Presenter: EJ McLaren
Copper-Catalyzed Electrophilic Amination of O-Acyl-N-Hydroxyamines with Alkenes for the Synthesis of Allylic Amines and Vicinal Diamines
Nitrogen atoms are ubiquitous in bioactive organic molecules where they are key contributors to molecular recognition, making the synthesis of nitrogen-containing molecules an important task in organic chemistry. Alkylamines are a privileged class of nitrogenous molecules common in pharmaceuticals. To improve the efficiency with which these important molecules can be synthesized, the development of catalytic methodology for C(sp3)-N bond construction is ongoing. One approach is the electrophilic amination of alkenes and other SOMOphiles to achieve multi-component cascade reactions. However, this strategy as well as other amination reactions frequently rely on specialized nitrogen sources lacking structural diversity.
The Wang laboratory has developed a copper-catalyzed platform for electrophilic amination using O-acyl-N-hydroxyamines as convenient precursors to diverse alkylamino groups. This thesis describes the development of methods for the synthesis of allylic amines and vicinal diamines using this platform.
The allylic amination reaction provides a method for the synthesis of tertiary N-alkyl allylamines from variously substituted alkenes. A sulfonic acid is used to enhance the electrophilicity of the radical aminating species while the π-bond is selectively transposed with selective elimination of β-hydrogen. Investigation of mechanism for this catalytic process revealed the presence of radical intermediates, an electronic influence on the desaturation step, and an absence of kinetic isotope effect in C-H cleavage. These findings support a turnover-limiting step that precedes desaturation of the radical intermediate and favors an oxidative elimination mechanism of C-H cleavage.
Vicinal diamine synthesis is accomplished by a copper-catalyzed three-component reaction of vinylarene, O-acyl-N-hydroxyamine, and alkylamine·BF3 complex. This reaction identifies trifluoroborate complexes as an effective means to overcome the challenges associated with nucleophilic amines in transition metal catalysis and obtain regioselective synthesis. In the presence of a chiral catalyst, unprecedented enantioselective benzylic amination by alkylamino groups is achieved. Preliminary reaction conditions yield up to 60% diamine product and 85% enantiomeric excess (e.e.).
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