Efficient Palladium-Catalyzed Alkoxycarbonylation of N-Heteroaryl Chlorides - A Practical Synthesis of Building Blocks for Pharmaceuticals and Herbicides

Abstract

The alkoxycarbonylation of various N-heteroaryl chlorides was examined in detail. Studies of the butoxycarbonylation of 2- and 3-chloropyridine revealed the importance of selecting both the right phosphine ligand and ligand concentration in order to obtain efficient conversion and selectivity. Amongst the different ligands tested, 1,4-bis(diphenylphosphino)butane (dppb) and 1,1'-bis(diphenylphosphino)ferrocene (dppf) led to the most efficient palladium catalyst systems for the conversion of 2- and 4-chloropyridines and similar heteroaryl chlorides. The best catalytic systems for the alkoxycarbonylation of less activated substrates, such as 3-chloropyridines, were found to be those containing 1,4-bis(dicyclohexylphosphino)butane. Good to excellent yields of a number of N-heterocyclic carboxylic acid esters were realized by applying the appropriate ligand in the right concentration at low catalyst loadings (0.005-0.5 mol% Pd). For the first time catalyst turnover numbers (TON) of up to 13,000 were obtained for the carbonylation of a (hetero)aryl chloride.