Microwave-assisted synthesis of tetrahydroindoles

Article abstract of DOI:10.1016/j.tetlet.2007.11.114

An efficient synthesis of tetrahydroindoles with different substituents in position 1 is described. Microwave-assisted aminolysis of 4-oxo-4,5,6,7-tetrahydrobenzofuran with different primary amines gives the corresponding tetrahydroindoles in few minutes.

Full text of DOI:10.1016/j.tetlet.2007.11.114

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 459–462
Microwave-assisted synthesis of tetrahydroindoles
Leonarda Piras a, Chiara Ghiron b, Giacomo Minetto a,b, Maurizio Taddei a,*
a
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
b Siena Biotech SpA, Via Fiorentina 1, 53100 Siena, Italy
Received 26 July 2007; revised 5 November 2007; accepted 20 November 2007
Available online 24 November 2007
Abstract
An efficient synthesis of tetrahydroindoles with different substituents in position 1 is described. Microwave-assisted aminolysis of
4-oxo-4,5,6,7-tetrahydrobenzofuran with different primary amines gives the corresponding tetrahydroindoles in few minutes. All
attempts to use microwave dielectric heating to reduce the time required for preparation of 4-oxo-4,5,6,7-tetrahydrobenzofuran, starting
from 1,3-cyclohexandione were on the other hand unsuccessful, demonstrating that in some cases, long time conventional heating may be
superior to microwaves.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Microwaves; Cyclocondensation; Benzofuran; Indol
Many libraries designed for hit discovery are based on a
central core scaffold carrying different functional groups
for further decoration. The scaffold establishes the nature
of the library and often affects the biological activity of
the library components. Amongst the broad range of pos-
sible templates, heterocyclic molecules represent the most
utilised scaffold for discovery of new synthetic entities.1
Tetrahydroindolones have been reported to present sev-
eral interesting biological activities as selective Kv1.5 block-
ers,2 antiproliferative and cytotoxic agents,3 as GABAA-a5
receptor ligands for enhancing cognition4 or as molecules
useful in treating psychotic disorders.5 Although the synthe-
sis of some tetrahydroindoles has been reported based on
cycloadditions or organometallic chemistry,6 an analysis of
the older literature suggests the direct ammonolysis of ben-
zofuran (or partially reduced benzofurane) as the most
practical route to 4-oxo-4,5,6,7-tetrahydroindoles.7 These
compounds are important intermediates for the preparation
of a wide variety of other indole derivatives through modifi-
cation of the oxo functional group.8 The starting benzofuran
derivative can be obtained through the Stetter cycloconden-
sation from cyclohexandione and bromopyruvic acid ester,
followed by a ring opening–closure reaction, which leads
to the final pyrrole ring system.9 Both reactions are carried
out at high temperature and for a long time. In particular,
the second step has been described to occur with a large
excess of the amine (generally ammonia or benzylamine) in
EtOH in a sealed tube at 150 °C for 12–24 h, thus preventing
an extensive application to the synthesis of more complex
molecules.10
Following our interest in the field,11 we decided to inves-
tigate the possibility to perform the Stetter synthesis of tet-
rahydrobenzofuran and the further transformation into
indoles under MW dielectric heating to find milder reaction
conditions and prepare a larger array of compounds
(Scheme 1).
The Stetter cyclocondensation has been described to
proceed by refluxing 1,3-cyclohexanedione 1 with ethyl
bromopyruvate in the presence of EtOH/KOH for 12 h.
Further acidification and heating for 30 min gives directly
carboxylic acid 2 as a white solid.9 Following this proce-
dure we obtained compound 2 in 75% overall yield. With
the idea of improving on this first step, we investigated dif-
ferent reaction conditions under microwave irradiation. In
*
Corresponding author. Tel.: +39 0577234280; fax: +39 0577234275.
E-mail address: taddei.m@unisi.it (M. Taddei).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.114

460
L. Piras et al. / Tetrahedron Letters 49 (2008) 459–462
Table 2
O
O
COOH
ref 7
Transformation of 2 into 4oxo-4,5,6,7-tetrahydroindolones
ref 9
O
O
COOH
+
O
O
1
2
See table
R-NH2
X
O
O
N
R
2
5-18
ref 8
Y
Entry R–NH2
Producta Power, internal
temperature, max
Yieldb
(%)
N
H
N
H
3
internal pressure, time
Scheme 1. General scheme for the synthesis of substituted indoles through
the Stetter cyclocondensation.
5c
6c
1
250 W, 120 °C, 200 psi,
10 min
85
84
2
250 W, 120 °C, 200 psi,
10 min
the first experiment, we modified the reported conditions,
and heated a mixture of 1 and ethyl bromopyruvate in
EtOH in the presence of NaOH in an open flask located
inside the microwave cavity of a Discover apparatus
(CEM). After 20 min of heating, the mixture was acidified
to pH 3 with HCl and heated additional 10 min using the
same microwave oven. No trace of 2 was found in the reac-
tion mixture. Then, we tried different conditions, changing
solvent, base, time of heating and mode of the reaction.
However, as reported in Table 1, all the attempts gave com-
pound 2 in much lower yield and purity with respect to the
standard procedure.
H
3
4
5
6
7
7
8
9
250 W, 120 °C, 200 psi,
10 min
70
91
70
91
92
N
Cbz
HN
250 W, 120 °C, 200 psi,
10 min
250 W, 120 °C, 200 psi,
10 min
Ph
N
10
250 W, 120 °C, 200 psi,
5 min
HO
11d
12
250 W, 120 °C, 200 psi,
10 min
8
9
250 W, 120 °C, 200 psi,
10 min
86
74
Table 1
Exploration of reaction conditions for microwave-assisted synthesis of 2
O
O
O
O
COOH
O
13
250 W, 120 °C, 200 psi,
10 min
Br
+
COOEt
O
O
2
1
10
11
12
13
14c
15
250 W, 120 °C, 200 psi,
20 min
75
35
76
79
76
O
HO
HCl/H2O
heating
MeOH/NaOH
heating
COOEt
OMe
O
250 W, 120 °C, 200 psi,
3 Â 10 min
4
Entry Conditions
Yield of 2
(%)
16e
17
250 W, 120 °C, 200 psi,
3 Â 10 min
MeO
1
2
(1) NaOH–EtOH (100 °C, open flask, 20 min)
(2) HCl/H2O (110 °C, open flask, 20 min)
0
250 W, 120 °C, 200 psi,
10 min
(1) NaOH EtOH/H2O 1/1 (100 °C, open flask,
20 min)
10
N
(2) HCl (110 °C, open flask, 20 min)
14
18
250 W, 120 °C, 200 psi,
10 min
N
3
(1) NaOH EtOH/H2O 1/1 (140 °C, sealed vial,
30 min)
(2) HCl (110 °C, sealed vial, 20 min)
>10
a
Except for compounds 6, 12 and 17, all the products are new and have
been fully characterised.
b
4
5
6
7
(1) NaOH H2O (110 °C, open flask, 20 min)
(2) HCl (110 °C, open flask, 20 min)
10
0
Isolated yields.
See Ref. 3a.
See Ref. 10.
See Ref. 6a.
c
d
(1) NaOH H2O (180 °C, sealed vial, 20 min)
(2) HCl (110 °C, open flask, 20 min)
e
(1) KOt-Bu/t-BuOH (130 °C, sealed vial, 20 min)
(2) HCl (110 °C, open flask, 20 min)
5
Thus, we isolated the reaction intermediate 412 and
monitored its formation during microwave heating. After
1 h of heating (MeOH/NaOH), compound 4 was present
(1) KOt-Bu/DMF (130 °C, sealed vial, 20 min)
(2) HCl (110 °C, open flask, 20 min)
>10

L. Piras et al. / Tetrahedron Letters 49 (2008) 459–462
461
presence of benzyl amine was unsuccessful. Even at
150 °C for more than 40 min, unreacted starting material
was recovered.
This result suggests that probably the furane ring open-
ing-pyrrole ring closing reaction is not a simple aminolysis
but the mechanism involves the carboxylic (or the carb-
oxylate) function.
In conclusion we have demonstrated that the overall
transformation of 1,3-cyclohexanedione 1 into indolones
5–18 can be accelerated by microwave irradiation of the
second step, whereas the Stetter cyclocondensation resulted
unaffected by exposure to microwave heating. Moreover,
we observed that the presence of the free COOH in position
3 is indispensable for effective cyclisation.
O
COOMe
c
11
O
O
COOH
19 (90%)
a
b
O
O
CONHBn
2
d
O
20 (73%)
Scheme 2. Reagents and conditions: (a) MeOH/SOCl2, rt, 12 h; (b)
BnNH2, MTMM, NMM, THF, rt, 12 h; (c) BnNH2, EtOH/H2O, MW,
120 °C, 200 psi, 30 min; (d) Me2CHCH2NH2, EtOH/H2O MW, 150 °C,
200 psi, 40 min.
in less than 5%, suggesting that its formation may be the
rate determining step. Although a complete kinetic study
was not done, we think that the temperature has a scarce
influence on the formation rate of 4, thus vanishing the
effect of the more efficient microwave heating.
Acknowledgement
This work was financially supported by Siena Biotech
SpA (Siena) including a grant to L.P.
The transformation of carboxylic acid 2 into the corres-
ponding substituted tetrahydroindoles 5–18 (see Table 2)
however, occurred rapidly under microwave dielectric heat-
ing using H2O/EtOH 5/1 as the solvent in a sealed vial at
120 °C for 10–30 min.13 The products were recovered sim-
ply by extraction with an organic solvent in an acceptable
degree of purity (1H NMR). Different amines, some of
which carrying groups suitable for further functionalisa-
tion, were employed, giving always the required indolones
in good yields. An hydroxy group and a secondary amine
can be present in the reagent without the need for protec-
tion (Table 2, entries 4–6). Only in the case of a less nucleo-
philic and hindered o-substituted aniline, 30 min of heating
were required and product 15 was isolated in lower yields
compared to the other examples. To compare results
obtained with microwave and conventional thermal heat-
ing, the sealed vial containing the reaction mixture
employed to prepare 11 was immersed in an oil bath previ-
ously heated at 130 ° and stirred for 20 min, but in this case
only 40% conversion to compound 11 was observed.
Unfortunately, in all cases explored, the carboxylic
group in position 3 of the starting furane was lost. Trying
to keep it intact by reducing the reaction temperature pro-
duced a mixture of the indolone and some starting material
(2) still carrying the COOH group. With the target of main-
taining the carboxylic function in position 3 of the hetero-
cycle, we tried to protect the carboxylic acid as the methyl
ester 19, obtained in good yields under standard conditions
(Scheme 2). However, when 19 was submitted to amino-
lysis with benzyl amine under our conditions, the decarb-
oxylated compound 11 (50%) was obtained exclusively
after heating at 120° for 30 min.
References and notes
1. (a) Tan, D. S. Nature Chem. Biol. 2005, 1, 74–76; (b) Cano, M.;
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Curr. Opin. Drug Disc. Devel. 2003, 6, 815–826.
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Bioorg. Med. Chem. Lett. 2006, 16, 5859–5863.
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Hanson, G. PCT WO 2006091963; (b) Pinna, G. A.; Sechi, M.;
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265.
To strengthen the group in position 3 with respect to
solvolysis, amide 20 was prepared by reaction of 2 with
2-methylpropan-1-amine in the presence of DMTMM
as the coupling agent.14 Unfortunately, any attempt to
transform 20 into the corresponding indolone in the
12. The presence of compound 4 in the reaction mixture was determined
by HPLC–MSESI analysis of the reaction mixture after 12 h of
reaction. This was the main component of the crude as 2 starts to
form after the addition of HCl.

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L. Piras et al. / Tetrahedron Letters 49 (2008) 459–462
13. Synthesis of 6,7-dihydro-1-phenethyl-1H-indol-4(5H)-one (13). Gen-
eral procedure. To a solution of 4,5,6,7-tetrahydro-4-oxobenzofuran-
3-carboxylic acid (200 mg, 1.11 mmol) in 2 ml of a mixture H2O/
EtOH (5:1), 2-phenylethanamine (400 mg, 3.33 mmol) was added.
The reaction mixture was heated under microwave irradiation
(250 W) at 110 °C for 10 min; the ethanol was evaporated at reduced
pressure, the aqueous solution was acidified with HCl 1 N and
extracted with ethyl acetate. The organic layer was dried over
anhydrous Na2SO4 and the solvent was evaporated under reduced
pressure, the crude obtained was purified by flash chromatography
(SiO2 petroleum ether/ethyl acetate 1:1) to give 226 mg of 6,7-
dihydro-1-phenethyl-1H-indol-4(5H)-one (13) (yield = 86%) and 1H
NMR (200 MHz, chloroform-d): d H NMR (400 MHz, chloroform-
1
d): d 7.17–6.93 (3H, m), 6.89–6.83 (2H, m), 6.47 (2H, s), 3.94 (t, 2H,
J = 6.5 Hz), 2.87 (t, 2H, J = 6.5 Hz), 2.31–2.15 (4H, m), 1.82 (2H,
m). 13C NMR (400 MHz, chloroform-d): 193.46, 143.30, 137.17,
128.19, 127.96, 127.58, 126.23, 121.23, 119.69, 105.06, 76.99, 47.61,
37.02, 36.98, 22.99, 20.75. MS (EI, 70 eV), 240 [M+H]+, 262
[M+Na]+.
14. DMTMM:
4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methyl-morphol-
inium chloride. See: Falchi, A.; Giacomelli, G.; Porcheddu, A.;
Taddei, M. Synlett 2000, 277–279.