Preparation of 5-substituted 2-carboxyindoles on solid support

Article abstract of DOI:10.1016/S0040-4039(00)00151-9

The preparation of 5-substituted 2-carboxyindoles on solid support is reported. In the approach, the indole moiety is synthesized in solution phase, followed by nitro-group reduction, reductive amination and alkylation on solid support. The method provides a simple and convenient route for the preparation of 5-substituted 2-carboxyindoles with high purity and good yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00151-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2443–2446
Preparation of 5-substituted 2-carboxyindoles on solid support
Jan Tois, Robert Franzén,∗ Olli Aitio, Katri Huikko and Jyrki Taskinen
University of Helsinki, Division of Pharmaceutical Chemistry, Department of Pharmacy, PO Box 56, FIN-00014 Helsinki,
Finland
Received 19 November 1999; accepted 18 January 2000
Abstract
The preparation of 5-substituted 2-carboxyindoles on solid support is reported. In the approach, the indole moiety
is synthesized in solution phase, followed by nitro-group reduction, reductive amination and alkylation on solid
support. The method provides a simple and convenient route for the preparation of 5-substituted 2-carboxyindoles
with high purity and good yield. © 2000 Elsevier Science Ltd. All rights reserved.
Combinatorial chemistry is a method by which large numbers of structurally distinct molecules may be
synthesized in a time- and resource-effective manner, and then be submitted for pharmacological tests.1,2
Our synthetic efforts in the area of lead discovery has led to the exploration of synthesis routes for the
high throughput preparation of structurally diverse compound libraries. As part of an ongoing project,
we required a flexible synthetic protocol for the preparation of 5-substituted 2-carboxyindoles.
Several indole-structures featuring a 5-substituent group have been reported.3–5 It has been suggested
that a substituent at C-5 would increase the binding affinity at various bioreceptors, for instance at
the NMDA-receptor,6 and at the rHLGPa-receptor.7 Moreover, the 5-substituent has been shown to be
important in structure–activity relationship (SAR) studies for improving the affinity and selectivity at the
5-HT1D receptor:8 a 5-substituent capable of participating in hydrogen bonding could be critical for the
binding affinity.9 In addition, at least one heteroatom attached to C-5 has been reported in several 5-HT1D
receptor agonists.10
Herein, we report a convenient method for a simple and inexpensive route for the modification of the
5-substituent in an indole moiety. The route we chose to study is illustrated in Scheme 1.
The template 5-nitro-2-carboxyindole (1)11 (Scheme 2) was synthesized by a Japp–Klingemann
reaction12 followed by Fisher indolization.13 The hydrazone (2) obtained in the reaction as an inter-
mediate was isolated, recrystallized from EtOH in 75% yield, and characterized by 1H NMR, 13C NMR
and ESI-MS.14 The cyclization was performed in polyphosphoric acid producing the desired indole (1)
in 83% yield. An attempt to utilize a modified Fisher indole synthesis on a solid support as described
∗
Corresponding author. E-mail: rfranzen@cc.helsinki.fi (R. Franzén)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00151-9
tetl 16431

2444
Scheme 1.
by Hutchins and Chapman15 did not produce the desired results and therefore we decided to prepare the
indole nucleus in solution followed by immobilization onto the resin.
Scheme 2.
The solid phase procedure is described in Scheme 3. The indole (1) was attached to Wang
resin using 1-(2-mesitylene-sulfonyl)-3-nitro-1,2,4-triazole (MSNT) and N-methylimidazole (NMI) in
dichloromethane16 followed by nitro-group reduction.17 The attachment was monitored by IR and
characteristic bands at 1350 cm−1 (NO2) and at 1700 cm−1 (RCOOR) could be observed. In the first
combinatorial step a reductive amination with several aromatic aldehydes in the presence of NaCNBH3
in DMA was performed.18 The polymer bound secondary amines obtained were not further characterized.
However, IR analyses and cleavage of a small amount of the product revealed that no starting material
could be observed. A further alkylation with benzylic bromides, thus providing the next combinatorial
step,18 was performed. Cleavage using the standard TFA–DCM method produced the final products in
40–75% total yield (calculations based on the commercially announced loading).
Scheme 3.
All products 3a19,20–3h were characterized by 1H NMR, and ESI-MS to assure that the reaction pro-
cedure had been succesfully accomplished. The preparation of 3a was also accomplished by attachment
of 1 to Merrifield resin. Attachment and cleavage was performed according to Frenette and Friesen.21 All

2445
compounds were purified by preparative TLC and in Table 1 the components used for the combinatorial
synthesis, the structures of products and total yields are summarized.
Table 1
Starting materials, products and yields summarized
In summary, we have demonstrated a simple and convenient method for the preparation of 5-
substituted-2-carboxyindoles on solid support. After cleavage from the support, only one product can
be observed and due to high purity, a preliminary screening in biological assays is possible. We are now
in a process of extending our studies toward using aliphatic aldehydes and bromides making this route
more useful for preparation of combinatorial libraries.

2446
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11. The data for compound (1) is as follows: 1H NMR (500 MHz, DMSO-d6) δ 7.37 (d, J=1 Hz, 1H), 7.58 (d, J=9 Hz, 1H),
8.11 (dd, J=9 and 2.5 Hz, 1H), 8.71 (d, J=2 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 109.6, 113.0, 119.0, 119.4, 125.9,
131.9, 139.8, 141.2, 161.9; mass spectrum (ESI) m/z 205 (M−H+).
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14. The data for compound (2) is as follows: 1H NMR (500 MHz, DMSO-d6) δ 1.28 (t, J=7 Hz, 3H), 2.12 (s, 3H), 4.23 (q, J=7
Hz, 2H), 7.39 (d, J=9 Hz, 2H), 8.20 (d, J=9 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 12.5, 14.2, 60.7, 113.1, 113.1,
125.7, 125.7, 137.0, 140.3, 164.3; mass spectrum (ESI) m/z 252 (M+H+).
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19. Typical procedure (3a): the attachment of 1 (2 equivalent) to Wang resin (0.2 g, 0.56 mmol/g) followed the procedure
by Nielsen and Lyngsjo,16 except that DMF was used instead of DCM in the reaction. Following filtration and washing
of the derivatized resin several times with DMF, THF, MeOH, and DCM, the reduction of the nitro-group was performed
according to the method by Wei and Phillips.17 Reductive amination with 4-trifluoromethyl benzaldehyde and alkylation with
2-methoxy-5-nitrobenzylbromide was performed in a similar manner to that described by Green.18 Cleavage was performed
in DCM/TFA (1:1) for 2 h at room temperature. Following filtration, the resin was washed with DCM and the filtrate was
evaporated to dryness. The residue was purified on silica gel (CHCl3/EtOAc, 1:1+1% AcOH) to obtain 17 mg (51%) of pure
3a.
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(m, 1H), 6.81 (m, 1H), 6.87 (m, 1H), 7.26 (d, J=9 Hz, 2H), 7.49 (d, J=8 Hz, 2H), 7.58 (d, J=8 Hz, 2H), 7.92 (m, 1H), 8.18
(dd, J=9 and 3 Hz, 1H); mass spectrum (ESI) m/z 498 (M−H+).
21. Frenette, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177.