Al(OTf)3 catalysed Friedel-Crafts Michael type addition of indoles to α,β-unsaturated ketones with PEG-200 as recyclable solvent

Article abstract of DOI:10.1071/CH13254

An Al(OTf)₃ catalysed efficient Friedel-Crafts Michael type addition of indoles to α,β-unsaturated ketones using recyclable PEG-200 as an alternative reaction solvent is disclosed. The reaction under microwave irradiation is clean, leads to exc

Full text of DOI:10.1071/CH13254

CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 1594–1599
Communication
http://dx.doi.org/10.1071/CH13254
Al(OTf) Catalysed Friedel-Crafts Michael Type Addition
3
of Indoles to a,b-Unsaturated Ketones with PEG-200
as Recyclable Solvent
A
A
A
Mukut Gohain, Jc Jacobs, Charlene Marais,
,
A B
and Barend C. B. Bezuidenhoudt
A
Department of Chemistry, University of the Free State, PO Box 339,
Bloemfontein 9300, South Africa.
B
Corresponding author. Email: bezuidbc@ufs.ac.za
An Al(OTf) catalysed efficient Friedel–Crafts Michael type addition of indoles to a,b-unsaturated ketones using
3
recyclable PEG-200 as an alternative reaction solvent is disclosed. The reaction under microwave irradiation is clean,
leads to excellent yields in minutes and reduces the use of volatile organic compounds.
Manuscript received: 14 May 2013.
Manuscript accepted: 31 August 2013.
Published online: 6 November 2013.
The indole nucleus is frequently found in pharmaceuticals and
has become widely identified as a ‘privileged’ structure for
pharmacophores displaying a broad range of biological activi-
their low vapour pressure, which minimises diffusion to the
[7]
atmosphere. However, ionic liquids comprise a very hetero-
geneous group of fluids that are not intrinsically green; some are
toxic and non-biodegradable, as seen in recent reviews on their
[
1]
ties. In this regard the indole framework is represented in
over 3000 naturally isolated and 40 medicinal agents identified
[
8]
biodegradability and environmental impact. Polyethylene
glycol (PEG) has recently been found to be a green solvent
[2]
for a range of diverse therapeutic actions. Among these,
-substituted indole moieties are very important and are pre-
cursors in the synthesis of various naturally occurring and
[
9]
system useful in many applications,
[10]
3
particularly in sub-
stitution, oxidation, and reduction reactions. Low cost, low
flammability, low toxicity, recyclability, the completely non-
halogenated composition, facile degradability, and its miscibi-
lity with a wide variety of organic solvents/compounds are
some of the properties that render PEG a benign alternative
[
3]
synthetic potential drugs. The Friedel–Crafts (FC) Michael
type addition of indole to a,b-unsaturated ketones, catalysed by
either protic acids (SiO -H SO , Bu NHSO ), Lewis acids
2
2
4
4
4
[GaI , SmI , InBr , CuCl , CeCl , Zr(OTf) , Bi(OTf) ,
3 3 3 2 3 3 3
[
11]
NaAuCl4, (salen)AlCl; salen ¼ 1,2-Bis(salicylideneamino)
solvent in organic synthesis.
Owing to their good biocom-
ethane], or other reagents (NO, I ), represent an important
2
patibility and low immunogenicity, PEGs are on the Food and
Drug Administration’s (FDA’s) GRAS (Compounds Generally
Recognised as Safe) list, and have been approved by the FDA
synthetic tool towards the preparation of these sought after
3
[4]
-substituted indole derivatives. Many of these methods are,
[
12]
however, hampered by harsh reaction conditions, toxic reagents,
high catalyst load, expensive catalysts, prolonged reaction times,
volatile and toxic solvents, poor yields, and low selectivity.
Green chemistry is becoming increasingly important in
for internal consumption.
covered PEG chemistry and its applications in biotechnology
Several recent reviews have also
[
13]
and medicine.
The use of metal triflates in organic synthesis has been well
[14]
documented; the main advantages of these compounds being
[5]
organic synthesis.
The development of environmentally
and economically more benign FC reactions that first requires
only catalytic amounts of a metal or acid catalyst and that
second can be performed in an environmentally benign solvent,
is thus desirable.
potent Lewis acidity, water tolerance, and low cost. Among
various metal triflates, Al(OTf) has attracted our attention as a
3
desirable catalyst from an environmental point of view as it
contains a readily available, non-toxic, cheap metal, and is
[
15]
Solvents commonly used in organic synthesis are often
flammable in nature, toxic, and volatile with subsequent poor
solvent recovery. Attempts have thus been made to develop
solvent-free chemistry, which, to some extent, have been suc-
furthermore highly water tolerant.
In our recent literature search, we have further noticed that
though various methodologies have been reported for the
synthesis of 3-substituted indoles via FC Michael type addition
[
6]
[16]
[17]
cessful for a few transformations. However, in performing the
majority of organic reactions, solvents play a critical role in
rendering the process homogeneous and for allowing efficient
molecular interactions. Ionic liquids have been extensively used
as a green alternative to traditional organic solvents because of
in green ionic liquids, or supercritical fluids, polyethylene
glycol has never been explored as a green solvent in this
[
18]
[19]
regard,
ther with Sc(OTf) as a surfactant in a supercritical fluid system
although Kobayashi and Komoto
did use it toge-
3
for the preparation of 3-substituted indoles. In continuation of
www.publish.csiro.au/journals/ajc
Journal compilation Ó CSIRO 2013

Al Triflate Catalysed Addition of Indoles to Ketones
1595
Al(OTf)3
ϩ
A
B
N
PEG-200
O
H
O
N
1a
2a
Scheme 1. Synthesis of 3-substituted indole by Al(OTf)
H
3aa
3
catalysis in PEG-200.
A
our interest in the applications of Al(OTf) as a Lewis acid
3
Table 1. Optimisation of the FC reaction between 1a and 2a
[
15a]
catalyst for various organic transformations,
would like to report an efficient Al(OTf) -catalysed FC Michael
we herein
3
3
Entry Al(OTf) [mol-%] PEG [mL] T [8C] Time [min] Yield [%]
type addition of indole to a,b-unsaturated ketones in the readily
available polymer solvent, polyethylene glycol (PEG-200),
which is non-toxic, inexpensive, of low volatility and reusable,
and gave only the 1,4-addition products.
To optimise reaction conditions, initial reactions were per-
formed with indole 1a (1 mmol) and a,b-unsaturated ketone 2a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5.0
1.0
0
2
60
70
80
90
100
80
80
80
80
80
100
80
90
rt
20
16
10
6
85
90
96
88
86
87
90
2
2
2
2
4
1
6
(
2
1.15 mmol) by using 2.5 mol-% of aluminum triflate in PEG-
00 as solvent (2 mL) at different temperatures (Scheme 1). The
3
16
20
8
B
2
90
90
86
–
2
rate of the reaction increased with increasing temperature and
we were pleased to find that the reaction was completed within
0
1
2
3
4
5
2
20
12
15
25
12h
65
2
1
0 min under microwave irradiation (300 W, power cycling
C
2.5
2.5
2.5
2.5
2
89
96
60
95
method) at 808C to give the desired product 3aa in excellent
yield (Table 1, entries 1–5). At temperatures above 808C, yields
decreased due to decomposition of the product. Below 808C
starting materials were recovered (Table 1, entries 1 and 2),
while a reduction in microwave power to below 300 W led to
prolonged reaction times accompanied by a reduction in yield
D
2
2.5
2
D
80
A
Reaction conditions: Microwave irradiation (300 W) of indole 1a (1 mmol)
and chalcone 2a (1.15 mmol) in PEG-200 with Al(OTf)
B
3
as catalyst.
Microwave power 200 W.
(
Table 1, entry 8).
To determine the effectiveness of the catalyst, reactions were
C
PEG-400 used as solvent.
D
Conventional heating.
run at different concentrations of Al(OTf) (1, 2.5, and 5 mol-%)
3
in PEG-200 at 808C with microwave irradiation (300 W) and
2
(
1
.5 mol-% was found to be the optimum catalyst concentration.
Table 1, entries 3, 9, and 10). Decreasing the catalyst load to
mol-% reduced the rate of the reaction significantly and also
The same reaction was also executed at room temperature
and under conditions of conventional heating. Although some
product was formed at room temperature, the reaction pro-
gressed much slower and only 60 % of the product was isolated
after 12 h of stirring (Table 1, entry 14). As expected, the
reaction was accelerated along with an increase in yield when
the temperature was raised to 808C where it was completed
within 65 min with a yield comparable to that found during
microwave heating (Table 1, entry 15 versus entry 3). In all
subsequent reactions, indole 1 (1 mmol) and a,b-unsaturated
ketone 2 (1.15 mmol, 1.15 equiv.) dissolved in PEG-200 (2 mL)
were thus subjected to microwave irradiation (300 W) at 808C
in the presence of 2.5 mol-% Al(OTf)3.
had a negative impact on the yield (Table 1, entry 10 versus 3).
Higher catalyst loading (5 mol-%) increased the rate of the
reaction slightly, but led to a reduction in yield due to either
decomposition of the product or the occurrence of side reactions
(Table 1, entry 9 versus 3). As expected, if the Al(OTf) is
3
omitted from the reaction mixture, no reaction could be detected
(
Table 1, entry 11).
It was also observed that the rate and yield of the reaction is
affected by the polarity of the polyethylene glycol being used as
solvent. If PEG-400 was employed as solvent, the reaction rate
dropped down and yields were reduced to 89 % (Table 1, entry
12). The negative impact on yield could probably be ascribed to
the higher polarity of PEG-400 when compared with that of the
To investigate the scope and general applicability of the
reaction, indoles having electron withdrawing (1b and 1c,
Table 2, entries 2 and 3) and electron donating groups (1d,
Table 2, entry 4) on the benzenoid ring were reacted with
chalcone 2a to give the 3-substituted products. We also explored
the FC Michael addition of N-methyl 1e, 2-methyl 1f, and
2-phenyl 1g indoles (Table 2, entries 5, 6, and 20) to enone
[
12]
lower molecular weight PG-200.
To optimise the quantity
of PEG-200 in the reaction, indole 1a and chalcone 2a dissolved
in 1, 2, and 3 mL of PEG-200 per mmol of indole 1a, were
subjected to microwave irradiation (300 W) at 808C at a catalyst
load of 2.5 mol-% (Table 1, entries 3, 6, and 7). Decreasing the
PEG from 2 to 1 mL had a negative impact on the yield and led to
the formation of impurities (Table 1, entry 6 versus 3), whereas
increasing the quantity of PEG from 2 to 3 mL significantly
decreased the rate of the reaction and also had a negative impact
on the yield (Table 1, entry 7 versus 3). We also noticed that
prolonged reaction times led to lower yields being obtained
under the same reaction conditions.
[
19–21,23–31]
2a.
3-Substituted indoles were obtained in excellent
yields in all these cases ($90 %, Table 2, entries 1–6 and 20),
although the strongly electron-deficient 5-nitroindole 1c
required a longer reaction time (20 min) (Table 2, entry 3).
The effect of electron withdrawing or electron donating sub-
stituents on one or both of the aromatic rings of a,b-unsaturated
ketones when reacted with indole 1a were subsequently
investigated.

1
596
M. Gohain et al.
A,B
Table 2. Reaction between indoles 1 and enones 2 to give 3-substituted indoles 3
R5
R4
R3
R3
AI(OTf)3
O
R2
R5
R4
ϩ
R2
N
PEG-200
N
O
R1
R1
1
2
3
C
D
Yield [%] Time [min] Yield [%]
E
Entry Indole
R
1
R
2
R
3
Enone
R
4
R
5
Time [min] Product
[
19]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
1a
1b
1c
1d
1e
1f
H
H
H
2a
2a
2a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
12
20
9
3aa
[20]
3ba
97
97
94
94
94
94
97
93
94
97
95
93
91
87
93
95
96
95
95
90
70
75
96
96
96
93
95
96
94
93
92
96
96
94
92
88
94
95
95
95
94
91
H
H
H
H
H
H
H
CH
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Cl
NO
Ph
Ph
Ph
Ph
Ph
Ph
[21]
2
3ca
100
70
[
20]
22]
23]
OMe 2a
3da
[
CH
H
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2a
2b
2c
2d
2e
2f
7
3ea
50
[
3
5
3fa
40
[24]
3ab
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1e
1g
H
C
C
6
H
H
4
(p-Cl)
6
45
[23]
H
6
4
(p-OMe) Ph
11
18
7
3ac
3ad
75
[
23]
24]
26]
H
Ph
Ph
C
6
C
6
C
6
C
6
C
4
C
4
H
H
H
H
H
H
4
4
4
4
3
3
(p-Cl)
120
70
[
0
1
2
3
4
5
6
7
8
9
0
H
(p-OMe)
(p-Cl)
3ae
[
H
C
C
6
H
H
4
(p-Cl)
16
14
13
12
6
3af
3ag
3ah
130
125
100
180
48
[
25]
H
2g
2h
2i
6
4
(p-OMe)
(p-OMe)
[
26]
H
Ph
Ph
Ph
Ph
S
[27]
H
O
3ai
[28]
3aj
H
2j
CH
H
3
[29]
3ak
H
2k
2l
5
50
[19]
3al
H
CH
CH
CH
Ph
3
3
3
H
4
40
[28]
3am
H
2m
2l
CH
H
3
8
45
[
30]
CH
H
3
4
3el
40
[31]
2a
Ph
20
3ga
180
A
3
Reaction conditions: Indole 1 (1 mmol), enone 2 (1.15 mmol) in PEG-200 (2 mL) with Al(OTf) (2.5 mol-%) with microwave irradiation (300 W) at 808C or
conventional heating at 808C.
B
No products arising from 1,2-addition were observed for either method.
C
References to full analytical data for known compounds.
D
Isolated yields for microwave irradiation reactions.
E
Isolated yields for conventional heating reactions.
The desired products were obtained in excellent yields
$90 %, Table 2, entries 7–12). The electron-withdrawing
Table 3. Reusability of PEG-200 in terms of product yield
(
p-Cl-substituent on the B-ring both increased the yield and the
rate (Table 2, entry 7 versus 1), whereas the electron releasing
p-OMe group on this ring slightly decreased the reaction rate
and also caused a slight decrease in yield (Table 2, entry 8 versus
Entry
Product
1st
2nd
3rd
4th
5th
6th
cycle
cycle
cycle
cycle
cycle
cycle
1
2
3aa
3ba
96
97
95
97
96
97
96
96
96
97
95
97
1
). The electron withdrawing p-Cl-substituent on the A-ring
A
decreased the yield and significantly decreased the rate (Table 2,
entry 9 versus 1), whereas the electron releasing p-OMe group
on this ring increased the reaction rate and also caused an
increase in yield (Table 2, entry 10 versus 1). Interestingly,
the addition of both electron-withdrawing and electron-donating
groups to both rings slowed the reaction rate down (Table 2,
entries 11 versus 7 and 9; entries 12 versus 8 and 10). The
reaction of a,b-unsaturated ketones with heteroatom-containing
aromatic thienyl and furanyl functionalities (Table 2, entries 13
and 14) also proceeded well under these reaction conditions and
gave the corresponding products in excellent to very good yields
Reaction conditions: microwave irradiation (300 W) of indole 1a (1 mmol)
and chalcone 2a (1.15 mmol) in PEG-200 (2 mL) with Al(OTf) (2.5 mol-%)
3
at 808C.
and the A-ring is removed, gave a yield comparable to that
obtained with chalcone 2a (96 versus 97 %) in only 4 min
(Table 2, entry 17 versus 1).
The addition of a methyl group to the b-carbon of methyl
vinyl ketone, i.e. pent-3-en-2-one 2m, caused a significant drop
in rate of the reaction (Table 2, entry 18 versus 17), although an
excellent yield was obtained. This result, together with the effect
observed when either electron-withdrawing or electron-donat-
ing substituents were added to the A-ring of chalcone, or when
the aromatic rings were replaced by heteroaromatic functions
such as thienyl 2h or furanyl 2i moieties (see above), points to
the sensitivity of the reaction to the b-carbon electron density.
To investigate the reusability of the solvent, ice-cold distilled
water was slowly added to the reaction mixture at the end of the
reaction, and the mixture was stirred until product precipitation
was completed (TLC). The solid product was filtered off and the
(91 and 87 %, respectively), although lower than that of the
phenyl A-ring counterparts. When the B-ring of chalcone 2a was
replaced by a methyl group, the yield dropped from 96 to 93 %,
although the reaction was completed within 6 min compared
with the 10 min for chalcone 2a (Table 2, entry15 versus 1).
Removal of the A-ring of the chalcone caused a small drop in
yield from 96 to 95 % with the reaction reaching completion
within 5 min (Table 2, entry 16 versus 1). Methyl vinyl ketone
2
l, where the B ring of chalcone is replaced with a methyl group

Al Triflate Catalysed Addition of Indoles to Ketones
1597
O01
the compounds were identical to those previously published
(see references in Table 2).
C12
C13
Supplementary Material
C10
Detailed general experimental procedures and NMR data of
selected products are available on the Journal’s website.
C11
C05
Acknowledgement
C03
C06
C04
We gratefully acknowledge Sasol for financial support.
C02
References
C07
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(
C09
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N01
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(
(
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Fig. 1. Crystal structure of product 3el.
(
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water removed from the PEG by vacuum distillation on a rotary
evaporator. The residual PEG could be re-used five times
without loss in activity (Table 3), although 5 % of the PEG
was lost per cycle of the reaction and had to be replenished for
consistency (Table 3).
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FC Michael type addition of indoles to a,b-unsaturated ketones
(
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8
08C under microwave irradiation or normal heating conditions.
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[
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(
General Procedure for Microwave Heating
(
Indole 1 (1 mmol) was added to a solution of a,b-unsaturated
ketone 2 (1.15 mmol) in polyethylene glycol-200 (2 mL) con-
tained in a 35 mL microwave vial. Al(OTf) (2.5 mol-%) was
(
3
(
added and the vial sealed with a septum. The reaction mixture
was stirred at 808C under microwave irradiation (300 W, power
cycling method) for the time period indicated in Tables 1 and 2.
After completion of the reaction (TLC), ice-cold water (10 mL)
was slowly added to the reaction mixture by dropping funnel
over a 10 min period and the mixture was allowed to stir until
solid precipitation was completed (monitored by TLC). After-
wards another batch of ice-cold water (10 mL) was added and
stirring continued for another 10 min. The solid was filtered off
and the water was removed from the PEG by vacuum distillation
on a rotary evaporator at 808C. The solid obtained by filtration
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[
General Procedure for Conventional Heating
76. doi:10.1111/J.1747-0285.2011.01216.X
(
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ketone 2 (1.15 mmol) in polyethylene glycol-200 (2 mL) and
Al(OTf) (2.5 mol-%) was added. The reaction mixture was
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J.BMCL.2011.05.010
(
3
c) J. A. Joule, In Science of Synthesis (Ed. E. J. Thomas) 2000,
heated to 808C for the time indicated in Tables 1 and 2. After
completion of the reaction (TLC) the products were isolated as
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