Nickel catalyzed cross-coupling of unactivated alkyl halides and synthesis and reactions of α-trifluoromethyl organoborons

Chapter 1. The Suzuki-Miyaura reaction has emerged as one of the most powerful cross-coupling strategies to unite alkyl electrophiles with aryl nucleophilic partners because of the properties of the organoboron compounds, including: low toxicity, air- and water stability, functional group compatibility and commercial availability. Nickel catalysts were reported to be one of the most successful in the field of C(sp2)-C(sp3) bond formation via the Suzuki-Miyaura reaction. Nevertheless, limitations to the developed methods remain: a significant excess of boronic acid is usually required, while sterically hindered and heteroarylboronic acids only cross-coupled to a very limited extent. Chapter 1 describes new methods that overcome the aforementioned limitations by the use of the more robust, tetracoordinate potassium organotrifluroborates in the presence of Ni catalysts. Screenings of reaction conditions were performed using High Throughput Experimentation (HTE), a very powerful tool for rapid reaction development or for quick discovery of new catalytic systems that allows fast progress to be achieved, with hundreds of reactions being carried out daily. Chapter 2. The importance of fluorine has been well established in the pharmaceutical, agrochemical, and materials industries. A facile SciFinder search shows that (trifluoroethyl)arenes are of great interest in industry, but current access to (Het)ArCH2(CF2)nCF3 substructures is extremely limited. These structures could be potentially accessed by Suzuki-Miyaura cross-coupling of methylene-interrupted polyfluoroalkyltrifluoroborates. With thousands of commercially available (hetero)aryl halides, our approach would allow rapid access to a wide range of novel fluorinated molecules that could not be synthesized via current methods. Potassium 2,2,2-trifluoroethyltrifluorborate was synthesized via Pd-catalyzed Miyaura-type borylation of 2,2,2-trifluoroiodoethane. Various organoborons bearing an alpha-trifluoromethyl substituent were synthesized from a wide variety of alkyl, alkenyl, alknyl, aryl, and heteroaryltrifluoroborates using 2,2,2-trifluorodiazoethane. These substrates represent the first isolated alpha-trifluoromethylated alkylboron building blocks, and their reactivity was investigated