Application of carbamoylimidazolium salts in small molecule and combinatorial synthesis.

摘要

This thesis is a summary of research conducted since February 2000 in the laboratories of Professor Robert A. Batey at the University of Toronto and is continuation of work performed here on carbamoylimidazolium salts. Chapter A covers the synthesis of the imidazolium salts, as well as their application in small molecule preparation. The salts are prepared in two steps with minimal purification, and have been successfully applied to the generation of amides from carboxylic acids. The amides are generated under mild conditions in excellent yields and are pure after aqueous work-up. Previous work in our laboratory has shown that derivatized anilines are unreactive towards the salts. Here the conditions were optimized for the reaction of salts with derivatized anilines to generate substituted ureas. Since imidazolium salts are capable of reacting with various nucleophiles a comparative study was carried out to determine the order of reactivity of the nucleophiles towards the salts. It was shown that sulfur based nucleophiles react significantly faster than any other nucleophile, while aliphatic alcohols and anilines do not react to any significant amount under weakly basic conditions. Synthetically useful selectivity levels between alkyl amines, phenols and carboxylic acids were not obtained.; Chapter B focuses on combinatorial synthesis. Firstly, a semicarbazide library was generated. Hydrazides were reacted with N,N '-carbonyldiimidazole to generate 1,3,4-oxadiazol-2-ones, which were ring opened with amines to generate semicarbazides. Secondly, N,N'-diacylated imidazolidines exhibit herbicidal activity. Thus, we attempted to create a combinatorially friendly method for their synthesis. A common imidazolium salt intermediate was generated from monoacylated imidazolidine, which was then reacted with various amines. Lastly, a small library of ureas, carbamates, thiocarbamates and amides was synthesized to demonstrate the utility of the salts as a common precursor to various functionalities, which can be synthesized in parallel and under same conditions with minimal purification.; Chapter C covers the application of carbamoylimidazolium salts in the generation of heterocyclic alkaloids. Very poor reactivity of anilines under mild basic conditions allowed for a 4-component Povarov reaction of unprotected p-aminophenol with carbamoylimidazolium salt, aldehyde and 2,3-dihydrofuran. Lastly, the imidazolium salts were used in a short synthesis of fused bicyclic lactams.