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Synlett 2004(6): 1049-1053  
DOI: 10.1055/s-2004-820052
LETTER
© Georg Thieme Verlag Stuttgart · New York

Solid-Phase Synthesis of Indol-2-ones by Microwave-Assisted Radical ­Cyclization

Hisashi Akamatsu, Koichi Fukase*, Shoichi Kusumoto
Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama 1-1, Toyonaka, Osaka 560-0043, Japan
Fax: +81(6)68505419; e-Mail: koichi@chem.sci.osaka-u.ac.jp;
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Publication History

Received 17 January 2004
Publication Date:
25 March 2004 (online)

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Abstract

Solid-phase synthesis of indol-2-ones (2-oxindoles) by means of aryl radical cyclization of resin-bound N-(2-bromo­phenyl)acrylamides using Bu3SnH is described. Among various solvents tested, DMF was found to be the best choice for the radical cyclization inducing a reagent concentration effect of the polymer support. The reaction proceeded smoothly under microwave irradiation to give the desired indol-2-ones within a very short reaction time in comparison to conventional thermal heating. In this reaction, various indol-2-ones were synthesized by using commercially available 2-bromoanilines and acryloyl chloride derivatives.

Key words

radical reactions - microwave - indol-2-one - combinatorial chemistry - solid-phase synthesis

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The reaction temperature rose to 100 ºC within 3 min, to 120 °C within 10 min and to 170 ºC within 20 min, and then remained constant.

12

The reaction of 2-bromoaniline 5 with resin-bound benzyl chloride, benzyl bromide, and trityl chloride did not proceed at all owing to low reactivity of the amino group of 5. Introduction of 2-bromoaniline 5 to 4-(formyl-3-methoxy-phenoxy)butyryl AM resin by reductive alkylation also failed.

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Focused microwave irradiations were carried out with a DiscoverTM Focused Microwave Synthesis (CEM Corporation).

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A vessel for microwave reaction was filled with the resin-bound N-(2-bromophenyl)-3-phenylacrylamide 7Aa (108 mg, 0.05 mmol), DMF (1 ml), Bu3SnH (0.134 ml, 0.50 mmol) and AIBN (8 mg, 0.05 mmol), and then sealed with a Teflon septum. The vial was positioned in the cavity of the microwave reactor and irradiated with a maximum power of 50 W for 45 min. After cooling, the resin was collected by filtration and washed with MeOH (5 × 1 mL) and CH2Cl2 (5 × 1 mL). The resin was treated with 10% TFA in CH2Cl2 (1 mL), and the mixture was agitated for 30 min at r.t. The reaction mixture was passed through VARIAN BOND ELUT® Jr-PSA and eluted with 5% MeOH in CH2Cl2 (3 mL) to give desired indol-2-one 8Aa. Compound 8Aa: 1H NMR (CDCl3) δ = 7.64 (d, J = 8.4 Hz, 2 H, ArH), 7.17-7.28 (m, 4 H, ArH), 7.08-7.10 (m, 2 H, ArH), 7.03 (d, J = 7.2 Hz, 1 H, ArH), 6.97 (dd, J = 7.6, 0.8 Hz, 1 H, ArH), 6.93 (d, J = 8.8 Hz, 2 H, ArH), 6.46 (d, J = 7.6 Hz, 1 H, ArH), 5.08 (d, J = 16.0 Hz, 1 H, NCH2Ar), 4.63 (d, J = 16.0 Hz, 1 H, NCH2Ar), 3.87 (dd, J = 8.0, 4.0 Hz, 1 H, COCHAr), 3.48 (dd, J = 13.6, 4.0 Hz, 1 H, CH2Ar), 3.18 (dd, J = 13.6, 8.0 Hz, 1 H, CH2Ar). ESI-MS (+ve): m/z = 357.2 [M + H]+.