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

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.

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

References

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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.

<A NAME="RU01704ST-12">12</A>

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 Discover^TM Focused Microwave Synthesis (CEM Corporation).

<A NAME="RU01704ST-14">14</A>

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]⁺.

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