Development of Aza-Prilezhaev Reactions for the Aminative Difunctionalization of Alkenes

Abstract

A range of alkene difunctionalization reactions have been developed by exploiting the aza-Prilezhaev aziridination platform that uses hydroxylamine-derived N-O donors. Under acidic conditions, an electrophilic nitrogen source is generated in situ via Boc-deprotection of N-tosyloxycarbamate derivatives. This aziridinates alkenes and, in the presence of a nucleophilic unit, triggers the intra- or intermolecular formation of many unprotected aminofunctionalized products, such as aziridines, azetidines, complex polyheterocycles and 1,2-amino alcohols.

Initial studies focused on the development of a transition metal free intramolecular alkene aziridination protocol to access highly strained azabicyclobutanes en route to substituted and unprotected aziridines. The method was also advanced to the synthesis of azetidines. Efforts have been made to improve reaction yields and to explore substrate scope, but only modest efficiencies have been obtained.

The project was developed further to achieve fully intramolecular stereospecific aza-Prilezhaev alkene aziridination/C-N cleavage sequences involving pendant nucleophiles. Using this approach, more than 20 different classes of polyheterocycle were synthesized. Notably, the products are equipped with an unprotected N-centre that is directly available for biological or chemical applications.

Subsequent studies applied the reactivity platform to cascades where intermolecular alkene aziridination is followed by stereospecific SN2-like ring-opening by pendant nucleophiles. This enabled the preparation of many useful heterocycles by using O-, N-, and C-based nucleophiles, allowing the installation of two contiguous stereocentres under operationally simple conditions.

Based on the studies above, stereospecific 1,2-aminohydroxylations of alkenes were achieved through intermolecular alkene aziridination and nucleophilic opening with H2O. Replacement of water by other nucleophiles allows 1,2-amino(thio)etherification, diamination, aminoazidation and aminofluorination reactions. Intramolecular processes are also feasible, including unusual variants that evoke azabicyclobutane-like reactivity, thus supporting the reaction pathway proposed in the early parts of this thesis.

Date of Award	1 Oct 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	John Bower (Supervisor) & M C Galan (Supervisor)