Palladium-catalyzed C-N cross-coupling reactions toward the synthesis of drug-like molecules
Author(s)McAvoy, Camille Z
Massachusetts Institute of Technology. Dept. of Chemical Engineering.
Stephen L. Buchwald and K. Dane Wittrup.
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The development of methodologies for C-N bond formation reactions is an important scientific challenge because of many academic and industrial applications. This work will focus particularly on palladium-catalyzed cross-couplings of amine-containing compounds with aryl halides. The scope of the BrettPhos precatalyst for the cross-coupling of ortho-substituted aryl iodides with amides is studied using substrates with a variety of functional groups. Due to potential metal-chelating issues with some of the substrates used in this study, a proposed ligand synthesis is discussed in which one of the methoxy groups of BrettPhos is replaced with a morpholine capable of occupying palladium's open coordination site during its catalytic cycle. A final C-N bond formation study focuses on the cross-coupling of aryl halides with amidine salts. For this cross-coupling, a methodology has been developed that can be applied to various electron-rich, electron-poor, and electron-neutral substrates. Furthermore, the products of this cross-coupling can be used for a subsequent electrocyclization through a reaction with aldehyde, demonstrating that a relatively simple two-pot methodology can be used to make relatively complex substrates with pharmaceutical applications. Both amides and amidines are common moieties in drug-like molecules because of the various biological activities of these functional groups. Potential medicinal applications of the developed cross-coupling of amidine salts with aryl halides methodology are described. Thus, methodologies for various palladium-catalyzed, C-N cross-couplings as well as a potential ligand synthesis to be used for palladium catalysis are herein discussed.
Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Chemistry; and, (S.B.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. ).
DepartmentMassachusetts Institute of Technology. Department of Chemical Engineering; Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology
Chemistry., Chemical Engineering.