An Efficient Palladium-Catalysed Aminocarbonylation of Benzyl Chlorides

Abstract

An improved procedure for the aminocarbonylation of benzyl chloride derivatives using carbon monoxide and either primary or secondary amines has been developed. Studying the competing background alkylation reaction allowed the solvent and base to be selected for a simple catalyst screen, which, in turn, enabled the discovery of a method for the preparation of 2-arylacetamides under mild conditions, with minimal side-products using an inexpensive phosphine ligand. This non-traditional optimisation strategy allowed us to overcome the background alkylation, which has been cited as justification for the development of more complex and less atom-economical approaches.

Key words

palladium catalysis - carbonylation - amides - reaction optimisation

• References and Notes

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• 28 General Procedure: To a round-bottomed ACE glass pressure flask containing a magnetic stirrer was added toluene (20 mL), chloromethylbenzene (1.0 g, 7.9 mmol) and N,N-diisopropylethylamine (1.5 equiv). The mixture was degassed with subsurface nitrogen purge for 5 minutes. Palladium(II) acetate (2.5 mol%) and bis(2-diphenylphosphinophenyl)ether (5 mol%) were added, followed by the primary or secondary amine (1.2 equiv) to give a pale-yellow solution. The flask was purged with nitrogen, filled with carbon monoxide to 50 psig and heated at 70 °C with magnetic stirring overnight. The reaction mixture was cooled to ambient temperature and residual CO vented. The reaction mixture was partitioned between EtOAc (200 mL) and 10% aq. citric acid (2 × 30 mL). The organic layer was washed with water then brine, dried over MgSO₄, filtered and evaporated. The residue was loaded to the top of a silica gel plug with CH₂Cl₂ and eluted with a gradient of EtOAc in isohexane to afford the amide products.