-butyl)-7-fluorobenzofuran-2-yl)-4-phenylquinoline-
3-carboxylate (3j): White solid; yield 54%; m.p. 175.9–176.5 °C;
2-(5-(tert-Butyl)-7-bromobenzofuran-2-yl)-4-phenylquinoline-3-
carboxylic acid (4l): Orange solid; yield 41%; m.p. 243.9–244.5 °C;
1
IR (KBr): ν 3324, 2965, 1715, 1543, 862, 755 cm–1; H NMR (600
MHz, DMSO-d6): δ 13.48 (s, 1H, COOH), 8.22 (d, J = 8.4 Hz, 1H,
ArH), 7.90 (t, J = 7.8 Hz, 1H, ArH), 7.81 (d, J = 1.2 Hz, 1H, ArH),
7.69 (s, 1H, furan–H), 7.67 (d, J = 1.2 Hz, 1H, ArH), 7.64 (t, J = 7.8
Hz, 1H, ArH), 7.55–7.60 (m, 3H, ArH), 7.47 (d, J = 8.4 Hz, 1H, ArH),
7.42–7.45 (m, 2H, ArH), 1.36 (s, 9H, tert-Butyl); 13C NMR (150 MHz,
DMSO-d6): δ 168.2, 154.4, 150.2, 148.5, 146.9, 143.6, 134.7, 131.1,
129.5, 129.2, 128.8, 128.4, 126.5, 126.2, 125.8, 117.9, 108.7, 102.9,
34.8, 31.5; HRMS calcd for C28H2379BrNO3, C28H2381BrNO3: [M + H]+:
500.0861, 502.0841; found: 500.0855, 502.0837.
1
IR (KBr): ν 3054, 2960, 1739, 1541, 823, 764 cm–1; H NMR (600
MHz, CDCl3): δ 8.20 (d, J = 8.4 Hz, 1H, ArH), 7.77 (t, J = 7.8 Hz,
1H, ArH), 7.65 (d, J=1.8 Hz, 1H, ArH), 7.57 (d, J = 8.4 Hz, 1H,
ArH), 7.43–7.51 (m, 7H, ArH), 7.13 (d, J = 7.8 Hz, 1H, ArH), 4.20 (q,
J = 7.2 Hz, 2H, CH2), 1.38 (s, 9H, tert-butyl), 1.05 (t, J = 7.2 Hz, 3H,
CH3); 13C NMR (150 MHz, CDCl3): δ 167.7, 155.4, 148.2, 147.8, 147.2,
146.6 (d, 1JC–F = 228.0 Hz), 144.4, 140.6, 134.9, 131.4, 130.6, 129.7, 129.6,
128.6, 128.2, 127.5, 126.6, 126.2, 125.5, 113.4, 109.9 (d, 2JC–F = 16.5 Hz),
108.1, 61.7, 35.0, 31.7, 13.7; HRMS calcd for: C30H27FNO3: [M + H]+:
468.1975; found: 468.1967.
Acknowledgements
The authors would like to thank the Scientific Research
Foundation of the National Natural Science Foundation of
China (Grant No. 21476028) for financial support.
Electronic Supplementary Information
The ESI (1H and 1C NMR spectra of the products) is available
through
2-(5-(tert-Butyl)-7-fluorobenzofuran-2-yl)-4-phenylquinoline-3-
carboxylic acid (4j): Orange solid; yield 35%; m.p. 230.3–231.1 °C;
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data.
1
IR (KBr): ν 3375, 2960, 1738, 1543, 851, 762 cm–1; H NMR (600
MHz, DMSO-d6): δ 13.60 (s, 1H, COOH), 8.21 (d, J = 8.4 Hz, 1H,
ArH), 7.88 (t, J = 7.8 Hz, 1H, ArH), 7.70 (s, 1H, ArH), 7.62 (t, J = 7.8
Hz, 1H, ArH), 7.60 (s, 1H, ArH), 7.54-7.58 (m, 3H, ArH), 7.43–7.46
(m, 3H, ArH), 7.39 (dd, J = 7.8, 1.2 Hz, 1H, ArH), 1.36 (s, 9H, tert-
butyl); 13C NMR (150 MHz, DMSO-d6): δ 168.4, 154.7, 148.2, 147.9
Received 18 June 2016; accepted 27 December 2016
Paper 1604156 doi: 10.3184/174751917X14839766277170
Published online: 17 January 2017
References
1
(d, JC–F = 217.5 Hz), 147.1, 146.8, 146.1, 145.8, 143.7, 143.5, 141.6,
1
2
3
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Ethyl 2-(5-(tert-butyl)-7-chlorobenzofuran-2-yl)-4-phenylquinoline-
3-carboxylate (3k): White solid; yield 45%; m.p. 220.0–220.5 °C; IR

JOURNAL OF CHEMICAL RESEARCH 2016 49
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