Iron-catalyzed oxidative homo-coupling of indoles via C-H cleavage

Article abstract of DOI:10.1016/j.tetlet.2010.10.088

A new method for the homo-coupling of indoles has been developed by the use of FeCl₃ as catalyst and molecular oxygen as the only oxidant. The protocol provides a practical and straightforward approach toward 3, 3'-biindolyls.

Full text of DOI:10.1016/j.tetlet.2010.10.088

Tetrahedron Letters 51 (2010) 6847–6851
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron-catalyzed oxidative homo-coupling of indoles via C–H cleavage
⇑
Tianmin Niu, Yuhong Zhang
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the homo-coupling of indoles has been developed by the use of FeCl3 as catalyst and
molecular oxygen as the only oxidant. The protocol provides a practical and straightforward approach
toward 3,30-biindolyls.
Received 16 August 2010
Revised 14 October 2010
Accepted 18 October 2010
Available online 28 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
3,30-Biindolyl
Iron catalyst
C–H activation
Homo-coupling
3, 3’-Biindolyls are useful structural units that are frequently
found in pharmaceuticals and functional materials.1 Accordingly,
synthesis and functionalization of 3,30-biindolyls have attracted
much attention over decades.2 The general method for the prepa-
ration of 3,30-biindolyls involves the nucleophilic attack of indoles
to istain in the presence of dimethylamine to give 3-(3-indoly)3-
hydroxyoxindole. The subsequent reduction by stoichiometric
NaBH4 and BF3ꢀEt2O affords the desired products in moderate
yields.3 Recently, transition metal-catalyzed cross-coupling reac-
tion has emerged as the powerful synthetic tools,4 and these pro-
tocols have successfully been employed in the synthesis of
biindolyls.5 For example, Chai reported the palladium catalyzed
Suzuki–Miyaura cross-coupling of the indolyl halides with indolyl
boronic compounds to give 3,30-biindolyls efficiently.6 However,
the prefunctionalization of indoles to their halides or boronic
derivatives is required for these transformations. From both scien-
tific and environmental points of view, the development of meth-
odology for direct activation of C–H bond is of great significance,
and metal catalyzed C–H bond functionalization has attracted
much attention currently.7 Recently, Shi et al. reported the oxida-
tive dimerization of indole derivatives to give 3,30-linked products
via Pd catalyzed direct C–H transformations in presence of stoichi-
ometric AgNO3 as oxidant and MgSO4 as additive.8 Our group also
developed a new access to 2,30-linked biindolyl scaffolds recently
using catalytic Pd(TFA)2 with 1.5 equiv Cu(OAc)2ꢀH2O as oxidant.9
Though these reactions represent the most attractive transforma-
tion for biindolyl formation, the use of expensive palladium and
stoichiometric heavy-metal oxidants limits their wider application.
Iron has been increasingly explored in organic transformations
because of its low price, nontoxicity, and environmentally benign
characters.10 Although the iron-catalyzed formation of C–C11 and
C-heteroatom12 bonds has been developed in recent years, the di-
rect formation of C–C bonds through iron-catalyzed C–H bond acti-
vation is still rare.13 Herein, we report a mild and selective method
for dimerization of N-free indoles by iron catalysis employing oxy-
gen as the oxidant to afford 3,30-biindolyls in good to moderate
yields (Scheme 1). The method using oxygen instead of heavy-met-
als as oxidant offers a more economical and environment benign
process.
On the outset of our study,9,14 2-phenylindole 1a was chosen as
the model substrate to probe the reaction conditions by use of
10 mol % FeCl3 catalyst in toluene at 90 °C for 20 h under nitrogen
atmosphere (Table 1). The desired 3,30-homo-coupling product 2a
was isolated in 7% yield when tert-butyl hydroperoxide (TBHP)
was used as stoichiometric oxidant (Table 1, entry 1). Although
the yield was quite low, it was promising since the result indicated
the possibility of oxidative homo-coupling of indoles at C3 position
via iron-catalyzed C–H presence activation. The developed result
was obtained when di-tert-butyl peroxide (tBuOOtBu) was utilized
as oxidant (Table 1, entry 2). No desired product was detected by
H
R1
N
10 mol % FeCl3
O2 (1 atm)
toulene, 90 oC, 20 h
R
R
2
R1
N
H
R
R1
N
H
⇑
Corresponding author. Tel.: +86 571 87952723; fax: +86 571 87953244.
E-mail address: yhzhang@zju.edu.cn (Y. Zhang).
Scheme 1. Iron(III) catalysed oxidative homo-coupling of 2-arylindoles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.088

6848
T. Niu, Y. Zhang / Tetrahedron Letters 51 (2010) 6847–6851
Table 1
the addition of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (Ta-
ble 1, entry 3). When potassium peroxomonosulfate (oxone) was
used as oxidant, the yield of 2a was remarkably increased to 45%
(Table 1, entry 4). To our delight, the desired homo-coupling prod-
uct was delivered in 37% yield in air instead of the hazardous and
toxic peroxides (Table 1, entry 5). The optimal result was further
revealed by the use of oxygen and a 61% isolated yield was ob-
tained (Table 1, entry 6). Treatment of 2-phenylindole with other
transition metals including copper, palladium, and nickel failed
to give the product (Table 1, entries 7–10). The desired 3,30-biind-
olyl product was also obtained when FeCl3ꢀ6H2O was applied as
catalyst, but in lower yield (43%) (Table 1, entry 11). Other iron re-
agents such as FeCl2, Fe(acac)3, and Fe2O3 were found to be ineffec-
tive (Table 1, entries12–14). No reaction was observed in the
absence of metal catalyst (Table 1, entry 15). A study of the reac-
tion in various solvents identified toluene as the suitable alterna-
tive to DCE, acetonitrile, DMF, EtOAc, and THF (Table 1, entries
16–20).
The generality of this transformation was examined under the
optimized reaction conditions, and the results are summarized in
Table 2. A broad range of 2-arylindole bearing both electron-donat-
ing and electron-withdrawing substituents on the 2-aryl ring of in-
dole could be successfully used in the homo-coupling reaction to
synthesize the desired 3,30-biindolyls in good to moderate yields
(Table 2, entries 1–19). Notably, the carbon–halogen bonds in 2-
aryl ring could tolerate the reaction conditions, which made it par-
ticularly attractive for the further assembly through the cross-cou-
pling reactions (Table 2, entries 8–14). The location of substituents
on 2-aryl rings played an important role in this reaction. Ortho-
substituted of 2-aryl ring of indoles gave the coupling products
in lower yields compared with para- or meta-substituted (Table
2, entries 4 and 11). This might be due to the increased steric hin-
drance during the coupling process. The reaction also proceeded
well when changing the substituents on the indole ring (Table 2,
entries 16–19). However, the reaction was sluggish when indole
and 2-methylindole were as the substrate.
Oxidative homo-coupling of 2-phenylindole under various conditionsa
H
N
10 mol % Catalyst
Oxidant
2
Solvent, 90 oC, 20 h
N
H
N
H
1 a
2 a
Entry
Catalyst
Oxidative
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
CuCl2
PdCl2
Pd(OAc)2
NiCl2
TBHP
tBuOOtBu
DDQ
Oxone
Air
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
7c
15d
n.rd
45d
37
61
n.r
n.r
n.r
n.r
43
12
9
FeCl3ꢀ6H2O
FeCl2
Fe(acac)3
Fe2O3
—
n.r
n.r
29
n.r
n.r
<10
n.r
42e
FeCl3
FeCl3
FeCl3
O2
O2
CH3CN
DMF
FeCl3
O2
EtOAc
FeCl3
O2
THF
FeCl3
O2
Toluene
a
Reaction conditions: 2-phenylindole (1 mmol), catalyst (0.1 mmol), solvent
(4 mL), at 90 °C for 20 h, under oxygen atmosphere.
b
Isolated yields based on 2-phenylindole.
TBHP (1.5 equiv, 1.5 mmol) 0.30 mL, 5–6 M in decane, under nitrogen
c
atmosphere.
d
Oxidant (1.5 equiv, 1.5 mmol) under nitrogen atmosphere.
1.5 equiv p-hydroquinone was added.
e
Table 2
Substrate scope of iron(III)-catalyzed oxidative homo-coupling of substituted 2-arylindolesa
H
R1
N
10 mol % FeCl3
R
R
O2 (1 atm)
2
R1
N
H
toulene, 90 oC, 20 h
R
R1
N
H
Entry
Substrate
Product
Yieldb (%)
H
N
N
H
1
61
N
H
H
N
N
H
2
56
N
H

T. Niu, Y. Zhang / Tetrahedron Letters 51 (2010) 6847–6851
6849
Table 2 (continued)
Entry
Substrate
Product
Yieldb (%)
H
N
N
H
3
4
5
6
7
8
73
43
51
48
55
71
N
H
H
N
N
H
N
H
H
N
N
H
N
H
H
N
N
H
N
H
H
N
OMe
MeO
N
H
OMe
N
H
H
N
Cl
Cl
N
H
Cl
N
H
H
N
Br
Br
Br
N
H
9
62
71
Br
N
H
H
N
N
H
Br
10
N
H
Br
Br
Br
H
N
N
H
11
12
49
N
H
Br
H
N
I
I
N
H
68
I
N
H
(continued on next page)

6850
T. Niu, Y. Zhang / Tetrahedron Letters 51 (2010) 6847–6851
Table 2 (continued)
Entry
Substrate
Product
Yieldb (%)
H
N
F
F
N
H
13
14
50c
F
N
H
F
H
N
N
H
F
73
N
H
F
H
N
CF3
F3C
N
H
15
16
17
18
56c
60
56
68
CF3
N
H
H
N
N
H
N
H
H
N
N
H
N
H
H
N
N
H
N
H
H
N
N
H
19
75
N
H
a
Conditions: 2-arylindoles (0.6 mmol), FeCl3 (0.06 mmol), toluene (4 mL), 90 °C, 20 h in 1 atm oxygen atmosphere unless otherwise noted.
Isolated yields.
The reaction condition was at 120 °C for 24 h.
b
c
1/2 O2
[Fe]
Catalyst
Selective SET
H
2
The detailed mechanism of this homo-coupling reaction is not
2
N
H
N
clear at the current stage. Based on the findings of previous stud-
ies,15 a tentative mechanism for the transformation as shown in
Scheme 2. The reaction is initiated by the iron assisted single-elec-
tron-transfer (SET) oxidation of the 2-phenylindole 1a to form the
nitrogen cation radical A. The following hydrogen abstraction of
radical A generates the intermediate B, which is combined with an-
other B to give the corresponding 3,30-biindolyls 2a.16 We per-
formed the reaction in the presence of 1.5 equiv free-radical
scavenge of p-hydroquinone and found that the yield was drasti-
cally decreased (Table 1, entry 21). This result supports the pro-
posed radical pathway.
H
2 e -
1a
A
2 H+
H
N
H
2
N
N
H
B
2 a
Scheme 2. Proposed mechanism.
In conclusion, we have demonstrated a new method for the di-
rect formation of 3,30-biindolyls by an iron-catalyzed dimerization

T. Niu, Y. Zhang / Tetrahedron Letters 51 (2010) 6847–6851
6851
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Acknowledgment
Funding from the Natural Science Foundation of China (No.
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phenyl-1H-indole (0.6 mmol, 116 mg) in toulene (4.0 mL) was added FeCl3
(10 mg, 0.06 mmol, 10 mol %). The resulting mixture was then heated under
oxygen atmosphere at 90 °C for 20 h. When the reaction was completed, as
determined by TLC analysis, the reaction mixture was cooled to room
temperature and filtered through a pad of cellite. The solvent was removed
under reduced pressure and the residue was purified on a silica gel column
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DMSO-d6) d 137.0, 135.1, 133.4, 129.9, 128.8, 127.3, 126.8, 122.3, 119.8, 119.6,
111.8, 106.8.
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