Novel Macrocyclisations of 2-Amino-Azines via Traceless Staudinger-SNAr-Cascade

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The proposed project focuses on the development of a novel macrocyclisation centred around pharmaceutically relevant 2-amino azines. We propose the development of a novel reagent that will be able to cyclise 2-chloro-azines with pendant azides under mild conditions. A modular synthesis route for the reagent will provide access to a diverse range of phosphine-thiol reagents that mediate an efficient macrocyclisation. This development will be aided by investigations into isolated mechanistic steps, specifically the initiating thiol SNAr and the iminophosphorane nucleophilic aryl-transfer, and the use of high throughput experimentation to optimise for yield and concentration. Further work will focus on applications of the developed reaction to DELs and the extension of the reactivity principles of the key intermediate to a single step alcohol amination.