Identification and Elimination of an Unexpected Catalyst Poison in Suzuki Coupling

Abstract

A Suzuki coupling reaction gave an uncharacteristically low conversion in a GMP campaign. Initial investigation revealed a palladium catalyst poison in the starting material. A temporary solution was developed along with contingency plans to enable successful material delivery. Further systematic studies led to the identification of elemental sulfur as the culprit. A “sulfur-free” synthesis of the starting material was developed for the next round of manufacturing.

Development of a Process to a 4-Arylated 2-Methylisoquinolin-1(2H)-one for the Treatment of Solid Tumors: Lessons in Ortho-Bromination, Selective Solubility, Pd Deactivation, and Form Control

“…This is supported by in-process assay yields obtained with lots containing various sulfur content as well as spiking experiments using elemental sulfur. This phenomenon has previously been documented by others in analogous Pd-mediated transformations …”

“…This phenomenon has previously been documented by others in analogous Pd-mediated transformations. 28 As a mitigation, we have modified our specifications for incoming hydroxyisoquinoline 5 to include a limit for residual sulfur, implemented a carbon treatment for greater control at the isolation of 7 to not more than 200 ppm, and finally, modified our cross-coupling procedure to include an optional kicker charge if required. Although the catalyst change was deemed to have only a moderate improvement over the prior system for bromide samples containing higher sulfur levels, the improved reaction speed, workup, and isolation were all deemed advantageous in terms of cost and cycle time.…”

Domino Sonogashira coupling/metal carbene-involved annulation enabled by Pd/Cu relay catalysis: rapid assembly of indazole-containing biheteroaryls

“…Meanwhile, the metal catalyst (Pd catalyst) can't be poisoned by sulfur species during the catalytic cycle, which presents another formidable challenge. 13 In this context, we now report a successful example of rapid assembly of indazole-containing biheteroaryls from 2-iododiazene 1a and ethynyl substituted thiocarbamate 2a , featuring simultaneous generation of C–C, C–N, and C–C bonds, as well as two rings in one step via domino Sonogashira coupling/azaenyne cycloisomerization/Barton–Kellogg under Pd/Cu relay catalysis (Fig. 2B).…”

Unearthing Novel Thiazolidinone Building Blocks As Carboxylic Acid Bioisosteres

“…Further studies here could include the use of prolonged heating and the incorporation of varying solvents, to optimise the Suzuki cross-coupling scheme [1]. Earlier incorporation of the aryl group prior to condensation with TZD may also be worth exploration in case the sulfur affects the catalyst [35]. However, evidence of Suzuki couplings in TZD-containing systems has been reported [34].…”