Sc(OTf)₃-Catalyzed Aza-Friedel–Crafts Reaction of Electron-Rich Arenes with Isatin-Derived Ketimines: Access to 3-Amino-3-Aryl-2-Oxindoles

Abstract

A Sc(OTf)₃-catalyzed aza-Friedel–Crafts reaction of electron-rich arenes with isatin-derived ketimines is disclosed, providing biologically interesting 3-amino-3-aryl-2-oxindoles in moderate to good yields with broad substrate scope. This reaction can be easily scaled up, and the Boc protecting group could be readily removed under mild reaction conditions to afford the free amine.

Key words

Lewis acids - aza-Friedel–Crafts - electron-rich arenes - isatin-derived ketimines - 3-amino-3-aryl-2-oxindoles

• References and Notes

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• 11 General Procedure for the Catalytic Synthesis of Products 3 To a dry 4 mL vial equipped with a magnetic stir bar, were added electron-rich arene 1 (0.15 mmol), isatin-derived ketamine 2 (0.1 mmol), 4 Å MS (100 mg, powder), Sc(OTf)₃ (0.01 mmol), and anhydrous MeCN (1 mL). The tube was sealed with a septum, and the reaction mixture was stirred at r.t. for another 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography using hexane–EtOAc = 4:1 as eluent to afford the desired product 3. tert-Butyl-[1-benzyl-2-oxo-3-(2,4,6-trimethoxyphenyl)indolin-3-yl]carbamate (3a) 41.4 mg, 82% yield, white solid, mp 164–165 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.52 (d, J = 7.5 Hz, 2 H), 7.36 (d, J = 7 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 2 H), 7.26 (t, J = 6.5 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.87 (t, J = 7.5 Hz, 1 H), 6.65 (d, J = 7.5 Hz, 1 H), 6.13 (s, 2 H), 5.07 (br, 2 H), 3.73 (s, 3 H), 3.63 (br, 6 H), 1.31 (br, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 176.6, 160.5, 159.0, 153.6, 143.9, 136.8, 131.4, 128.4, 128.3, 127.7, 127.1, 123.4, 122.0, 108.7, 108.4, 93.1, 79.2, 62.6, 56.3, 55.2, 44.6, 28.3. ESI-HRMS: m/z calcd for C₂₉H₃₂N₂O₆Na⁺: 527.2158; found: 527.2167.
• 12 For a similar product with sulfinyl as the protecting group prepared from Bi(OTf)₃-catalyzed aza-Friedel–Crafts reaction of indoles with isatin-derived ketimines, see: Chen J.-P. Chen W.-W. Li Y. Xu M.-H. Org. Biomol. Chem. 2015; 13: 3363
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