Copper-Catalyzed Electrophilic Amination of sp2 and sp3 C-H Bonds

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2015

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McDonald, Stacey Leigh

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Abstract

The wide presence of C-N bonds in biologically and pharmaceutically important compounds continues to drive the development of new C-N bond-forming transformations. Among the different strategies, electrophilic amination is an important synthetic approach for the direct formation of C-N bonds. Compared to electrophilic amination of organometallic reagents, direct amination of C-H bonds will provide a potentially more effective route towards C-N bond formation. Towards this, we proposed an electrophilic amination of C-H bonds via their reactive organometallic surrogate intermediates. Specifically, we are interested in organozinc intermediates and their in situ formation from C-H bonds.

This dissertation reports our development of direct amination of various C-H bonds using a H-Zn exchange/electrophilic amination strategy as a rapid and powerful way to access a variety of functionalized amines. We were able to achieve C-H zincation using strong and non-nucleophilic bases Zn(tmp)2 or tmpZnCl*LiCl and subsequent electrophilic amination of the corresponding zinc carbanions with copper as a catalyst and O-benzoylhydroxylamines as the electrophilic nitrogen source. With such a one-pot procedure, the synthesis of various amines from C-H bonds has been achieved, including alpha-amination of esters, amides, and phosphonates. Direct amination of heteroaromatic and aromatic C-H bonds has also been developed in good to high yields. It is important to note that mild reactivity of organozinc reagents offers a good compatibility with different functional groups, such as esters, amides, and halides.

Success in developing direct and efficient syntheses of these various amines is highly valuable. These new amination methods will greatly expand the chemical diversity and space of available amine skeletons, and will contribute to future advances in material science, medicinal chemistry and drug discovery.

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McDonald, Stacey Leigh (2015). Copper-Catalyzed Electrophilic Amination of sp2 and sp3 C-H Bonds. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/9851.

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