Highly effective and regioselective Michael addition of indoles to α,β-unsaturated ketones promoted by pentafluorophenylammonium triflate

Article abstract of DOI:10.1016/j.crci.2012.08.002

A simple, inexpensive, environmentally friendly and efficient route for Michael addition of indoles to α,β-unsaturated ketones using pentafluorophenylammonium triflate (PFPAT) as a catalyst is described. Various indole derivatives were synthesized in good

Full text of DOI:10.1016/j.crci.2012.08.002

C. R. Chimie 16 (2013) 144–147
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Highly effective and regioselective Michael addition of indoles to
-unsaturated ketones promoted by pentafluorophenylammonium
triflate
a,b
*
Samad Khaksar , Seyed Mohammad Vahdat, Fatemeh Rezaee
Chemistry Department, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
A B S T R A C T
A R T I C L E I N F O
Article history:
A simple, inexpensive, environmentally friendly and efficient route for Michael addition of
Received 27 May 2012
indoles to
a,b-unsaturated ketones using pentafluorophenylammonium triflate (PFPAT)
Accepted after revision 7 August 2012
Available online 15 September 2012
as a catalyst is described. Various indole derivatives were synthesized in good to excellent
yields. The preparation of PFPAT catalyst from simple and readily available starting
materials makes this method more affordable.
Keywords:
Organocatalyst
Michael
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Regioselective
Ketone
1. Introduction
However, the acid catalyzed addition of indoles on olefin
often requires careful control of the acidity to prevent side
The Michael reaction of indoles with
a
,
b
-unsaturated
reactions such as dimerization, isomerization, and poly-
merization, etc. Furthermore, acidic conditions also
prevent the use of acid-labile substrates. As a result,
carbonyl compounds is one of the most important organic
transformations and plays a key role in the total synthesis
of complex natural products such as diolmycins [1] and
hapalindole [2]. Many indole ligands with high-affinity for
G-protein coupled receptors have been identified [3]. The
hapalindole alkaloids are mostly obtained from the blue-
green algae Hapalosiphon fontinalis [2] and exhibit potent
antibacterial and antimycotic activity [4]. They are
accessed by Friedel-Crafts Michael type addition of indole
to electron-deficient olefins in the presence of either protic
[5] or Lewis acids [6–8]. Existing methods of synthesis
require metal catalysts and stoichiometric amounts of the
reagents with cumbersome isolation procedures and
longer reaction times. The extra expense and effort to
process this inevitably generated toxic metal waste hinder
them from being adopted for large scale synthesis.
excess amounts of indoles or
a,b-unsaturated carbonyl
compounds are required to obtain high yields in many
cases. In view of these drawbacks, the synthetic protocols
utilizing new catalysts devoid of metals are becoming
more important due to the growing concern for sustainable
chemistry. The metal (ion)-free catalysis of organic
reactions is a contemporary challenge that is just being
taken up by chemists [9]. Recently, pentafluorophenylam-
+
¯
monium triflate (C6F5N H3.OTf; PFPAT) has received
increasing attention as a water-tolerant Brønsted acid
catalyst for organic synthesis demonstrating highly
chemo-, regio- and stereoselective results [10]. Compared
to conventional Lewis acids, it has advantages of water
stability, recyclability, operational simplicity, strong toler-
ance to oxygen and nitrogen-containing substrates and
functional groups, and it can often be used in catalytic
amounts. In continuation of our investigations on the
development of new synthetic methodologies [11], we
* Corresponding author.
E-mail addresses: S.khaksar@iauamol.ac.ir,
Samadkhaksar@yahoo.com (S. Khaksar).
herein report
a new, convenient, mild and efficient
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.08.002

S. Khaksar et al. / C. R. Chimie 16 (2013) 144–147
145
R3
O
O
R4
R2
R2
PFPAT(10 mol%)
+
R3
R4
N
r.t, 5 h
2
1
R1
N
R1
3a- n
R1= H, Me
R2= H, OMe, Br
Scheme 1. C3-Alkylation of indole with enone.
procedure for Michael addition of indoles to
a
,
b
-unsatu-
PFPAT was sufficient to obtain the corresponding 3-alkylated
product in 95% yield within 5 h at room temperature in
CH3CN using 2-cyclohexen-1-one (Table 1, entry1).
rated ketones in the presence of pentafluorophenylam-
monium triflate (PFPAT) as an effective and novel
organocatalyst under mild reaction conditions (Scheme 1).
With the reaction conditions being optimized, we
extended the scope to a variety of different indoles and
enones. Substituted indoles such as 5-methoxy, 5-bromo, and
N-methyl derivatives participated well in this reaction (Table
1, entries 2, 6–7). In addition, various electron-deficient
olefins such as benzylideneacetophenone, benzylideneace-
tone, methyl vinyl kethone, 1-cyclohex-2-enone and
1-cyclopent-2-enone were examined for this transformation.
2. Results and discussion
First, we studied the reaction of 2-cyclohexen-1-one with
indole (1:1 molar ratios) in order to optimize the reaction
conditions with respect to temperature, time, and the molar
ratio of PFPAT to the substrate. We found that 10 mol% of
Table 1
Pentafluorophenylammonium triflate catalyzed Michael addition of indoles to enones.
Entry
1
Enone
Indole
Product
3a
Yield %ref
95[7d]
O
N
H
2
3
3b
3c
90[8e]
O
N
90[8e]
O
N
H
4
5
6
7
8
3d
3e
3f
92[7d]
95[7d]
90[8e]
90[8e]
92[8c]
O
O
O
O
O
O
N
H
N
Br
N
H
3g
3h
MeO
N
H
N
H
9
3i
85[8c]
N

146
S. Khaksar et al. / C. R. Chimie 16 (2013) 144–147
Table 1 (Continued )
Entry
10
Enone
Indole
Product
3j
Yield %ref
92[8e]
Br
O
O
N
H
11
3k
80[8e]
MeO
N
H
12
13
3l
85[8c]
O
O
N
H
3k
80[8e]
Br
N
H
14
15
3m
3n
90[8e]
Cl
O
O
N
H
90[8c]
N
As shown in Table 1 (entries 1–15), all examples reacted
smoothly at room temperature for 5 h, and the isolated yields
were good in almost all cases (80–95%). The yields were not
sensitive to the substrates employed. Nearly all reactions are
similarly in isolated yields, and the reaction is clean with no
formation of side products like dimers or trimers, which are
normally observed by the influence of strong acids. We also
examined the effect of solvents. While the best yield was
obtained in acetonitrile, much lower yields were observed
with other solvents (dichloromethane and toluene).
In addition, the PFPAT catalyst was easily removed from
the reaction mixture after work-up, by washing with an
aqueous NaOH solution to remove the CF3SO3H, followed
by distillation under reduced pressure (C6F5NH2: bp 153 8C
at 760 mmHg).
existing methods using potentially hazardous catalysts/
additives, the present method offers the following
competitive advantages:
(i) PFPAT is easy to prepare from commercially available
pentafluoroaniline and triflic acid;
(ii) short reaction time;
(iii) ease of product isolation/purification by non-aqueous
work-up;
(iv) no side reaction;
(v) low costs and simplicity in process and handling and;
(vi) the corresponding 3-alkylated indoles are produced by
an environmentally benign process.
3. Experimental
Mechanistically, the reaction proceeds via the activa-
tion of enone by PFPAT followed by indole addition on
olefin. The resulting intermediate undergoes subsequent
tautomerization to give the C3-alkylated product as shown
in Scheme 2.
3.1. Typical experimental procedure
A mixture of indole (1 mmol),
a,b-unsaturated ketone
In summary, we describe a mild, clean and efficient
(1 mmol), and PFPAT (0.04 g), was stirred at r.t. in a vial.
After completion of the reaction as indicated by TLC, the
organic phase was washed with 1 M NaOH aqueous
solution (1 ml). The separated organic phase was evapo-
rated under reduced pressure to give a crude residue,
which was purified by recrystallization (solid product) or
by column chromatography (hexane–EtOAc). Products
were characterized by comparison of their physical and
spectral data with those of authentic samples. Spectro-
scopic data for selected examples follow:
protocol for the conjugate addition of indoles to
a,b-
unsaturated ketones using pentafluorophenylammonium
triflate (PFPAT) as a new organocatalyst. In contrast to the
PFPAT
O
O
..
N
PFPAT
H
ꢀ
3a: 1H NMR (400 MHz,CDCl3):
d= 1.75–2.04 (m, 3H), 2.20
(m, 1H), 2.35–2.55 (m, 2H), 2.61 (m, 1H), 2.77 (m, 1H),
O
3.42 (m, 1H), 6.92 (d, 1H, J = 2.0 Hz), 7.08–7.61 (m, 4H),
8.17 (br s, 1H, NH);13C NMR (100 MHz, CDCl3):
d= 24.9,
H
31.8, 36.0, 41.6, 48.1, 111.4, 119.1, 119.4, 119.6, 120.5,
122.2, 126.2, 136.5, 212.2; IR (KBr): 3337, 3179, 2904,
2853, 1706, 1638, 1443 cmÀ1; MS (EI): m/z = 213;
O
N
N
H
ꢀ
3d: 1H NMR (400 MHz, CDCl3):
d
= 3.72 (dd, J = 7.6, 7.6 Hz,
Scheme 2. A plausible reaction mechanism.
1 H); 3.81 (dd, J = 6.8, 6.8 Hz, 1 H), 5.07 (t, J = 7.2 Hz, 1 H),

S. Khaksar et al. / C. R. Chimie 16 (2013) 144–147
147
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