At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.
A catalyst for the intramolecular direct arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver salts which also permits these reactions to occur at lower temperature. The utility of the methodology is illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered tetra-ortho-substituted biaryls via ring-opening reactions of the direct arylation products. Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C-H bond cleavage in palladium-catalyzed direct arylation of simple arenes. Knowledge garnered from these studies has led to the development of new intermolecular arylation reactions with previously inaccessible arenes, opening the door for the development of other new direct arylation processes.
Direct arylation reactions of pyridine N-oxides occur in excellent yield with complete selectivity for the 2-position with a wide range of aryl bromides. This reactivity permits the use of inexpensive, commercially available, and bench-stable pyridine N-oxides as replacements for problematic 2-metallapyridines in palladium-catalyzed cross-coupling reactions.
We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries.
Cross-coupling reactions, which were discovered almost 50 years ago, are widely used in both industry and academia. Even though cross-coupling reactions now represent mature technology, there is still a significant amount of research in this area that aims to improve the scope of these reactions, develop more efficient catalysts, and make reactions more practical. In this tutorial, a brief background to cross-coupling reactions is provided, and then the major advances in crosscoupling research over the last 20 years are described. These include the development of improved ligands and precatalysts for cross-coupling and the extension of cross-coupling reactions to a much wider range of electrophiles. For example, cross-coupling reactions are now common with sp 3 -hybridized electrophiles as well as ester, amide, ether, and aziridine substrates. For many of these more modern substrates, traditional palladium-based catalysts are less efficient than systems based on first-row transition metals such as nickel. Conventional cross-coupling reactions have also inspired the development of a range of related reactions, such as cross-electrophile and decarboxylative couplings as well as couplings based on metallaphotoredox chemistry. The development of these new reactions is probably at the same stage as traditional cross-coupling reactions 30 years ago, and this tutorial highlights how many of the same strategies used to improve cross-coupling reactions may also be applicable to making the new reactions more practical.
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