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Mild, Green and Catalytic: Ortho-Iodoarylboronic Acids for Direct Amide Bond Formation at Room Temperature Open Access


Other title
ortho-iodoarylboronic acids
direct amide bond formations
thiomarinol analogues
Type of item
Degree grantor
University of Alberta
Author or creator
Al-Zoubi, Raed M.
Supervisor and department
Hall, Dennis G. (Chemistry)
Examining committee member and department
Hanna, Gabriel (Chemistry)
Lowary, Todd L. (Chemistry)
Hall, Dennis G. (Chemistry)
West, Frederick G. (Chemistry)
Chong, J. Michael (Chemistry, University of Waterloo)
Kaur, Kamaljit (Pharmacy and Parmaceutical Sciences)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Although the thermal direct formation of amide bonds has been known since 1858, the mechanism of the reaction remains poorly understood and is still a major scientific issue. The direct reaction between amines and carboxylic acids generates a thermodynamically stable ammonium carboxylate salt. In order to generate amide bonds from these salts, harsh reaction conditions with temperatures as high as 250 degrees Celsius are required. The majority of the methods in the literature use stoichiometric reagents, which have very poor atom economy and are associated with many limitations such as poor reactivity, low conversions, toxicity, racemizations, and cumbersome purifications. Recently, boron reagents have provided a prospect for much “greener” alternatives for this long standing problem. The use of catalytic arylboronic acids for direct amide formation offers more environmentally benign reaction conditions. This thesis describes the exceptional reactivity of ortho-iodoarylboronic acids as catalysts for mild, green and waste-free direct amide bond formation at ambient temperature. Chapter Two of this thesis discusses my efforts toward the discovery of ortho-substituted arylboronic acids, and especially ortho-haloarylboronic acids as catalysts for direct amide bond formation at ambient temperature. Ortho-iodoarylboronic acid (termed IBA, first generation catalyst) was found to be the best ortho-haloarylboronic acid catalyst providing higher yields of the amide product. Extensive study of the steric and electronic effects on the reactivity of the first generation boronic acid catalyst in order to design a better catalyst for direct amide bond formation is disclosed in Chapter Three. In particular, Chapter Three outlines the development of 5-methoxy-2-iodoarylboronic acid (termed MIBA, second generation catalyst) and 4-iodo-3-furanboronic acid (termed FIBA, third generation catalyst). Chapter Four will delineate a methodology for regioselective ortho-iodination of arylboronic acids. This methodology provided the desired iodoarylboronic acid compounds in only a one step synthesis and directly from cheap and available starting materials. As a second part of my thesis, Chapter Five will discuss a diversity-oriented synthesis of a 30-member library of thiomarinol analogues via the oxa[4+2] cycloaddition/allylboration methodology developed in the Hall laboratory. This library was designed through a collaboration study between Prof. Hall and Prof. Waldmann in Germany using the protein structure similarity clustering (PSSC) computational approach.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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