Preparation of indoles via iron catalyzed direct oxidative coupling

Article abstract of DOI:10.1039/b923971e

Iron-catalyzed aryl C-H and vinyl C-H bonds activation to give valuable substituted indole products was reported. The reaction shows high functional group tolerance.

Full text of DOI:10.1039/b923971e

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Preparation of indoles via iron catalyzed direct oxidative couplingw
Zheng-Hui Guan,ab Ze-Yi Yan,a Zhi-Hui Ren,ab Xue-Yuan Liua and Yong-Min Liang*a
Received (in Cambridge, UK) 16th November 2009, Accepted 15th January 2010
First published as an Advance Article on the web 2nd February 2010
DOI: 10.1039/b923971e
Iron-catalyzed aryl C–H and vinyl C–H bonds activation to give
valuable substituted indole products was reported. The reaction
shows high functional group tolerance.
Table 1 Optimization of Fe-catalyzed direct C–H activation reactiona
Iron salts have been extensively investigated as alternative and
promising catalysts for many organic transformations because
of their ready availability, low price and environmentally
friendly characters.1 Recently, iron catalyzed carbon–carbon2
and carbon–heteroatom3 cross-coupling reactions have been
successfully developed. Iron catalyzed C–H bond activation4
and functionalization for C–C bond formation reactions have
also been reported by several groups. Nakamura et al.
described an efficient iron catalyzed ortho arylation of aryl
C–H bonds under mild conditions.5 Li et al. developed an iron
catalyzed carbon–carbon bond formation via activation of
benzylic C–H bonds or C–H bonds adjacent to heteroatoms.6
Yu and co-workers reported an iron mediated arylation of aryl
C–H bond using arylboronic acid.7 However, in comparison
with other transition metals, such as Pd,8 Rh,9 Ru,10 iron
catalyzed C–H bond activation and functionalization has
remained largely undeveloped.11
Yieldb
(%)
Entry Catalyst
Oxidant
Base
Solvent
1
2
3
4
5
6
7
8
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
CuCl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
44
Cu(OAc)2
CuBr2
CuO
Cu(OTf)2
Tempo
Oxone
15
43
18
d
—
o10
30
K2S2O8
PhI(OAc)2
Cu(OAc)2ÁCuCl2
o10
o10
72
9
c
10
11
12
13
14
15
16
17
18
19
20
21
22
Cu(OAc)2/CuCl2
36
c
Cu(OAc)2ÁCuCl2c K2CO3
Cu(OAc)2ÁCuCl2c K2CO3
Cu(OAc)2ÁCuCl2c Cs2CO3
Dioxane o10
Toluene o10
DMF
31
50
70
68
65
55
15
Cu(OAc)2ÁCuCl2c Na2CO3 DMF
Cu(OAc)2ÁCuCl2
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
c
Fe(acac)3 Cu(OAc)2ÁCuCl2
The indole unit is probably the most abundant and ubiqui-
tous heterocycle in natural products and pharmaceuticals.12,13
Although there are numerous methods for the preparation of
indole and its derivatives,14 it is highly desirable to synthesize
this type of molecule via direct C–H bond functionalization.15
It is required to explore a new catalyst system that involves
cheap and environmentally friendly catalysts, albeit some
important progress has been made by Glorius et al. using
palladium as the catalyst.16 Herein, we report an efficient iron
catalyzed intramolecular oxidative coupling of aryl C–H and
vinyl C–H bonds for preparation valuable substituted indole
products.
c
Fe(acac)2 Cu(OAc)2ÁCuCl2c K2CO3
FeSO4
—
CuI/phen
Cu(OAc)2ÁCuCl2c K2CO3
Cu(OAc)2ÁCuCl2
K2CO3
Cs2CO3
K2CO3
—
n.r.
70
c
c
499.99% Cu(OAc)2ÁCuCl2
f
FeCl3
FeCl2
23
Cu(OAc)2ÁCuCl2
K2CO3
DMF
22e
a
Reaction conditions: 1a (0.2 mmol), Fe catalyst (10 mol%), oxidant
(0.6 mmol), base (0.6 mmol), in solvent (2 mL) at 120 1C for 2 h.
Isolated yield. See ESI for details. 1a was decomposed. The
b
c
d
e
f
reaction under Ar atmosphere. Aldrich.
(Table 1, entries 2–4). The use of Cu(OTf)2 as the oxidant
resulted in the rapid decomposition of the substrate 1a and
therefore aniline was obtained in 60% yield (Table 1, entry 5).
Other oxidants such as TEMPO, Oxone, K2S2O8, PhI(OAc)2
were employed, but did not improve the yield of 2a as well
(Table 1, entries 6–9). To our delight, when the complex of
Cu(OAc)2ÁCuCl2 was used as the oxidant, the reaction
proceeded smoothly to give the indole product 2a in 72%
yield (Table 1, entry 10). However, a physical mixture of
Cu(OAc)2 and CuCl2 shows no special characteristics in the
transformation (Table 1, entry 11). Further experiments
indicated that DMF was the best solvent and K2CO3
was the most suitable base for this transformation (Table 1,
entries 12–15). No significant improvement of the yield of the
desired product 2a was observed when other iron salts were
used as the catalyst, such as FeCl2, Fe(acac)3, Fe(acac)2 and
FeSO4 (Table 1, entries 16–19).17 Control experiments
We initiated our investigation by cyclization of methyl
3-(phenylamino)but-2-enoate 1a to form the corresponding
indole 2a (Table 1). We were pleased to find that treating 1a
with FeCl3 (10 mol%), CuCl2 (3 equiv.), K2CO3 (3 equiv.) in
DMF resulted in a moderate but promising yield of the
cyclization product 2a (Table 1, entry 1). Screening of other
Cu salts, such as Cu(OAc)2, CuBr2 and CuO as the oxidant
showed that only moderate yields of 2a were obtained
a State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582;
Tel: +86-931-8912593
b Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Department of Chemistry,
Northwest University, Xi’an 710069, P. R. China
w Electronic supplementary information (ESI) available: A complete
description of experimental details and product characterization. See
DOI: 10.1039/b923971e
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Table 2 Preparation of indoles by Fe-catalyzed direct C–H activationa
confirmed that only low conversion was obtained in the
absence of the iron catalyst (Table 1, entry 20). Very recently,
a similar transformation of N-aryl enaminone to the indole
skeleton using CuI as the catalyst has been reported.18
However, the reaction of methyl 3-(phenylamino)but-2-enoate
1a did not proceed under the reported conditions (Table 1,
entry 21).18 This experiment indicated that the reaction of
3-phenylamino)but-2-enoate derivatives possibly proceed from
a different pathway than the reaction of N-aryl enaminones.19
Under the optimized conditions, for this direct C–H activa-
tion process, we have explored the substrate scope. The results
are summarized in Table 2. This transformation displayed
high functional group tolerance. Arenes with methyl, methoxyl,
acetyl and chloro groups all gave moderate to good yields of
corresponding indoles (Table 2). In general, better yields were
obtained with arenes possessing an electron-donating group at
the para position compared to those with same substituent at
the ortho position (Table 2, entries 2–3,20 and 6–7). Similarly,
higher yields were obtained with arenes possessing an electron-
withdrawing grope at the ortho position rather than at the para
position (Table 2, entries 9–10).21 Furthermore, the reaction
was insensitive to the steric hindrance of the substitutent on
the arenes. Arenes possessing a methyl group at the meta
position gave a 2 : 1 ratio of the 4- and 6-substituted indole
regioisomers (Table 2, entries 4–5), contrary to palladium
catalyzed reaction of this type, while an arene with chloro
substituent at the meta position resulted in a ratio of 1 : 1 of the
two regioisomers (Table 2, entry 11). In addition, the substrate
derived from naphthylamine also underwent the desired
reaction to give the corresponding product 2j in good yield
(Table 2, entry 12).
Notably, cyclization of arenes bearing a Br or I substitutent
were achieved by this iron catalyzed C–H activation reaction
(Table 3). Methyl 7-bromo-2,5-dimethyl-1H-indole-3-carboxylate
2o was formed exclusively in 70% yield (Table 3, entry 2) while
the 5-bromoindole derivative 2n was obtained with slightly
lower yield (Table 3, entry 1). An arene possessing an iodo
group at the ortho position resulted in 37% of the product 2q
along with 30% yield of the C–I cross coupling product 2b
(Table 2, entry 4). These results were superior to those
obtained by using palladium or copper as the catalyst.16,18
Evidently, the iron catalyst exhibits different properties from
the palladium in this C–H activation reaction.22 In this
manner, the resulting Br or I substituted indole products,
which are versatile building blocks for subsequent synthetic
modification, could be further expanded to a wider variety
of functionalized indoles by undergoing cross-coupling
reactions.23 That is a distinct advantage of this indole synthesis.
In light of the foregoing experiments, a proposed mecha-
nism for the present oxidative coupling reaction is shown in
Scheme 1. As previously mentioned, the copper(II) promoted
coupling reaction of methyl 3-(phenylamino)but-2-enoate 1a
in the absence of iron catalyst did not proceed to an appreci-
able extent. Furthermore, the identical result was observed
when 499.99% FeCl3 was used as the catalyst (Table 1,
entry 22).24 However, control experiment shows that only
low yield was obtained when FeCl2 was employed under argon
atmosphere (Table 1, entry 23). These results indicate that
Fe(III) species probably act as the catalyst. Based on above
a
Reaction conditions: 1 (0.3 mmol), FeCl3 (4.8 mg, 10 mol%),
Cu(OAc)2ÁCuCl2 (142 mg, 0.45 mmol), K2CO3 (124 mg, 0.9 mmol),
in DMF (3 mL) at 120 1C for 2 h. b Isolated yields (average of two
runs). c K2CO3 (248 mg, 1.8 mmol) was used as the base and Na2SO4
(85 mg, 0.6 mmol) was used as the additive. d Bu4NCl (166 mg,
0.6 mmol) was used as the additive.
results and previously reported,25 we assumed that the copper
and iron bimetallic chelate complex B would be formed by the
coordination of the nitrogen and the double bond of 1a, which
would significantly enhance the reaction activity of the
enoates. The key intermediate C is formed by electrocyclic
ring closure. Finally, the subsequent proton elimination and
tautomerization gives the indole product 2a.
In summary, we have developed an efficient and general
method for the iron catalyzed C–H activation reaction for
preparation of functionalized indoles. This iron catalyzed C–H
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Table 3 Exploration of the scope of the Fe-catalyzed direct C–H
activation reactiona
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a
Reaction conditions: 1 (0.3 mmol), FeCl3 (4.8 mg, 10 mol%),
Cu(OAc)2ÁCuCl2 (142 mg, 0.45 mmol), K2CO3 (124 mg, 0.9 mmol),
in DMF (3 mL) at 120 1C for 2 h. b Isolated yields (average of two
runs). c K2CO3 (248 mg, 1.8 mmol) was used as the base and Na2SO4
(85 mg, 0.6 mmol) was used as the additive. d Bu4NCl (166 mg,
0.6 mmol) was used as the additive.
¨
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Scheme 1 Proposed mechanism.
activation reaction shows high functional group tolerance and
exhibits different properties from the palladium catalyzed
reactions of this type. The cheap and environmentally benign
iron catalyst combined with the highly active Cu(OAc)2ÁCuCl2
makes this C–H activation reaction practical and attractive in
organic synthesis.
16 S. Wurtz, S. Rakshit, J. J. Neumann, T. Droge and F. Glorius,
¨
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¨
17 Fe(II) shows identical reactivity with Fe(III), probably due to rapid
oxidation of Fe(II) to give Fe(III) in air during the reaction.
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19 N-Aryl enaminones, such as 4-(phenyl amino)pent-3-en-2-one,
showed diminished reactivity and formed only 16% yield of desired
product under our standard reaction conditions.
The authors gratefully acknowledge the NSFC
(NSFC20732002, NSFC20090443, NSFC20872052) for
financial support.
20 In some cases, the decomposition of the substrate was inhibited
when Na2SO4 was used as a dehydrant.
21 Bu4NCl was reported to improve the efficiency in Pd-catalyzed
coupling reactions, see: R. C. Larock, Pure Appl. Chem., 1990, 62,
653.
22 In palladium catalyzed C–H activation reaction, a significant
amount of the debrominated indole product was observed; see
ref. 16.
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Chem. Commun., 2010, 46, 2823–2825 | 2825