If you haven’t been keeping up with High-Throughput Experimentation (HTE)1 methods lately, then the recent article by chemists at Merck & Co published in the journal Science may come as a big surprise. The Merck & Co team reports a method to run palladium-catalyzed cross-coupling reactions on 0.02 mg of material per reaction—1536 reactions can be run in less than a day! Using a TTP Mosquito liquid handling robot borrowed from biochemistry colleagues, tiny drops of reagent solutions could be mixed in a 1536-well microtiter plate. This allows a lot of reaction data to be generated from very little material. “Biologists have been running miniaturized high-throughput experiments for decades”, says Spencer Dreher, one of the paper’s corresponding authors, “having lots of data is just as valuable to the study of chemical reactions.” Indeed, they show that studying up to 48 different combinations of ligand and base per milligram of starting material, they can locate productive cross-coupling conditions on high complexity molecules that were otherwise unreactive or unstable. This most recent experimentation feat was led by Merck & Co postdoctoral fellows Alexander Buitrago Santanilla and Erik Regalado.
Another key to the method was the evolution of existing cross-coupling methods to work at room temperature in DMSO so that nanoliters of liquid could be dosed without rapid evaporation of the reaction drop. Most palladium-catalyzed reactions shut down at room temperature in the presence of DMSO, but the combination of modern phosphine ligands with organic superbases allowed the reactions to proceed at rt. For instance, the combination of tBuXPhos-Pd-G3 catalyst with P2Et phosphazene base allowed a variety of room temperature C-N couplings to occur in DMSO.
This is not the first time Merck & Co chemists have used high-throughput experimentation to accelerate their medicinal and process chemistry programs, they have been leading the field for years both within Merck & Co and in collaboration with many leaders in academia, as demonstrated by numerous publications in the area of cross-coupling,2(a-f) additive testing,3 C-H activation,9 and hydrogenation with base metals.10 Additionally, they have helped to set up reaction screening centers at the University of Pennsylvania, Princeton, Michigan State, UC Berkeley, ICIQ Spain, Yeshiva University, and Baylor University.
To read the full article published in Science click here.
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