Oxidative Copper-Catalyzed Arylation of sp3-Carbon Centers via Decarboxylation

• Author / Creator

  Fahandej-Sadi, Anis

• Transition-metal catalyzed cross-coupling reactions are a broad set of tools that enable the generation of molecular complexity by coupling together molecular pieces. This is done by the use of activating groups on the molecular pieces and a metal-based catalyst. These methods are widely used in synthetic chemistry, including (but not limited to) the production of materials (such as polymers), pharmaceuticals, and agrochemicals. Typical cross-coupling reactions involve the coupling of nucleophilic partners to electrophilic species. Alternatively, oxidative cross-coupling reactions, which enables the coupling of two nucleophilic reactants, have undergone significant developments since their initial discovery over a century ago. The functional group selectivity of these transformations is in complement to established nucleophile-electrophile cross-coupling reactions, due to the reactivity profile of the metal catalyst used and the conditions employed therein. Oxidative cross-couplings to generate carbon- heteroatom bonds are well established. Less work has been conducted into the development of carbon-carbon forming reactions under mild oxidative conditions.
  Decarboxylation reactions of carboxylic acids, to generate both carbanions and carbon- based radicals, have been extensively utilized in synthetic chemistry. These reactions have been demonstrated to occur under a variety of conditions, utilizing both metals catalysts and organocatalysts, and undergoing both one and two-electron chemistry. The myriad of initiation methods for the decarboxylation of carboxylic acids makes these functional groups an attractive source of radical and nucleophilic carbon centres. However, typical conditions to initiate decarboxylation are quite harsh, usually consisting of elevated temperatures above 100C. This thesis will cover two reactions that merge the areas of decarboxylative chemistry and oxidative cross-coupling reactions, in order to facilitate the arylation reactions of sp3-carbon centers.
  Organic molecules containing at least one fluorine atom play an important role in the pharmaceutical and agrochemical industries. This is due, in part, to the unique properties that fluorine can impart onto a molecule. These unique properties drive the demand for the develop of synthetic methods to generate molecules containing carbon-fluorine bonds. Copper(II) triflate mediated the synthesis of alpha-aryl-alpha-fluoro acetates by the oxidative decarboxylative coupling of arylboroxines and arylboronic esters with monofluoro malonate half esters. The reaction proceeded with good to excellent yields across a variety of substrates under mild conditions. Functional group tolerances included electrophilic moieties that would be prone to reactions under traditional coupling conditions, such as aryl halides and Michael acceptors.
  Diarylmethanes are found in many biologically active compounds and tailored pharmaceuticals. Recent work into synthesizing these molecular templates focused on the generation of benzyl anions by decarboxylation of ortho or para-nitrophenyl acetates and their use in palladium-catalyzed cross-coupling reactions. The conditions for this process are quite harsh, utilizing temperatures in excess of 100C. With temperatures as low as 35C, we have developed a copper(II)acetate mediated reaction to generate diarylmethanes by the oxidative coupling of ortho-nitrophenyl acetates and arylboronic esters. This reaction exhibits exceptional chemoselectivity, as it is tolerant towards electrophilic functionalities such as aryl-halides, Michael acceptors, and aldehydes, as well as protic functionalities such as secondary amides and primary alcohols. The utility of these diarylmethane molecules was further exemplified in functionalization work that diversified both the nitroarene and the methylene position of these molecules. We proposed a mechanism for this reaction centered on a decarboxylation event preceding the oxidative carbon-carbon bond formation.

• Subjects / Keywords

  • oxidative
  • cross
  • copper
  • catalysis
  • decarboxylative
  • coupling
  • cross-coupling

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3J09WM1J

• License

  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.