Development of Stable, Active, and High-Throughput Experimentation Compatible Palladium Precatalysts




Huang, Jingjun

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Palladium-catalyzed cross-coupling has an approximately 50-year history, with seminal work in the 1970s leading to widespread use today, resulting in the 2010 Nobel Prize in Chemistry. The robustness of this chemistry, which enables constructions of C–C, C–H, C–N, C–O, and so on, has led to rapid growth and extensive applications of cross-coupling approaches in modern synthesis in the last decade. Alongside this, mechanistic studies of many Pd-catalyzed cross-coupling reactions are well-developed, with a wide range of catalytic systems established to maximize the reaction performance. Despite widespread acceptance of LPd0 species as key intermediates in the catalytic cycle, new developments with Pd0 precursors remain rare. Instead, PdII sources are the preferred precursor compounds; however, activation of these precatalysts involves reduction steps that can be complicated and challenging to elucidate. The works presented here describe the development of a series of new Pd0 precatalysts and one PdII precursor, which collectively resolve specific limitations of existing catalytic systems. The first palladium(0) precursor, DMPDAB–Pd–MAH, is an easily prepared, bench-stable, high-throughput screen compatible, and highly active precatalyst stabilized by an α-diimine ligand (N,N'-bis(2,6-dimethylphenyl)diazabutadiene, DMPDAB) and maleic anhydride (MAH). This precursor is an effective alternative to Pd2dba3•CHCl3 (the most commonly used palladium(0) source) for in situ catalyst formation. Furthermore, single-component phosphine-ligated palladium(0) precursors derived from DMPDAB–Pd–MAH exhibit superior performance in both catalytic cross-coupling reactions and stereoselective asymmetric allylic alkylations. Finally, to address limitations identified for systems based on DMPDAB–Pd–MAH, we report a new palladium(II) precursor, DMPDAB–Pd–(CH2TMS)2, for oxidative addition complex generation, high-throughput experimentation, and preparative-scale synthesis. This system takes advantage of straightforward PdII to Pd0 activation via reductive elimination of the alkyl ligands. Notably, DMPDAB–Pd–MAH is now commercially available at MilliporeSigma, and the other new precursors reported here are the subjects of filed patent applications. Thus, these new precursors have the potential for positive impact on improving reaction performance in industry-scale syntheses for complex organic molecules, including pharmaceuticals and agrochemicals.



Palladium precatalysts, cross-coupling, high-throughput experimentation