Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Patrick J. Walsh

Abstract

Chapter 1 details the discovery and development of the addition of 2-azaallyl anions, derived from N-benzyl ketimines, to the highly strained hydrocarbon [1.1.1]propellane. This new reaction provides access to bicyclo[1.1.1]pentane (BCP) analogues of diaryl methanamines, a ubiquitous scaffold in medicinal chemistry. The reaction proceeds rapidly at room temperature, and tolerates a broad substrate scope, providing straightforward access to new BCP benzylamine derivatives. Initial experiments as well as computational insight support the intermediacy of a BCP carbanion, highlighting the novelty of this transformation in the historical and modern context of [1.1.1]propellane chemistry.Chapter 2 extends the anionic propellylation principle of Chapter 1 to the development of a 2-azaallyl anion addition/borylation to [1.1.1]propellane, producing highly sought 1,3-difunctionalized BCP products. The versatility of the boronate ester handle is demonstrated via downstream functionalization through a variety of reactions, including a challenging Pd-catalyzed (hetero)arylation that exhibits a broad substrate scope. Together, these methods enable the synthesis of high-value BCP benzylamines which are inaccessible by existing methods. Furthermore, we demonstrate the successful v application of these newly developed (hetero)arylation conditions to a variety of challenging tertiary pinacol boronates, including nitrogen-containing heterocycles, 1,1-disubstituted cyclopropanes, and other BCP cores. Chapter 3 addresses the synthesis of enantioenriched BCP benzylamines. We report the stereoselective synthesis of BCP benzylamine derivatives in a single step from [1.1.1]propellane and mesityl sulfinimines via a metal hydride hydrogen atom transfer (MH HAT) reaction. Medicinally relevant heterocyclic BCP amines are prepared with high diastereoselectivity and the strategic impact of the method is demonstrated via the streamlined synthesis of the BCP analogue of a key intermediate. Notably, the optimized conditions deviate significantly from reported procedures for MH HAT to [1.1.1]propellane; NMR studies provide mechanistic evidence for a competitive H2 evolution pathway which may explain the sensitivity of the reaction to initiation temperature and rate of silane addition.

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