Efficient palladium-catalyzed alkoxycarbonylation of N-heteroaryl chlorides - A practical synthesis of building blocks for pharmaceuticals and herbicides

The alkoxycarbonylation of various N-heteroaryl chlorides was examined in d etail. Studies of the butoxycarbonylation of 2- and 3-chloropyridine reveal ed the importance of selecting both the right phosphine ligand and ligand c oncentration in order to obtain efficient conversion and selectivity. Among st the different ligands tested, 1,4-bis(diphenylphosphino)butane (dppb) an d 1,1'-bis(diphenylphosphino)ferrocene (dppf) led to the most efficient pal ladium catalyst systems for the conversion of 2- and 4-chloropyridines and similar heteroaryl chlorides. The best catalytic systems for the alkoxycarb onylation of less activated substrates, such as 3-chloropyridines, were fou nd to be those containing 1,4-bis(dicyclohexylphosphino)butane. Good to exc ellent yields of a number of N-heterocyclic carboxylic acid esters were rea lized 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 (he tero)aryl chloride.