Invention of novel palladium-catalysed three-component couplings

Abstract

A three component synthesis of N-tert-butyl substituted amidines from aryl halides, tert-butyl isonitrile and a tin amide component was developed. The optimum catalyst was tris-(dibenzylideneacetone)dipalladium(0) chloroform with 2 equivalents of 1,1'-bis (diphenylphosphino)ferrocene as ligand. An improvement to this method, allowing for the use of free amines in the presence of caesium carbonate as base, thus avoiding tin compounds, was subsequently established. The optimum catalyst was palladium dichloride or palladium diacetate with 2 equivalents of 1,1'-bis (diphenylphosphino)ferrocene as ligand. A wide range of N-tert-butyl substituted amidines were synthesised from electron rich, electron poor, electronically neutral, and heterocyclic aryl bromides or triflates and primary or secondary, cyclic or acyclic, aliphatic or aromatic amines. The stereochemistry of the amidines so formed was established by NMR and molecular modelling (including DFT calculations) and found to be the thermodynamically less stable (Z)-imine stereoisomer. Removal of the tert-butyl group with strong sulphuric acid was found to be viable to give secondary amidines. Intramolecular insertions to afford cyclic amidines were accomplished. The tin-free methodology was then applied to the synthesis of imidates and thioimidates from aryl bromides, isonitriles and the sodium salts of alcohols, phenols and thiols in high yields. It was found that a wide range of isonitriles were compatible with this reaction (primary, secondary, and tertiary). Phenoxyimidates formed in the above way reacted with amines with weak acid catalysis to afford amidines variously substituted on the nitrogen derived from an isonitrile thus avoiding the limitation to tertiary alkyl isonitriles found in the direct amidine synthesis.

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