Transition metal catalyzed methods for the synthesis and functionalization of primary amides and nitroalkanes

Date
2017
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University of Delaware
Abstract
The synthesis of nitrogen-containing organic compounds is of the utmost importance to organic chemistry. For this reason, new methods for the construction of these frameworks are highly sought-after. This thesis will describe novel methods that use transition metal catalysts to form nitrogen-containing compounds. ☐ The first chapter will describe the development and application of a novel strategy for the alkylation of primary amides utilizing alkylboronic acids or esters as alkylating agents. While amide synthesis is a workhorse reaction in organic synthesis, its application comes with significant drawbacks that make catalytic methods highly desirable. We have found that a unique variation of the Chan-Lam reaction is applicable to the selective mono-alkylation of primary amides. The key to this discovery was the use of di-tert-butyl peroxide as a mild oxidant capable of promoting this reaction. Our initial discovery, while interesting, was significantly limited by access to alkylboronic acid starting materials. Subsequent advances allowed the use of alkylboronic esters, which are much more stable and easily handled. This method was applied to the synthesis of a broad array of secondary amides with a variety of interesting functional groups and structural motifs. ☐ The second chapter will describe a novel alkylation reaction of nitroalkanes to form β-cyanonitroalkanes. In this reaction, a copper catalyst in combination with a diketimine ligand catalyzes the alkylation of nitroalkanes using α-bromonitriles as alkylating agents. This reaction is one in a series of new reactions focused on novel methods for the functionalization of nitroalkanes, which are versatile synthetic intermediates, but are difficult to alkylate directly using alkyl halide electrophiles. The products of this reaction, β-cyanonitroalkanes, are shown to be broadly applicable and versatile synthetic building blocks. In a few steps, these compounds can be converted efficiently into cyano-alkenes, nitrogen-rich heterocycles, and biologically relevant diamine motifs. This chapter will also describe mechanistic investigations into this reaction, all of which point to a mechanism involving the intermediacy of alkyl radicals.
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