Microwave-assisted synthesis of indole-derivatives via cycloisomerization of 2-alkynylanilines in water without added catalysts, acids, or bases

Article abstract of DOI:10.1016/j.tetlet.2009.09.135

An unprecedented green methodology is described for the preparation of differently substituted indoles via microwave-assisted cycloisomerization of 2-alkynylaniline derivatives in water. Moderate to good yields in the cyclization can be achieved for a variety of 2-aminoaryl alkynes. Reactions are run without any added metal catalyst, acid, or base, and do not take place by applying conventional heating.

Full text of DOI:10.1016/j.tetlet.2009.09.135

Tetrahedron Letters 50 (2009) 6877–6881
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of indole-derivatives via cycloisomerization
of 2-alkynylanilines in water without added catalysts, acids, or bases
Adriano Carpita a, Arianna Ribecai b,
*
a Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Risorgimento 35, I-56126 Pisa, Italy
b Chemical Development Department, GlaxoSmithKline S.p.A., via Fleming 4, I-37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2009
Revised 19 September 2009
Accepted 22 September 2009
Available online 27 September 2009
An unprecedented green methodology is described for the preparation of differently substituted indoles
via microwave-assisted cycloisomerization of 2-alkynylaniline derivatives in water. Moderate to good
yields in the cyclization can be achieved for a variety of 2-aminoaryl alkynes. Reactions are run without
any added metal catalyst, acid, or base, and do not take place by applying conventional heating.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Water
Cycloisomerization
Microwaves
2-Alkynylanilines
Green chemistry
The indole ring system is a structural component of a vast num-
ber of biologically active natural and unnatural compounds, and it
can be found in many pharmaceutical agents.1 The synthesis and
functionalization of indoles has been a major area of focus for
synthetic organic chemists and numerous methods have been
developed.2 Among the many described approaches, the cycliza-
tion reaction of both N-substituted and N-unsubstituted-2-alkyny-
laniline derivatives is a major procedure for the construction of
2,3-disubstituted and 2-substituted indoles.2 In fact, there is the
significant advantage of ready availability of the starting 2-alkyny-
lanilines which can be prepared easily by Sonogashira-type
alkynylations from a large variety of commercially available sub-
strates.3 Typically, the cyclization is achieved using strong bases
(like metal alkoxides, metal hydrides, and metal amides)4 or tran-
sition metals.2,5–14 Furthermore, a recent example describes elec-
trochemical-mediated cyclization of 2-alkynylanilines without
metal catalysts.15 However, most of the cited methods require
the use of moisture-sensitive bases, harsh or strongly basic condi-
tions which are incompatible with a wide range of functional
groups. As regards the use of transition metals, the cyclization of
2-alkynylanilines and 2-alkynylanilides typically takes place in
the presence of catalytic amounts of Pd(II) salts or Pd(0)
complexes,2g,5 stoichiometric or catalytic Cu(I) and Cu(II) salts or
complexes,6 and catalytic Au(III) salts.7 In addition, also the use
of platinum,8 molybdenum,9 iridium,10 rhodium,2f,11 zinc,12 mer-
cury,13 iron,14 and indium16 has recently been described for pre-
paring substituted indoles. Nonetheless, only a small number of
these methods deal with N-unprotected 2-alkynylanilines, which
cyclize in the presence of expensive metal sources and/or high cat-
alyst loadings, with the additional drawback of potential metal
contamination of the products.
Curiously, a very few examples describe the application of
microwave irradiation in this type of cyclization.17 On the other
hand, the need to develop cleaner and more benign processes is
becoming ever more urgent.18 In this novel perception, reactions
conducted in aqueous media as well as the application of micro-
waves for heating the reaction mixture have been receiving
increasing attention. Recently, microwave irradiation was applied
with significant advantages in heterocyclic synthesis allowing to
reach higher temperatures quickly and to obtain faster reactions
than by conventional heating.19 Many examples of microwave-as-
sisted reactions are reported in water20 or without solvent.21 Par-
ticularly worthy of note are synthetic organic reactions run in
water and under superheated conditions.20b,c An interesting exam-
ple is represented by the hydration of terminal alkynes in super-
heated water at 200 °C under microwave irradiation described by
Vasudevan et al.22 In 2006 Alami and co-workers23a expanded
the scope of hydration of alkynes and demonstrated the positive
effect of microwave heating toward the hydration of arylalkynes,
diarylalkynes as well as arylpropargylic alcohols performed in eth-
anol with p-toluenesulfonic acid.23 Recently, the same authors
* Corresponding author. Tel.: +39 0458219360; fax: +39 0458218117.
E-mail address: arianna.ribecai@gsk.com (A. Ribecai).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.135

6878
A. Carpita, A. Ribecai / Tetrahedron Letters 50 (2009) 6877–6881
Table 2
showed that this methodology can successfully afford 2-arylsubsti-
tuted benzofurans and benzothiophenes from diarylalkynes.23c
Bearing in mind all these considerations, we put forward the
idea that a microwave-assisted cycloisomerization of 2-alkynylan-
ilines taking place via an intramolecular hydroamination might be
a feasible way to prepare substituted indoles. In particular, we
wanted to explore the use of water as the solvent and apply micro-
wave irradiation to reach the water ‘near critical’20b,c region. To the
best of our knowledge, this methodology is unprecedented and
represents the first example of microwave-assisted cyclization of
2-alkynylanilines achieved without any added metal catalyst. As
model substrates we chose one terminal alkyne, the commercially
available 2-ethynylaniline, 1a, to give the un-substituted indole,
2a, and one diarylalkyne, 2-(phenylethynyl)aniline, 1b, to obtain
2-phenylindole, 2b. The main results of our first attempts are
summarized in Table 1.
Solvent screening for the microwave-assisted cycloisomerization of 2-phenylethyny-
laniline, 1ba
Entry
Solvent
Water
(v/v %)
Temperature,
°C (time, min)
Yieldb
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
EtOH
n-BuOH
DMF
CH3CN
THF
—
—
—
—
—
—
—
—
—
—
25
25
25
25
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
200 (30)
2
3
1
1
1
2
2
—
NMP
1,2-Dichlorobenzene
Toluene
DMSO
[BMIm]BF4
EtOH
NMP
DMF
[BMIm]BF4
c
—
—
6
3
10c
c
—
For the preparation of the required 1b without significant
metal-contamination, we applied a copper-free procedure we
had previously developed with Pd EnCatTM catalysts.24 The product
was obtained with a Pd content lower than 0.1 ppm by AAS.25 To
test the cyclization in water, we prepared a suspension of the
substrate (0.1 mmol) in 2 ml of water and we applied microwave
irradiation to heat it to 200 °C.26 In order to avoid potential metal
contaminants, we used ACS UltraTrace water, where most common
transition and nontransition metals are present at a 10À5 ppm
level. In addition, we always employed new glassware. In a first in-
stance, we worked to identify the temperature required for the
cyclization, starting with 2-ethynylaniline, 1a. Although this sub-
strate showed some instability with temperature, a certain amount
of indole, 2a, could be obtained at 200 °C (Table 1, entry 1), while at
lower temperatures no significant conversions were observed.
However, prolonged heating at 200 °C proved detrimental since
degradation of both product and starting material occurred and,
what is more, 2-aminoacetophenone, resulting from the hydrolysis
of the starting alkyne, was formed along with the desired indole, 2a
(Table 1, entries 2 and 3). The second model compound, 1b,
showed a good stability in the applied conditions without signifi-
cant hydrolysis but proved rather less reactive than 1a in shorter
reaction times. However, a not negligible amount of indole 2b
was formed when the reaction mixture was heated to 200 °C for
longer times (Table 1, entries 5 and 6).
a
b
c
Reaction conditions: 0.1 mmol of 1b, solvent (2 ml).
Yields in solution determined by HPLC, using a calibration curve.
Significant degradation of starting material observed.
(phenylethynyl)aniline, 1b, using pressure-resistant sealed tubes.
In the trials, 0.3 mmol of substrate was suspended in 2 ml of Ultra-
Trace water and the reaction was heated to 200 °C in an oil bath
and monitored for 7 h, sampling at different reaction times. No
trace of 2-phenylindole, 2b, could be found and the not reacted
starting material was the only recovered product (Table 1, entry
7). Since the experiments with thermal heating were conducted
in transparent pressure-resistant glass vials we could also verify
that the compound was soluble in water under the applied
conditions.
In order to understand if the cycloisomerization of 1b could oc-
cur more efficiently under different conditions, we tested many of
the common solvents and we found, to our surprise, that the reac-
tion was not giving significant amounts of 2-phenylindole in media
different from water (Table 2, entries 1–10). The addition of small
amounts of water to the screened solvents did not give significant
advantages (Table 2, entries 11–14).
Since the presence of water appears so important for the cyclo-
isomerization, we worked on the optimization of these conditions
by trying in a first instance to extend microwave irradiation times
in order to further improve the yields. However, prolonged heating
at 200 °C (for 2 h or more) was often accompanied in our equip-
ment by leakage from the reaction caps with loss of water and
compounds and some degradation of the substrates. For this rea-
son we thought that the application of short cycles of microwave
heating could provide an overall long irradiation but under condi-
tions less stressing for the equipment, since reaction vials are
cooled and de-pressurized between one cycle of heating and the
other. The effect of microwave short cycles was investigated for
four different substrates, as shown in Table 3. Also substrates 1c
and 1d were prepared according to our procedure24 with Pd con-
tents lower than 0.1 ppm by AAS.25
To make a comparison between thermal heating and micro-
wave irradiation, we did some cycloisomerization trials on 2-
Table 1
First attempts in microwave-assisted cycloisomerizationa
R
H2O
MW heating
R
N
H
2
NH2
1
Entry
R
1
Temperature (°C)
Time (min)
2
Yield of 2b (%)
What we immediately observed was that not only leakages and
degradations were minimized but also yields were significantly
improved when shorter cycles were applied (see Table 3, compare
entries 2–4, entries 7–9, and entries 12–14), except for 2-ethyny-
laniline, 1a, where the yield remained low (compare Table 1, en-
tries 1 and 2 and Table 3, entry 1). Having in hands these
interesting results, we focused our attention on 2-arylethynylani-
lines and we tried to increase the concentration of substrates up
to a 0.3 mmol scale. However, when concentrations were doubled
lower yields were observed for 2b and 2d (Table 3, entries 5 and
15), except for 2c (Table 3, entry 10), mainly as a result of the pres-
ence of not reacted starting materials. A further increase in the
1
2
3
4
5
6
7
H
H
H
Ph
Ph
Ph
Ph
1a
1a
1a
1b
1b
1b
1b
200
200
200
200
200
200
200
10
30
60
30
60
120
7 h
2a
2a
2a
2b
2b
2b
2b
23
17c
6c
14
17
33
0d
a
b
c
Reaction conditions: 2-alkynylaniline (0.1 mmol), water (2 ml).
Yields in solution determined by HPLC, using a calibration curve.
2-Aminoacetophenone was the main product, isolated in a 65% yield and 60%
yield, respectively.
d
Thermal heating was applied to a mixture of 2-(phenylethynyl)aniline, 1b,
(0.3 mmol) and water (2 ml).

A. Carpita, A. Ribecai / Tetrahedron Letters 50 (2009) 6877–6881
6879
Table 3
Optimization of conditions for the cycloisomerization of 2-aminophenylalkynesa
R
H2O, 200 ºC
MW heating
R
N
H
NH2
1
2
Entry
R
1
MW cycles
mmol of 1
Total time (h)
2
Yieldb (%)
Cycles number
Cycle time (min)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
Ph
Ph
Ph
Ph
Ph
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
3
3
9
18
18
18
3
5
30
10
5
5
5
30
10
5
5
5
30
10
5
5
5
0.1
0.1
0.1
0.1
0.2
0.3
0.1
0.1
0.1
0.2
0.3
0.1
0.1
0.1
0.2
0.3
0.25
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2a
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2d
2d
2d
2d
2d
16c
63
65
69
59
44
56
58
77
78
31
36
49
65
40
26
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
9
18
18
18
3
9
18
18
18
a
Reaction conditions: the specified amounts of 2-aminoaryl alkyne were suspended in water (2 ml) and heated to 200 °C by microwave irradiation for the time reported in
the table.
b
Yields in solution determined by HPLC, using a calibration curve.
Degradation observed; 2-aminoacetophenone was the main product.
c
concentrations caused a more drastic decrease in the yield for all
the substrates (Table 3, entries 6, 11, and 16).
degradation of starting materials occurred (Table 4, entries 1–
3). If lower amount of palladium was applied, down to
a
With the objective to verify that our cycloisomerization reac-
tions were not taking place because of the presence of Pd salts,
we studied the potential effect of Pd possibly contaminating
our starting arylalkynes. In other words, we wanted to show
that the effect of Pd was negligible at concentrations surely
lower than 0.1 ppm (corresponding to a loading lower than
2 Â 10À5 mol %). These results are reported in Table 4. A first
screening of catalyst loadings showed that the presence of Pd
salts has indeed an important effect at certain concentrations.
When the reaction was run with a 0.1 mol % of palladium, cycli-
zation of 1b to 2b was visibly accelerated even if considerable
0.01 mol %, cyclization yields were not significantly higher than
in the absence of added catalyst (compare Table 1, entry 4 and
Table 4, entries 4 and 5). Also, a low yield was observed when
a Pd-contaminated starting alkyne was used without added Pd
species (Table 4, entry 6).
With the aim of extending the scope of our cyclization condi-
tions, we explored the reactivity of different substrates. We pre-
pared a series of differently substituted 2-aminophenylacetylenes
and applied the most efficient conditions found to achieve cycliza-
tion. After the screening of concentration we chose the 0.1 mmol/
ml concentration to run our reactions, which is, as already shown,
a good compromise between efficiency and applicability. In Table
5, we summarized our results. Moderate to good isolated yields
could be obtained for 2-(arylethynyl)anilines (Table 5, entries
2–9), except for 1j (20%, Table 5, entry 10), with the best cycliza-
tion yields obtained with substrates bearing electron-donating
substituents. Low yields in 2a were obtained starting from both
1a and the corresponding trimethylsilyl derivative 1l (Table 5, en-
tries 1 and 12), whereas the (alkylethynyl)aniline 1k gave 2k in a
very low yield (Table 5, entry 11).
In summary, we demonstrated that indole and 2-substituted in-
doles can be obtained by a simple and straightforward methodol-
ogy which involves the microwave-promoted cycloisomerization
from the corresponding 2-alkynylanilines in water. Neither acid
or basic additives, nor metal catalysts were added to promote the
reactions. The residual Pd salts (ppb) that could be present in the
precursors do not seem to affect the yields significantly, whereas
microwave heating proved necessary. Moderate to good yields
can be achieved for a variety of substrates; higher yields are ob-
tained for compounds bearing electron-donating substituents.
More experiments are ongoing to elucidate the mechanism of this
microwave-assisted cycloisomerization as well as to improve its
scope.
Table 4
Cyclization of 1b with Pd sourcesa
R
H2O, 200 ºC
Pd catalyst
R
N
H
MW heating
NH2
1
2
Entry
R
Palladium
Time
(min)
Ratio 2/
1
Yieldb
(%)
Catalyst
Loading
(mol %)
1
2
3
4
5
6
Ph PdCl2
Ph Pd(OAc)2 0.1
Ph Pd(OAc)2 0.1
Ph PdCl2
Ph Pd(OAc)2 0.01
0.1
30
30
90
30
30
30
99/1
56
15
51
16
19
12
17/83
70/30
18/82
20/80
15/85
0.01
Ph n.d.
0.013c
a
Reaction conditions: 1b (0.3 mmol), water (2 ml), and the specified amount of
Pd catalyst. Reactions were heated to 200 °C under microwave irradiation for the
time reported in the table.
b
Yields in solution determined by HPLC, using a calibration curve.
c
Palladium present as a contaminant in the starting material.25

6880
A. Carpita, A. Ribecai / Tetrahedron Letters 50 (2009) 6877–6881
Table 5
Table 5 (continued)
Preparation of indole-substrates via cycloisomerization reactions of different 2-
Entry
Arylalkynes 1
Aryl indole 2
Yieldsb (%)
aminoaryl alkynesa
R
H2O, 200 ºC
11
9d
R'
R
R'
N
H
MW heating
NH2
1
NH2
Si
2k
N
H
1k
2
Entry
1
Arylalkynes 1
Aryl indole 2
Yieldsb (%)
12
20
N
H
H
2a
1l
NH2
23
46
N
a
Reactions were run in sealed tubes with 0.4 mmol of 2-aminoaryl alkyne sus-
pended in 4 ml of water and the suspension was heated to 200 °C under microwave
irradiation applied in 18 cycles of 5 min for a total time of 90 min.
2a
H
1a
NH2
NH2
b
Isolated yields.
c
Microwave irradiation was applied in 10 cycles of 5 min for a total time of
N
H
2
3
4
50 min until complete consumption of starting material was achieved.
The main product was 1-(2-aminophenyl)-1-octanone which was isolated in
67% yield.
d
2b
1b
Acknowledgments
O
O
N
H
We thank Dr. Claudio Evangelisti (Dipartimento di Chimica e
Chimica Industriale, Università di Pisa) and Sig. Marco Carlo Mas-
cherpa (C.N.R., Institute of Chemical and Physical Processes, Pisa)
for atomic absorption analysis and Dr. Paolo Stabile (GlaxoSmithK-
line, Verona) for his valuable contributions.
79
34
2c
2d
NH2
NH2
1c
Cl
Cl
N
H
Supplementary data
1d
Supplementary data (experimental procedures and character-
ization data for all substrates 1a–k and the cyclization products
2a–k) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2009.09.135.
O
5
6
59c
O
N
H
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2f
NH2
1e
O
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