A R T I C L E S
Guo et al.
Table 1. Optimization of the Reaction Conditionsa
redox processes involving iron catalysts in C-C bond formation
reactions. Some significant works in iron-catalyzed cross-
coupling reactions10 and selective C-H bond oxidations11 have
been documented in the literature. Importantly, Bolm recently
reported iron-catalyzed Sonogashira reactions of terminal
alkynes and aryl halides.12 Nakamura disclosed for the first time
iron-catalyzed biaryl syntheses via direct sp2 C-H bond
activation.13 We recently developed iron-catalyzed reactions of
benzyl derivatives or heteroatom-containing molecules and 1,3-
dicarbonyl compounds,14,15 which are formal oxidative coupling
reactions of sp3 C-H bond and sp3 C-H bond.16 Our efforts
in the field of C-H bond oxidation and C-C bond formation
promoted us to investigate the present iron-catalyzed oxidative
reaction, which involved the selective oxidative coupling of sp2
C-H bond and sp3 C-H bond. Here we wish to report our
efforts to realize a novel and practical synthesis of polysubsti-
tuted benzofurans using iron salt as a catalyst and organic
peroxide as an oxidant (Scheme 1, path B).
entry
catalyst
1a (equiv)
oxidant
yield (%)b
1
2
3
4
5
6
7
8
9
FeCl2
FeBr2
FeCl3
1
1
1
1
1
1
3
3
3
3
3
3
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
t-BuOOH
PhCOOO-t-Bu
(t-BuO)2
-
8
9
30
46
16
47
75
FeCl3 ·6H2O
Fe(ClO4)3 ·xH2O
Fe(ClO4)2 ·xH2O
FeCl3 ·6H2O
FeCl3 ·6H2O
FeCl3 ·6H2O
FeCl3 ·6H2O
-
N.D.c d
,
11
8
10
11
12
N.D.
FeCl3 ·6H2O
22e
a Conditions: 2a (0.5 mmol), FeCl3 (0.05 mmol), peroxide (1.0 mmol)
and DCE (1.0 mL), 100 °C, 1 h; unless otherwise noted; DCE )
dichloroethane. b NMR yields are determined by 1H NMR using
mesitylene as an internal standard. c Not detected by 1H NMR. d 4 Å
molecular sieve (25 mg) was added. e FeCl3 ·6H2O (0.5 mmol) was
used.
Results and Discussion
Optimization of the Iron-Catalyzed Oxidative Reaction. The
reaction of phenol 1a and ethyl 3-oxo-3-phenylpropanoate 2a
was chosen as a model system to investigate the proposed
transformation (Table 1). To our delight, substituted benzofuran
3a was obtained in the presence of FeCl2 and FeBr2, albeit in
low yields (Table 1, entries 1 and 2). 3a was formed in 30%
yield when FeCl3 was used as a catalyst (Table 1, entry 3).
Interestingly, the yield of 3a was improved to 46% yield when
hydrated iron catalyst FeCl3 ·6H2O was employed (Table 1, entry
4). Although 3a was obtained in 16% in the presence of
Fe(ClO4)3 ·xH2O, the yield of 3a was raised to 47% when
Fe(ClO4)2 ·xH2O was used (Table 1, entries 5 and 6). Other iron
salts, such as Fe2(CO)9, FeI2, Fe(acac)2, Fe(acac)3, Fe(OAc)2,
Fe(dbm)3, FeSO4 · 9H2O, Fe2(SO4)3 · xH2O, FeF3, FeF3 · 3H2O,
Fe(NO3)3 ·3H2O, were not effective for the benzofuran forma-
tion. In order to rationalize the role of the counterion, various
additives such as KCl, NaCl, CaCl2, KBr, etc. were added into
the reactions together with inactive iron catalysts. However, the
desired benzofuran 3a was not observed in those experiments.
In addition, 3a was not observed in the presence of the copper
catalysts such as CuBr, CuBr2, CuCl, CuCl2, CuI, Cu(acac)2,
Cu(OAc)2, CuSO4 ·5H2O, CuF2.17 Importantly, the yield of 3a
was further improved to 75% when 3 equiv of 1a was used
(Table 1, entry 7).18 The desired benzofuran 3a was not observed
when 4 Å molecular sieve was added into the reaction (Table
1, entry 8). This result indicated that a certain amount of water
is essential for the present process. Other peroxides were much
less efficient compared with di-tert-butyl peroxide (Table 1,
entries 9 and 10). No desired products were formed in the
absence of a catalyst (Table 1, entry 11). 3a was obtained in
22% yield when a stoichiometric amount of FeCl3 ·6H2O was
used in the absence of a peroxide (Table 1, entry 12). In this
case, iron is proposed to act as both a catalyst and an oxidant
in the reaction. Moreover, a variety of solvents were screened
for the present reaction. Optimization revealed that the use of
1,2-dichloroethane (DCE) is very important, considering the
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(17) Both the purity and the source of the FeCl3 may play a role in the
some cross-coupling reactions, see: Buchwald, S. L.; Bolm, C. Angew.
Chem., Int. Ed. 2009, 48, 5586. For our reactions, we also checked
the influences of the purity and source of FeCl3 ·6H2O in the present
oxidative annulation. The results proved that the yields of 3a were
independent of the purity and source of FeCl3 ·6H2O, which was
purchased from Alfa (purity: 97-102%), Aldrich (purity: 97-102%),
and KANTO (purity: 99%).
(18) tert-Butyl-substituted benzofuran 3c was also obtained as a byproduct
in ∼8% for this case. By analyzing the reaction mixture, we found 1c
was generated in ∼10%, which was formed by Friedel-Crafts
alkylation of 1a.
9
17388 J. AM. CHEM. SOC. VOL. 131, NO. 47, 2009