E-Z isomerization in Suzuki cross coupling of 1, 2-dichlorovinyl phenyl ketone: Ligand effects in controlling selectivity and mechanistic studies for loss of stereochemical integrity.

Abstract

While studying site selective palladium catalyzed Suzuki cross coupling on E-1,2-dichlorovinylphenyl ketone, a loss of stereochemistry was observed in the cross coupled product. It was soon discovered that extent of the isomerized cross coupled product formed was dependent on the phosphine ligand employed in the Suzuki cross coupling reaction conditions. With the careful choice of the phosphine ligand, the reaction conditions were designed to form either retention Suzuki cross coupled product or isomerized Suzuki cross coupled product selectively. The use of DPEphos or Xantphos ligand resulted in 96% selectivity of the isomerized cross coupled product whereas reactions in the presence t-Bu-Xantphos or no phosphine ligand resulted in 94% selectivity of the retention cross coupled product. While studying the pathway by which the loss of stereochemistry could take place in the Suzuki cross coupling reaction, many well accepted pathways such as thermal isomerization, photo-isomerization, reversible Michael addition of phosphine, isomerization due to intrinsic zwitterionic character of the vinyl palladium species, generation of palladium hydrides in the reaction conditions etc. were ruled out. It was found that E-Suzuki cross coupled product isomerizes to Z-Suzuki cross coupled product in the presence of just palladium catalyst. This observation along with other experimental results are well explained by a mechanism first proposed by Canovese and Visentin for the isomerization of dimethyl maleate in the presence of palladium catalyst. According to this mechanism, an isomerization takes place by a mere coordination of the substrate to the palladium catalyst without any external promoter. The isomerized outcome in the reactions is usually unwanted but the ability to supress or promote isomerization nearly completely is remarkable. The experimental data not only suggests that the isomerization takes place by a mere coordination of the Suzuki cross coupled product with palladium catalyst but also demonstrates that the Suzuki cross coupling reaction is indeed stereospecific in nature and that the isomerization occurs by a separate catalytic cycle. It was also observed that the presence of a single conjugated carbonyl group is sufficient to induce the isomerization. Based on this observation, one can expect isomerization in the substrates possessing an enone functionality. This is a significant observation as enone substrates are one of the important classes in the organic synthesis and prior knowledge of how these substrates can behave during Pd/phosphine catalyzed reactions is very useful.