Clean and efficient assembly of functionalized benzofuro[2,3-c]pyridines via metal-free one-pot domino reactions

Article abstract of DOI:10.1039/c3gc42234h

A clean and efficient method for the domino synthesis of new functionalized benzofuro[2,3-c]pyridines from easily accessible 2-hydroxychalcones, α-bromo ketones and ammonium acetate is described. Furan and pyridine ring moieties are ingeniously formed in

Full text of DOI:10.1039/c3gc42234h

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Clean and efficient assembly of functionalized
benzofuro[2,3-c]pyridines via metal-free one-pot
domino reactions†
Cite this: Green Chem., 2014, 16,
2213
Yin Rao, Zhexian Li and Guodong Yin*
Received 30th October 2013,
Accepted 9th January 2014
A clean and efficient method for the domino synthesis of new functionalized benzofuro[2,3-c]pyridines
from easily accessible 2-hydroxychalcones, α-bromo ketones and ammonium acetate is described. Furan
and pyridine ring moieties are ingeniously formed in a one-pot operation in this tricyclic system.
DOI: 10.1039/c3gc42234h
www.rsc.org/greenchem
phenol4 (path I) as well as transition metal-catalyzed intra-
molecular dehydrohalogenation5 or reductive dehalocoupling
Introduction
Benzofuropyridines and their derivatives are common struc- of phenyl pyridyl ether derivatives6 (path II). The construction
tural motifs in many biologically active compounds and drug of a pyridine ring is yet another approach, while benzofuran
candidates.1,2 Molecules containing these structural units derivatives are usually employed as precursors in these reac-
have been shown to exhibit activity against cancer and tions7 (path III). Recently, Tanaka reported an interesting syn-
tuberculosis.3
thesis of benzofuropyridines by rhodium-catalyzed [2 + 2 + 2]
A variety of routes have so far been reported for the syn- cycloadditions of phenol-linked 1,6-diynes with nitriles.8 As
thesis of benzofuropyridine frameworks,4–10 which are sum- one of the important tricyclic systems, a few reports focus on
marized in Scheme 1. One approach is to construct the furan- the preparation of benzofuro[2,3-c]pyridine heterocycles.7–9
ring moiety of the tricyclic system, which can be achieved Generally, these approaches for benzofuropyridines often
by the intramolecular SNAr etherification of 2-(halopyridyl)- required lengthy multistep synthesis due to the use of not
easily available starting materials or harsh reaction conditions
including expensive air/water-sensitive transition metal cata-
lysts, strong organic bases and high temperature. Accordingly,
the development of a concise and cost-effective synthetic
method for benzofuro[2,3-c]pyridines is still of significant
interest.
Recently, we reported an efficient domino synthesis of
functionalized 4H-chromenes and methylene-bridged [3.3.1]-
bicyclic molecules from 2-hydroxychalcones with varied
nucleophilic reagents.11 In addition, we have found a three-
component reaction of aromatic aldehydes, acetophenone
derivatives and ammonium acetate for the direct synthesis of
hydroxylated triarylpyridines under microwave irradiation.12 In
continuation of our efforts to develop new synthetic protocols
for constructing heterocyclic frameworks, we herein describe a
one-pot domino reaction for the synthesis of substituted
benzofuro[2,3-c]pyridines from easily accessible 2-hydroxychal-
cones, α-bromo ketones and ammonium acetate.
Scheme 1 Synthetic approaches for benzofuropyridines.
Hubei Collaborative Innovation Center for Rare Metal Chemistry, College of
Chemistry and Chemical Engineering, Hubei Normal University, Huangshi 435002,
China. E-mail: gdyin@hbnu.edu.cn
†Electronic supplementary information (ESI) available: Full characterization
data, copies of 1H NMR, 13C NMR spectra for all new products and CIF file of
6aa. CCDC 966680. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3gc42234h
Results and discussion
As shown in Scheme 2, a retro-synthetic analysis of the desired
product 1,3-disubstituted benzofuro[2,3-c]pyridines (6) shows
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Scheme 2 Retro-synthetic approach for substituted benzofuro[2,3-c]-
pyridines.
that they can be prepared starting from 1,5-diketone (5)
bearing the 2,3-disubstituted dihydrobenzofuran moiety and
ammonium acetate by a modified Kröhnke reaction.13
A
sequential O-alkylation/intramolecular Michael addition reac-
tion of 2-hydroxychalcones (3) and α-bromo ketones (4) can
deliver 5. And compound 3 can be easily synthesized by
Claisen–Schmidt condensation of salicylaldehyde (1) with
methyl ketones (2) according to a reported method.14
Fig. 1 X-ray structure of 6aa.†
We initiated the investigation by optimizing the reaction
conditions (bases and solvents) for the synthesis of 1,3-diphe-
nylbenzofuro[2,3-c]pyridine (6aa) (Table 1). The reaction of
(E)-3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one (3a, 1.0 mmol),
2-bromo-1-phenylethanone (4a, 1.0 mmol) and potassium car-
bonate (1.0 mmol) was carried out in ethanol at room tempera-
ture for 12 h, then ammonium acetate (8.0 mmol) and acetic
acid (1.0 mL) were added, and the mixture was heated at reflux
for 8 h. We were pleased to observe that when the reaction
mixture was slowly cooled to room temperature overnight,
yellow crystals of 6aa precipitated in 65% yield (Table 1, entry
1), which were found to be pure enough for structural analysis.
Its structure was identified by means of 1H NMR, 13C NMR,
HRMS, IR spectra and X-ray single-crystal diffraction analysis
(Fig. 1).15 When 1.5 equiv. of potassium carbonate was
employed, the reaction resulted in a high yield (Table 1, entry
2). Increasing the amount of potassium carbonate to 2.0 equiv.
did not obviously improve the yield (Table 1, entry 3). Chan-
ging the base from potassium carbonate to sodium bicarbon-
ate, triethylamine and N,N-diisopropylethylamine (DIPEA), the
reactions gave the expected product in 38–41% yield (entries
4–6). No product was formed using pyridine or in the absence
of a base (Table 1, entries 7 and 8). This transformation was
also attempted in other solvents, such as methanol, tetra-
hydrofuran, methyl cyanide and acetone, and 6aa was isolated
in 45–75% yield (Table 1, entries 9–12). Excess ammonium
acetate was required for the second-step reaction (Table 1,
entries 13 and 14) and the reaction gave the product in a
slightly low yield without acetic acid (Table 1, entry 15).
Accordingly, the optimized conditions were identified as the
reaction of 3a with 1.0 equiv. of 4a in ethanol at room tempera-
ture using 1.5 equiv. of potassium carbonate as the base, and
then 8.0 equiv. of ammonium acetate was added at reflux in
the presence of acetic acid.
Table 1 Optimization of the reaction conditions for the synthesis of
6aaa
Entries
Base (mmol)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3 (1.0)
K2CO3 (1.5)
K2CO3 (2.0)
NaHCO3
TEA
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
THF
MeCN
Acetone
EtOH
EtOH
EtOH
65
79
80
38
40
41
0
DIPEA
Py
c
—
0
9
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
68
64
75
45
42d
79e
74f
10
11
12
13
14
15
With the optimum reaction conditions in hand, we investi-
gated the reactions of a variety of substituted 2-hydroxy-
chalcones with 2-bromo-1-phenylethanone, and the results are
summarized in Scheme 3. It was observed that substrates in
which R1 = H and R2 is a phenyl ring bearing electron-donat-
ing substituents [–OCH3, –(OCH3)2] or electron-withdrawing
substituents (–F, –Cl and –Br) gave the expected products
a Unless otherwise noted, reactions were performed with 3a (1.0 mmol)
and 4a (1.0 mmol) in solvent (15 mL) at room temperature for 12 h;
then ammonium acetate (8.0 mmol) and acetic acid (1.0 mL) were
added at reflux for 8 h. b Isolated yield. c None of the base was used.
d 4.0 equiv. of NH4OAc was used. e 12.0 equiv. of NH4OAc was used.
f None of AcOH was used.
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Scheme 3 Scope of 2-hydroxychalcones (3) and α-bromo ketones (4). Reaction conditions: the mixture of 3 (1.0 mmol), 4 (1.0 mmol) and K2CO3
(1.5 mmol) in EtOH (15 mL) was stirred at room temperature for 8–16 h; then NH4OAc (8.0 mmol) and AcOH (1.0 mL) were added at reflux for
another 6–12 h. Isolated yield.
6aa–6af in 73–78% yields. The substrates for R2 were naphthal- 5-bromo- and 4-methoxy-substituted 3-(2-hydroxyphenyl)-
ene ring and heterocycles (furan and thiophene) gave 6ag–6ai 1-phenylprop-2-en-1-ones (R1) also furnished 6al–6an in
in 68–74% yields. Moreover, an alkenyl [–CHvC(CH3)2] and 75–79% yields.
alkyl group (–CH3) substrate were also suitable for this trans-
Next, we further extended the substrates to other α-bromo
formation with isolation of the products 6aj and 6ak in ketones for the synthesis of the structurally diverse and func-
64% and 60% yields respectively. To our delight, 5-chloro-, tionalized benzofuro[2,3-c]pyridine derivatives. It was found
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effective for α-iodonation of aromatic ketones in domino syn-
thesis.18 We also found that 6aa was obtained in 60% overall
yield directly from 3a and acetophenone in the presence of
copper(II) oxide and iodine (Scheme 6). Nevertheless, column
chromatography was required for separating the target
product.
Conclusions
In summary, we have developed a clean and efficient method
for the domino synthesis of new functionalized benzofuro-
[2,3-c]pyridine derivatives, which were characterized by means
of 1H NMR, 13C NMR, HRMS and IR spectra. It should be
noted that furan and pyridine ring moieties were ingeniously
formed in a one-pot operation in this tricyclic system. Easily
available starting materials (2-hydroxychalcones, α-bromo
ketones and ammonium acetate), a wide range of substrates,
metal catalyst-free conditions, ease of purification (no column
chromatography) and good yields are the main advantages of
this method.
Scheme 4 The possible reaction mechanism.
that several representative α-bromo ketone substrates (4) in
which R3 is a phenyl ring bearing 4-methoxy (4b), 4-chloro (4c)
and 4-fluoro (4d) substituents or R3 is a furan ring (4e) could
react with various 2-hydroxychalcones smoothly to give the
corresponding products 6ba–6bd, 6ca–6cd, 6da–6dd and 6ea–
6ec in satisfied yields.
Subsequently, a possible reaction mechanism was pro-
posed, as shown in Scheme 4. First, intermediate I was formed
through the O-alkylation reaction between (E)-3-(2-hydroxy-
phenyl)-1-phenylprop-2-en-1-one (3a) and 2-bromo-1-phenyl-
ethanone (4a) in the presence of potassium carbonate. Then
an intramolecular Michael addition reaction of I furnished
1,5-diketone 5aa, which was successfully isolated from the
Experimental
General information
All the chemicals were commercially available and used
without further purification. All the organic solvents were
dried and freshly distilled before use. 1H and 13C NMR spectra
were recorded using Bruker AV 300 MHz spectrometers with
CDCl3 as the solvent. Chemical shifts are reported relative to
TMS (internal standard). High resolution mass spectra (ESI)
were recorded using a Waters GCT Premier. IR spectra were
obtained as KBr pellet samples using a Nicolet 5700 FTIR
spectrometer. Melting points were determined using an X-4
apparatus and are uncorrected. The X-ray crystal structure
determination was performed using a Bruker SMART APEX
CCD system.
1
first-step reaction mixture in 87% yield. H NMR showed that
the thermodynamically favorable trans-isomer was the major
product with the coupling constant of approximately 5.5 Hz
between H2 and H3 in the 2,3-dihydrobenzofuran moiety.16
A
condensation reaction of 5aa with NH3, generated from
ammonium acetate, gave intermediate II. Cyclization of II deli-
vered intermediate III, which could be easily oxidized to stable
π-conjugated structure 1,3-diphenylbenzofuro[2,3-c]pyridine
(6aa) by air. In order to confirm this reaction process, heating
the mixture of 5aa and ammonium acetate in refluxing
ethanol provided 6aa in 94% yield (Scheme 5).
Next, we expected to synthesize product 6aa from a more
easily available starting material acetophenone instead of
2-bromo-1-phenylethanone17 by a one-pot operation. The com-
bination of copper(II) oxide and iodine was proved to be
General one-pot procedure for the synthesis of 6
A mixture of 2-hydroxychalcones 3 (1.0 mmol), α-bromo
ketones 4 (1.0 mmol) and potassium carbonate (207 mg,
1.5 mmol) in anhydrous ethanol (15 mL) in a sealed-tube
vessel was stirred at room temperature. After the reaction was
completed (8–16 h, monitored by thin layer chromatography),
NH4OAc (615 mg, 8.0 mmol) and AcOH (1.0 mL) were added
under reflux temperature; then the reaction was continued for
another 6–12 h. The mixture was slowly cooled to room temp-
erature overnight; then yellow crystals of 6 precipitated, which
were filtrated and washed with a small amount of anhydrous
ethanol to give the pure product.
Scheme 5
Synthesis of 1,3-diphenylbenzofuro[2,3-c]pyridine (6aa) from
1,5-diketone (5aa)
A
mixture of 2-(2-benzoyl-2,3-dihydrobenzofuran-3-yl)-1-
Scheme 6
phenylethanone (5aa, 342 mg, 1.0 mmol), NH4OAc (615 mg,
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8.0 mmol) and AcOH (1.0 mL) in anhydrous ethanol (15 mL)
was heated at reflux for 8 h. After the reaction was completed,
the mixture was slowly cooled to room temperature overnight;
then yellow crystals of 6aa precipitated, which were filtrated
and washed with a small amount of anhydrous ethanol to give
the pure product 302 mg (94% yield).
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Synthesis of 6aa from acetophenone and 3a
Acetophenone (120 mg, 1.0 mmol), copper(II) oxide (80 mg,
1.0 mmol) and iodine (254 mg, 1.0 mmol) were added into
anhydrous ethanol (15 mL) in a sealed-tube vessel to stir at
reflux for 2 h. Compound 3a (224 mg, 1.0 mmol) and potass-
ium carbonate (207 mg, 1.5 mmol) were added to the mixture.
After 6 h, NH4OAc (615 mg, 8.0 mmol) and AcOH (1.0 mL)
were added and the reaction was continued for another 8 h.
Then the mixture was cooled to room temperature, and the
desired product 6aa was isolated as a white solid (192 mg,
60%) by column chromatography eluted with petroleum ether–
ethyl acetate.
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Acknowledgements
We gratefully acknowledge support from the National Natural
Science Foundation of China (21102042) and Training Pro-
grams of Innovation and Entrepreneurship for Undergraduates
of Hubei Province (201310513028).
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