Browsing by Subject "Hydrofunctionalization"

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.

The construction of complex structural motifs from simple precursors is a compelling goal in organic synthesis. Within this context, enantioselective hydrofunctionalization of carbon–carbon multiple bonds is an attractive strategy due to the broad accessibility and/or simple preparation of starting materials and because of the inherent atom economy of this process. The hydrofunctionalization of conjugated multiple bonds provides additional opportunities and challenges. Conjugated dienes and enynes can be more reactive in transition metal catalysis than isolated olefins or alkynes; however, such hydrofunctionalization processes frequently give rise to multiple stereo- and regioisomers. Achieving both site and facial selectivity for nucleophile additions to these requires careful catalyst design. This research describes the development of palladium catalysts bearing electron-deficient phosphinooxazoline (PHOX) ligands for highly efficient regio- and enantioselective addition of amine and carbon-based nucleophiles to conjugated dienes and enynes. These reactions proceed under exceptionally mild conditions to afford a variety of high-value enantioenriched products. Throughout these studies, questions regarding the mechanisms of these transformations have been answered using an experimental approach.