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Title:Palladium (II) / sulfoxide - promoted strategies for efficient and selective allylic C-H oxidations
Author(s):Ammann, Stephen E
Director of Research:White, Maria C
Doctoral Committee Chair(s):White, Maria C
Doctoral Committee Member(s):Denmark, Scott E; Katzenellenbogen, John A; Weitzel, Alison R
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Catalysis
C–H activation
Sulfoxide ligands
Abstract:The scientific community has born witness to incredible advancements in organic chemistry. Exemplified by total syntheses of molecules of astonishing complexity, it is becoming more clear that the conquest of a molecular target is less a question of overall feasibility, and more a question of practical resources. This has consequently provoked the need for transformations that allow for the rapid generation of molecular complexity with high efficiency and practicality. Selective C–H activation reactions provide a novel approach for synthesizing complex small molecules, which traditionally have been designed with sites of preincorporated oxidation for further manipulation. The ability to introduce sites of functionality directly onto simple hydrocarbon precursors offers immense potential for streamlined synthetic routes and improved chemical efficiency. Palladium(II) / sulfoxide catalysis has demonstrated broad applicability toward a wide array of allylic C–H functionalizations, starting from abundant and simple α-olefins. The development of such transformations has been classically guided by the reaction’s serial ligand catalysis mechanism, requiring weakly-binding ligands for the palladium catalyst, and the requirement for utilizing non-basic nucleophiles. Developing advancements toward addressing these major challenges has been the subject of this work. By leveraging the serial ligand catalysis mechanism via a combination of palladium(II)/bis-sulfoxide C–H activation and Lewis acid co-catalysis, we have accomplished the synthesis of six-membered oxygenated heterocycles (chromans, isochromans, and pyrans). The discovery that a wide range of alcohols were competent nucleophiles under uniform reaction conditions (catalyst, solvent, temperature) highlighted the generality of the method. From mechanistic studies, we have hypothesized that the reaction proceeds via an initial C–H activation, followed by chelation-assisted deprotonation and inner-sphere reductive elimination functionalization pathway. Consistent with this, the reaction displayed orthogonal reactivity trends to traditional Pd(0)–catalyzed allylic substitutions. Due to the weakly-coordinating nature of the bis-sulfoxide ligand, we required a different approach toward achieving asymmetric catalysis. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. We have reported the enantioselective synthesis of isochromans via Pd(II)-catalyzed allylic C–H oxidation from terminal olefin precursors. The reaction proceeds with broad scope and high levels asymmetric induction (avg. 92% ee). Additionally, we observed stereochemically-defined substitution on the isochroman to be well-tolerated, with asymmetric catalysis affording either enhanced diastereoselectivity or a modest turnover. Mechanistic insights indicated that functionalization of the π-allylpalladium intermediate is the enantiodetermining step. Additionally, the utility of the Pd/ArSOX platform is demonstrated with an enantioselective intermolecular allylic C–H alkylation reaction, which proceeds with high levels of asymmetric induction under conditions open to air and moisture.
Issue Date:2017-10-05
Type:Text
URI:http://hdl.handle.net/2142/99471
Rights Information:Copyright 2017 Stephen E Ammann
Date Available in IDEALS:2018-03-13
2020-03-14
Date Deposited:2017-12


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