Communication
alent of AcOH to the reaction mixture delivered 2a in a repro-
ducible yield of 40% (Table 1, entry 7). A similar result was ob-
tained when undried air was directly bubbled into the solution
Table 1. Optimization of the Cu-catalyzed oxidative coupling/skeletal re-
arrangement of 2,4-di-tert-butylphenol 1a.
[
a]
(
Table 1, entry 8). Further optimization showed that the yield
of 2a could be improved to 59% by employing 0.3 equivalents
of AcOH as an additive (Table 1, entry 9). The competent enol
or lactone derivative was not formed when 10.0 equivalents of
H O was added to the reaction mixture (Table 1, entry 10). De-
2
creasing the amount of CuCl to 25 mol% and changing the ox-
idant from air to molecular oxygen afforded 2a in slightly
lower yields of 47% and 40%, respectively (Table 1, entries 12
and 13). Using other copper(I) or copper(II) salts, such as CuBr,
CuI, CuCl , Cu(OAc) , and Cu(NO ) ·3H O, as the catalyst could
[
b]
Entry
Catalyst (mol%)
Oxidant Additive (equiv) Yield [%]
1
2
3
4
5
6
7
8
9
CuCl (50)
none
air
air
none
none
none
33
0
32–60
0
0 (49)
0 (10)
40
41
59
42
45
47
40
0 (19)
0
0 (4)
0 (9)
0
CuCl (50)
CuCl (50)
CuCl (50)
CuCl (50)
CuCl (50)
CuCl (50)
CuCl (50)
CuCl (50)
CuCl (20)
CuCl (25)
CuCl (25)
CuBr (25)
CuI (25)
dry air
dry air
dry air
dry air
dry air
air
air
air
air
air
2
2
3 2
2
K
K
CF
2
HPO
CO
COOH (1.0)
4
(1.0)
2
3
(1.0)
not deliver 2a, although the homocoupled product 5 was ob-
tained in some cases (Table 1, entries 14–18). The final opti-
mized reaction condition was as follows: 50 mol% of CuCl as
the catalyst and 30 mol% of AcOH as the additive in MeOH so-
lution with air bubbling through the reaction mixture.
3
[
c]
AcOH (1.0)
AcOH (1.0)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
[
d]
1
0
1
1
Benzofuran derivatives are frequently found in natural prod-
1
1
1
1
1
1
1
2
3
4
5
6
7
8
[12]
[13]
ucts,
bioactive molecules, pharmaceuticals,
and organic
O
2
[
14]
materials. With the optimized reaction conditions in hand,
we next investigated the substrate scope. As summarized in
Table 2, phenols bearing alkyl substituents at the C2 and C4
positions reacted smoothly with methanol and ethanol to give
the corresponding products 2 under the optimized reaction
conditions (Table 2, 2a–d). Other alcohols, such as isopropanol,
benzyl alcohol, and allyl alcohol, only afforded the homocou-
pled product and the desired benzofurans were not formed.
However, when the C4 position of phenols was substituted
with an aryl group, the desired products were obtained, albeit
in less than 20% yields. Consequently, other oxidants such as
1,4-benzoquinone (BQ), 4,5-dichloro-3,6-dioxocyclohexa-1,4-
diene-1,2-dicarbonitrile (DDQ), 2-(tert-butylperoxy)-2-methyl-
propane (DTBP), 2-hydroperoxy-2-methylpropane (TBHP),
Ag CO , and K S O were screened to improve the product
air
air
air
air
air
CuCl
Cu(OAc)
Cu(NO ·3H
2
2
(25)
(25)
O (25)
2
3
)
2
[
a] Reaction conditions: 2,4-Di-tert-butylphenol 1a (1.0 mmol), catalyst, air
or O (bubbling), additive, and MeOH (10 mL) at 658C for 12 h. [b] Yield
of isolated product. The yield of 5 is given in parenthesis. [c] An average
of three runs. [d] 10.0 equivalents of H O were added.
2
2
Initially, we attempted to perform homocoupling of 2,4-di-
tert-butylphenol 1a in the presence of 50 mol% of CuCl in
MeOH under air atmosphere. To our surprise, 3-furyl-2-methoxy
benzofuran 2a was obtained in 33% yield instead and the de-
sired homocoupled product 3,3’,5,5’-tetra-tert-butyl-[1,1’-bi-
phenyl]-2,2’-diol 5 was not observed (Table 1, entry 1). The
2
3
2
2
8
yields. Using 2.0 equivalents of Ag CO3 as the oxidant was
2
found to efficiently promote the reactions and the desired
benzofuran products were obtained in 50–70% yields (Table 2,
2e–j). Both electron-withdrawing and electron-donating
groups on the phenyl ring could be tolerated (Table 2, 2 f–i).
Notably, a bulky 2-alkyl group was crucial for the smooth oc-
currence of these reactions. Even the oxidative homocoupling
reaction was not observed in the absence of such a bulky
group.
1
13
structure of 2a was confirmed by H and C NMR spectrosco-
py, high-resolution mass spectrometry (HRMS), and single crys-
[11]
tal X-ray analysis (Figure 1). A control experiment showed
that no reaction happened in the absence of CuCl (Table 1,
entry 2). When dry air was bubbled through the reaction mix-
ture, 2a was obtained in higher, albeit irreproducible yields
(
32–60%; Table 1, entry 3). Pleasingly, the addition of 1.0 equiv-
Surprisingly, when K S O was used as the oxidant, dibenzo-
2
2
8
furans instead of benzofurans were obtained. Considering that
dibenzofuran derivatives are an important class of naturally oc-
curring products and have wide applications in a variety of
[
15,16]
fields,
we then used 1b as the model substrate to opti-
mize the reaction conditions (see the Supporting Information,
Table S1). The desired dibenzofuran 3a was obtained in the
highest yield of 65% by using 25 mol% CuCl as the catalyst
and 2.0 equivalents of K S O as the oxidant in MeOH at 808C
2
2
8
for 24 h [Eq. (1)]. This catalytic reaction did not occur in the ab-
sence of CuCl, demonstrating the crucial role of CuCl for the
smooth occurrence of the reaction (see the Supporting Infor-
mation, Table S1, entry 3).
Figure 1. ORTEP representations of 2a (left) and 4a (right) with thermal el-
lipsoids drawn at 50% probability level. Hydrogen atoms were omitted for
clarity.
Chem. Eur. J. 2015, 21, 13913 – 13918
13914
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim