Rapid and easy access to indoles via microwave-assisted Hemetsberger-Knittel synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.01.129

Hemetsberger-Knittel indole synthesis can be carried out under microwave activation. The optimum reaction conditions were found by using different solvents and by varying irradiation times and temperature. After 10 min of microwave irradiation, high conversion into the corresponding indole products was achieved without formation of any side products.

Full text of DOI:10.1016/j.tetlet.2009.01.129

Tetrahedron Letters 50 (2009) 1708–1709
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Tetrahedron Letters
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Rapid and easy access to indoles via microwave-assisted
Hemetsberger–Knittel synthesis
Frank Lehmann a, Melanie Holm a, Stefan Laufer a,
*
a Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Hemetsberger–Knittel indole synthesis can be carried out under microwave activation. The optimum
reaction conditions were found by using different solvents and by varying irradiation times and temper-
ature. After 10 min of microwave irradiation, high conversion into the corresponding indole products was
achieved without formation of any side products.
Received 19 December 2008
Revised 20 January 2009
Accepted 23 January 2009
Available online 29 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Hemetsberger–Knittel
Microwave
Indole derivatives display a wide range of biological activities as
exemplified by the amino acid tryptophan, the hormones serotonin
and melatonin, the anti-inflammatory drug indomethacin, the psy-
chotropic drug LSD and the anti-tumour agent vinblastine.1
Accordingly, the synthesis of indole derivatives has been a major
topic in organic and medicinal chemistry over the past several dec-
ades.2 For over 100 years, the Fischer indole synthesis has been one
of the most used methods for the preparation of indoles.3 However,
the Fischer indole synthesis suffers from the shortcomings of low
yields and numerous side products.4
In our design of kinase inhibitors, we were interested in differ-
ent substituted indole-2-carboxylates. Although a multitude of
methods exist for the synthesis of these compounds, they afford
only relatively low to modest yields. The Hemetsberger–Knittel in-
dole synthesis involves the condensation between an arylaldehyde
able aldehydes as shown in Scheme 1. The ring closing reaction
(Scheme 2) to form the indoles 2 was carried out in a microwave
oven (MW).
To ascertain the optimal reaction conditions to form the indoles,
different solvents were tested. An initial attempt with 1f in toluene
with microwave irradiation for 15 min at 200 °C and a pressure of
8.1 bar gave a full conversion to the corresponding indole. In a fur-
ther step, we used more polar solvents at the same conditions with
a high total acid number (TAN) d value, which should improve the
conversion of the electromagnetic energy into heat. As outlined in
Figure 1, ethanol and 1-butanol were poorer solvents compared to
toluene, as indicated by the lower yields of indoles and the pres-
ence of many side products. Dioxane takes an intermediate posi-
tion. The indole was formed in a comparatively good yield, but
various side products were also formed. To determine whether
the high conversion rate in the presence of toluene depends on
its high boiling point or the reaction proceeds better in non-polar
solvents, we used n-hexane under the same reaction conditions.
Like toluene, n-hexane gave full conversion ( Fig. 1). In view of
the fact that the indoles that were obtained crystallized out in
the presence of n-hexane, we chose this particular solvent for opti-
mizing irradiation exposure and temperature.
and an azidoacetate to provide
a-azidocinnamates which upon
heating give indoles. The process has been applied using high boil-
ing solvents such as xylene5, toluene,6 and mesitylene and a reac-
tion time of approximately 4 h to obtain the corresponding indoles
and a variety of aromatic N-heterocycles in yields between 53%
and 79%. Recently, Stokes et al. described a mild procedure for
the ring closure using rhodium(II) perfluorobutyrate as catalyst
and an extended reaction time of 16 h.7 We present here a rapid
and simple method using 10 min microwave irradiation to synthe-
size different indole-2-carboxylates in good yields.
O
The synthesis begins with recently described7 preparation of
the intermediates 1 from the corresponding commercially avail-
COOMe
N3
i
H
R
R
1a-f
* Corresponding author. Tel.: +49 7071 295037; fax: +49 7071 2972459.
E-mail address: stefan.laufer@uni-tuebingen.de (S. Laufer).
Scheme 1. Synthesis of
azidoacetate, NaOMe, À20 °C, 4 h.
a-azidocinnamates. Reagents and conditions: (i) methyl 2-
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.129

F. Lehmann et al. / Tetrahedron Letters 50 (2009) 1708–1709
1709
Table 1
COOMe
N3
i
Synthesis of indole-2-carboxylates
COOMe
N
H
R
R
Compound
Product
Conversion
2a-f
COOMe
2a
94%
Scheme 2. Synthesis of indole-2-carboxylates. Reagents and conditions: (i) MW,
n-hexane, 200 °C, 10 min, 15 bar.
N
H
COOMe
2b
2c
2d
90%
N
H
O
100
80
60
40
20
0
COOMe
COOMe
Quantitative
89%
N
F
H
N
Cl
Cl
H
ethanol 1-butanol
toluene
hexane
sdoiolvxaennt
2e
2f
Quantitative
Quantitative
COOMe
Figure 1. The effect of different solvents on the % conversion to indoles.
N
H
Br
100
80
60
40
20
0
COOMe
N
H
Ultimately, we selected the conditions 200 W, 200 °C and
10 min MW irradiation time as the standard method to synthesize
all indole-2-carboxylates (2a–f) outlined in Table 1. Excellent con-
versions to the indole products were attained in all cases.
In summary, we have developed a convenient microwave-as-
sisted, economical and fast method for synthesis of indole-2-car-
boxylates. This method can be easily adapted for ring closure of
A
B
C
D
E
reaction conditions
Figure 2. The effect of reaction conditions on the % conversion to indoles. (A)
200 °C, 15 min, 13.5 bar. (B) 200 °C, 10 min, 13.5 bar. (C) 200 °C (only 136 °C were
reached), 5 min, 6.2 bar. (D) 150 °C, 10 min, 6.9 bar. (E) 100 °C, 10 min, 4.2 bar.
all previously described a-azidocinnamates and therefore provides
an easy and rapid access to different substituted indoles and a vari-
ety of aromatic N-heterocycles.
As shown in Figure 2A, formation of indoles took place with
99.9% yield as indicated by HPLC at 200 W, 200 °C and 15 min irra-
diation time, and thereby achieved 13.5 bar in n-hexane. When we
reduced only the reaction time to 10 min, we still achieved a quan-
titative conversion (Fig. 2B), but irradiation for only 5 min (C) gave
no product.
Perhaps the yield was reduced because a temperature of only
136 °C was attained in this short reaction time. Next, we limited
the temperature to 150 °C (D) and 100 °C (E), but maintained
10 min microwave activation time. A reaction temperature of
150 °C resulted in 97.9% conversion (D), but essentially no transfor-
mation to the indole occurred at lower temperature (E). Pressure
was not a determinant factor in all reactions, but it was not al-
lowed to exceed 15 bar. Different values of pressure were achieved,
depending on the different given temperatures as well as on irradi-
ation times.
References and notes
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