Synthesis of N-Alkoxyindol-2-ones by Copper-Catalyzed Intramolecular N-Arylation of Hydroxamates

Abstract

The first example of copper-catalyzed intramolecular N-arylation of hydroxamic acid derivatives is presented. Based on this transformation a new method for the synthesis of N-alkoxyindol-2-ones from 2-(2-bromoaryl)acetylhydroxamates has been developed. The reaction conditions tolerate standard hydroxyl protecting groups on the hydroxylamine moiety and are also applicable for the synthesis of six-membered N-alkoxybenzolactams.

copper - arylation - cyclization - lactams - hydoxamic ­acids

References and Notes

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General Procedure
To an oven-dried vial equipped with a stirrer bar, hydroxamate (1.0 equiv, 0.2 mmol), copper(II) bromide (10 mol%), K₂CO₃ (2.0 equiv, 0.4 mmol) and 3 Å MS (100 wt%) were added. The vial was closed using an aluminium open-top seal with PTFE-faced septum, flushed with argon before addition of dry toluene (2 mL) and DMEDA (20 mol%) and stirred at the appropriate temperature for the appropriate time (Table  [¹] ). After cooling the reaction mixture was diluted with EtOAc (5 mL) then filtered through a short silica plug and washed with EtOAc. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography on silica gel eluting with EtOAc-hexane (1:5) to give the product.

<A NAME="RD16811ST-26">26</A>

Compound 2a was obtained in 61% yield from iodo hydroxamate 1b if K₃PO₄ was used as base. For a report of the advantage of K₃PO₄ as compared to K₂CO₃ in copper-catalyzed amidation of aryliodides, see ref. 19.

<A NAME="RD16811ST-27">27</A>

Product 2a from chloro hydroxamate 1c was obtained in 43% yield if reaction was carried out for 1 h in MeCN at sample concentration 0.2 mmol/mL.

<A NAME="RD16811ST-28">28</A>

Crystallographic data for 3 have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-827122, and may be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CD2 1EZ, UK; fax: [phone]; or [e-mail].

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