Direct C-3 arylation of N-acetylindoles with anisoles using phenyliodine bis(trifluoroacetate) (PIFA)

Article abstract of DOI:10.1016/j.tetlet.2010.02.022

The direct C-3 arylation of N-acetylindoles with anisoles was described in this Letter. In the presence of phenyliodine bis(trifluoroacetate) (PIFA) and BF₃·Et₂O, the reaction of N-acetylindoles with anisoles provided C-3 arylindoles with high regioselectivity under mild conditions.

Full text of DOI:10.1016/j.tetlet.2010.02.022

Tetrahedron Letters 51 (2010) 2004–2006
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Tetrahedron Letters
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Direct C-3 arylation of N-acetylindoles with anisoles using phenyliodine
bis(trifluoroacetate) (PIFA)
*
Yonghong Gu , Dawei Wang
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct C-3 arylation of N-acetylindoles with anisoles was described in this Letter. In the presence of
phenyliodine bis(trifluoroacetate) (PIFA) and BF3ꢀEt2O, the reaction of N-acetylindoles with anisoles pro-
vided C-3 arylindoles with high regioselectivity under mild conditions.
Received 5 December 2009
Revised 2 February 2010
Accepted 5 February 2010
Available online 8 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Indole derivatives are one of the most important structural mo-
tifs found in natural products and pharmaceuticals.1 As an impor-
tant class of indoles, arylindoles exhibit a wide range of biological
activities, such as antibacterial, antifungal, antiprotozoal activities,
gonadotropin-releasing hormone antagonists and h5-HT2A recep-
tor antagonists.2 Therefore, the development of efficient methods
for the syntheses of arylindoles has attracted great research inter-
est in the last several decades.3 Among them, transition metal-cat-
alyzed direct arylation of indoles has been a major objective in the
synthetic community.4 This approach offers the possibility of direct
C–H arylation of indoles with aryl halides, aryl boron compounds.
Several highly selective Pd-catalyzed C-3 arylations of indoles have
been developed by Sames’s5, Zhang and He’s6 Djakovitch’s7 Bellina
and Rossi’s8 groups. In addition, Gaunt and co-workers reported a
Cu(II)-catalyzed C-3 arylation of indoles with aryliodonium salts.9
Remarkably, Fagnou and co-workers proposed a new strategy to
synthesize arylindoles by the Pd-catalyzed direct coupling of N-
acetylindoles with unfunctionalized arenes, both C-2 and C-3 ary-
lindoles could be accessed by changing the Pd concentration and
additives.10 While these methods have proven to be the most pow-
erful towards C-3 arylindoles, some of them suffered disadvan-
tages from using excess transition metals, high temperatures and
limitation of substrate scope. With an increasing emphasis on envi-
ronmentally friendly synthesis, we are prompted to develop green-
er alternatives.
tive cross-coupling of thiophenes and pyrroles using PhI(OH)(OTs)
as an oxidant.13a In addition, Canesi and co-workers reported a no-
vel method for the cross-coupling of N-aryl methanesulfonamide
and thiophenes using PhI(OAc)2.13c To achieve the effective cross-
coupling of two arenes, two aspects have to be considered: (1)
selective activation of one of the aromatic compounds with hyper-
valent iodine reagents. (2) One arene must have a higher nucleo-
philicity than the specific aromatic compound being activated.
Herein, we present a highly regioselective C-3 arylation of N-acet-
ylindoles with anisoles using hypervalent iodine(III) reagents.
Initial attempts at C-3 arylation of free NH indole with anisole
(2a) in the presence of phenyliodine(III) diacetate (PIDA) or pheny-
liodine(III) bis(trifluoroacetate) (PIFA) in various solvents (CH2Cl2,
CF3CH2OH, CH3CN and TFA) at room temperature failed to provide
any desired products; only homodimer 4,40-dimethoxybiphenyl
was observed. Gladly, when N-acetylindole was subjected to the
1.5 equiv of PIFA and 1.0 equiv of 2a in CH2Cl2 at room temperature
for 24 h, the desired C-3 arylindole 3a was obtained in 30% yield
with 20% of homodimer 4,40-dimethoxybiphenyl as a byproduct
(Table 1, entry 1). When excess 2a (2.0 equiv) was used, the prod-
uct 3a was obtained with a better yield (entry 2). Notably, activa-
tion of PIFA with Lewis acid BF3ꢀOEt2 improved the reaction
dramatically (entry 3).14 In contrast, PIDA was ineffective in this
transformation (entry 4). After careful optimization of the reaction
conditions (solvent and temperature), the best result was achieved
when the reaction was carried out in the presence of 1.5 equiv of
PIFA and 1.5 equiv of BF3ꢀOEt2 in CH2Cl2 at 35 °C (entry 8).
Recently, utilization of hypervalent iodine compounds as metal-
free reagents in oxidative reactions received great attention for
their low toxicity and mild reaction conditions.11 Many new appli-
cations of hypervalent iodine compounds in C–C bond formation
have been developed.12 However, few examples of direct cross-
coupling of two arenes with hypervalent iodine compounds were
reported due to the difficulty to control homodimer formation
and regioselectivity.13 Kita and co-workers achieved a highly selec-
With optimized conditions in hand, we started on an investiga-
tion of the reaction scope (Table 2). In the presence of 1.5 equiv of
PIFA and 1.5 equiv of BF3ꢀOEt2 in CH2Cl2, the coupling reaction of
N-acetylindoles 1 with anisoles 2 proceeded smoothly to give only
C-3 arylated products 3, no C-2 arylindoles were observed in this
transformation. Notably, this coupling reaction occurred only at
the para-position of anisole, no coupling product at the ortho-posi-
tion of anisole was detected either. The reaction is compatible with
both electron-withdrawing and electron-donating groups on the
* Corresponding author. Tel.: +86 551 3602470; fax: +86 551 3601592.
E-mail address: ygu01@ustc.edu.cn (Y. Gu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.022

Y. Gu, D. Wang / Tetrahedron Letters 51 (2010) 2004–2006
2005
Table 1
Table 2
Optimization of reaction conditions for the direct oxidative coupling of N-acetylin-
Oxidative cross-coupling of N-acetylindoles with anisoles using PIFAa
doles and anisolesa
OMe
OMe
OMe
R1
R1
PIFA (1.5equiv)
OMe
BF3.OEt2 (1.5 equiv)
R2
+
Oxidant (1.5 equiv)
CH2Cl2, 35 oC, 10 h
N
+
R2
N
Additive (1.5 equiv)
solvent, rt
Ac
N
N
Ac
3
1
2
Ac
Ac
3a
1a
2a
Entry
Indole
Anisole
Product
Yieldb (%)
Entry
Oxidant
Additive
Solvent
Yieldb (%)
1
R1
2
R2
3
1
2
3
4
5
6
7
8
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
None
None
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CF3CH2OH
TFA
30c
41
56
0
50
0
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
1a
H
NO2
CO2CH3
OCH3
Br
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
60
85
75
35
67
53
72
61
76
80
0
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
H
2-Me
3-Me
3-t-Bu
2-OMe
3-OMe
2-CO2Me
2-Br
2-l
CH3CN
CH2Cl2
0
60d
a
Unless otherwise specified, all the reactions were carried out using 0.2 mmol of
1a, 0.4 mmol of 2a, 0.3 mmol of oxidant and 0.3 mmol of additive in 1 mL solvent at
room temperature for 24 h.
3j
2g
2h
2i
b
3k
3l
25
23
Isolated yield after column chromatography.
0.2 mmol of 2a was employed.
The reaction was carried out at 35 °C for 10 h.
c
H
d
a
Reactions were carried out using 0.2 mmol of 1, 0.4 mmol of 2, 0.3 mmol of PIFA
and 0.3 mmol of BF3ꢀOEt2 in 1 mL of CH2Cl2 at 35 °C for 10 h.
b
Isolated yield after column chromatography.
indole substituents. The electron-withdrawing substituents on the
indole facilitate the reaction. For example, when a strong electron-
withdrawing group, such as nitro or ester, was introduced to 5-po-
sition of N-acetylindole, the reaction provided the corresponding
products 3b and 3c in 85% and 75% yields, respectively (entries 2
and 3). However, when an electron-donating group, such as meth-
oxy, was introduced to the 5-position of N-acetylindole, the reac-
tion was much less efficient and the coupling product 3d was
obtained in a lower yield with some unidentified polar byproducts
(entry 4). Importantly, this reaction tolerates halogen substituents
which serve as valuable synthetic handles for further manipulation
of the product. The coupling reaction of N-acetyl-5-bromoindole
(1e) with 2a proceeded well to give the product 3e in 67% yield
(entry 5). Next, we examined the substitution effect on the ani-
soles. The reaction of 2-methylanisole (2b) with N-acetylindole
(1a) provided the product 3f in 53% yield (entry 6). Comparably,
when the methyl group was introduced to the meta-position of
anisole, the reaction gave the product 3g in 72% yield (entry 7).
Furthermore, when the bulky t-butyl group was substituted at
the meta-position of anisole, the reaction provided the correspond-
ing product 3h in a slight lower yield, probably due to steric hin-
drance (entry 8). On the contrary, electron-donating groups on
the anisoles favored this transformation. The reactions of 2-meth-
oxyanisole (2e) and 3-methoxyanisole (2f) with N-acetylindole
(1a) afforded the products 3i and 3j in 76% and 80% yields, respec-
tively (entries 9 and 10). However, when an electron-withdrawing
group, such as ester, was introduced to the ortho-position of ani-
sole, the reaction failed to occur at room temperature or elevated
temperature (60–70 °C) (entry 11).15 This could be attributed to
the fact that the electron-withdrawing group significantly lowers
the nucleophilicity of anisole. Finally, when bromine and iodine
were substituted at the ortho-position of anisole, the reactions gave
the coupling products 3k and 3l in moderate yields. Notably, these
products are generally difficult to prepare with Pd-catalyzed cross-
coupling reactions due to the incompatibility of C–Br and C–I
bonds with the metal catalysts.
A possible mechanism of PIFA-induced C-3 arylation of N-acety-
lindoles is proposed in Scheme 1. The mechanism of this reaction
proceeds through a radical cation intermediate generated by single
electron transfer (SET) process, similar to that previously postulated
Path a:
OMe
R2
OCOCF3
Ph
OCOCF3
R1
I
R1
R1
PIFA
SET
e-
2
N
N
N
Ac
OMe
Ac
e-, 2H+
Ac
1
B
A
R1
R2
Path b:
R1
OCOCF3
OCOCF3
OMe
N
Ph
OMe
Ac
3
I
N
OMe
SET
Ac
PIFA
1
R2
R2
R2
e-
e-, 2H+
2
C
D
Scheme 1. Proposed mechanism for oxidative cross-coupling of N-acetylindoles with anisoles induced by PIFA.

2006
Y. Gu, D. Wang / Tetrahedron Letters 51 (2010) 2004–2006
for the oxidative cross-coupling of two arenes by PIFA.13b First, PIFA
coordinates with N-acetylindoles to form complex A, followed by
SET to generate radical cation intermediate B (Path a). Trapping
the intermediate B by anisoles followed by one electron transfer
and deprotonation leads to the coupling product 3. Another possible
way is that PIFA coordinates with anisole to form complex C firstly to
generate radical cation intermediate D, which is attacked by N-acet-
ylindoles to provide the coupling product 3 (Path b).
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12. For recent examples of hypervalent iodine reagents in oxidative C–C bonds
formation reaction, see: (a) Liang, J.; Chen, J.; Du, F.; Zeng, X.; Li, L.; Zhang, H.
Org. Lett. 2009, 11, 2820; (b) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417; (c)
Ye, Y.; Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156; (d) Dohi, T.; Minamitsuji, Y.;
Maruyama, A.; Hirose, S.; Kita, Y. Org. Lett. 2008, 10, 3559; (e) Dohi, T.;
Morimoto, K.; Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.;
Kita, Y. J. Org. Chem. 2007, 72, 109; (f) Dohi, T.; Morimoto, K.; Maruyama, A.;
Kita, Y. Org. Lett. 2006, 8, 2007; (g) Dohi, T.; Morimoto, K.; Kiyono, Y.;
Maruyama, A.; Tohma, H.; Kita, Y. Chem. Commun. 2005, 2930; (h) Dohi, T.;
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2001, 66, 59.
In conclusion, we have developed a novel method for the direct
oxidative cross-coupling of N-acetylindoles with anisoles to pro-
vide C-3 arylindoles using PIFA as an oxidant. The attractive fea-
tures of these reactions are
a metal-free procedure, high
regioselectivity and mild conditions. Further work on hypervalent
iodine-mediated cross-coupling reactions of other heterocyclic
compounds with arenes is underway in our laboratory.
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 20602033) and National Basic Research Pro-
gram of China (2006CB922001) for financial support.
References and notes
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14. Lewis acid BF3ꢀOEt2 usually improved the PIFA-mediated oxidative coupling
reaction. It is believed that trifluoroacetoxy ligand of PIFA might coordinate to
BF3ꢀOEt2 and generate a reactive cationic iodine(III) intermediate. See Ref. 13b
and references cited therein.
15. Most of starting 2-methoxycarbonylanisole (2g) was recovered and N-
acetylindole (1a) was slowly decomposed during the extended reaction
times or at the elevated temperatures.