Macro Strides on a Nano-scale: Merck & Co Scientists Leading the Way in High-Throughput Experimentation

High-Throughput Experimentation

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.


Schmink JR, Bellomo A, Berritt S. 2013. Aldrichimica Acta. , 46, 71–80..
Dreher SD, Lim S, Sandrock DL, Molander GA. 2009. Suzuki?Miyaura Cross-Coupling Reactions of Primary Alkyltrifluoroborates with Aryl Chlorides. J. Org. Chem.. 74(10):3626-3631.
Sandrock DL, Jean-Ge?rard L, Chen C, Dreher SD, Molander GA. 2010. Stereospecific Cross-Coupling of Secondary Alkyl ?-Trifluoroboratoamides. J. Am. Chem. Soc.. 132(48):17108-17110.
Molander GA, Argintaru OA, Aron I, Dreher SD. 2010. Nickel-Catalyzed Cross-Coupling of Potassium Aryl- and Heteroaryltrifluoroborates with Unactivated Alkyl Halides. Org. Lett.. 12(24):5783-5785.
Molander GA, Trice SLJ, Dreher SD. 2010. Palladium-Catalyzed, Direct Boronic Acid Synthesis from Aryl Chlorides: A Simplified Route to Diverse Boronate Ester Derivatives. J. Am. Chem. Soc.. 132(50):17701-17703.
Fleury-Brégeot N, Raushel J, Sandrock DL, Dreher SD, Molander GA. 2012. Rapid and Efficient Access to Secondary Arylmethylamines. Chem. Eur. J.. 18(31):9564-9570.
Molander GA, Trice SLJ, Kennedy SM, Dreher SD, Tudge MT. 2012. Scope of the Palladium-Catalyzed Aryl Borylation Utilizing Bis-Boronic Acid. J. Am. Chem. Soc.. 134(28):11667-11673.
Bellomo A, Celebi-Olcum N, Bu X, Rivera N, Ruck RT, Welch CJ, Houk KN, Dreher SD. 2012. Rapid Catalyst Identification for the Synthesis of the Pyrimidinone Core of HIV Integrase Inhibitors. Angew. Chem. Int. Ed.. 51(28):6912-6915.
DiRocco DA, Dykstra K, Krska S, Vachal P, Conway DV, Tudge M. 2014. Late-Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis. Angew. Chem. Int. Ed.. 53(19):4802-4806.
Friedfeld MR, Shevlin M, Hoyt JM, Krska SW, Tudge MT, Chirik PJ. 2013. Cobalt Precursors for High-Throughput Discovery of Base Metal Asymmetric Alkene Hydrogenation Catalysts. Science. 342(6162):1076-1080.

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