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Title:Zirconium-mediated alkyene-aldehyde coupling, rhodium-catalyzed alkene hydrothiolation, and copper-catalyzed alkyne hydroarylation: Reaction development and mechanistic investigations
Author(s):Kortman, Gregory Dean
Director of Research:Hull, Kami L
Doctoral Committee Chair(s):Hull, Kami L
Doctoral Committee Member(s):Denmark, Scott E; Rauchfuss, Thomas B; White, M. Christina
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Alkene
Alkyne
Hydrothiolation
Hydroarylation
Rhodium
Copper
Zirconium
Mechanism
Methodology
Abstract:In the last 150 years, we have seen a boon in the development of new methodologies for the synthesis of organic compounds, which has led to the ability for one to synthesize any compound of interest given enough time and resources. Of course, time and resources are finite, thus development of methods that can reduce the time and resources required to synthesize libraries of compounds are of extreme import. This goal can be achieved by reducing step count, increasing the modularity by diverging from common synthetic intermediates, or by reducing waste from reaction byproducts. Our group is interested in developing transition-metal-catalyzed reactions which utilize ubiquitous starting materials such as alkynes and alkenes for the synthesis of compounds which are valuable synthetic intermediates or desirable final products which reduce the time and resources required compared to current methods. α,β-unsaturated carbonyl compounds are common synthetic intermediates and pharmaceuticals targets which are often synthesized though the olefination of a carbonyl with an ylide. These reactions produce a stoichiometric amount of byproduct, such as triphenylphosphine oxide in the Wittig olefination. We sought the develop a zirconium–oxo-catalyzed alkyne-aldehyde coupling reaction to access α,β-unsaturated ketones as this would be a completely atom economical approach to this motif. Each step in the catalytic cycle was investigated stoichiometrically, and the scope of alkynes and aldehydes was explored. The most critical step of the transformation is a retro-[4+2]-cycloaddition from a dioxazirconacyclohexene. It was found that this step is thermodynamically unfavorable which prevented a catalytic reaction from being developed; however, by using chalcone as a trap for the zirconium-oxo, we were able to show that the retro-[4+2]-cycloaddition does occur and that the strong Zr–O bond in the dioxazirconacyclohexene can be broken via this mechanism. The ability to access multiple products selectively from a single set of starting materials is a highly desirable process as it rapidly affords a vast library of compounds which can be utilized in drug discovery and structure activity relationships. We have discovered that allyl amines and imines undergo a rhodium-catalyzed regiodivergent hydrothiolation reaction to afford either 1,2- or 1,3-aminothioethers. The regiodivergence is a result of the ligand employed. Ligands with small bite angles afford the 1,3-isomer, while ligands with large bite angles afford the 1,2-isomer. Mechanistic experiments suggest that both reactions proceed through an oxidative addition into the S–H bond, followed by migratory insertion, and finally reductive elimination. The regiodivergence in the reaction is a result of the selectivity for the migratory insertion. The anti-Markovnikov reaction undergoes a Rh–H insertion, followed by Rh–S reductive elimination, while the Markovnikov-selective conditions proceed by Rh–S insertion, followed by Rh–H reductive elimination. The regio- and diastereoselective synthesis of trisubstituted olefins remains a challenge for organic chemists. Herein is reported the synthesis of 1,1-diaryl, trisubstituted olefins, which are commonly found in pharmaceutical compounds. The reaction is catalyzed by a copper/dppf complex and combines an in situ generated copper–hydride with an alkyne and an aryl iodide to afford trisubstituted olefins in good to excellent yields, excellent regioselectivities and as single diastereomers. The scope of the transformation is presented both in terms of alkyne and aryl iodide. Mechanistic studies suggest that the reaction proceeds through an initial hydrocupration followed by a two-electron oxidative addition/reductive elimination.
Issue Date:2017-11-17
Type:Text
URI:http://hdl.handle.net/2142/99327
Rights Information:Copyright 2017 Gregory Dean Kortman
Date Available in IDEALS:2018-03-13
Date Deposited:2017-12


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