Carbonylation of Aryl Halides: Extending the Scope of the Reaction

Carbonylation reactions are being increasingly favoured in pharmaceutical chemistry for the atom-efficient introduction of carbonyl centres in aldehydes, acids, esters, and amides. Convenient procedures for simple aryl iodides and bromides are well established, and now the need is to develop improved conditions to allow the reactions to be extended to the more unreactive substrates, such as sterically hindered compounds and aryl chlorides. Sterically hindered compounds such as 2-iodo- or 2-bromo- m -xylenes can be converted using alkoxy and aminocarbonylation, while dehalogenation becomes a significant side reaction for reductive carbonylation. Less hindered compounds such as 2-iodo- or bromotoluene can be reacted successfully. Changing the aryl ligands of PdCl 2 {Ph 2 P(CH 2 ) 3 PPh 2 } to alkyl groups improves the rate of oxidative addition but slows the carbonyl insertion step such that rates for the majority of aryl bromides are not improved by this change. Complexes such as PdCl 2 {Cy 2 P(CH 2 ) 3 PCy 2 } offer better performance for alkoxy and aminocarbonylation of aryl chlorides. However, for reductive carbonylation dehalogenation is a significant side reaction. Increasing CO pressure results in additional CO coordination to the catalytic intermediates and slows the reaction, while the dehalogenation is little affected, so reaction selectivity suffers. Thus, CO pressure is a critical parameter, particularly for reductive carbonylation, in achieving the optimum performance.