Facile and efficient synthesis of polyfunctionalized benzofurans: three-component coupling reactions from an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine by a Cu(I)-Cu(II) cooperative catalytic system

Article abstract of DOI:10.1016/j.tetlet.2008.03.111

The combination of 5 mol % Cu(OTf)₂ and CuCl in the presence of DMAP effectively catalyzed a three-component coupling reaction involving an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine. The reaction proceeded via intramolecular 5-exo-dig cyclization, resulting in direct synthesis of the corresponding benzofuran derivatives in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.03.111

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3437–3440
Facile and efficient synthesis of polyfunctionalized benzofurans:
three-component coupling reactions from an alkynylsilane, an
o-hydroxybenzaldehyde derivative, and a secondary amine by
a Cu(I)–Cu(II) cooperative catalytic system
Norio Sakai *, Naoki Uchida, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
Received 18 February 2008; revised 15 March 2008; accepted 21 March 2008
Available online 28 March 2008
Abstract
The combination of 5 mol % Cu(OTf)2 and CuCl in the presence of DMAP effectively catalyzed a three-component coupling reaction
involving an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine. The reaction proceeded via intramolecular
5-exo-dig cyclization, resulting in direct synthesis of the corresponding benzofuran derivatives in moderate to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Copper catalyst; Multi-component reaction; Benzofuran; Alkynylsilane
Multi-component reactions (MCR) are attractive to
many organic and pharmaceutical chemists, as these reac-
tions allow construction of basic and important com-
pounds, that serve as molecular skeletons for many
naturally occurring products and biologically active sub-
stances in a single step.1 Among the MCR, Mannich or
Mannich-type reactions have been widely used as central
and practical reactions.2–4 Petasis and co-workers recently
developed an improved Mannich-type reaction, in which
a boronic acid, such as aryl/vinyl boronic acid, is used as
an effective and easy-to-handle nucleophile.5 Development
of this synthetic protocol permits facile production of a
variety of amine derivatives. Alternatively, organosilicon
compounds have been employed as convenient partners
in Hiyama coupling reactions, due to their availability,
relatively low toxicity and high tolerance of functional
groups.6,7 However, use of common organosilicon
compounds, such as alkynylsilanes, as the substrate in
multi-component coupling reactions, such as the Petasis
reaction, has not been extensively examined.8,9 Thus, based
on our previous studies,10 the focus of our research shifted
to the development of a novel three-component coupling
reaction using an aldehyde, an amine, and an organosilicon
compound, such as an alkynylsilane, to produce a propar-
gylic amine. During ongoing research toward this goal, we
found that use of o-hydroxybenzaldehyde as the aldehyde
leads to the production of a benzofuran derivative via
intramolecular 5-exo-dig cyclization through a propargyl-
amine derivative. The synthesis of polysubstituted benzo-
furans is of considerable interest to organic and
pharmaceutical chemists.11 In this letter, we report a facile
and practical preparation of polyfunctionalized benzofuran
derivatives via both a Cu-cocatalyzed three-component
coupling reaction from an o-hydroxybenzaldehyde
derivative, a secondary amine, and an alkynylsilane, and
the subsequent intramolecular cyclization.
Initially, we examined the three-component coupling
reaction of 1-phenyl-2-(trimethylsilyl)acetylene (1a),
o-hydroxybenzaldehyde (2a), and piperidine (3a) using a
typical copper catalyst. When the reaction mixture
*
Corresponding author.
E-mail address: sakachem@rs.noda.tus.ac.jp (N. Sakai).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.111

3438
N. Sakai et al. / Tetrahedron Letters 49 (2008) 3437–3440
Table 2
Effect of a base
comprising the alkynylsilane (1.5 equiv), the aldehyde
(1 equiv), and the secondary amine (1.2 equiv) was treated
with 5 mol % Cu(OTf)2 under CH3CN reflux conditions,
the expected cascade reaction, involving both alkynylation
and subsequent intramolecular 5-endo cyclization, pro-
ceeded, producing the desired benzofuran derivative 4 in
35% yield.12 The structure of benzofuran 4 was determined
from spectral data. Thus, to improve the chemical yield, we
ran the reaction using both different molar ratios of the
substrate and other copper catalysts. The results are sum-
marized in Table 1. When CuCl was used, the chemical
yield decreased slightly (run 2). Additionally, a copper
catalyst, such as CuOTf and Cu2O, was ineffective for the
reaction (runs 3 and 4). Interestingly, when the reaction
was performed using a catalytic system consisting of both
Cu(OTf)2 and CuCl, the yield improved to 60% (run 5).
Additionally, this result implies that the excess base pro-
motes intramolecular cyclization, enhancing the chemical
yield. Thus, we changed the molar ratio of piperidine to
other substrates. For example, when the reaction was car-
ried out with 2 equiv of amine to 1 equiv of aldehyde, the
yield decreased to 49% (run 6). In contrast, reducing the
molar ratio of the base to aldehyde to 0.66 caused the yield
to decline dramatically to only 8% (run 7). We found that
the product yield was extremely dependent on the molar
ratios of the amine. Moreover, increasing the amount of
catalyst to 10 mol % did not improve reaction yield, prob-
ably due to deactivation of the amine nucleophile by the
coordination of the copper catalyst (runs 8 and 9).
CHO
Cu cat.
base
N
OH
+
Ph
SiMe3
+
N
H
CH3CN
reflux
18 h
1a (1.5 equiv)
O
Ph
2a (1 equiv)
Cu : 5% Cu(OTf)2 + 5% CuCl
Run Base (1 equiv)
3a
4
(1.2 equiv)
Yielda,b (%)
1
2
3
4
5
6
7c
Et3N
i-Pr2NEt
DBU
Pyridine
2,6-Lutidine
DMAP
41 (11)
44 (7)
3 (ND)
62 (3)
48 (3)
71 (ND)
91d (ND)
DMAP
a
NMR yield.
b
c
Yield of the corresponding propargylamine is shown in parentheses.
Alkynylsilane 1a (1.5 equiv), aldehyde 2a (1.5 equiv), and amine 3a
(1 equiv).
d
Isolated yield.
improved heterocycle yield (runs 4–6). Among the pyridine
bases, addition of DMAP resulted in the highest cascade-
reaction yield. Moreover, when the reaction was run using
1.5 equiv of alkynylsilane 1a, 1.5 equiv of aldehyde 2a, and
1 equiv of amine 3a, in the presence of both these copper
catalysts and 1 equiv of DMAP under CH3CN reflux
conditions, the yield of the corresponding benzofuran 4
dramatically improved to nearly quantitative yield (run
7). Thus, the combination of 5 mol % of both Cu(OTf)2
and CuCl in the presence of DMAP gave the best
coupling-reaction yield.13,14
To extend the generality of the reaction, the coupling
reaction was carried out under optimized conditions using
various alkynylsilanes, o-hydroxybenzaldehydes, and sec-
ondary amines. The results are displayed in Table 3. The
reaction accommodated not only electron-withdrawing
groups, such as a nitro group and a halogen, but also elec-
tron-donating substituents for the o-hydroxyaldehyde
derivative. When the reaction was run using a secondary
amine, such as morpholine (3b), diallylamine (3c), or diben-
zylamine (3d), the corresponding benzofuran derivatives
were produced in moderate to excellent yields. When dial-
lylamine was used, the yield decreased drastically to less
than 30%. There is no clear explanation for the lower reac-
tivity using this amine. Use of an alkynylsilane was general-
ized to versatile alkynes with an aliphatic group and a
hydrogen atom, such as 1-hexyl-2-(trimethylsilyl)acetylene
(1b) and trimethylsilylacetylene (1c), besides alkyne 1a hav-
ing an aromatic group. The alkynylsilane, which is derived
from methyl propiolate, did not form the desired benzo-
furan derivative, but gave the corresponding propargylic
amine derivative.
Based on the result shown in Table 1, we then investi-
gated several bases as an additive to enhance the cascade
reaction. The results are summarized in Table 2. When
the reaction was run under standard conditions using a
typical tertiary amine, such as Et3N or i-Pr2NEt, the
product was obtained in 41% and 44% yield, respectively.
Propargylic amine, which is the reaction precursor of
benzofuran 4 (runs 1 and 2), was also produced. DBU
was ineffective. However, bases with pyridine skeletons
Table 1
Examination of reaction conditions using copper catalysts
CHO
cat.
N
OH
Ph
SiMe3
+
+
CH3CN
reflux
18 h
N
H
1a
O
Ph
2a
3a
4
Run
Cat. (mol %)
Ratio 1a:2a:3a
Yield of 4a (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2 (5)
CuCl (5)
CuOTf (5)
Cu2O (5)
Cu(OTf)2 (5) + CuCl (5)
Cu(OTf)2 (5) + CuCl (5)
Cu(OTf)2 (5) + CuCl (5)
Cu(OTf)2 (10) + CuCl (10)
Cu(OTf)2 (10)
1.5:1.0:1.2
1.5:1.0:1.2
1.5:1.0:1.2
1.5:1.0:1.2
1.5:1.0:1.2
1.5:1.0:2.0
1.5:1.5:1.0
1.5:1.0:1.2
1.5:1.0:1.2
35
27
21
7
60
49
8
49
31
A plausible mechanism for the copper-cocatalyzed cou-
pling reaction that yields the benzofuran derivative is
shown in Scheme 1. We assumed that CuCl generates a
a
NMR yield.

N. Sakai et al. / Tetrahedron Letters 49 (2008) 3437–3440
3439
Table 3
Synthesis of various benzofuran derivativesa
5% Cu(OTf)2
5% CuCl
DMAP (1 equiv)
R
R2
R
N
CHO
OH
R2
R
R
R1
SiMe3
+
+
N
H
CH3CN, reflux, 6 h
R1
1 (1.5 eqiuv)
O
4-15
2 (1.5 equiv)
3 (1 equiv)
N
N
N
N
Me
O2N
Br
O
O
O
O
Ph
Ph
Ph
Ph
4: 91%
5: 90%
6: 50%
7: 65%
O
O
N
N
N
N
Me
Me
O
Ph
O
Ph
O
O
Ph
Ph
Ph
11: 30%
10: 27%
9: 97%
8: 99%
Bn
Bn
Bn
N
Bn
N
N
N
O
Me
15: 28%
C7H15
Me
O
O
O
14: 10% (22%)b
12: 78%
13: 65%
a
Isolated yield.
Molar ratio of 1:2:3 = 1.5:1.0:1.2.
b
R
R
N
R2
R
R
Cu(OTf)2
R1
R
R
N
R2
N
Cu(OTf)2
R1
R2
O
H
R1
O
O
H
Cu(OTf)2
X
R1
2 + 3
X = DMAP or OH
Cu Cl
Me3Si
1
R2
Ar =
R
R
R
R
OH
N
N
Cu(OTf)2
Me3Si Cl
Cu
R1
OH
Ar
OH
Ar
Scheme 1.
copper acetylide intermediate from alkynylsilane 1,9e,15 and
that Cu(OTf)2 has a dual role: (i) it behaves as a Lewis acid
for in situ generation of the iminium intermediate, which
forms from the starting materials, aldehyde 2 and amine
3; and (ii) it activates the alkyne moiety to facilitate
intramolecular nucleophilic attack by a hydroxy group
via 5-exo-dig cyclization.
produce multi-functionalized benzofuran derivatives in
moderate to excellent yields. Moreover, we found that
addition of a base, such as DMAP, to the reaction system
enhances intramolecular 5-exo-dig cyclization of the in situ
generated propargylic amine, thereby improving both the
chemical and the practical yields.
In summary, we have demonstrated that a Cu(I)–Cu(II)
cooperative catalytic system effectively catalyzes a three-
component coupling reaction of alkynylsilanes, o-hydroxy-
benzaldehyde derivatives, and secondary amines to
Acknowledgments
This work was partially supported by a grant for a
‘High-Tech Research Center’ Project awarded to Private

3440
N. Sakai et al. / Tetrahedron Letters 49 (2008) 3437–3440
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12. General procedure for the synthesis of 3-aminobenzofuran: To a
CH3CN solution (300 lL) in a screw-cap vial under N2 atmosphere,
alkynylsilane 1 (0.45 mmol), o-hydroxybenzaldehyde 2 (0.45 mmol),
secondary amine
3 (0.30 mmol), DMAP (0.3 mmol), Cu(OTf)2
(5.4 mg, 0.015 mmol), and CuCl (1.5 mg, 0.015 mmol) were succes-
sively added, and the vial was then sealed with a cap containing a
PTFE septum. The reaction mixture was heated at 100 °C for 6 h.
After completion of the reaction, the mixture was directly subjected to
silica gel without the usual extraction, and was purified by flash
column chromatography (hexane–AcOEt) to give the corresponding
3-aminobenzofuran in the yield shown in Table 3. Spectral data for
selected novel compounds. 1-(2-Benzyl-1-benzofuran-3-yl)piperidine
(4): A pale brown needle (CH2Cl2–hexane); mp 61–63 °C; 1H NMR
(500 MHz, CDCl3) d 1.58 (quint, 2H, J = 5.5 Hz), 1.71 (quint, 4H,
J = 5.5 Hz), 3.13 (t, 4H, J = 5.5 Hz), 4.15 (s, 2H), 7.15 (m, 2H), 7.19
(m, 1H), 7.27 (m, 4H), 7.33 (d, 1H, J = 7.5 Hz), 7.64 (d, 1H,
J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) d 24.3, 26.8, 32.5, 53.8,
111.5, 120.1, 121.7, 123.2, 126.3, 126.7, 128.4, 128.6, 130.2, 138.6,
148.9, 153.5. MS (EI): m/z 291 (M+, 100%); HRMS (FAB): calcd for
C20H22NO: 292.1701, found: 292.1685.
1-(2-Benzyl-5-methyl-1-benzofuran-3-yl)piperidine (5): A yellow nee-
dle (CH2Cl2–hexane); mp 80–81 °C; 1H NMR (500 MHz, CDCl3) d
1.58 (quint, 2H, J = 5.5 Hz), 1.70 (quint, 4H, J = 5.5 Hz), 2.41 (s,
3H), 3.11 (t, 4H, J = 5.5 Hz), 4.13 (s, 2H), 6.97 (d, 1H, J = 8.0 Hz),
7.18 (m, 1H), 7.21 (d, 1H, J = 8.0 Hz), 7.26 (m, 4H), 7.42 (s, 1H); 13C
NMR (125 MHz, CDCl3) d 21.4, 24.3, 26.8, 32.5, 53.7, 111.0, 120.0,
124.3, 126.2, 126.7, 128.4, 128.5, 130.0, 131.1, 138.6, 149.1, 151.9. MS
(EI): m/z 305 (M+, 100%); HRMS (EI): calcd for C21H23NO:
305.1780, found: 305.1779.
1-(2-Methyl-1-benzofuran-3-yl)piperidine (14): Pale yellow oil; 1H
NMR (500 MHz, CDCl3) d 1.58 (quint, 2H, J = 5.5 Hz), 1.71 (quint,
4H, J = 5.5 Hz), 2.43 (s, 3H), 3.11 (t, 4H, J = 5.5 Hz), 7.14 (m, 2H),
7.33 (d, 1H, J = 7.5 Hz), 7.59 (d, 1H, J = 7.5 Hz); 13C NMR
(125 MHz, CDCl3) d 12.3, 24.4, 26.9, 53.5, 111.0, 119.6,121.7, 122.8,
127.0, 129.5, 146.3, 153.0. MS (EI): m/z 215 (M+, 100%); HRMS
(FAB): calcd for C14H18NO: 216.1388, found: 216.1404.
13. When the reaction using phenylacetylene instead of silylacetylene 1a
was carried out under optimized conditions, the yield of 4 reduced to
75%.
14. When the reaction ran with other solvents under optimal conditions
shown in Table 2, the benzofuran 4 was produced in 44% (DMF) and
40% (DMI) yields.
9. For selected papers on reactions using alkynylsilanes, see: (a)
Kitazawa, T.; Minowa, T.; Mukaiyama, T. Chem. Lett. 2006, 35,
1002; (b) Lettan, R. B.; Scheidt, K. A. Org. Lett. 2005, 7, 3227; (c)
Dilman, A. D.; Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.;
15. Nishihara, Y.; Takemura, M.; Mori, A.; Osakada, K. J. Organomet.
Chem. 2001, 620, 282.