Controlling Reactivity and Selectivity in the Mizoroki-Heck Reaction: High Throughput Evaluation of 1,5-Diaza-3,7-diphosphacyclooctane Ligands

22 December 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


We report a high throughput evaluation of the Mizoroki-Heck reaction of diverse olefin coupling partners. Comparison of different ligands revealed the 1,5-diaza-3,7-diphosphacyclooctane (P2N2) scaffold to be more broadly applicable than common ‘gold standard’ ligands, demonstrating that this family of readily accessible diphosphines have unrecognized potential in organic synthesis. In particular, two structurally related P2N2 ligands were identified to enable the regiodivergent arylation of styrenes. By simply altering the phosphorus substituent from a phenyl to tert-butyl group, both the linear and branched Mizoroki-Heck products can be obtained in high regioisomeric ratios. Experimental and computational mechanistic studies were performed to further probe the origin of selectivity, which suggests that both ligands coordinate to the metal in a similar manner, but that rigid positioning of the phosphorus substituent forces contact with the incoming olefin in a pi-pi interaction (for P-Ph ligands) or with steric clash (for P-tBu ligands), dictating the regiocontrol


High throughput experimentation
Pd catalysis

Supplementary materials

Supporting Information
Experimental procedures, optimization tables, troubleshooting, characterization of organic molecules, and mechanistic studies


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