The Development of Palladium and Cobalt-Catalyzed Methods for the Syntheses of alpha-Trifluoromethyl and Alkyl Amines

The prevalence of nitrogen-containing compounds in medicinal chemistry has driven the need for the development of methodologies for the construction of chiral amines in organic synthesis. Amongst these chiral amines, a-trifluoromethyl and alkyl amines are an important subclass that have been sought after because of their relevance in drug discovery. With respect to a-trifluoromethyl amines, the role of fluorine in altering lipophilicity, influencing pKa, and affecting conformational bias of bioactive compounds has caused a surge in the development of new synthetic strategies for the construction of this functionality. Umpolung methods are robust technologies that enable streamlined synthesis of different types of chiral amines that are more challenging to obtain with a normal polarity approach. For example, the addition of nucleophiles to electrophilic imines, which is one commonly used strategy, limits the chemical space that may be generated for the preparation of chiral amines. Thus, other enabling strategies are desired.In this work, we describe three methods for the preparation of different chiral amine motifs, detailing 1) the synthesis of a-trifluoromethyl benzylic amines through a vicinal fluoroarylation of difluoroazadienes, 2) the diastereo- and enantioselective synthesis of a-trifluoromethyl homoallylic amines via a catalytic hydroalkylation of dienes as well as 3) the enantioselective synthesis of alkyl amines enabled by a 5,6- hydroalkynylation of substituted 2-azatrienes.