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.

Key words

carbonylation - palladium - homogeneous catalysis - pyridines - coupling reactions

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10

Mägerlein, W.; Indolese, A.; Beller, M. Angew. Chem., Int. Ed. 2001, in press.

12

2- and 3-Chloropyridine are a factor of 10-50 more expensive than 2- and 3-picoline.

16

The respective n-butyl ethers are formed as side-products in 13-15% yield.

20

For experiments at different temperatures, CO pressures, and catalyst concentrations, or with other ligands and bases, the conditions given in the respective tables were used.