Transition metal catalyzed methods for the synthesis and functionalization of primary amides and nitroalkanes
Date
2017
Authors
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Journal ISSN
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Publisher
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.