373297 Strategy to Avoid Catalyst Deactivation in Telescoped Miyaura Borylation/Suzuki Cross-Coupling Reaction

Tuesday, November 18, 2014: 4:55 PM
Crystal Ballroom B/E (Hilton Atlanta)
Marimuthu Andiappan, Jeremy Merritt, Gregory Brown and Jennifer Kuehne-Willmore, Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN

The telescoped Miyaura borylation/Suzuki cross-coupling reaction is one of the most efficient methods used for the synthesis of a biaryl compounds in pharmaceutical industry. This reaction involves borylation of an aryl halide compound with a boron compound catalyzed by palladium catalyst to form non-isolated intermediate, which is then telescoped in Suzuki coupling reaction with another aryl halide to form the biaryl compound. Catalyst deactivation is one of the critical problems often faced during this reaction and results in (i) lower yield towards the desired biaryl compound, (ii) formation of non-catalyzed undesired byproducts and/or (iii) inconsistent reaction completion time.

In this contribution, we will show that the palladium (Pd) catalyst deactivation can be avoided by controlling the relative quantities of the reagents charged. Specifically, we will demonstrate that when the aryl halide compound is used as limiting reagent in the borylation reaction, the palladium catalyst precipitates (or blacks out) at the end of the borylation and results in a slower Suzuki reaction rate and variable reaction completion time. We will show that by changing the limiting reagent to the boron compound we can avoid Pd blackout at the end of borylation and achieve faster Suzuki reaction rate and consistent reaction completion times.  We will discuss the molecular mechanisms that govern the palladium blackout and potential strategies to avoid the palladium inactivation.

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