Palladium-catalyzed functionalization of indoles with 2-acetoxymethyl substituted electron-deficient alkenes

Article abstract of DOI:10.1016/j.tetlet.2004.08.178

The Pd-catalyzed cross coupling of indole with 2-acetoxymethyl-substituted electron-deficient alkenes under mild conditions was reported. A new functionalization of indoles via palladium-catalyzed reaction of indoles and 2-acetoxymethyl substituted electron-deficient alkenes is reported. The reaction was carried out under neutral condition and no isomerization of the carbon-carbon double bond was observed.

Full text of DOI:10.1016/j.tetlet.2004.08.178

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8419–8422
Palladium-catalyzed functionalization of indoles with
2-acetoxymethyl substituted electron-deficient alkenes
Shengming Ma* and Shichao Yu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, PR China
Received 11 June 2004; revised 23 August 2004; accepted 27 August 2004
Abstract—A new functionalization of indoles via palladium-catalyzed reaction of indoles and 2-acetoxymethyl substituted electron-
deficient alkenes is reported. The reaction was carried out under neutral condition and no isomerization of the carbon–carbon
double bond was observed.
Ó 2004 Elsevier Ltd. All rights reserved.
Indoles are a class of intensively studied heterocycles,
which are important subunits in many naturally occur-
ring biologically active compounds.1,2 For example,
NVP-LAQ824,2a currently undergoing human clinical
trials, is a potent HDAI and antitumor agent against
both solid tumors and leukemia while the Teleocidin
family2b is a class of tumor promoters. Thus, functionaliz-
ation at the 3-position of indole skeleton is of great
importance for the synthesis of indole derivatives with
potential biological activities Figure 1.3,4
The Lewis acid-catalyzed alkylation between indoles
and an electrophile is a well-established method for
the functionalization at the 3-position of the indole
nucleus,3 however, the necessity to utilize a stoichiometric
amount of Lewis acid does not meet the contemporary
requirement for green chemistry. On the other hand,
palladium-catalyzed Heck reactions of 3-halo-substi-
tuted indoles5 and palladium-catalyzed nonselective
Friedel–Crafts allylation of indoles with allyl acetate,
allylic alcohols, 1,3-dienes,6 affording a mixture, have
also been reported. Herein, we wish to present the first
report on the coupling of 2-acetoxymethyl-substituted
electron-deficient alkenes with indoles affording 3-func-
tionalized indole derivatives bearing a conjugated
carbon–carbon double bond in a highly regioselectivity
(Scheme 1). In addition, this new approach makes it
possible to install an electron-deficient carbon–carbon
double bond ready for further elaboration at an almost
unprecedented position.
H
N
O
OH
Me
H
N
HN
N
OH
In an initial attempt, we examined the reaction of 1a
with 2-acetoxymethyl acrylic acid methyl ester in 1,4-
dioxane under several combinations of Pd(OAc)2 with
monodentate or bidentate nitrogen ligands. With the
O
OH
N
H
R
N
H
teleocidin family
NVP-LAQ824
Figure 1.
OAc
EWG
?
+
EWG
Keywords: Palladium; C–H activation; Indoles; 2-Acetoxymethyl sub-
stituted electron-deficient alkene.
cat. Pd
N
H
N
H
*
Corresponding author. Tel.: +86 21 6416 3300; fax: +86 21 6416
7510; e-mail: masm@mail.sioc.ac.cn
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.178

8420
S. Ma, S. Yu / Tetrahedron Letters 45 (2004) 8419–8422
Table 1. Ligand effects on the Pd-catalyzed coupling of 1a with 2-acetoxymethyl acrylic acid methyl ester7
5% Pd(OAc)2
OAc
ligand
CO2Me
CO2Me
+
1,4-dioxane
N
H
N
H
1a
2a
Entry
1
Ligand
Temp. (°C)
Time (d)
3
Yield of 2a (%)
0
80
80
N
CO2Et
2
3
3
3
0
N
N
NH2
N
80
10
4
80
80
4
3
9
N
N
5
57
N
N
N
N
6a
100
80
2
1
0
0
b
7
Pd(PPh3)4
a No Pd(OAc)2 was added.
b Pd(PPh3)4 was used as the catalyst.
Table 2. Pd-catalyzed coupling of indoles 1 with 2-acetoxymethyl acrylic acid methyl ester8
H
N
R
5% Pd(OAc)2
10% bipyridine
H
N
OAc
CO2Me
+
R
1,4-dioxane
80 oC
CO2Me
1
1 : 1
2
Entry
1
Indole
Product
Time (d)
Yield of 2 (%)
1b
CO2Me
N
H
3
45
2b
N
H
CO2Me
2
3
1c
2c
2
2
66a
N
H
N
H
CO2Me
1d
2d
33
(52)a
N
H
Br
N
H
Br
MeO
CO2Me
MeO
4
1e
2e
2
50
53
N
H
N
H
OMe
OMe
CO2Me
CO2Me
5
6
1f
2f
3
3
N
H
N
H
Br
Br
1g
2g
37
(48)a
N
H
N
H
a 10mol% of Pd(OAc)2 was used as catalyst.

S. Ma, S. Yu / Tetrahedron Letters 45 (2004) 8419–8422
8421
addition of 20mol% of pyridine (Table 1, entry 1) or
H
N
ethyl nicotinate (Table 1, entry 2), no cross coupled
product 2a was observed. However, when bidentate
nitrogen ligands 4-amino-1,8-naphthyridine (Table 1,
entry 3) and 1,10-phenanthroline (Table 1, entry 4) were
used, we obtained 2a in 10% and 9% yields, respectively.
In an effort to improve the yield of the reaction, we next
examined bipyridine derivatives as ligands. To our
delight, the catalytically active complex arising from 5%
Pd(OAc)2 and 10% bipyridine in 1,4-dioxane gave the
desired cross coupled product in 57% isolated yield
(Table 1, entry 5). We also screened some substituted
bipyridines, but the results are not impressive (See Sup-
porting Information). It is important to note that the
reaction in the absence of bipyridine and Pd(OAc)2
did not result in the formation of product 2a (Table 1,
entry 6).
10% bpy
5% Pd(OAc)2
H
N
OAc
CN
tert-amyl alcohol
+
80 oC, 3 d
56%
CN
1a
3a
H
N
10% bpy
5% Pd(OAc)2
H
OAc O
N
+
tert-amyl alcohol
80 oC, 3 d
61%
O
1a
Scheme 2.
4a
A variety of indoles were next examined to generate the
desired coupling products under the standard conditions
(Table 2, entry 5). The results are summarized in Table
2. The yield of this reaction is generally modest. It is
interesting to see that a bromo substituent is compatible
under the cross coupling conditions (Table 2, entries 3
and 6).
out in an atmosphere of air, and a bromo substituent
can be tolerated implied a Pd(II)-catalyzed mechanism.
Although intermediate A10,11 followed by an intermo-
lecular carbopalladation with the allylic acetate would
provide intermediate B, Pd(OAc)2-mediated direct for-
mation of intermediate B may also be possible.3,12 b-
OAc elimination of intermediate B would lead to the
product and regenerate Pd(OAc)2 (Scheme 3).13
In addition, the reaction is not limited to 2-acetoxy-
methyl acrylic acid methyl ester. 2-Acetoxymethyl
acrylonitrile and 3-acetoxymethylbut-3-en-2-one are
also effective affording 3a and 4a in tert-amyl alcohol
in 56% and 61% yields, respectively (Scheme 2). It
should be noted that the results in 1,4-dioxane are not
good.
In conclusion, we have developed a Pd-catalyzed cross
coupling of indole with 2-acetoxymethyl-substituted
electron-deficient alkenes under mild conditions via regio-
selective functionalization of indoles. This reaction was
carried out under neutral conditions and does not require
the use of any additive. Compared with the Lewis acid-
catalyzed conjugate addition, this protocol is efficient
and may open up a new area for the functionalization of
indoles. Further studies including the mechanistic study
in this area are being carried out in our laboratory.
The presence of an electron-withdrawing group is neces-
sary since no reaction was observed with simple allyl
acetate. Although the mechanism may not be very
clear,9 the facts that no reaction was observed with
Pd(PPh3)4 (Table 1, entry 7), the reaction can be carried
OAc
OAc
CO2Me
MeO2C
PdOAc
N
bipyridine
HOAc
N
+
Pd(OAc)2
R
R
N
H
N
H
1
B
β− OAc elimination
.
N
N
Pd(OAc)2 bipyridine
PdOAc
R
N
H
CO2Me
A
R
N
H
2
Scheme 3.

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S. Ma, S. Yu / Tetrahedron Letters 45 (2004) 8419–8422
7. In the reactions affording the product in low yields, the
formation of a Pd mirror was usually observed.
Acknowledgements
8. Typical procedure: a reaction tube equipped with a
magnetic stirring bar was charged with indole 1a
(117mg, 1mmol), 2-acetoxymethyl acrylic acid methyl
ester (158mg, 1mmol), Pd(OAc)2 (5mol%, 12mg), bipyr-
idine (10mol%, 18mg), and 1,4-dioxane (2mL). Then the
tube was heated to 80°C and allowed to stir for 3days (the
reaction was monitored by TLC). Filtration of the
reaction mixture through a small pad of silica gel
(Et2O), concentration and purification of the dark oil by
flash chromatography on silica gel (ether/petroleum
Financial support from the National Natural Science
Foundation of China and the Major State Basic
Research Development Program is greatly appreciated.
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1
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