New domino approach for the synthesis of 2,3-disubstituted benzo[b]furans via copper-catalyzed multi-component coupling reactions followed by cyclization

Article abstract of DOI:10.1016/j.tetlet.2009.02.204

An efficient domino process for the construction of 2,3-disubstituted benzo[b]furans has been developed via copper-catalyzed three-component coupling reactions of salicylaldehydes, amines, and alkynes followed by base-assisted O-annulation reaction.

Full text of DOI:10.1016/j.tetlet.2009.02.204

Tetrahedron Letters 50 (2009) 2353–2357
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Tetrahedron Letters
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New domino approach for the synthesis of 2,3-disubstituted benzo[b]furans via
copper-catalyzed multi-component coupling reactions followed by cyclization
Hongfeng Li a, Jun Liu a, Bin Yan b, Yanzhong Li a,
*
a East China Normal University, Institute of Medicinal Chemistry, and Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry,
East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China
b Shanghai Institute of Organic Chemistry, State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient domino process for the construction of 2,3-disubstituted benzo[b]furans has been developed
via copper-catalyzed three-component coupling reactions of salicylaldehydes, amines, and alkynes fol-
lowed by base-assisted O-annulation reaction.
Received 20 November 2008
Revised 17 February 2009
Accepted 27 February 2009
Available online 4 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalysis
Three-component coupling
Domino reaction
Benzo[b]furan
1. Introduction
wave13 and ultrasound14 were also disclosed. It could be envi-
sioned that, if the o-hydroxy-benzaldehydes were employed in
The benzo[b]furans are important heterocyclic compounds,
which not only act as key structural subunits in naturally occurring
compounds that exhibit remarkable biological activities but also
represent useful building blocks in the synthesis of natural prod-
ucts.1 Consequently, much attention has been paid to the develop-
ment of new methodologies for their preparation. The synthetic
strategies for the construction of benzo[b]furans mainly are dehyd-
the A3 Coupling reaction, a sequential intramolecular nucleophilic
attack of the oxygen to the triple bond of the propargyl amine
intermediate might occur to furnish the benzo-fused heterocycles
in one pot. Herein, we wish to report an efficient domino process
leading to 2,3-disubstituted benzo[b]furans via copper-catalyzed
three-component coupling reactions of various salicylaldehydes,
amines, and alkynes, followed by base-assisted intramolecular C–
O bond formation.
rative cyclization of (a
-(phenoxy)-alkyl ketones,2 decarboxylation
of o-acylphenoxyacetic acids or esters,3 [3,3]-sigmatropic rear-
rangement of various arenes,4 palladium-catalyzed cyclization of
the corresponding 2-(1-alkynyl)phenols,5 etc.6 However, most of
the methods reported were multi-step operations and lacked gen-
erality. It is very attractive to develop an efficient protocol for the
synthesis of benzo[b]furan derivatives from readily accessible
starting materials and in a one-pot procedure. On the other hand,
multi-component coupling reactions have received much consider-
ation in synthetic organic chemistry recently.7 This strategy allows
the formation of several bonds including new C–C, C–O and C–N
bonds in the same vessel. Especially the three-component coupling
reactions of aldehydes, amines, and alkynes (A3 Coupling) to prop-
argyl amines mediated or catalyzed by Cu,8 Ag,9 Au,10 Ru/Cu,11 and
Ir12 were well documented. Other procedures promoted by micro-
To optimize the process, we first investigated the coupling reac-
tions of salicylaldehyde (1a), morpholine (2a), and phenylacety-
lene (3a) using 20 mol % CuI as catalyst. It was found that the
propargylic amine derivative 4a was produced in 84% yield by stir-
ring at 110 °C for 3 h in toluene (Table 1, entry 1). However, 4a did
not undergo cyclization under the Cu-catalyzed conditions. It
might due to the low nucleophilicity of the hydroxy group attached
to the benzene ring. We considered that generation of a phenoxide
ion may facilitate nucleophilic attack to the triple bond. Thus,
K2CO3 and Bu4NBr were added to the reaction mixture. To our de-
light, the intermediate of 4a could be smoothly cyclized to afford
4-(2-benzyl-benzofuran-3-yl)-morpholine 5a in 85% isolated yield
(Table 1, entry 2). It was confirmed that both K2CO3 and Bu4NBr are
essential for this one-pot cyclization (Table 1, entries 3, 4).
Decreasing the amount of CuI resulted in the yield decreasing con-
siderably (Table 1, entry 5). When K2CO3 was reduced to 1.0 equiv,
the yield of the desired product was similar to that of 3.0 equiv.
* Corresponding author.
E-mail address: yzli@chem.ecnu.edu.cn (Y. Li).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.204

2354
H. Li et al. / Tetrahedron Letters 50 (2009) 2353–2357
Table 1
Screening of the reaction conditions
O
O
N
N
CHO
O
Ph
catalyst
or
+
+
Ph
toluene, 110 ºC, 3 h
OH
O
OH
N
H
4a
5a
Entry
Catalyst
K2CO3 (equiv)
Bu4NBr (equiv)
Product
Yielda (%)
1
2
3
4
5
6
7
20 mol % CuI
20 mol % CuI
20 mol % CuI
20 mol % CuI
10 mol % CuI
20 mol % CuI
20 mol % CuI
None
3.0
1.0
None
1.0
1.0
None
1.0
None
1.0
1.0
1.0
4a
5a
4a
4a
5a
5a
5a
84
85
b
—
—
b
46
81
69c
1.0
1.0
a
Isolated yields, the ratio of aldehyde:morpholine:acetylene is 2.0:1.0:1.5.
Observed by TLC.
1.5 equiv of salicyaldehyde was used.
b
c
After a brief survey of the experimental conditions as shown in Ta-
ble 1, it was clear that the optimized reaction condition was to use
20 mol % CuI as the catalyst, 1.0 equiv K2CO3 as the base combined
with 1.0 equiv Bu4NBr in toluene at 110 °C.
Fortunately, when CuI was changed to CuCN under the similar
reaction conditions, it uneventfully gave rise to benzofuran 5m
in 33% yield, along with 30% dihydrobenzofuran 6 (Table 3, entry
1). It should be noted that also in this case, CuCN and K2CO3/
Bu4NBr were added stepwise. It is important to first achieve
CuCN-catalyzed A3 Coupling reactions before base-assisted cycliza-
tion. Other alkyl-substituted alkynes bearing a heteroatom such as
1-(prop-2-ynyl)-1H-indole (3f), N,N-diphenyl-prop-2-ynyl-amine
(3g), and N-methyl-N-phenyl-prop-2-ynyl-amine (3h) reacted
with 1a and 3a smoothly to furnish the desired benzofurans
5n–p in good yields (Table 3, entries 2–4).
In conclusion, we have successfully established a highly effi-
cient and general synthetic method for 2,3-disubstituted benzo[b]-
furans via a copper-catalyzed A3 Coupling/annulation sequence. A
number of functional groups such as chloro, bromo, nitro, amino,
and pyridyl groups are tolerated under the reaction conditions to
provide structurally interesting benzo[b]furans in moderate to
high yields. Further studies to extend the scope of synthetic utility
leading to diverse heterocyclic compounds are in progress in our
laboratory.
Having established an effective catalytic system for the one-pot
benzo[b]furan-forming reaction, we next utilized a variety of sali-
cylaldehydes, amines, and alkynes to explore the scope of this no-
vel cascade A3-coupling-annulation reaction under the optimal
conditions. The representative results are shown in Tables 2 and
3. Although similar reactions were reported,15,16 the alkynes em-
ployed were limited to those aliphatic alkynes bearing a hetero-
atom, such as propargyl alcohols or propargyl amines, and in
most cases, only dihydrobenzofurans were obtained. First, various
types of amine substrates were examined (Table 2, entries 1–4).
When piperidine (2b) was used, the corresponding benzofuran
5b was obtained in 79% yield (Table 2, entry 2). Dibenzylamine
(2c) and N-benzyl-butylamine (2d) were also compatible for this
reaction, generating the corresponding benzofurans 5c and 5d in
70% and 51% yields, respectively (Table 2, entries 3 and 4). It should
be noted that while the current system is quite effective for sec-
ondary amines, however, the substrates of primary amine such
as PhNH2 could not afford the desired benzofuran. Substituted sal-
icylaldehydes 1b–d cyclized smoothly to afford the corresponding
5e–g in 64–86% yields, and the functionalities of –Cl, –Br, and –NO2
were tolerated well during the reactions (Table 2, entries 5–7).
Likewise, when 2-hydroxy-1-naphthaldehyde (1e) was employed,
the desired product 5h was obtained in 61% yield (Table 2, entry
8). The scope of this reaction was further examined by applying
the optimized conditions to various alkynes. It was found that
the aryl alkynes bearing electron-withdrawing or electron-donat-
ing group were all effective for the cyclization, furnishing the de-
sired benzofurans 5i and 5j in 56% and 75% yields, respectively
(Table 2, entries 9 and 10). It is noted that in these cases, a stepwise
addition of copper catalyst and K2CO3/Bu4NBr was required to
achieve the better yields. Interestingly, when pyridylacetylene
was employed, the reaction proceeded smoothly with salicylalde-
hyde and piperidine or dibenzylamine to produce 5k and 5l in
46–69% yields (Table 2, entries 11 and 12). The structure of benzo-
furans was further confirmed by X-ray crystallographic analysis of
5b.
2. Experimental
2.1. General procedure for the preparation of benzo[b]furan
derivative 5a through CuI-catalyzed multi-component coupling
reactions
A mixture of CuI (0.038 g, 0.2 mmol), K2CO3 (0.138 g, 1.0 mmol),
Bu4NBr (0.32 g, 1.0 mmol), salicylaldehyde (0.20 mL, 2.0 mmol),
phenylacetylene (0.17 mL, 1.5 mmol), and morpholine (0.087 mL,
1.0 mmol) in toluene (5mL) was heated at 110 °C for 3 h. Then
the reaction mixture was filtered through Celite and washed with
ethyl acetate. After removal of the solvent, the residue was purified
by column chromatography on silica gel using petroleum ether/
ethyl acetate (10:1) as eluent, affording compound 5a as a light
yellow solid in 81% yield. Alternatively, after the reaction was com-
plete, the reaction mixture was poured into water, and extracted
with ethyl acetate. The organic layer was washed with water and
dried over anhydrous Na2SO4. After removal of the solvent, the res-
idue was purified by column chromatography on silica gel.
4-(2-benzyl-benzofuran-3-yl)-morpholine (5a), mp 105–
108 °C. 1H NMR (CDCl3, Me4Si) d 3.16 (dd, J = 4.5, 4.8 Hz, 4H),
3.83 (dd, J = 4.5, 4.8 Hz, 4H), 4.15 (s, 2H), 7.15–7.37 (m, 8H),
7.63–7.66 (m, 1H); 13C NMR (CDCl3, Me4Si) d 32.23, 52.54, 67.66,
In addition to aryl-substituted alkynes, alkyl-substituted al-
kynes were submitted to the optimized reaction conditions. How-
ever, the reaction of 1-octyne with salicylaldehyde and morpholine
resulted in no formation of the coupling product even after 6 h.

H. Li et al. / Tetrahedron Letters 50 (2009) 2353–2357
2355
Table 2
Preparation of benzofuran derivatives from salicylaldehydes, acetylenes, and amines
Entry
Aldehyde
Amine
Alkyne
Product
Yielda (%)
R1
R2
O
X
CHO
OH
N
X
Ph
N
H
O
1
2
X = H, 1a
2a
3a
3a
X = H, 5a
81
79
2b
1a
X = H, 5b
N
H
Bn
N
Bn
3
4
1a
1a
3a
3a
X = H, 5c
X = H, 5d
70
51
2c
H
Bn
N
C4H9
2d
H
5
6
7
X = Cl, 1b
X = Br, 1c
X = NO2, 1d
2a
2a
2a
3a
3a
3a
X = Cl, 5e
X = Br, 5f
X = NO2, 5g
64
86
86
CHO
OH
N
Ph
8
2b
2a
2a
3a
61
O
1e
5h
O
O
N
Cl
p-ClC6H4
9
1a
56b
3b
O
5i
N
MeO
p-MeOC6H4
10
1a
75b
3c
O
5j
N
N
N
11
1a
2b
69
N
3d
O
5k
Bn2N
12
1a
2c
3d
46
O
5l
a
Isolated yields. The ratio of aldehyde:amine:acetylene is 2.0:1.0:1.5. Unless noted, all the reactions were carried out using 20% CuI, 1.0 equiv K2CO3, and 1.0 equiv Bu4NBr
at 110 °C for 2–3 h.
b
Reaction conditions: 20% CuI, 110 °C, 3 h, then 1.0 equiv K2CO3 and 1.0 equiv Bu4NBr, 110 °C, 1 h.

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H. Li et al. / Tetrahedron Letters 50 (2009) 2353–2357
Table 3
Preparation of benzofuran derivatives from alkyl alkynes
Entry
Aldehyde
Amine
Alkyne
Product
Yielda (%)
O
O
Hex
N
N
1
1a
2a
33b
Hex
+
3e
Hex
O
O
5m
6
O
N
N
2
3
1a
1a
1a
2a
2a
2a
61
50
68
N
5n
2
3f
O
O
O
N
Ph
N
Ph
Ph
N
Ph
3g
5o
5p
2
O
Me
N
N
Ph
4
Me
N
Ph
3h
2
O
a
Isolated yields. The ratio of aldehyde:amine:acetylene is 1.0:1.2:1.5. Reaction conditions: (i) 20% CuCN, rt 1 h, 110 °C, 4–9 h, in toluene. (ii) 1 equiv K2CO3, 1 equiv Bu4NBr,
110 °C, 3 h.
b
A dihydrofuran of (Z)-4-(2-heptylidene-2,3-dihydro-benzofuran-3-yl)-morpholine 6 was also isolated in 30% yield.
Iwanami, H.; Tanaka, T.; Hasegawa, E.; Shimizu, T. J. Chem. Soc., Chem. Commun.
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138.13, 150.19, 153.43. HRMS (EI) for C19H19NO2: calcd 293.1416,
found 293.1428.
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We are grateful to the National Natural Science Foundation of
China (No. 20572025 and 20872037) for financial support. We also
thank Lab of Organic Functional Molecules, the Sino-French Institute
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Supplementary data
Experimental details and spectroscopic characterization of all
new compounds and X-ray crystal structure of compounds 5b
are available. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.02.204.
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2357
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