A novel one-pot three-step synthesis of 2-(1-benzofuran-2-yl)quinoline-3- carboxylic acid derivatives

Article abstract of DOI:10.1590/S0103-50532010000500007

A facile and efficient one-pot three-step procedure for the preparation of 2-(1-benzofuran- 2-yl)quinoline-3-carboxylic acid derivatives is described, featuring three different synthetic transformations, namely Williamson ether synthesis, hydrolysis of an ester group at the quinoline ring C-3 position, and intramolecular electrophilic cyclization reaction between the aldehyde group of salicylaldehyde and the methylene at the quinoline ring C-2 position.

Full text of DOI:10.1590/S0103-50532010000500007

J. Braz. Chem. Soc., Vol. 21, No. 5, 806-812, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-
3-carboxylic Acid Derivatives
Wentao Gao,* Chaohua Zhang and Yang Li
Institute of Superfine Chemicals, Bohai University, Keji Street, Jinzhou, 121000, P. R. China
Neste trabalho é descrito um protocolo eficiente e simples para a síntese de ácidos
2-(1-benzofurano-2-il)quinolina-3-carboxílicos, envolvendo três etapas realizadas em um único
pote: síntese de éter de Williamson, hidrólise do grupo éster na posição 2 da quinolina e ciclização
por condensação intramolecular entre o aldeído e o metileno na posição 2 da quinolina.
A facile and efficient one-pot three-step procedure for the preparation of 2-(1-benzofuran-
2-yl)quinoline-3-carboxylic acid derivatives is described, featuring three different synthetic
transformations, namely Williamson ether synthesis, hydrolysis of an ester group at the quinoline
ring C-3 position, and intramolecular electrophilic cyclization reaction between the aldehyde group
of salicylaldehyde and the methylene at the quinoline ring C-2 position.
Keywords: one-pot, three-step, benzofuran, quinoline
Introduction
tribromide-promoted tandem deprotection-cyclization
of 2-methoxyphenylacetones,14 (2-methoxyphenyl)
methanols,15 and 2-hydroxy-3-arylpropenoic acids16 leading
respectively to 2-methyl, 2-carboxy, and 2-arylbenzo[b]
furans. However, these methods often require expensive
catalysts and/or multi-step synthesis.
In nature’s collection of biologically active heterocycles,
benzo[b]furan derivatives constitute a major group.1-3
Especially, benzo[b]furan ring systems bearing various
substituents at the C-2 position are widely distributed in
nature and have been reported to have antiviral, antioxidant
and antifungal activities.4,5 Since the pioneering work
of Foster et al.6 on the study of benzo[b]furan at the
2-position, there is an ever increasing number of synthetic
approaches towards the construction of the 2-substituted
benzo[b]furan compounds. Among these, the most widely
used approach for the synthesis of 2-substituted benzo[b]
furans involves the palladium-catalyzed heteroannulation
of 2-halophenols with a terminal alkyne via a tandem
Sonogashira coupling-5-endo-dig-cyclization, largely
based on the methods of Larock and his co-workers.7-10
Recently, other less popular approaches for the synthesis
of 2-substituted benzo[b]furans include p-toluenesulfonic
acid-mediated cyclization of o-(1-alkynyl)anisoles to
obtain 2-arylsubstituted benzofurans,11 rearrangement and
cyclization reactions of 2-hydroxybenzophenones with
Corey-Chaykovsky reagent,12 cyclization of 2-acyloxy-1-
bromomethylareneswithCr(II)Cl2/BF3-OEt2 catalyt,13 boron
On the other hand, the quinoline ring system is an
essential structural fragment of a large number of natural
and unnatural compounds displaying interesting biological
activities such as antimalarial, antibacterial, anti-asthmatic,
antihypertensive, and anti-inflammatory.17-20 Quinolines
and their derivatives have been found applications as
pharmaceuticals and agrochemicals, as well as being general
synthetic building blocks.21-24 For example, chimanine
alkaloids, simple 2-substituted quinolines, isolated from
the bark of Galipea longiflora trees of the Rutaceae family,
are effective against the parasites Leishmania sp., which
are the reagents of leishmaniasis, a protozoan disease of
the tropical areas in South America. On the basis of the
results obtained in studies with 2-substituted quinolines,
the World Health Organization (WHO) has established
as a priority their ability to provide oral treatment for
cutaneous leishmaniasis.25-27 Therefore, significant effort
continues to be directed toward the development of new
2-substituted quinoline structures and new methods for their
construction.28-33 Recently, there is much current interest in
*e-mail: bhuzh@163.com

Vol. 21, No. 5, 2010
Gao et al.
807
assembling quinoline ring with heterocyclic systems, which
represent privileged moieties in medicinal chemistry, and
are ubiquitous sub-structures associated with biologically
active natural products.34-38 For example, 2-(furan-2-yl)
quinoline-4-carboxylic acid as well as analogues (Figure 1)
was reported to have the inhibition of C. albicans prolyl-
tRNA synthetase and showed potent in vitro antifungal
activities against dermatophytes.39,40
situ formation of ether by Williamson reaction between
compound 1 and various substituted salicylaldehydes 2a-i
followed by the hydrolysis and intramolecular cyclization
reactions. This novel procedure provides quick and easy
access to the incorporation of benzo[b]furan core to the
quinoline nucleus at 2-position, with good yields and
simple workup.
Recently, we have reported the one-pot two-step reaction
of bromomethylquinolines with substituted phenols or
naphthols to give the corresponding quinoline carboxylic
acid ethers as key precursors of heterocycle-fused quinoline
compounds.42,43 In order to continue our interest in the
development of bioactive quinoline alkaloids, our initial
intention was to extend the method to the reaction of
monobromide 1 with salicylaldehydes, in which the presence
ofaldehydefunctionalitymayprovideopportunityforfurther
manipulation. Thus, monobromide 1 was first subjected to
the Williamson reaction with salicylaldehyde (2a) to give
the corresponding ethyl 2-[(2-formylphenoxy)methyl]
quinoline-3-carboxylate (4), which structure has already
been characterized by spectroscopic method. Because the
resulting 4 does not interfere with further hydrolysis reaction,
purification at this stage is unnecessary. Thus, we simply
added 10% ethanolic potassium hydroxide solution 10 mL
to this reaction mixture under reflux. After the reaction
was complete, it was found that the major product was
identified as 2-(1-benzofuran-2-yl)quinoline-3-carboxylic
acid (3a). In its 1H NMR spectrum the presence of a distinct
singlet, integrating for one proton resonating at d 7.56 ppm,
assignable to be the proton attached on the furan moiety
and the absence of both the exocyclic methylene protons
and the aldehyde proton resonances in product 3a indicated
the possibility of cyclization through intramolecular
condensation along with the elimination of H2O. Moreover,
the proposed structure of 3a was also confirmed by its
13CNMRspectrum, whichrevealedbesidesthesignalsdueto
aromatic carbons the presence of carboxyl carbon at 168.16
ppm and the absence of the exocyclic methylene carbon as
well as the aldehyde carbon. The IR spectrum also showed
the absence of aldehyde group and exocyclic methylene
OH
O
O
O
N
N
Figure 1. Structure of 2-furanylquinoline and 2-furanylquinoline-4-
carboxylic acid.
In light of the above reports and because of the
potent biological activities of quinoline ring system and
2-substituted benzo[b]furan derivatives, we felt that
there is a real need for the synthesis of new prototypes
by combining both quinoline ring system and benzo[b]
furan moiety in the same molecule at 2-position, which
might be important for pharmacological studies or
creating new medicinal properties. Therefore, we would
like to report herein a facile and inexpensive one-pot
three-step procedure for the preparation of novel hybrid
molecules 2-(1-benzofuran-2-yl)quinoline-3-carboxylic
acid derivatives under mild conditions.
Results and Discussion
In Scheme 1 is outlined the synthetic route developed in
our laboratory. The starting material ethyl 2-(bromomethyl)
quinoline-3-carboxylate (1) was prepared according to
the method of literature.41 The one-pot three-step reaction
reported here represents a new synthetic method for the
preparation of novel 2-(1-benzofuran-2-yl)quinoline-
3-carboxylic acid derivatives (3a-i), involving the in
O
O
OH
OHC
HO
R2
1) K2CO3, CH3CN, reflux
OEt
N
2) 10% KOH
3) 1 mol L-1 HCl
R2
N
CH2Br
O
R1
R1
1
2a-i
3a-i
Scheme 1. One-pot three-step synthesis of 2-(1-benzofuran-2-yl)quinoline-3-carboxylic acid derivatives (3a-i).

808
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
absorption bands. Further, the structure assigned for this
reaction product was fully supported by its mass spectrum,
which showed molecular ion (M+) peak at 289 m/z and
matched the expected molecular weight of 3a. Moreover,
the obtained elemental analysis values are also in agreement
with theoretical data.
salicylaldehydes (2b-i) with differing electronic properties
under the similar conditions, furnishing the respective
2-benzofuranyl-quinoline-3-carboxylic acids (3b-i) in good
yields as shown in Table 1.
In Table 1, a series of salicylaldehydes 2a-i (entries 1-9)
reacted with 1 to give the corresponding 2-benzofuranyl-
quinoline-3-carboxylic acids (3a-i) in 55-75% yields. It
seems that the electronic nature of the substituents has no
significant effect on the reactions; all the salicylaldehydes
with electron-donating (entries 2 and 3), electron-
withdrawing (entries 4-6), or the halo- and t-butyl-
disubstituted groups (entries 7-9) worked well and gave
the corresponding 2-benzofuranyl-quinoline-3-carboxylic
acids in good yields, showing little distinction. The ease of
isolation of all the products was notable; after acidification
workup with 1 mol L-1 HCl, the products were isolated as
the main products.
Additionally, since the naphthofuran backbone is a part
of some natural compounds such as maturin, maturin acetate
and 14-methoxydehydrocacalohastine, and novel strategies
for the synthesis of naphthofuran backbone continue to
receive considerable attention in the field of synthetic organic
chemistry,45-47 we also attempted the reaction of 1 with
The formation of 3a may be interpreted by the following
proposed mechanism as shown in Scheme 2. The in situ
base-mediated ester hydrolysis of the initially formed 4
resulted in the abstraction of acidic proton of the active
methylene within the molecule 6 and subsequent attack of
the carbanion at aldehydic carbon to form a five-membered
cyclic system 8. After this cyclization, dehydration led
to the formation of a benzofuran ring 3a. The proposed
mechanism was similar to that of the formation of
naphthofurans via intramolecular condensation under the
action of triethyl amine reported by Srivastava et al.44
It is noteworthy that the use of 10% ethanolic potassium
hydroxide solution is sufficient to promote the reaction and
there were no improvements in the reaction rates and yields
by increasing the amount of KOH or using other bases.
Encouraged by the experimental result, we attempted
the reaction of monobromide 1 with a series of other
O
O
OHC
O
OEt
OH
OEt
10% KOH
HO
OEt
N
N
reflux
O
O
O
OHC
4
K2CO3
CH3CN, reflux
N
CH2Br
1
5
O
OH
N
O
3a
- H2O
H+
O
COO
H
O
COO
H
N
OH
OH
O
N
O
N
O
O
O
6
8
7
Scheme 2. Possible mechanistic pathway of formation of 2-(1-benzofuran-2-yl)quinoline-3-carboxylic acid (3a).

Vol. 21, No. 5, 2010
Gao et al.
809
Table 1. Synthesis of 2-benzofuranyl-quinoline-3-carboxylic acids (3a-i)a
Entry
Salicylaldehyde
R1
H
H
H
H
H
H
F
R2
H
Product
3a
Yield / (%)b
mp / oC
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
58
57
64
67
65
63
55
75
67
245.5-245.6
240.3-241.0
229.2-229.6
244.8-245.0
244.0-244.2
269.9-270.0
224.1-224.5
217.4-218.1
224.3-225.1
Me
t-Bu
Cl
3b
3c
3d
Br
3e
NO2
t-Bu
t-Bu
t-Bu
3f
2g
2h
2i
3g
Cl
Br
3h
3i
aAll reactions were performed at 1 mmol scale in 12 mL of CH3CN. bYield of isolated product.
O
O
O
CHO
OH
1) K2CO3, CH3CN, reflux
HO
OEt
N
2) 10% KOH
3) 1mol L-1 HCl
N
CH2Br
2j
3j
1
Scheme 3. Synthesis of 2-naphtho[2,1-b]furan-2-ylquinoline-3-carboxylic acid (3j).
1
2-hydroxy-1-naphthaldehyde (2j) (Scheme 3) under similar
conditions with the aim to construct novel naphthofuran
derivative. Interestingly, 2-hydroxy-1-naphthaldehyde
was equally amenable to the conditions and gave the
corresponding 2-naphtho[2,1-b]furan-2-ylquinoline-3-
carboxylic acid (3j) in a good yield of 66%.
uncorrected. H NMR and 13C NMR spectra were
recorded on a Varian Inova 400 MHz or Brucker
AVANCE 600 MHz NMR spectrometer using CDCl3 or
DMSO-d6 as the solvent. The reported chemical shifts
(d values) are given in parts per million downfield from
tetramethylsilane (TMS) as the internal standard. EI-MS
(70 eV): Finningan-MAT-8430 mass spectrometer. The
elemental analyses was performed for C, H, and N using
an Elementar Vario EL-III element analyzer and found
within 0.4%. The progress of reactions was monitored
by thin-layer chromatography (TLC) on silica gel GF254
using ethyl acetate as eluent.
Conclusions
In summary, the present method offered a facile
synthetic route to a variety of 2-benzofuranyl-quinoline-3-
carboxylic acids (3a-i) as well as 2-naphtho[2,1-b]furan-2-
yl-quinoline-3-carboxylic acid (3j), which would provide
new leads in the search for future drug candidates. Readily
availability of starting material, mild reaction conditions,
short reaction times, experimental simplicity and satisfactory
yields contribute to the usefulness of this method. Possible
biological activity of the described compounds possessing
the benzofuran and quinoline skeletons remains to be
studied. In addition, the products represent potentially useful
synthetic building blocks in medicinal chemistry.
The mass spectra and elemental analysis data were in
agreement with the proposed structures.
General procedure for the preparation of 2-(1-benzofuran-
2-yl)quinoline-3-carboxylic acids 3a-i
A mixture of ethyl 2-(bromomethyl)quinoline-3-
carboxylate (1 mmol, 0.294 g), each salicylaldehyde
(1 mmol) and K2CO3 (4 mmol, 0.552 g) was stirred in
refluxing CH3CN (12 mL). The conversion was monitored
by TLC. After completion, 10% ethanolic potassium
hydroxide solution 10 mL was added to the reaction mixture
and continued to reflux for 2 h, cooled, and acidified with
1 mol L-1 HCl solution. The resulting crude product was
recrystallized from ethanol to afford the corresponding
products 3a-i in 55-75% yields.
Experimental
Chemical analysis
Melting points (uncorrected) were determined
by using WRS-1B melting points apparatus and are

810
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
The melting pints and yields of all the compounds are
summarized in Table 1 and the spectral and analytical data
are given below.
2-(5-Chloro-1-benzofuran-2-yl)quinoline-3-carboxylic
acid (3d)
Orange solid. 1H NMR (DMSO-d6, 400 MHz): d 7.42-
7.44 (m, 1H, Ar-H), 7.54 (s, 1H, furan-H), 7.69 (d, 1H,
J 8.7 Hz, Ar-H), 7.72-7.75 (m, 1H, Ar-H), 7.87 (d, 1H, J
2.15 Hz, Ar-H), 7.91-7.94 (m, 1H, Ar-H), 8.13-8.17 (m,
2H, Ar-H), 8.81 (s, 1H, Ar-H), 13.6 (s, 1H, OH); 13C NMR
(DMSO-d6, 75 MHz): d 106.89, 113.11, 121.50, 125.59,
126.28, 127.88, 128.28, 128.77, 128.89, 129.80, 132.06,
137.92, 145.48, 147.36, 153.28, 155.75, 168.41; EI-MS m/z
(%) = 324 (60%, M+), 279 (55, [M-COOH]+), 278 (100),
323 (84); IR (KBr)νmax/cm-1:3442 (COOH), 1719 (C=O),
1618, 1593, 1558, 1491, 1457, 1376, 1323, 1231, 1173,
795, 743; Anal. Calc. for C18H10ClNO3: C, 66.78; H, 3.11;
N, 4.33. Found: C, 66.82; H, 3.14; N, 4.29.
2-(1-Benzofuran-2-yl)quinoline-3-carboxylic acid (3a)
1
Orange solid. H NMR (DMSO-d6, 400 MHz): d 7.32-
7.35 (m, 1H, Ar-H), 7.41-7.44 (m, 1H, Ar-H), 7.56 (s, 1H,
furan-H), 7.64 (d, 1H, J 8.0 Hz, Ar-H), 7.71-7.74 (m, 1H,
Ar-H), 7.79 (d, 1H, J 6.12 Hz, Ar-H), 7.90-7.93 (m, 1H,
Ar-H), 8.12-8.16 (m, 2H, Ar-H), 8.17 (s, 1H, Ar-H), 13.5 (s,
1H, OH); 13C NMR (DMSO-d6, 75 MHz): d 107.29, 111.49,
122.15, 123.52, 125.72, 126.14, 126.33, 128.05, 128.17,
128.71, 128.84, 131.91, 137.62, 145.78, 147.35, 154.20,
154.83, 168.64; EI-MS m/z (%) = 289 (5%, M+), 244 (100,
[M-COOH]+), 245 (26), 288 (18); IR(KBr) νmax/cm-1: 3449
(COOH), 1719 (C=O), 1618, 1590, 1560, 1491, 1443, 1420,
1337, 1349, 1234, 1142, 793, 753;Anal. Calc. forC18H11NO3:
C, 74.73; H, 3.83; N, 4.84. Found: C, 74.69; H, 3.87; N, 4.79.
2-(5-Bromo-1-benzofuran-2-yl)quinoline-3-carboxylic
acid (3e)
1
Gray solid. H NMR (DMSO-d6, 600 MHz): d 7.54-
2-(5-Methyl-1-benzofuran-2-yl)quinoline-3-carboxylic
acid (3b)
7.56 (complex m, 2H, Ar-H and furan-H), 7.64 (d, 1H,
J 8.7 Hz, Ar-H), 7.72-7.75 (m, 1H, Ar-H), 7.91-7.94 (m,
1H, Ar-H), 8.01 (d, 1H, J 2.0 Hz, Ar-H), 8.13-8.18 (m, 2H,
Ar-H), 8.82 (s, 1H, Ar-H), 13.6 (s, 1H, OH); EI-MS m/z
(%) = 368 (25%, M+), 323 (90, [M-COOH]+), 324 (44),
367 (65); 13C NMR (DMSO-d6, 150 MHz): 107.55, 113.53,
115.34, 124.05, 127.16, 127.24, 127.72, 128.81, 129.55,
130.89, 133.50, 136.37, 144.91, 145.88, 153.27, 155.97,
171.18; IR (KBr) νmax/cm-1: 3439 (COOH), 1714 (C=O),
1619, 1593, 1559, 1491, 1434, 1377, 1324, 1254, 1232,
795, 743; Anal. Calc. for C18H10BrNO3: C, 58.72; H, 2.74;
N, 3.80. Found: C, 58.67; H, 2.79; N, 3.76.
Orange solid. 1H NMR (DMSO-d6, 400 MHz): d 2.44
(s, 3H, CH3), 7.22-7.24 (m, 1H, Ar-H), 7.49-7.53 (m, 2H,
Ar-H), 7.57 (s, 1H, furan-H), 7.70-7.73 (m, 1H, Ar-H),
7.89-7.92 (m, 1H, Ar-H), 8.12-8.15 (m, 2H, Ar-H), 8.77
(s, 1H, Ar-H), 13.5 (s, 1H, OH); 13C NMR (DMSO-d6,
75 MHz): d 21.46, 107.28, 111.50, 121.65, 124.97, 125.72,
126.06, 126.32, 127.92, 128.69, 128.80, 131.85, 135.78,
137.49, 145.82, 147.36, 153.63, 155.31, 168.74; EI-MS m/z
(%) = 303 (55%, M+), 258 (100, [M-COOH]+), 259 (38),
302 (71); IR(KBr) νmax/cm-1: 3445 (COOH), 1716 (C=O),
1618, 1592, 1558, 1490, 1445, 1417, 1376, 1326, 1231,
1200, 793, 742; Anal. Calc. for C19H13NO3: C, 75.24; H,
4.32; N, 4.62. Found: C, 75.27; H, 4.39; N, 4.57.
2-(5-Nitro-1-benzofuran-2-yl)quinoline-3-carboxylic acid
(3f)
Yellow solid. 1H NMR (DMSO-d6, 400 MHz): d 7.75-
7.78 (complex m, 2H, Ar-H and furan-H), 7.90-7.97 (m,
2H, Ar-H), 8.16-8.21 (m, 2H, Ar-H), 8.28-8.31 (m, 1H,
Ar-H), 8.77 (d, 1H, J 2.3 Hz, Ar-H), 8.88 (s, 1H, Ar-H),
13.6 (s, 1H, OH); 13C NMR (DMSO-d6, 75 MHz): d 108.00,
112.42, 118.70, 121.14, 126.17, 126.45, 128.52, 128.87,
128.96, 132.22, 138.32, 144.12, 147.39, 157.44, 168.16;
EI-MS m/z (%) = 334 (5%, M+), 289 (100, [M-COOH]+),
290 (25), 333 (27); IR(KBr) νmax/cm-1: 3438 (COOH), 1712
(C=O), 1620, 1589, 1555, 1520, 1491, 1451, 1377, 1344,
1266, 789, 746; Anal. Calc. for C18H10N2O5: C, 64.67; H,
3.02; N, 8.38. Found: C, 64.76; H, 3.07; N, 8.34.
2-(5-tert-Butyl-1-benzofuran-2-yl)quinoline-3-carboxylic
acid (3c)
White solid. 1H NMR (CDCl3, 400 MHz): d 1.38 (s, 9H,
t-butyl), 7.36-7.38 (m, 1H, Ar-H), 7.42 (d, 1H, J 8.7 Hz,
Ar-H), 7.52 (s, 1H, furan-H), 7.59-7.62 (m, 1H, Ar-H),
7.64 (d, 1H, J 1.7 Hz, Ar-H), 7.79-7.82 (m, 1H, Ar-H),
7.88 (d, 1H, J 8.0 Hz , Ar-H), 8.21 (d, 1H, J 8.4 Hz , Ar-H),
8.63 (s, 1H, Ar-H); 13C NMR (CDCl3, 150 MHz): d 31.80,
34.75, 108.58, 110.96, 118.07, 123.82, 124.00, 125.98,
127.83, 128.12, 128.32, 129.21, 132.09, 139.19, 146.33,
146.76, 148.16, 153.66, 153.94, 171.31; EI-MS m/z (%) =
345 (36%, M+), 300 (100, [M-COOH]+), 301 (42), 302 (7),
344 (94), 346 (8); IR(KBr) νmax/cm-1: 3441 (COOH), 1712
(C=O), 1619, 1597, 1492, 1453, 1411, 1324, 1240, 1166,
800, 752; Anal. Calc. for C22H19NO3: C, 76.50; H, 5.54; N,
4.06. Found: C, 76.45; H, 5.58; N, 4.11.
2-(5-tert-Butyl-7-fluoro-1-benzofuran-2-yl)quinoline-3-
carboxylic acid (3g)
1
White solid. H NMR (CDCl3, 400 MHz): d 1.36
(s, 9H, t-butyl), 7.10-7.13 (m, 1H, Ar-H), 7.41 (d, 1H, J

Vol. 21, No. 5, 2010
Gao et al.
811
1.6 Hz, Ar-H), 7.52 (s, 1H, furan-H), 7.61-7.65 (m, 1H,
Ar-H), 7.82-7.85 (m, 1H, Ar-H), 7.91 (d, 1H, J 8.0 Hz,
Ar-H), 8.20 (d, 1H, J 8.4 Hz, Ar-H), 8.67 (s, 1H, Ar-H);
13C NMR (DMSO-d6, 150 MHz): 31.42, 34.87, 107.79,
109.74, 109.84, 113.98, 126.26, 128.21, 128.77, 128.87,
131.36, 132.01, 137.94, 139.55, 139.63, 145.51, 145.86,
147.34, 147.49, 148.05, 155.41, 168.39; EI-MS m/z (%) =
363 (80%, M+), 318 (100, [M-COOH]+), 319 (30), 362
(95); IR(KBr) νmax/cm-1: 3442 (COOH), 1711 (C=O), 1611,
1598, 1561, 1492, 1449, 1376, 1327, 1233, 1183, 798, 750;
Anal. Calc. for C22H18FNO3: C, 72.72; H, 4.99; N, 3.85.
Found: C, 72.78; H, 5.01; N, 3.83.
was monitored by TLC. After completion, 10% ethanolic
potassiumhydroxidesolution10mLwasaddedtothereaction
mixture and continued to reflux for 2 h, cooled, and acidified
with 1 mol L-1 HCl solutuon. The resulting crude product was
recrystallizedfromethanoltoaffordthecorrespondingproduct
o
1
3j in 66% yield; red solid, mp 246.3-246.4 C. H NMR
(DMSO-d6, 400 MHz): d 7.57-7.60 (m, 1H,Ar-H), 7.68-7.74
(complex m, 2H, Ar-H and furan-H), 7.84 (d, 1H, J 8.9 Hz,
Ar-H), 7.92-7.96 (m, 2H,Ar-H), 8.09 (d, 1H, J 8.1 Hz,Ar-H),
8.15-8.17 (m, 2H, Ar-H), 8.26 (s, 1H, Ar-H), 8.48 (d, 1H, J
8.1Hz,Ar-H), 8.81(s, 1H,Ar-H), 13.6(s, 1H, OH);13CNMR
(DMSO-d6, 75 MHz): d 106.81, 112.43, 123.70, 123.96,
125.21, 126.07, 126.23, 126.80, 127.01, 127.53, 127.89,
128.74, 130.15, 131.92, 137.65, 145.83, 147.44, 152.64,
153.81, 168.78; EI-MS m/z (%) = 339 (15%, M+), 294 (100,
[M-COOH]+),295(47),296(10),338(57);IR(KBr)νmax/cm-1:
3442 (COOH), 1696 (C=O), 1620, 1589, 1557, 1492, 1452,
1384, 1255, 1194, 796, 751; Anal. Calc. for C22H13NO3: C,
77.87; H, 3.86; N, 4.13. Found: C, 77.85; H, 3.89; N, 4.10.
2-(5-tert-Butyl-7-chloro-1-benzofuran-2-yl)quinoline-3-
carboxylic acid (3h)
Orange solid. 1H NMR (CDCl3, 600 MHz): d 1.39 (s, 9H,
t-butyl), 7.40 (d, 1H, J 1.2 Hz, Ar-H), 7.57 (d, 1H, J 1.8 Hz,
Ar-H), 7.58 (s, 1H, furan-H), 7.65 (s, 1H, Ar-H), 7.86 (s, 1H,
Ar-H), 7.94 (d, 1H, J 7.8 Hz, Ar-H), 8.24 (d, 1H, J 8.4 Hz,
Ar-H), 8.68 (s, 1H, Ar-H); 13C NMR (CDCl3, 150 MHz): d
31.70, 34.82, 108.61, 115.49, 116.19, 116.81, 123.88, 124.00,
Preparation of Ethyl 2-[(2-Formylphenoxy)methyl]
126.19, 128.10, 128.36, 129.21, 129.63, 132.23, 139.17,
146.11, 147.98, 149.64, 170.13; EI-MS m/z (%) = 380 (35%,
M+), 335 (35, [M-COOH]+), 213 (33), 215 (11), 334 (95),
378 (98), 379 (22); IR(KBr) νmax/cm-1: 3429 (COOH), 1702
(C=O),1620,1580,1556,1479,1460,1394,1364,1286,1258,
1165, 790, 752; Anal. Calc. for C22H18ClNO3: C, 69.57; H,
4.78; N, 3.69. Found: C, 69.64; H, 4.80; N, 3.65.
quinoline-3-carboxylate (4)
A mixture of ethyl 2-(bromomethyl)quinoline-3-
carboxylate (1 mmol, 0.294 g), salicylaldehyde (1 mmol,
0.122g)andK2CO3 (4mmol, 0.552g)wasstirredinrefluxing
CH3CN (12 mL). The conversion was monitored by TLC.
After completion, reaction mixture was quenched with H2O.
Theprecipitatedcrudeproductwasrecrystallizedfromethanol
to afford the corresponding product 4 in 61% yield; white
solid,mp88.6-89.1oC.1HNMR(CDCl3,600MHz):d1.35(t,
3H, J 7.2 Hz, OCH2CH3), 4.38 (q, 2H, J 5.6 Hz, OCH2CH3),
5.81 (s, 2H, Ar-CH2-O), 7.01-7.04 (m, 1H, Ar-H), 7.17 (d,
1H, J 8.4 Hz Ar-H), 7.51-7.54 (m, 1H, Ar-H), 7.62-7.64 (m,
1H, Ar-H), 7.82-7.86 (m, 2H, Ar-H), 7.92 (d, 1H, J 7.8 Hz,
Ar-H), 8.12 (d, 1H, J 8.4 Hz,Ar-H), 8.79 (s, 1H,Ar-H), 10.52
(s, 1H, CHO); 13C NMR (CDCl3, 150 MHz): d 14.12, 61.77,
71.53,113.32,121.00,123.63,125.17,126.58,127.78,128.08,
128.47, 129.33, 131.94, 135.81, 140.26, 148.15, 154.62,
161.40, 165.96, 189.86; EI-MS m/z (%) = 335 (100%, M+);
IR(KBr) νmax/cm-1: 2966 (C-H, CH3), 2899 (C-H, CH2), 2852
(C-H, CHO), 1710 (CHO, C=O), 1685 (COOC2H5, C=O),
1622, 1592, 1565, 1457, 1425, 1363, 1314, 1277, 1204, 1133,
787, 751; Anal. Calc. for C20H17NO4: C, 71.63; H, 5.11; N,
4.18. Found: C, 71.69; H, 5.04; N, 4.23.
2-(7-Bromo-5-tert-butyl-1-benzofuran-2-yl)quinoline-3-
carboxylic acid (3i)
1
Orange solid. H NMR (CDCl3, 600 MHz): d 1.39 (s,
9H, t-butyl), 7.55 (s, 1H, furan-H), 7.61-7.65 (m, 3H,Ar-H),
7.84-7.87 (m, 1H, Ar-H), 7.93 (d, 1H, J 7.8 Hz, Ar-H), 8.25
(d, 1H, J8.4Hz,Ar-H), 8.68(s, 1H,Ar-H);13CNMR(CDCl3,
150 MHz): d 31.73, 34.94, 103.57, 108.55, 117.47, 124.22,
126.18, 126.66, 128.04, 128.35, 129.26, 132.13, 139.01,
146.10, 148.31, 151.04, 171.11; EI-MS m/z (%) = 424 (97%,
M+), 379 (75, [M-COOH]+), 257 (26), 378 (80), 423 (95);
IR(KBr) νmax/cm-1: 3415 (COOH), 1703 (C=O), 1619, 1578,
1554, 1479, 1461, 1420, 1393, 1363, 1323, 1284, 1258, 1163,
791, 751; Anal. Calc. for C22H18BrNO3: C, 62.28; H, 4.28;
N, 3.30. Found: C, 62.33; H, 4.32; N, 3.26.
Preparation of 2-naphtho[2,1-b]furan-2-ylquinoline-3-
carboxylic acid (3j)
Supplementary Information
A mixture of ethyl 2-(bromomethyl)quinoline-3-
carboxylate (1 mmol, 0.294 g), 2-hydroxy-1-naphthaldehyde
(1 mmol, 0.172 g) and K2CO3 (4 mmol, 0.552 g) was stirred
in CH3CN (12 mL) at reflux temperature. The conversion
Supplementary information is available free of charge
at http://jbcs.sbq.org.br, as PDF file.

812
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
Acknowledgments
25. Fournet,A.; Hocquemiller, R.; Roblot, F.; Cavé,A.; Richomme,
P.; Bruneton, J.; J. Nat. Prod. 1993, 56, 1547.
26. Franck, X.; Fourner, A.; Prina, E.; Mahieux, R.; Hocquemiller,
R.; Figadère, B.; Bioorg. Med. Chem. Lett. 2004, 14, 3635.
27. Fournet,A.; Ferreira, M. E.; Rojas deArias,A.; Torres de Ortiz,
S.; Fuentes, S.; Nakayama, H.; Schinini, A.; Hocquemiller, R.;
Antimicrob. Agents Chemother. 1996, 40, 2447.
28. Du, W.; Curran, D. P.; Org. Lett. 2003, 5, 1765.
29. Lindsay, D. M.; Dohle, W.; Jensen,A. E.; Kopp, F.; Knochel, P.;
Org. Lett. 2002, 4, 1819.
The authors thank the Foundation of Liaoning
Province Key Laboratory ofApplied Chemistry (Grant No.
2008s001) for financial support.
References
1. Schneiders, G. E.; Stevenson, R.; J. Org. Chem. 1979, 44, 4710.
2. Carlsson, B.; Singh, B. N.; Temciue, M.; Nilsson, S.; Li,Y. L.;
Mellin, C.; Malm, J.; J. Med. Chem. 2002, 45, 623.
3. Shirota, O.; Pathak, V.; Sekita, S.; Stake, M.; Nagashima, Y.;
Hirayama, Y.; Hakamata, Y.; Haysahi, T.; J. Nat. Prod. 2003,
66, 1128.
30. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.;
McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P.;
J. Org. Chem. 2003, 68, 467.
31. Ghorbani-Vaghei, R.; Akbari-Dadamahaleh, S.; Tetrahedron
Lett. 2009, 50, 1055.
4. Fuganti, C.; Serra, S.; Tetrahedron Lett. 1998, 39, 5609.
5. Abdel-Wahab, B. F.; Abdel-Aziz, H. A.; Ahmed, E. M.; Eur. J.
Med. Chem. 2009, 44, 2632.
32. Wang, G. W.; Jia, C. S.; Dong, Y. W.; Tetrahedron Lett. 2006,
47, 1059.
6. Foster, R. T.; Robertson, A.; Bushra, A.; J. Chem. Soc. 1948,
2254.
33. Zolfigol, M.A.;Salehi, P.;Ghaderi,A.;Shiri, M.;Tanbakouchian,
Z.; J. Mol. Catal. A: Chem. 2006, 259, 253.
7. Yue, D.;Yao, T.; Larock, R. C.; J. Org. Chem. 2005, 70, 10292.
8. Larock, R. C.;Yum, E. K.; Doty, M. J.; Sham, K. K. C.; J. Org.
Chem. 1995, 60, 3270.
34. Lavrado, J.; Paulo, A.; Gut, J.; Rosenthal, P. J.; Moreira, R.;
Bioorg. Med. Chem. Lett. 2008, 18, 1378.
35. Chen, Y. L.; Hung, H. M.; Lu, C. M.; Li, K. C.; Tzeng, C. C.;
Bioorg. Med. Chem. 2004, 12, 6539.
9. Yue, D.; Larock, R. C.; J. Org. Chem. 2002, 67, 1905.
10. Larock, R. C.;Harrison, L.W.;J.Am. Chem. Soc. 1984, 106, 4218.
11. Jacubert, M.; Hamze, A.; Provot, O.; Peyrat, J. F.; Brion, J. D.;
Alami, M.; Tetrahedron Lett. 2009, 50, 3588.
36. Yang, D. Q.; Jiang, K. L.; Li, J. N.; Xu, F.; Tetrahedron 2007,
63, 7654.
37. Zora, M.; Veliogluğlu, Ö.; J. Organomet. Chem. 2008, 693,
2159.
12. Chittimalla, S. K.; Chang, T. C.; Liu, T. C.; Hsieh, H. P.; Liao,
C. C.; Tetrahedron 2008, 64, 2586.
38. Majumdar, K. C.; Taher, A.; Debnath, P.; Synthesis 2009, 793.
39. Yu, X. Y.; Hill, J. M.; Yu, G.; Yang, Y. F.; Kluge, A. F.; Keith,
D.; Finn, J.; Gallant, P.; Silverman, J.; Lim, A.; Bioorg. Med.
Chem. Lett. 2001, 11, 541.
13. Ledoussal, B.; Gorgues, A.; Le Coq, A.; Tetrahedron 1987, 43,
5841.
14. Dupont, R.; Cotelle, P.; Synthesis 1999, 1651.
15. Dupont, R.; Cotelle, P.; Tetrahedron 2001, 57, 5585.
16. Dupont, R.; Cotelle, P.; Tetrahedron Lett. 2001, 42, 597.
17. Larsen, R. D.; Corley, E. G.; King, A. O.; Carrol, J. D.; Davis,
P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.;
Xiang, Y. B.; Zamboni, R. J.; J. Org. Chem. 1996, 61, 3398.
18. Bilker,O.;Lindo,V.;Panico,M.;Etiene,E.A.;Paxton,T.;Dell,A.;
Rogers, M.; Sinden, R. E.; Morris, H. R.; Nature 1998, 392, 289.
19. Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.; Ghia, M.;
Eur. J. Med. Chem. 2000, 35, 1021.
40. Meléndez Gómez, C. M.; Kouznetsov, V. V.; Sortino, M. A.;
Alvarez, S.; Zacchino, S. A.; Bioorg. Med. Chem. 2008, 16,
7908.
41. Wu, L. H.; Yang, D. Q.; Chin. J. Org. Chem. 2009, 7, 1122.
42. Gao, W. T.; Zhang, C. H.; Li,Y.; Jiang,Y.; Chin. J. Org. Chem.
2009, 29, 1423.
43. Li, Y.; Zhang, C. H.; Sun, M. C.; Gao, W. T.; J. Heterocycl.
Chem. 2009, 46, 1190.
44. Srivastava, V.; Negi, A. S.; Kumar, J. K.; Faridi, U.; Sisodia, B.
S.; Daroka, M. P.; Luqman, S.; Khanuja, S. P. S.; Bioorg. Med.
Chem. Lett. 2006, 16, 911.
20. Chen, Y. L.; Fang, K. C.; Sheu, J. Y.; Hsu, S. L.; Tzeng, C. C.;
J. Med. Chem. 2001, 44, 2374.
21. Kalluraya, B.; Sreenivasa, S.; Il Farmaco 1998, 53, 399.
22. Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.;
Zilberstein, A.; J. Med. Chem. 1994, 37, 2129.
45. Goel, A.; Dixit, M.; Tetrahedron Lett. 2004, 45, 8819.
46. Piloto, A. M.; Costa, S. P. G.; Goncalves, M. S. T.; Tetrahedron
Lett. 2005, 46, 4757.
23. Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J.;
Tetrahedron Lett. 2002, 43, 6485.
47. Srivastava, V.; Negi, A. S.; Kumar, J. K.; Faridi, U.; Sisodia, B.
S.; Darokar, M. P.; Luqman, S.; Khanuja, S. P. S.; Bioorg. Med.
Chem. Lett. 2006, 16, 911.
24. Dube, D.; Blouin, M.; Brideau, C.; Chan, C. C.; Desmarais, S.;
Ethier, D.; Falgueyret, J. P.; Friesen, R. W.; Girard, M.; Girard,
Y.; Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N.; Bioorg.
Med. Chem. Lett. 1998, 8, 1255.
Received: October 19, 2009
Web Release Date: February 4, 2010

J. Braz. Chem. Soc., Vol. 21, No. 5, S1-S12, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-
carboxylic Acid Derivatives
Wentao Gao,* Chaohua Zhang and Yang Li
Institute of Superfine Chemicals, Bohai University, Keji Street, Jinzhou, 121000, P. R. China
Figure S1. 1H NMR spectrum of 3a.
*e-mail: bhuzh@163.com

S2
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
Figure S2. 13C NMR spectrum of 3a.
Figure S3. 1H NMR spectrum of 3b.

Vol. 21, No. 5, 2010
Gao et al.
S3
Figure S4. 13C NMR spectrum of 3b.
Figure S5. 1H NMR spectrum of 3c.

S4
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
Figure S6. 13C NMR spectrum of 3c.
Figure S7. 1H NMR spectrum of 3d.

Vol. 21, No. 5, 2010
Gao et al.
S5
Figure S8. 13C NMR spectrum of 3d.
Figure S9. 1H NMR spectrum of 3e

S6
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
Figure S10. 13C NMR spectrum of 3e.
Figure S11. 1H NMR spectrum of 3f.

Vol. 21, No. 5, 2010
Gao et al.
S7
Figure S12. 13C NMR spectrum of 3f.
Figure S13. 1H NMR spectrum of 3g.

S8
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
Figure S14. 13C NMR spectrum of 3g.
Figure S15. 1H NMR spectrum of 3h.

Vol. 21, No. 5, 2010
Gao et al.
S9
Figure S16. 13C NMR spectrum of 3h.
Figure S17. 1H NMR spectrum of 3i.

S10
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
Figure S18. 13C NMR spectrum of 3i.
Figure S19. 1H NMR spectrum of 3j.

Vol. 21, No. 5, 2010
Gao et al.
S11
Figure S20. 13C NMR spectrum of 3j.
Figure S21. 1H NMR spectrum of 4.

S12
A Novel One-pot Three-step Synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic Acid Derivatives
J. Braz. Chem. Soc.
Figure S22. 13C NMR spectrum of 4.