Efficient synthesis of 3-acyl-5-hydroxybenzofurans via copper(II) triflate-catalyzed cycloaddition of unactivated 1,4-benzoquinones with 1,3-dicarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2010.02.066

A method to prepare a variety of substituted 3-acyl-5-hydroxybenzofurans efficiently that relies on copper(II) triflate-catalyzed cycloaddition of unactivated 1,4-benzoquinones with 1,3-dicarbonyl compounds is reported. The reaction was shown to be operat

Full text of DOI:10.1016/j.tetlet.2010.02.066

Tetrahedron Letters 51 (2010) 2136–2140
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Tetrahedron Letters
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Efficient synthesis of 3-acyl-5-hydroxybenzofurans via copper(II)
triflate-catalyzed cycloaddition of unactivated 1,4-benzoquinones with
1,3-dicarbonyl compounds
*
Srinivasa Reddy Mothe, Dewi Susanti, Philip Wai Hong Chan
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A method to prepare a variety of substituted 3-acyl-5-hydroxybenzofurans efficiently that relies on cop-
per(II) triflate-catalyzed cycloaddition of unactivated 1,4-benzoquinones with 1,3-dicarbonyl compounds
is reported. The reaction was shown to be operationally straightforward and proceeds expediently under
mild conditions to give the corresponding products in good to excellent yields (up to 95%) and with com-
plete regioselectivity.
Received 9 December 2009
Revised 2 February 2010
Accepted 12 February 2010
Available online 16 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Benzofurans are found in a wide variety of bioactive natural
products and compounds of current therapeutic interest.1,2 How-
ever, while this has led to a myriad of methods for benzofuran
synthesis under strongly acidic and basic conditions, examples
of the analogous reactions catalyzed by a Lewis acid have re-
ceived less attention.1,3 To our knowledge, approaches to benzo-
furans that explore the use of ecologically benign Lewis acid
catalysts in combination with low cost and readily available sub-
strates under mild conditions are limited to only three reported
methods.4,5 The first two reported the 1,4-conjugate addition/
cyclization of 1,4-benzoquinones with 1,3-dicarbonyl compounds
in the presence of a stoichiometric amount of ZnCl2 as a catalyst
that was achieved in low to moderate product yields.4 More re-
cently, De Kimpe and co-workers showed that Yb(OTf)3 mediated
the cycloaddition of activated 1,4-naphthoquinones with 1,3-
dicarbonyl compounds and provided the corresponding 3-acyl-
5-hydroxynaphtho[1,2-b]furans in good to excellent yields and
regioselectivity.5 As part of an ongoing programme on develop-
ing new Lewis acid-catalyzed reactions,6 we report herein the
use of Cu(OTf)2 as a catalyst for the cycloaddition of unactivated
1,4-benzoquinones with 1,3-dicarbonyl compounds (Scheme 1).
The 3-acyl-5-hydroxybenzofuran products were obtained in
yields and regioselectivities comparable to those reported for
the closely related Yb(III)-mediated approach to this syntheti-
cally useful O-heterocyclic building block.
OH
O
O
R1
R3
R2
R4
R1
R3
R2
Cu(OTf)2 (5 mol%)
O
O
O
+
R4
R5
PhMe, Δ, 10 h
R5
O
1
2
3
R1-R3 = H, Me, OMe
R4-R5 = alkyl, aryl
Scheme 1. Cu(OTf)2-catalyzed formation of 3-acyl-5-hydroxybenzofurans from
unactivated 1,4-benzoquinones and 1,3-dicarbonyl compounds
was furnished in 95% yield, and was comparable to the analo-
gous Yb(OTf)3-catalyzed cycloaddition of 1,4-naphthoquinones
with 1,3-dicarbonyl compounds.5 The structure of the benzofu-
ran product was confirmed by 1H NMR analysis and X-ray crys-
tal structure determination of two closely related products (see
below). A slightly lower product yield was observed when the
reaction was carried out in 1,2-dichloroethane as a solvent (en-
try 2). In contrast, changing the solvent from toluene to THF,
CH3CN or DMF was found to give no reaction and both starting
materials were recovered in near quantitative yields (entries
3–5). Similarly, analogous reactions conducted with Yb(OTf)3,
In(OTf)3 or TfOH in the place of Cu(OTf)2 as the catalyst gave
the product in lower yields of 45–79% (entries 6, 7 and 10).
On the other hand, switching the catalyst to FeCl3, ZnCl2, p-
TsOHÁH2O or TFA was found to result in either a trace amount
of product or no reaction based on TLC and 1H NMR analysis
of the crude mixtures (entries 8, 9, 11 and 12).
Initially, we found that treating 2,5-dimethylcyclohexa-2,5-
diene-1,4-dione 1a (1 equiv) with dibenzoylmethane 2a (2 equiv)
and 5 mol % of Cu(OTf)2 in toluene at reflux for 10 h gave the
best result (Table 1, entry 1).7 Under these conditions, (5-hydro-
xy-4,7-dimethyl-2-phenylbenzofuran-3-yl)(phenyl)methanone 3a
To define the scope of the present procedure, we next exam-
ined the reactions of a variety of unactivated 1,4-benzoquinones
and 1,3-dicarbonyl compounds (Table 2). Experiments revealed
that with Cu(OTf)2 as the catalyst, 1,4-benzoquinones 1a–c
* Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961.
E-mail address: waihong@ntu.edu.sg (P.W.H. Chan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.066

S. R. Mothe et al. / Tetrahedron Letters 51 (2010) 2136–2140
2137
Table 1
and 1,3-dicarbonyl compounds 2a–h underwent the cycloaddi-
tion process and gave the corresponding benzofuran products
in good to excellent yields (entries 1–17). Notably, this included
the cycloaddition of 1a–c with the less acidic b-ketoester 2d
which gave the corresponding adducts 3d, 3i and 3o in good
to excellent yields (entries 3, 8 and 14). Moreover, in instances
where it was envisaged that reactions with 1,3-dicarbonyl com-
pounds containing two different aryl substituents as in 2g–h
would lead to a mixture of isomers, only one regioisomer was
obtained (entries 10, 11 and 17). Similarly, the analogous cyc-
loadditions of unactivated 1,4-benzoquinones with 1,3-dicar-
bonyl compounds bearing both an aryl and alkyl group as in
2c and 2e were found to provide the corresponding 3-acyl-5-
hydroxybenzofurans as the sole product (entries 2, 7, 13 and
15). This was further confirmed by X-ray structure analysis of
3k and 3o as shown in Figure 1.8 With the cycloaddition pro-
cess proceeding at either the more electropositive or less steri-
cally hindered carbonyl carbon centre of the 1,3-dicarbonyl
compound under our conditions, this suggested that the present
procedure was regioselective. Under the standard conditions,
reaction of 1d with 2a was the only example where no reaction
could be detected on the basis of 1H NMR and TLC analysis of
the crude reaction mixture (entry 18).
Optimization of the reaction conditionsa
OH
O
O
Me
Ph
Me
catalyst (5 mol%)
O
O
O
+
Me
Ph
Ph
solvent, Δ, 10-24 h
Me
Ph
O
1a
2a
3a
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Yb(OTf)3
In(OTf)3
FeCl3
PhMe
(CH2Cl)2
THF
CH3CN
DMF
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
10
12
12
12
12
10
24
24
24
24
24
24
95
85
c
—
—
—
c
c
79
76
c
—
—
d
ZnCl2
TfOH
10
11
12
45
c
p-TsOHÁH2O
—
—
d
TFA
a
All reactions were performed at reflux temperature with a ratio of catalyst/1a/
2a = 1:20:40.
b
Isolated yield.
c
No reaction based on TLC and 1H NMR analysis.
Trace amount (<1%) of product was obtained.
A tentative mechanism for the present reaction is shown in
Scheme 2. This could involve initial activation of both 1 and 2
d
Table 2
Copper(II) triflate-catalyzed cycloaddition of unactivated 1,4-benzoquinones 1a–d with 1,3-dicarbonyl compounds 2a–ha
O
O
O
O
O
O
R3
R2
Me
Me
O
O
R4
R5
R1
R6
Br
MeO
OMe
O
O
1d
1b, R1 = R2 = R3 = H
2b, R4 = R5 = Me
2f
2g, R6 = OMe
2h, R6 = Cl
1c, R1 = Me, R2 = R3 = OMe
2c, R4 = Ph, R5 = Me
2d, R4 = Ph, R5 = OEt
2e, R4 = Ph, R5 = (CH2)10Me
Entry
Substrates
Product
Yieldb (%)
O
1
2
3
1a + 2b
1a + 2c
1a + 2d
3b, R4 = R5 = Me
40
81
88
R5
R4
Me
Me
Me
Me
3c, R4 = Ph, R5 = Me
HO
3d, R4 = Ph, R5 = OEt
O
O
Br
O
HO
HO
4
1a + 2g
3e
78
OMe
5
6
7
8
1b + 2a
1b + 2b
1b + 2c
1b + 2d
3f, R4 = R5 = Ph
3g, R4 = R5 = Me
91
45
83
87
O
R5
3h, R4 = Ph, R5 = Me
3i, R4 = Ph, R5 = OEt
R4
O
MeO
O
9
1b + 2f
3j
68
HO
OMe
O
(continued on next page)

2138
S. R. Mothe et al. / Tetrahedron Letters 51 (2010) 2136–2140
Table 2 (continued)
Entry
Substrates
Product
Yieldb (%)
Br
O
10
11
1b + 2g
3k
79
HO
OMe
O
Br
O
1b + 2h
3l
64
HO
Cl
O
O
R5
R4
Me
12
13
14
1c + 2a
1c + 2c
1c + 2d
3m, R4 = R5 = Ph
71
67
69
3n, R4 = Ph, R5 = Me
HO
3o, R4 = Ph, R5 = OEt
O
O
MeO
OMe
Me
O
Me
( )10
HO
15
1c + 2e
3p
62
Ph
MeO
OMe
Me
OMe
OMe
O
HO
16
17
1c + 2f
3q
62
65
O
MeO
OMe
Me
Br
O
HO
1c + 2g
3r
3s
OMe
O
MeO
OMe
O
Me
Ph
Ph
HO
Me
c
18
1d + 2a
—
O
a
All reactions were performed at reflux temperature for 10 h in PhMe with a ratio of catalyst/1/2 = 1:20:40.
Isolated yield.
b
c
No reaction detected based on TLC and 1H NMR analysis of the crude reaction mixture.
through coordination with the metal catalyst in a manner similar
with activated 1,4-naphthoquinones and 1,3-dicarbonyl compounds
mediated by Yb(OTf)3.5 In addition, the present method was shown
tobepracticalandoperationallystraightforwardandgivesgoodprod-
uct yields. Efforts to apply this method to natural product synthesis
are currently underway and will be reported in due course.
to that proposed by De Kimpe and co-workers for the Yb(OTf)3-cat-
alyzed cycloaddition of activated 1,4-naphthoquinones with 1,3-
dicarbonyl compounds. Subsequent 1,4-conjugate addition of the
resulting enolate A to the copper-activated 1,4-benzoquinone 1 af-
fords the cyclic enolate B. Aromatization of this newly formed
intermediate gives the hydroquinone C which can undergo intra-
molecular 5-exo-trig cyclization. Elimination of H2O from 2,3-dihy-
drobenzofuran-2-ol adduct D then delivers the product 3.9
In summary, an efficient and regioselective copper-catalyzed syn-
thetic route to 3-acyl-5-hydroxybenzofurans based on cycloaddition
of unactivated 1,4-benzoquinones with 1,3-dicarbonyl compounds
has been reported. These results show that the reaction tolerates a
structurally diverse set of substrates and complements earlier work
Acknowledgements
This work is supported by a College of Science Start-Up Grant
from Nanyang Technological University (NTU) and Science & Engi-
*
neering Research Council Grant (092 101 0053) from A STAR, Sin-
gapore. A stipend to D. S. from NTU under the Undergraduate
Research Experience on CAmpus (URECA) programme is also
acknowledged.

S. R. Mothe et al. / Tetrahedron Letters 51 (2010) 2136–2140
2139
[Cu]
OH
O
[Cu]
[Cu]
O
R1
H
R2
R3
−H+
H+
R1
R2
R3
O
O
O
O
O
R5
R5
R4
R5
R4
−[Cu]
H
R4
O
O
2
1
A
B
OH
OH
OH
R1
R1
R2
R3
O
R1
H
R2
R3
OH
R2
H+
−H2O
R5
O
O
H
R5
R5
R4
O
R4
HO
O
R3
R4
O
3
D
C
Scheme 2. Tentative mechanism for Cu(OTf)2-catalyzed cycloaddition of 1 with 2.
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2005, 46, 2185; (b) Tseng, C.-M.; Wu, Y.-L.; Chuang, C.-P. Tetrahedron 2004, 60,
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7. Typical experimental procedure: To a suspension of 2 (0.72 mmol) and Cu(OTf)2
(5 mol %) in toluene (2 mL) under a nitrogen atmosphere was added drop wise a
solution of 1 (0.36 mmol) dissolved in toluene (1 mL). The reaction mixture was
stirred at reflux for 10 h and monitored by TLC analysis using a 4:1 n-hexane/
EtOAc solvent system. Upon completion, the reaction mixture was quenched
with 10 mL of saturated NH4Cl solution and extracted with EtOAc (3 Â 10 mL).
The combined organic layers were washed with brine (10 mL), dried over
anhydrous MgSO4, concentrated under reduced pressure and purified by flash
silica gel column chromatography (n-hexane/EtOAc as eluent) to give the title
compound 3. Compound 3a: Pale yellow solid; mp 114–116 °C; 1H NMR (CDCl3,
400 MHz): d 7.95 (d, 2H, J = 7.5 Hz), 7.67 (d, 2H, J = 6.7), 7.54 (t, 1H, J = 7.2 Hz),
7.41–7.25 (m, 5H), 6.68 (s, 1H), 4.55 (s, 1H), 2.53 (s, 3H), 1.98 (s, 3H); 13C NMR
(CDCl3, 125 MHz): d 195.3, 153.4, 149.5, 147.8, 137.8, 133.9, 129.9, 129.8, 129.0,
128.8, 128.6, 128.0, 126.9, 119.3, 116.9, 115.2, 112.7, 14.8, 12.0; IR (neat, cmÀ1):
3018, 1215, 767; HRMS (ESI): calcd for C23H19O3 [M+H]+ 343.1334, found
343.1328. Compound 3d: Pale yellow solid; mp 133–135 °C; 1H NMR (CDCl3,
400 MHz): d 7.81 (d, 2H, J = 7.5 Hz), 7.47–7.40 (m, 3H), 6.65 (s, 1H), 4.76 (s, 1H),
4.40 (q, 2H, J = 7.1 Hz), 2.45 (s, 3H), 2.37 (s, 3H), 1.32 (t, 3H, J = 7.1 Hz); 13C NMR
(CDCl3, 125 MHz): d 166.4, 155.8, 149.6, 147.9, 130.0, 129.4, 128.4, 127.6,
Figure 1. ORTEP drawings of (a) 3k and (b) 3o with thermal ellipsoids at 50%
probability levels.8
References and notes
1. (a) Donnelly, D. M. X.; Meegnan, M. J.. In Furans and Their Benzo Derivatives: (iii)
Synthesis and Application In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: New York, 1984; Vol. 4, p 657; (b) Bird, C.
W.; Cheeseman, G. W. H.. In Synthesis of Five-Membered Rings with One
Heteroatom In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.

2140
S. R. Mothe et al. / Tetrahedron Letters 51 (2010) 2136–2140
126.2, 119.3, 114.9, 112.6, 111.1, 61.5, 14.7, 13.9, 11.6; IR (neat, cmÀ1):
3018, 1215, 756; HRMS (ESI): calcd for C19H19O4 [M+H]+ 311.1283, found
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
311.1286.
9. It is possible that the copper(II) catalyst could also act as a simple electron-
oxidizing agent and that more complex radical processes are involved, this
cannot be ruled out at this time.
8. CCDC 754898 (3o) and 754899 (3k) contains the supplementary
crystallographic data for this Letter. These data can be obtained free of charge