An Organocatalytic Tethering Strategy: Aldehyde-Catalyzed Cope-type Hydroaminations of Allylic Amines

Abstract

Intermolecular reactions have long been a challenge in organic chemistry due to their high negative entropy and difficult nature, which often includes achieving regioselectivity and stereoselectivity. One strategy that has showed promise in overcoming these obstacles is the use of stoichiometric tethers to effectively temporarily make the reaction an intramolecular system. Therefore in several steps, the formation of a temporary tether, performing the desired reaction, and removal of the tether can enable a selective intermolecular reaction. The clear drawbacks to this method are the several steps required for a single transformation, the inherent waste and reduced overall yield for the synthetic sequence. This work aims at creating a catalytic approach to tethering to by-pass the above limitations and showcase how small organic molecules are effective catalysts’ and can induce asymmetry simply via temporary intramolecularity. The first part of this thesis illustrates this organocatalytic tethering approach via the application of the Cope-type hydroamination of alkenes. The intermolecular reaction of this methodology is extremely difficult and the goal of this work was to create a solution for the harsh conditions and low yields. This chapter describes a proof of concept for our approach using allylic amines and hydroxylamines, and a preliminary look at an asymmetric version of this reaction. The second part of this thesis describes a mechanistic study of our catalytic cycle and provides a detailed look at inhibition and off-cycle pathways. Through this research a second-generation catalyst, formaldehyde, was discovered and an advanced scope is presented. II" The final portion of the thesis focuses on an enantioselective and diastereoselective Cope-type hydroamination of alkenes via the organocatalytic tethering strategy. Optimization and substrate scope are presented, along with a discussion of the origins of selectivity. Derivatization of the final products is explored and future applications of the strategy are discussed.