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Oxidative C-H Bond Functionalization in the Synthesis of Nitrogen- and Oxygen-Containing Heterocycles

Miller, Jenna (2023) Oxidative C-H Bond Functionalization in the Synthesis of Nitrogen- and Oxygen-Containing Heterocycles. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Oxygen- and nitrogen-containing heterocycles are ubiquitous scaffolds in biologically active and commercially relevant compounds. Developing synthetic methods to access useful compounds in an atom and step economical manner under mild reaction conditions can increase the applicability in late-stage complex molecule functionalization. Hydride abstraction reactions mediated by organic oxidants offer a site-selective way to functionalize otherwise unreactive carbon-hydrogen bonds. This document describes a detailed mechanistic analysis of three organic hydride abstracting agents. Substrate design and experimental kinetic data give insight into how different substrate parameters affect the reactivity of each oxidant. Computational results support experimental findings, and aid in reaction prediction. Observation and conclusions led to the discovery of a new reaction pathway, the oxidation of N-allyl compounds by oxoammonium salts to access N-acyl iminium ions.
Acyl iminium ions are powerful electrophilic intermediates, especially in the construction of heterocyclic scaffolds. The second chapter describes the construction of various nitrogen-containing heterocycles via oxoammonium ion-mediated hydride abstraction of N-allyl amides, carbamates, and sulfonamides. The scope showcases functional group and nucleophile compatibility, as well as toleration of cleavable groups and functional handles substituted on nitrogen. Incorporation of an alkyl branching group allows access to 2,6-disubstituted piperidine structures in good to excellent diastereoselectivity. Novel 1H NMR techniques aid in conformational analysis and stereochemical assignments and deuterium labeling experiments give insight into the transition state for cyclization.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Miller, Jennajlm440@pitt.edujlm440
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFloreancig,
Committee MemberLiu,
Committee MemberWang,
Committee MemberHuryn,
Date: 6 September 2023
Date Type: Publication
Defense Date: 13 July 2023
Approval Date: 6 September 2023
Submission Date: 9 August 2023
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 288
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Organic Synthesis
Date Deposited: 06 Sep 2023 19:00
Last Modified: 06 Sep 2023 19:00


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