W. Hess, J. Burton
Nov 2, 2010
Citations
0
Influential Citations
25
Citations
Journal
Chemistry
Abstract
Pyrrolidines and pyrrolidinones are highly important structural motifs in organic chemistry. They are present in many ligands for asymmetric catalysis, as catalysts in the ever-growing field of organocatalysis, and in a vast number of natural products. Moreover, pyrrolidines and nitrogen heterocycles, in general, are exceedingly important motifs in medicinal chemistry. The pursuit of new and efficient methods for the synthesis of pyrrolidines and pyrrolidinones, therefore remains an important goal in modern organic synthesis. We envisaged a novel approach to pyrrolidines by palladium-catalysed intramolecular cyclisation of aminomalonates onto alkynes, which would result in the formation of two C C bonds and a stereodefined alkene in a single step (1!2!3, Scheme 1); an analogous scheme has been employed successfully for the cyclisation of 4-alkynyl malonates and related compounds, and a related three-component reaction for the synthesis of 3-alkylidene pyrrolidines has been developed by Balme and co-workers. Apart from the beautiful indium-catalysed Conia-ene reaction for the formation of pyrrolidines and pyrrolidinones reported from Hatakeyama s group, the cyclisation of a-aminomalonates onto alkynes has barely been studied. Our initial efforts focussed on the cyclisation of N-benzylprotected aminomalonate 4 to form 5 a under palladium and copper catalysis (Table 1). Thus, exposure of 4 to 5.0 mol % [PdCl2ACHTUNGTRENNUNG(dppf)] (dppf=1,1’-bis(diphenylphosphino)ferrocene), 10.0 mol % CuI and stoichiometric tBuOK in THF at 60 8C delivered the desired pyrrolidine 5 a in 18 % yield, along with a fully substituted alkene by-product product 13 g (Table 1, entry 1). Reducing the catalyst loading to