Selective C3-C3 oxidative cross-coupling between unactivated anilines and indoles

Article abstract of DOI:10.1002/adsc.201000603

A selective C3-C3 oxidative cross-coupling between unactivated anilines and indoles catalyzed by copper bromide together with iodobenzene diacetate as the oxidant is described. This methodology provides a novel approach to biaryl synthesis. Copyright

Full text of DOI:10.1002/adsc.201000603

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DOI: 10.1002/adsc.201000603
À
Selective C3 C3 Oxidative Cross-Coupling between Unactivated
Anilines and Indoles
Linfei Wang,a Zhaomeng Han,a and Renhua Fana,*
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Peopleꢀs Republc of China
Fax : (+86)-216-510-2412; phone: (+86)-216-564-2019; e-mail: rhfan@fudan.edu.cn
Received: July 28, 2010; Revised: September 30, 2010; Published online: December 1, 2010
À
Abstract: A selective C3 C3 oxidative cross-cou-
pling between unactivated anilines and indoles cata-
lyzed by copper bromide together with iodobenzene
diacetate as the oxidant is described. This method-
ology provides a novel approach to biaryl synthesis.
À
Keywords: aromatic substitution; biaryls; C C cou-
pling; oxidation; regioselectivity
As the important polyaryl compounds, arylindoles
Figure 1. X-ray diffraction structure of 2a.
appear as basic skeltons in a wide range of biochemi-
cal, biological and medicinal compounds.[1] The regio-
selective formation of aryl-aryl bonds between aryl oxygen-containing functional group is normally re-
moieties and indoles has received considerable atten- quired to act as the directing group. In most of cases,
tion over the past decades.[2] From atom- and step- the new carbon-carbon or carbon-heteroatom bond is
economic points of view, the direct oxidative cross- selectively formed at the ortho position. Interestingly,
À
coupling reactions between two different C H bonds when we investigated the oxidative cross-coupling be-
of aromatic molecules without recourse to extra tween unfunctionalized aniline derivatives and in-
À
chemical activation are quite attractive processes in doles, we isolated a C3 C3 cross-coupling product 2a
the synthesis of polyaryl compounds.[3] The purpose of (Figure 1)[8] from the reaction of N-Ts protected p-tol-
À
this communication is to document the selective C3
C3 oxidative cross-coupling between unactivated ani- lyst and PhI
uidine 1a and free indole with Cu
ACHTUNGRTEN(NGNU OAc)2 as the cata-
A
lines and indoles catalyzed by copper bromide togeth- only in 2% yield [Eq. (1)].
er with iodobenzene diacetate as the oxidant.
The screening of solvents revealed that the coupling
Recently, because of the economic attractiveness product was only formed in alcohols, and methanol
and the potential in industrial applications, copper was the best choice. While the reaction in methanol
catalysis has attracted significant interest in organic afforded product 2a in 7% yield, one of the by-prod-
synthesis.[4] Since the pioneering studies by Yuꢀs ucts was identified as N-Ts-4-methoxy-4-methylcyclo-
group[5] and others, copper salts or complexes have hexa-2,5-dienimine 3a. When compound 3a was treat-
À
proved to be effective in various C H activation reac- ed with indole and CuACHTNUTRGNEUNG(OAc)2, the generation of prod-
tions.[6,7] To realize the transition metal-catalyzed re- uct 2a was observed [Eq. (2)]. Moreover, the control
À
gioselective C H functionalization, a nitrogen- or experiments indicated that compound 3a could be
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Adv. Synth. Catal. 2010, 352, 3230 – 3234

À
Selective C3 C3 Oxidative Cross-Coupling between Unactivated Anilines and Indoles
generated from the reaction of substrate 1a with withdrawing protecting group on the nitrogen atom of
PhI
indole.
Since indole also showed a reactivity towards a suitable substrate, the reaction of N-Bn-p-toluidine
PhI(OAc)2, the coupling reaction was then carried out was complicated and did not afford any coupling
in a stepwise way. Before indole and catalyst were product. Additionally, the C-4 substitution of N-tosyl-
added, substrate was premixed with PhI(OAc)2 in aniline had a strong influence on the coupling reac-
MeOH at 258C for 15 min. To improve the yields, var- tion. N-Ts-4-(trifluoromethyl)benzenamine showed
ious ratios of p-toluidine and indole as well as iodo- no reactivity toward PhI(OAc)2. When N-tosylaniline
ACHTUNGTRENNUNG(OAc)2 in MeOH in the absence of CuCAHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
benzene diacetate were examined. The best yield was was employed, no corresponding coupling product 2w
obtained when the ratio of p-toluidine/indole/iodo- was detected. The 1H NMR of the crude reaction mix-
benzene diacetate was 1:2:1.1. Various copper salts ture indicated the formation of p-quinone
were examined as the catalysts for the coupling reac- monosulfon
tion (Table 1). Cu(OTf)2, CuCl2 and CuBr2 proved to thoxy-, 4-chloro-, and 4-bromo-substituted N-tosylani-
be the best catalysts. Cu(OAc)2, CuCl, and CuI line derivatives also only afforded p-quinone mono-
imide.[9] Moreover, reactions of 4-me-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
showed lower catalytic activities. While no reaction sulfonimides as the product. 4-Butyl- and 4-phenyl-N-
was observed in the absence of copper catalyst, tosylaniline derivatives were found to be effective
5 mol% CuBr2 was sufficient to achieve 87% conver- partners and the desired products 2q–2t were isolated
sion after 1 h.
in moderate to good yields. When the ortho- and
These conditions are compatible with a range of para-positions of the N-tosylaniline were blocked
substrates as shown in Scheme 1. The desired cross- with methyl groups, the cross-coupling reaction still
coupling products were obtained in good to excellent occurred and gave rise to the product 2u in 50%
À
yields with excellent C3 C3 selectivities. The reaction yield.
was found to tolerate a variety of different groups
Compared with the normal ortho/para substitution,
with different electronic demands on the indole rings, a meta-selective functionalization of aromatic molecu-
both electron-donating and electron-withdrawing lar remains a big challenge and an elusive problem.[10]
groups. Only a trace amount of product was detected Gaunt and co-workers have developed an efficient
À
from the reaction of N-acetylindole. An electron- copper-catalyzed meta-selective C H bond arylation
of anilide with Ph2IOTf.[11] A meta-C H bond cupra-
À
tion was proposed to be the key step. However, our
experimental results indicated that the obtained
C3 C3 coupling product 2 might not be formed via a
similar metal-catalyzed cross-coupling pathway. Al-
though, so far, we cannot be certain of the precise
Table 1. Selection of the copper catalyst.
À
À
mechanism of this selective C3 C3 cross-coupling, the
first step of the reaction is most likely the oxidative
dearomatization of the aniline derivative by iodoben-
zene diacetate to form the intermediate I (Scheme 2).
Entry
Catalyst
Cu(OAc)2 (10 mol%)
Yield [%][a]
When the C-4 substitution is a strong electron-with-
drawing group (CF3), the substrate is electron-poor
and does not show reactivity toward the oxidant.
When the C-4 substitution is methoxy, chloro, or
bromo, the corresponding intermediate is sensitive to
the generated AcOH. In the presence of a trace of
water in the solvent, these intermediates hydrolyze to
form the unreactive p-quinone monosulfonimide. In
the case of N-tosylaniline, the formed intermediate
will undergo an aromatization to form 4-methoxy-N-
tosylaniline followed by a further oxidation to yield
1
2
3
4
5
6
7
8
9
G
13
90
87
68
89
20
87
33
0
Cu(OTf)2 (10 mol%)
ACHTUNGTRENNUNG
CuCl2 (10 mol%)
CuCl (10 mol%)
CuBr2 (10 mol%)
CuI (10 mol%)
CuBr2 (5 mol%)
CuBr2 (1 mol%)
no
[a]
Isolated yield based on 1a.
Adv. Synth. Catal. 2010, 352, 3230 – 3234
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Linfei Wang et al.
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Scheme 1. Reactions of indoles with anilines.
the p-quinone monosulfonimide. When the C-4 substi- cross-coupling product of aniline with indole is
tution is an alkyl or an aryl group, the intermediate I formed.
À
is stable and reactive to the copper-catalyzed addition
In conclusion, we have developed a selective C3
with indoles. After an acid-catalyzed rearomatization C3 oxidative cross-coupling between unactivated ani-
À
of the resultant intermediate II, the selective C3 C3 lines and indoles catalyzed by copper bromide togeth-
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Adv. Synth. Catal. 2010, 352, 3230 – 3234

À
Selective C3 C3 Oxidative Cross-Coupling between Unactivated Anilines and Indoles
Scheme 2. Tentative mechanism for the oxidative coupling of anilines and indoles.
er with iodobenzene diacetate as the oxidant. This Acknowledgements
methodology provides a novel approach to biaryl syn-
Financial support from National Natural Science Foundation
of China (21072033) and Fudan University is gratefully ac-
knowledged.
thesis. Besides optimization for a ꢂgreenerꢀ procedure,
currently studies are underway to extend its scope, to
explore its reaction mechanism and to disclose possi-
ble synthetic applications.
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;
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Adv. Synth. Catal. 2010, 352, 3230 – 3234