Synthesis of imidazolidinones and indolines via aza-Heck cyclizations & phosphonate-directed C-H borylation
Date
2020
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Nitrogen-containing heterocycles are prevalent in bioactive natural products and synthetic molecules. For this reason, the discovery of new methods to prepare those fragments is an important research field in organic synthesis. In this thesis, I will describe the synthesis of imidazolidinones and indolines via the strategies of Heck cyclization using nitrogen electrophiles. In addition, the development of iridium- catalyzed ortho C–H borylation of aryl phosphonates will be presented. This method provides rapid access to aryl phosphonates bearing complex ortho substitutions from simple starting materials. ☐ The first chapter will describe the development of imidazolidinone-forming aza-Heck cyclization. Using easily accessible starting materials, this method allows the synthesis of unprotected imidazolidinones, including the ones containing two free N–H groups. This reaction uses commercially available catalytic components, has broad functional group tolerance, and can be applied to complex ring topologies. The synthesis of a factor Xa inhibitor was demonstrated using this method. With the addition of halide source, dihydroimidazolones can be accessed from the same starting materials via in situ isomerization. Moreover, this improved reaction condition can also be used for the preparation of unprotected lactam substrates. ☐ In Chapter 2, I will describe the development of aza-Heck cyclization to synthesize indolines and related heterocycles. Using palladium catalysis and N-hydroxy anilines as electrophiles, which can be easily prepared from nitroarenes in a single step, this reaction provides steady access to indolines. Difficult substrates, such as the ones containing fully-substituted carbon centers at the C2 position, which is known to be a synthetic challenge, can also be prepared via this strategy. This is the first time that the use of N-aryl amine electrophiles has been demonstrated in the field of aza-Heck cyclization. ☐ The third chapter will describe the development of aryl phosphonate-directed C–H borylation. This method provides quick access to ortho-phosphonate aryl boronic esters from simple aryl phosphonates. Those borylated products can serve as versatile intermediates for the synthesis of highly-substituted aryl phosphonates, which can be easily converted into aryl phosphine ligands. The in situ downstream functionalization of products will also be discussed in this chapter.
Description
Keywords
C-H borylation, Heck cyclizations, Heterocycle synthesis, Metal catalysis, Organic synthesis, In situ