Selective Terminal Heck Arylation of Vinyl Ethers with Aryl Chlorides:  A Combined Experimental−Computational Approach Including Synthesis of Betaxolol

Abstract

Reaction conditions have been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers with high regioselectivity using inexpensive aryl chlorides as starting materials and the P( t -Bu) 3 releasing preligand [( t -Bu 3 )PH]BF 4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to minimize handling and processing times and uses aqueous DMF or environmentally friendly PEG-200 as the reaction medium. The selectivity for linear β-product in PEG-200 is slightly higher than in aqueous DMF. DFT calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of bulky P( t -Bu) 3 ligand provides improved β-selectivity in the essential insertion step also with electron-rich aryl chlorides. A tentative computational rationalization of the improved selectivity in non-methylated PEG is discussed. Finally the synthetic methodology was used to provide efficient access to linear p -[2-(cyclopropylmethoxy)ethyl] phenol from p -nitrophenyl chloride, a key intermediate in the synthesis of the β-adrenergic blocking agent Betaxolol.