Selective formation of secondary amides via the copper-catalyzed cross-coupling of primary amides with alkylboronic esters

Rossi, Steven
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University of Delaware
Chapter 1 begins with an abbreviated introduction into traditional formation of amides as published in the chemical literature. Previous examples for this transformation, including Buchwald-Hartwig type couplings and the copper catalyzed Ullmann and Lam-Chan cross-couplings, are reviewed, followed by a short, but detailed summary of the alkyl Lam-Chan protocols and available methods to date. The limitations of the known procedures are also examined. Chapter 2 describes the first ever report of exclusive mono-alkylation of a primary amide via a copper-catalyzed cross-coupling with an alkylboronic acid. In order to demonstrate generality of the method, a multitude of substrates with varying functional groups were synthesized. After optimization from standard Lam-Chan reaction conditions using a model system, the optimal conditions were tested on a variety of commercially available and on-site synthesized substrates. Variations to both the primary amide and the alkylboronic acid were tested and analyzed thoroughly. A detailed discussion on the suitable coupling partners, in addition to the examination of intolerant functional groups, is also presented. Chapter 3 describes the next step in the formation of new C-N bonds using alkyl boronates. Further investigation has shown successful alkylation with alkylboronic acid pinacol esters, which are of great interest due to their abundance and ease of synthesis, temperature and air stability, and commercial availability. Preliminary optimization and investigation into the generality of this reaction, in addition to the synthesis of novel alkyl boronates, is reported.