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Synthesis of 3-Functionalized and 3-Labeled Piperidines by Radical Cyclization

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Synthesis of 3-Functionalized and 3-Labeled Piperidines by Radical Cyclization The Synthesis of Novel N-Heterocyclic Scaffolds and Diazirine-Based Molecular Tags by Gerardo X. Ortiz Jr. Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Qiu Wang, Supervisor ___________________________ Steven W. Baldwin ___________________________ Dewey G. McCafferty ___________________________ Ross A. Widenhoefer Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2016 i v ABSTRACT The Synthesis of Novel N-Heterocyclic Scaffolds and Diazirine-Based Molecular Tags by Gerardo X. Ortiz Jr. Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Qiu Wang, Supervisor ___________________________ Steven W. Baldwin ___________________________ Dewey G. McCafferty ___________________________ Ross A. Widenhoefer An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2016 Copyright by Gerardo X. Ortiz Jr. 2016 Abstract N-Heterocycles are ubiquitous in biologically active natural products and pharmaceuticals. Yet, new syntheses and modifications of N-heterocycles are continually of interest for the purposes of expanding chemical space, finding quicker synthetic routes, better pharmaceuticals, and even new handles for molecular labeling. There are several iterations of molecular labeling; the decision of where to place the label is as important as of which visualization technique to emphasize. Piperidine and indole are two of the most widely distributed N-heterocycles and thus were targeted for synthesis, functionalization, and labeling. The major functionalization of these scaffolds should include a nitrogen atom, while the inclusion of other groups will expand the utility of the method. Towards this goal, ease of synthesis and elimination of step-wise transformations are of the utmost concern. Here, the concept of electrophilic amination can be utilized as a way of introducing complex secondary and tertiary amines with minimal operations. Molecular tags should be on or adjacent to an N-heterocycle as they are normally the motifs implicated at the binding site of enzymes and receptors. The labeling techniques should be useful to a chemical biologist, but should also in theory be useful to the medical community. The two types of labeling that are of interest to a chemist and iv a physician would be positron emission tomography (PET) and magnetic resonance imaging (MRI). Coincidentally, the 3-positions of both piperidine and indole are historically difficult to access and modify. However, using electrophilic amination techniques, 3- functionalized piperidines can be synthesized in good yields from unsaturated amines. In the same manner, 3-labeled piperidines can be obtained; the piperidines can either be labeled with an azide for biochemical research or an 18F for PET imaging research. The novel electrophiles, N-benzenesulfonyloxyamides, can be reacted with indole in one of two ways: 3-amidation or 1-amidomethylation, depending on the exact reaction conditions. Lastly, a novel, hyperpolarizable 15N2-labeled diazirine has been developed as an exogenous and versatile tag for use in magnetic resonance imaging. v Dedication This work is dedication to my family: past, present, and future. vi Contents Abstract ......................................................................................................................................... iv List of Tables .............................................................................................................................. xiii List of Figures .............................................................................................................................xiv List of Schemes ...........................................................................................................................xvi Abbreviations .............................................................................................................................. xx Acknowledgements .................................................................................................................. xxv Chapter 1: Synthesis of 3-functionalized and 3-labeled piperidines by radical cyclization ...................................................................................................................................... 1 1. Synthesis of 3-functionalized and 3-labeled piperidines by radical cyclization .............. 2 1.1 Introduction ....................................................................................................................... 2 1.1.1 Previous synthesis of functionalized piperidines ..................................................... 3 1.1.1.1 Hydrogenation of pyridines ............................................................................... 3 1.1.1.2 Synthesis of piperidines by alkylation .............................................................. 4 1.1.1.3 Reductive amination ............................................................................................ 5 1.1.1.4 Cycloadditions ...................................................................................................... 5 1.1.1.5 Transition metal-catalyzed methods ................................................................. 6 1.1.1.6 The Hofmann–Löffler–Freytag reaction ........................................................... 7 1.1.1.7 Aziridinium ring expansion to 3-functionalized piperidines ........................ 9 1.1.2 Aminyl radical addition to unsaturated bonds ....................................................... 15 1.1.2.1 Aminyl radical addition to olefins vs. proton abstraction ........................... 16 vii 1.1.2.2 Tandem cyclization and aziridinium rearrangement to 3- chloropiperidines ........................................................................................................... 17 1.1.2.3 Iodide-catalyzed cyclization of N-chloramines to 3-chloropiperidines ..... 17 1.1.2.4 Use of N-iodoamines in the total synthesis of azasugars ............................. 19 1.2 Synthesis of 3-functionalized piperidines ................................................................... 20 1.2.1 Optimization of 3-azidopiperidines .......................................................................... 21 1.2.2 Substrate scope for the synthesis of 3-azidopiperidines ........................................ 23 1.2.3 3-Azidopiperidine derivatization .............................................................................. 26 1.2.4 Synthesis of other 3-functionalized piperidines ...................................................... 27 1.2.5 Rapid synthesis of 3-fluoropiperidines .................................................................... 30 1.2.6 Attempt at an enantioselective synthesis of 3-functionalized piperidines .......... 31 1.3 Toward the synthesis of azasugars by intramolecular cyclization .......................... 36 1.3.1 Attempts to use S,S’-acetals to direct regioselectivity ............................................ 37 1.3.2 Attempts to use O,O’-acetals to direct regioselectivity .......................................... 39 1.3.3 Conclusion on the use of acetals ................................................................................ 41 1.4 Synthesis of labeled σ1 receptor ligands ...................................................................... 41 1.4.1 Introduction .................................................................................................................. 41 1.4.1.1 123I-labeled piperidine-based σ1 receptor ligands .......................................... 42 1.4.1.2 11C-labeled piperidine-based σ1 receptor ligand ............................................ 42 1.4.1.3 18F-labeled σ1 receptor ligands that do not involve the aziridinium intermediate .................................................................................................................... 43 1.4.1.4 18F− ring-opening of azetidinium and aziridinium intermediates for PET imaging ............................................................................................................................ 44 viii 1.4.2 18F-labeling with the aminofluorination protocol ................................................... 46 1.4.3 Initial synthetic route to 3-fluorinated σ1 receptor ligand ..................................... 47 1.4.4 Revised synthetic route and biochemical outcome ................................................ 49 1.4.5 Synthesis of 2nd generation ligands and biochemical outcome ............................. 52 1.5 Conclusion ....................................................................................................................... 54 1.6 Supplemental information ............................................................................................ 55 1.6.1 General information .................................................................................................... 55 1.6.2 Experimental procedures and characterization data .............................................. 57 Chapter 2: Electrophilic amidation of indoles and pyrroles using N- benzenesulfonyloxyamides ..................................................................................................... 105 2.1 Introduction ..................................................................................................................
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