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Reductive 1,2-Arylation of Isatins

Amrah Nasim, Gilian T. Thomas, Jeffrey S. Ovens and Stephen G. Newman*

*Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada, Email: stephen.newmanuottawa.ca

A. Nasim, G. T. Thomas, J. S. Ovens, S. G. Newman, Org. Lett., 2022, 24, 7232-7236.

DOI: 10.1021/acs.orglett.2c03042


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Abstract

An intermolecular Ni-catalyzed reductive coupling of aryl iodides and isatins provides 3-hydroxyoxindoles in the presence of sec-butanol as a mild stoichiometric reductant. This formal 1,2-addition reaction is facilitated by a 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligand.


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proposed mechanism



General Procedure

Inside the glovebox, to a dry 8 mL screw-capped reaction vial equipped with a magnetic stir bar, NiBr2.diglyme (0.10 equiv, 0.015 mmol) and PCy2NArCF32(0.24 equiv, 0.036 mmol) were added and dissolved in dry toluene (0.75 mL). Base (2 equiv, 0.3 mmol), aryl halide (1 equiv, 0.15 mmol), and selected isatin derivative (1 equiv, 0.15 mmol) were added to the stirring solution followed by the reducing agent (4 equiv, 0.6 mmol). The vial was capped, removed from the glovebox, and placed in a stirring (350 rpm) pre-heated mineral oil bath at 100C. After stirring for 16 hours, the reaction vial was removed from the oil bath and cooled down to room temperature. The reaction was filtered through a frit layered with silica gel, sodium sulfate, and celite. For very polar products, a mixture of ethyl acetate and acetone was used to flush the compound off the silica gel. The filtrate was diluted to an appropriate concentration and analyzed by GC-MS. Solvent was removed under vacuum and the crude sample was analyzed with NMR spectroscopy. The sample was then dry loaded onto silica and purified by column chromatography on a CombiFlash automated column system. Contamination with the isatin starting material was common, and most products isolated were 95-98% pure. Purity of >98% can be achieved with multiple purification steps.


Key Words

oxindoles, 2-butanol


ID: J54-Y2022