Copper-catalyzed decarboxylative intramolecular C-O coupling: Synthesis of 2-arylbenzofuran from 3-arylcoumarin

Article abstract of DOI:10.1039/c3ra46414h

A copper-catalyzed decarboxylative intramolecular C-O coupling reaction was established. Under aerobic conditions in the presence of cupric chloride/1,10-phenathroline, a variety of 2-arylbenzofurans were prepared from 3-arylcoumarins in one-pot with yields from 26% to 84%. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ra46414h

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Copper-catalyzed decarboxylative intramolecular
C–O coupling: synthesis of 2-arylbenzofuran from
3-arylcoumarin†
Cite this: RSC Adv., 2014, 4, 903
a
a
Wen-Chen Pu,ab Guan-Min Mu,ac Guo-Lin Zhang and Chun Wang
Received 5th November 2013
Accepted 14th November 2013
*
*
DOI: 10.1039/c3ra46414h
www.rsc.org/advances
A copper-catalyzed decarboxylative intramolecular C–O coupling
2-Arylbenzofurans and their analogues, involving both
reaction was established. Under aerobic conditions in the presence of natural and synthetic origins, are of particular interest
cupric chloride/1,10-phenathroline, a variety of 2-arylbenzofurans because of their broad range of biological activities and
were prepared from 3-arylcoumarins in one-pot with yields from 26% signicant pharmacological potentials.4 Several synthetic
to 84%.
approaches to 2-arylbenzofuran skeleton were reported.5
However, these approaches suffer from some fundamental
drawbacks. For instance, it is hard to purify cross-coupling
intermediate in o-hydroxylstilbene approach,5b and, in o-
hydroxylphenylacetylene approach,5a great difficulty existed in
phenylacetylene preparation. The conversion of 3-arylcou-
marin to 2-arylbenzofuran was previously reported by
Kinoshita,5d,e in which a reductive ring-opening and an
oxidative elimination of formaldehyde were involved. The use
of strong reducing reagent (AlH3) and oxidant (DDQ) limited
the substrate scope and yields. There is still a demand for new
synthetic methods to obtain versatile 2-arylbenzofurans.
Herein, we report a decarboxylative intramolecular C–O cross-
coupling in the presence of copper and base, and the appli-
cation of this coupling for the preparation of 2-arylbenzofuran
from 3-arylcoumarin in a one-pot manner. Coumarins are
abundant in nature and can be easily synthesized. Thus, this
method provides a novel and easy access to a variety of
2-arylbenzofurans.
The transition metal catalyzed decarboxylative cross-coupling is
one of the most attractive methodologies in organic synthesis.
Starting from low-cost, conveniently available and structurally
diverse carboxylic acids (and their derivatives), transition metal
catalyzed decarboxylative C–H, C–C, C–N, C–P, C–S and
C–halogen bond formation was achieved in the past few
decades.1 Recently, decarboxylative intermolecular C–O cross-
coupling utilizing catalytic amounts of copper salts was devel-
oped by Gooßen et al.2a Han et al. reported Ir(I)-catalyzed
decarboxylative intramolecular allylic etherication from aryl
allyl carbonates.2b We are interested in the development of new
methods for the construction of heterocyclic compounds from
easily available starting materials. We rationalized that oxygen-
containing heterocycles could be accomplished from corre-
sponding lactones with a formal extrusion of a carbonyl group,
via a three-step transformation involving (1) ring-opening, (2)
decarboxylation and (3) intramolecular Chan–Evans–Lam type
C–O cross-coupling (Scheme 1). In our preliminary study,
benzofuran was successfully prepared from coumarin via
decarboxylative intramolecular C–O coupling in the presence of
copper powder.3 To the best of our knowledge, this is the rst
example of direct decarboxylative intramolecular C–O coupling
without converting the nucleophile into borate or silicate ester2a
or aryl allyl carbonates.2b
Our initial work focused on the conversion of coumarin 1bb
into benzofuran 2bb under air at 190 ꢀC in the presence of
copper powder, quinoline and sodium hydroxide. The model
reaction was proved to be successful with 26% isolated yield.
Aer adding some grinded molecular sieve and maintaining the
temperature at 110 ꢀC for an hour before raising to 190 ꢀC, the
yield was improved to 41% (Scheme 2).
aChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
E-mail: wangchun@cib.ac.cn; zhanggl@cib.ac.cn
bUniversity of Chinese Academy of Sciences, Beijing 100049, China
cSchool of Materials and Science Engineering, Southwest University of Science and
Technology, Mianyang 621010, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46414h
Scheme 1 Three-step transformation.
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synthesized through classical Perkin condensation, which
was perhaps the most practical route among the plethora of
methods available for coumarin motif.7 As shown in Table 2,
most of the 3-arylcoumarins were successfully converted to
corresponding 2-arylbenzofurans with yields between 26%
and 84%. 6-Chloro-3-arylcoumarins were easier to be con-
verted to corresponding benzofurans (entries 9–19). Trans-
formations were hampered by 40-hydroxyl and 40-acetoxyl
substituents on coumarins (entries 30 and 31). 8-Methoxyl
substituents (entries 1–8, 25–29) were less favoured than
8-chloride ones (entries 15–19). 20-Methoxyl (entries 11 and
18) or successive three methoxyls at C-30, 40 and 50 (entries
4 and 12) were unfavored. 30,40-Dimethoxyl, 40-methoxyl, 30-
methoxyl, 40-chloro or 40-uoro substitutions had relatively
slight impact on the yields.
Scheme 2 Synthesis of 2-arylbenzofuran from 3-arylcoumarin.
We also noticed that air was necessary for the above
transformation. Thus, copper(0) was unlike the active cata-
lytic species, though copper powder was added in the above
catalytic process. To nd optimal catalytic conditions for the
transformation, copper(0), copper(I) and copper(II), ligands
and bases were screened. As shown in Table 1, cupric chlo-
ride (15 mol%), 1,10-phenathroline (15 mol%), sodium
hydroxide (3 eq.) and DMSO at 150 ꢀC for 24 hours (ref. 6)
came out to be the favorable conditions (entry 17). Air
seemed to have signicant impact on the yields (entries 3–6,
9, 10, 17, 19, 24 and 25).
Except 2ea, which was obtained with 26% yield (entry 25), the
other 5-bromo-2-arylbenzofurans were not obtained from
With the conditions in hand, we further explored the
scope of the methodology. A series of 3-arylcoumarins were
Table 2 Scope of 3-arylcoumarinsa
Table 1 Optimization of reaction conditionsa
Entry
R1
R2
Phenyl
Product
Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
Br
Br
Br
Br
Br
Cl
Cl
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
H
30,40-Dimethoxyl
40-Methoxyl
2aa
2ab
2ac
36
34
41
n.d.
30
42
36
45
76
72
63
52
71
74
82
73
67
60
84
47
52
56
61
69
26
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
30-Methoxyl
Entry
[Cu]
Ligandd
Base
Solvent
Air
Yieldb (%)
30,40,50-Trimethoxyl
c
—
2af
1
2
3
4
5
6
7
8
Cu
None
None
None
None
Phen
Phen
Phen
None
Phen
Phen
Phen
DMEDA
PPh3
None
Phen
None
Phen
Phen
Phen
Phen
DMEDA
PPh3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
NaOH
NaOH
NaOH
KOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
None
Q
Q
Q
Q
Y
N
Y
N
Y
N
Y
Y
Y
N
Y
Y
Y
Y
Y
Y
Y
Y
N
Y
Y
Y
Y
Y
N
9
40-Chloro
2ag
2ah
2an
2ba
2bb
2bd
2be
2bg
2bn
2ca
2cb
2cc
2cd
2cf
2da
2db
2dc
2df
2dh
2ea
Cu
Trace
41
2
34
2
40-Fluoro
Cuc
40-Nitro
Cuc
30,40-Dimethoxyl
40-Methoxyl
20-Methoxyl
30,40,50-Trimethoxyl
40-Chloro
Cuc
DMSO
DMSO
DMSO
Q
DMSO
DMSO
DMSO
DMSO
DMSO
Q
9
Cuc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Cuc
38
43
CuI
CuI
CuI
CuI
CuI
CuI
Cu2O
Cu2O
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
Cu(OH)2
Cu(OH)2
Cu(OH)2
9
41(52)
16(18)
47(53)
12(15)
22(26)
Trace
5
43(49)
72(79)
n.d.(3)
13(17)
67(75)
43(45)
38(42)
Trace(2)
64(70)
16(17)
40-Nitro
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
30,40-Dimethoxyl
40-Methoxyl
30-Methoxyl
20-Methoxyl
c
—
DMSO
Q
30,40-Dimethoxyl
40-Methoxyl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
30-Methoxyl
c
—
NaOH
KOH
NaOH
NaOH
None
40-Fluoro
30,40-Dimethoxyl
c
—
40-Chloro
Phen
Phen
Phen
40-Fluoro
NaOH
NaOH
20,50-Dimethoxyl
40-Hydroxyl
40-Acetoxyl
a
Reaction condition: [Cu] (15 mol %), ligand (15 mol %), base (3 eq.) and
H
MS 4 A were used under heating (in quinoline at 190 ꢀC or in DMSO at
˚
a
b
150 ꢀC) for 24 h. Isolated yield. HPLC yield given in parentheses.
Reactions were carried out in DMSO under air for 24 h in the presence
of cupric chloride (15 mol%), 1,10-phenathroline (15 mol%), sodium
c
d
50 mol% Cu powder was used. Phen ¼ phenathroline, DMEDA ¼
b
c
N,N0-dimethylethylenediamine, PPh3
quinolone. MS ¼ molecular sieve. n.d. ¼ not detectable.
¼
triphenylphosphine,
Q
¼
hydroxide (3 eq.) and MS 4 A. Isolated yield. No substitution. n.d.
˚
¼ not detectable.
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corresponding 6-bromo coumarins (entries 26–29). Instead, of coumarin. However, the presence of sodium hydroxide aer
5-hydrogen, 5-chloro and 5-methylthio 2-arylbenzofurans, were ring opening of coumarin resulted in a reduced yield from 85%
found from the reactions of 1ef, 1eg and 1eh. Only 5-chloro-2- (Scheme 5(1)) to 78% (Scheme 5(3)), implying sodium hydroxide
arybenzofuran 2ek was isolated from the reaction of 1ek was unfavourable for the decarboxylative C–O coupling reac-
(Scheme 3). These phenomena might be due to the activation of tion. Finally, the addition of molecular sieves improved the
C–Br bond on the aromatic ring by copper during the trans- yield from 64% (Scheme 5(2)) to 85% (Scheme 5(1)), revealing
formation.8 To explain the formation of 5-chloro-2-arylbenzo- that molecular sieves had signicant inuence on the yield. The
furan, we replaced cupric chloride with cupric hydroxide. role of molecular sieves in the reaction was not clear but not
However, even no chlorines were added in the catalytic likely acting as water absorbent.
processes, the chlorinated by-products still existed. Thus, the
A proposed mechanism is outlined in Fig. 1. The metal–
chlorine might come from hydrochloric acid in the quenching carboxylate and phenoxide intermediate A is formed in situ by
step. The methanthiol by-products might be derived from base hydrolysis of coumarin. This intermediate is favored for
DMSO. To overcome the difficulty of the transformation of the decarboxylative C–O coupling because protonolysis by
hydroxyl or acetoxyl bearing 3-arylcoumarins (entries 30 and hydroxyl group is avoided, which would cease the C–O
31), the hydroxyl group was protected by benzyl. As depicted in coupling.1,9 The vinylmetal intermediate B is then resulted from
Scheme 4, 1bjdb was successfully converted to corresponding Cu(II)-catalyzed decarboxylation. Based on previous reports and
2-arylbenzofuran 2bjdb with 69% yield.
our experimental data, a copper(III)-mediated C–O coupling
We subsequently tested the impact of water (generated from pathway is proposed in the following Chan–Evans–Lam type
base hydrolysis of coumarin), sodium hydroxide and molecular coupling.10 Copper(III) intermediate C could be generated from
sieve on the yield. To avoid the generation of water in situ, 1bbs oxidation of copper(II) intermediate B by oxygen11 or another
was used as starting material for the reaction. Comparing with equivalent of copper(II) species.12 2-Arylbenzofuran was nished
Table 1 entry 17 (water was generated in situ) and Scheme 5(3) by reductive elimination of intermediate D.
(no water generated in situ), there is a negligible difference of
In summary, a decarboxylative intramolecular C–O cross-
the yields (79% vs. 78%). This indicated water generated from coupling reaction capable of forming oxygen-containing
base hydrolysis of coumarin did not signicantly inuence the heterocyclic compounds from lactones was developed.
reaction. Sodium hydroxide was needed for the base hydrolysis This reaction was successfully applied for the conversion of
3-arylcoumarins to 2-arylbenzofurans.
Scheme 6 Transformation of coumarin.
Scheme 3 By-products via C–Br activation.
Scheme 4 Strategy for hydroxyl or acetoxyl 3-arylcoumarins.
Scheme 5 The influences of water, sodium hydroxide and molecular
sieve on the yields.
Fig. 1 Proposed mechanism.
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7 For the synthesis of 3-arylcoumarin, see: (a)
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Acknowledgements
This work was nancially supported by National Natural
Science Foundation of China (Grants 20932007 and 21372213).
˜
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6 See ESI for time prole.†
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