A simple, multidimensional approach to high-throughput discovery of catalytic reactions

Abstract

Transition metal complexes catalyze many important reactions that are employed in medicine, materials science, and energy production. Although high-throughput methods for the discovery of catalysts that would mirror related approaches for the discovery of medicinally active compounds have been the focus of much attention, these methods have not been sufficiently general or accessible to typical synthetic laboratories to be adopted widely. We report a method to evaluate a broad range of catalysts for potential coupling reactions with the use of simple laboratory equipment. Specifically, we screen an array of catalysts and ligands with a diverse mixture of substrates and then use mass spectrometry to identify reaction products that, by design, exceed the mass of any single substrate. With this method, we discovered a copper-catalyzed alkyne hydroamination and two nickel-catalyzed hydroarylation reactions, each of which displays excellent functional-group tolerance.

Fig. 1

Contents of a single well in the multidimensional experiments for reaction discovery. The combination of 17 substrates was placed into each reaction well. Twelve ligands were dispensed, one into each well of a column, and eight metal catalyst precursors were dispensed, one into each well of a row. The plate was sealed and heated at 100°C for 18 hours. After this time, the contents of the wells in the plate were analyzed by mass spectrometry. The number of substrates is arbitrary; the 17 substrates contain a representative set, not a comprehensive set, of typical organic functional groups. A group of catalysts derived from Mn, Fe, Cr, Co, Cu, Ni, and W was chosen because of its abundance and low cost. In addition, we examined catalysts derived from Ru and Mo because these are inexpensive relative to the more precious metals, Yb as a representative f-block metal, and Au because of its wide range of reactivity that has recently been uncovered. The ligands we combined with these metals included common phosphines and amines, as well as less explored phosphine oxides, phosphine sulfides, and amidinates (table S1). Excess of the metal complexes were used in this system to alleviate poisoning all of the potential catalysts by one substrate. Reactions discovered in such a system would be rendered catalytic after initial identification of the transformation and metal-ligand combination that induces the transformation. The 17 substrates, in combination with catalysts derived from 15 metal centers and 23 ligands or the absence of a ligand, correspond to more than 50,000 reactions. These reactions were conducted in a few days, after developing our protocol. Bu, butyl; tBu, tert-butyl; Me, methyl; Ph, phenyl.

Fig. 2

GC–mass spectrum of the combination of reactions in the row containing Cu(OAc)₂ as a metal catalyst precursor. The product from Cu-catalyzed oxidative coupling was observed. The peak at 17.9 min corresponds to material with an m/z value of 281, which is the mass of the amination product. MW, molecular weight.

Fig. 3

Cu-catalyzed alkyne hydroamination with 4-nBu-aniline. THF, tetrahydrofuran.

Fig. 4

Deconvolution strategy to identify coupling partners for products observed in high-throughput reaction discovery.

Fig. 5

Ni-catalyzed hydroarylation of diphenylacetylene with phenylboronic acid and bromobenzene.

Fig. 6

Nickel-catalyzed alkyne hydroarylation with aryl and heteroaryl boronic acids. The ratio given is cis/trans (Z/E) olefin geometry.

Fig. 7

Nickel-catalyzed alkyne hydroarylation with aryl and heteroaryl bromides. The ratio given is Z:E olefin geometry. Et, ethyl.