Intermolecular Cope-Type Hydroamination with Boron-Containing Species

Abstract

Advances in synthesis of boron-containing molecules significantly enlarged the usage of boron-containing subunits in medicinal chemistry. Interestingly, few recently approved drugs are boron analogues of natural amino acid derivatives. They contain an aminoboronic subunit. This subunit is also known to serve as a useful synthetic intermediate. However, despite its unique properties, limited examples of its synthesis are reported. In this work, a new method of obtaining aminoboronic acids derivatives is discussed. In Chapter 2 conditions towards obtaining β-aminoboronic acid derivatives via anti-Markovnikov Cope-type hydroamination are presented. Cope-type hydroamination with boron containing species have shown to proceed at lower temperatures compared to unsubstituted alkene derivatives. The products of Cope-type hydroamination reaction are new: to our knowledge similar oxazaborolidine heterocycles have not been reported. Despite reduced stability of the synthesised products and their proneness to conduct bora-Cope type elimination reaction, it was possible to demonstrate oxazaborolidine synthetic utility by various derivatization reactions. A scope with primary and secondary hydroxylamines is presented for a vinylboronate substrate. This work required access to a range of hydroxylamines. Recently our group discovered simple conditions to oxidize amines to hydroxylamines. In Chapter 3 an investigation of isolation conditions for a variant of this newly developed hydroxylamine synthesis is presented. While the oxidation is generally efficient in the presence of excess amine, the main challenge proved to be the propensity of the unreacted amine and hydroxylamine product to interact together. The efficiency and main limitations of different isolation strategies are presented. In general, the best results of removal of the excess amine via filtration were obtained using oxalic acid to form the corresponding amine salt. This filtration was followed by a short silica plug to further remove the amine salt causing contamination.