[reaction: see text] beta-Ketonitriles are important precursors for a wide variety of biologically active heterocycles. A facile procedure for the high-yielding acylation of nitrile anions with unactivated esters to provide beta-ketonitriles is reported. The procedure is successful with enolizable and nonenolizable esters as well as hindered nitrile anions.

An exothermic decomposition was observed during a metalation/acylation of 3,4-difluoroanisole (5), resulting in a significant thermal hazard. The lithiated anion 6 was found to decompose exothermically at temperatures above −47 °C showing an adiabatic temperature rise at a peak rate of 120 °C/min. A literature search revealed similar observations for metalation/acylation in analogous aromatic difluoro compounds. This sequence of reactions was evaluated thermochemically. Control experiments at −55 °C over 2 h indicated anion 6 was stable at temperatures below −55 °C under dilute reaction concentrations. This runaway hazard could be addressed using MgCl2 to stabilize the reactive species and thereby decrease its decomposition rate. Thermochemical experiments suggested MgCl2 forms a weak interaction with lithiated species 6, rather than via complete lithium−magnesium exchange. The process was successfully piloted on a multikilo scale by use of MgCl2 as an additive.

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