Double carbonylation of aryl halides to a-keto acid derivatives

1 Double carbonylation of aryl halides to a-keto acid derivatives 

The catalytic cycle is common with the single carbonylation of aryl hafides in the steps of oxidative addition of aryl halide to a Pd(0) species and the subsequent CO insertion process. Since successive CO insertion into the acylpalladium bond is not thermodynamically favorable, incorporation of another CO molecule takes the route of coordination of the CO molecule to the acylpalladium(II) intermediate. Attack by a nucleophile such as secondary amine, alcohol, and water in the presence of an appropriate base, including the amine itself, gives bis acyl type intermediate which reductively efiminates a-keto acid derivatives [131]. 

Although the scope of catalytic double carbonylation was considered to be limited to aryl and vinyl hafides and the process was not applicable to aliphatic hafides because of ready direct reaction of alkyl hafides with amines, later examination revealed that allyl hafides could be double carbonylated when the reaction was carried out in the presence of a limited amount of an amine under CO pressure (Eq. 1.19). 

The influence of the amount of amine can be elucidated by mechanistic considerations of the double carbonylation. An allyl halide readily forms an allypalladium halide by oxidative addition to Pd(0) species and the amine can attack the allyl ligand to generate allylamine. However, the nucleophilic attack is a reversible process and CO insertion into the allylpalladium species can take place in the presence of a small amount of amine to allow the formation of the acylpalladium species. Attack of the amine on the coordinated CO giving the carbamoylpalladium species followed by reductive elimination by coupling with another alkenoyl ligand produces the a-keto amide [132], 

As further application of the double carbonylation a one-pot synthesis of a-amino amides has been achieved by using primary amines [133] 

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