I. Development of three-component alkene carboamination reactions II. Palladium-catalyzed anti-Markovnikov oxidative amination of alkenes III. Chloroform as a carbon monoxide precursor: in or ex situ generation of co for pd-catalyzed carbonylations IV. Hydroalkylation of alkenes via photoredox catalysis

Gockel, Samuel Noah

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Description

Title

I. Development of three-component alkene carboamination reactions II. Palladium-catalyzed anti-Markovnikov oxidative amination of alkenes III. Chloroform as a carbon monoxide precursor: in or ex situ generation of co for pd-catalyzed carbonylations IV. Hydroalkylation of alkenes via photoredox catalysis

Author(s)

Gockel, Samuel Noah

Issue Date

2019-06-03

Director of Research (if dissertation) or Advisor (if thesis)

Hull, Kami L

Doctoral Committee Chair(s)

Hull, Kami L

Committee Member(s)

• Denmark, Scott E
• Zimmerman, Steven C
• Fout, Alison R

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

organic chemistry, organic synthesis, methodology, method development, carbonylation, amination, hydroamination, oxidative amination, carboamination, hydroalkylation, photoredox, catalysis, catalyst, palladium, copper, iridium, amine, ether, aniline

Abstract

The design of methods that streamline the synthesis of small organic molecules is a critical facet of organic chemistry, impacting core scientific fields with important societal implications. In the medical sciences, for instance, the treatment of diseases is a major public health concern that relies heavily on the availability of effective pharmaceuticals. The facility with which drugs are discovered and developed is dependent on the availability of synthetic methods. In the agricultural sciences, in an era of tumultuous climate change and increasing food demands, production capacity hinges on advancements in agrochemistry, fertilizers, fungicides, and herbicides. As everyday energy consumption continues to rise, the strive for sustainability pivots around the engineering of highly efficient methods for molecule construction. Organic synthesis is the engine with which scientific progress in these critical fields is made, and reaction development lies at the core. In assessing compound classes found in the fields of medicinal chemistry and agrochemistry, it was recognized that nitrogen functionalities play an important role in imparting function to molecules. In a survey of nearly 3600 drug candidates synthesized between 2008 and 2011 by GlaxoSmithKline, Pfizer, and AstraZeneca, 80% of compounds contain at least one amine and 65% of compounds feature amide moieties. In a separate analysis it was found that 84% of structurally unique small-molecule drugs approved by the Food and Drug Administration contain at least one nitrogen atom. In a 1995 statement from the United States Department of the Interior, 85% of the top 96 herbicides used in the U.S. contained nitrogen functionalities. A more recent disclosure by the United States Department of Agriculture shows that in 2012, 68% of the twenty-five most used pesticides and herbicides contained nitrogen. Given the high value of nitrogen-containing functionalities, the development and refinement of amination methodology for organic synthesis is a critical objective in the discovery and development of functional molecules. We have developed three approaches for the three-component carboamination of alkenes. The first leverages the umpolung tactic, using electrophilic amines and nucleophilic carbon components. An uncatalyzed mechanism involving radical intermediates was elucidated. The reaction displays poor chemoselectivity due to the formation of an oxyamination byproduct. The alkene scope is modest, with electron rich vinylarenes representing a uniquely chemoselective substrate class. This initial foray into carboamination yielded important mechanistic insight and informed the development of the Cu-catalyzed carboamination of alkenes with alkyl halides and amines. The phenomenon of neighboring group assistance in a copper-mediated amination step was elucidated, allowing for the further development of this system to achieve general three-component carbofunctionalization. The third approach, the oxidative carboamination of alkenes, uses alkylboronic acids to access broader classes of alkylamine products. The anti-Marknovnikov oxidative amination of alkenes represents a critical regioselectivity gap in the aza-Wacker reaction. We have developed a palladium catalyst capable of promoting a sterically-controlled outer-sphere aminopalladation process to selectively forge anti-Markovnikov adducts. A chain-walking process was discovered and later leveraged for the formation of aminoketones from homoallylic alcohols. The carbonylation of organic halides utilizing chloroform as the carbonyl source has also been developed. This new carbonylation method allows for the amino-, thio-, and alkoxycarbonylation of aryl and vinyl halides to access diverse carboxylic acid derivatives. The method has also been applied to the carbonylative Suzuki-Miyaura reaction for the synthesis of ketones. A key discovery in the development of this method is the rapid hydrolysis of chloroform promoted by heterogeneous cesium hydroxide as a base. Finally, the hydroalkylation of alkenes utilizing a photocatalyst has been achieved. Soft organometallic species and carboxylic acids serve as shelf-stable alkyl fragments and can be appended to vinylarenes through a radical mechanism. The functional group tolerance of this reaction is excellent, owing to very mild conditions. C(sp3)–C(sp3) bonds can be forged in an approach alternative to traditional coupling reactions.

Graduation Semester

2019-08

Type of Resource

text

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Copyright 2019 Samuel N. Gockel

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