Functionalization of Arenes, Amines, Alkenes, and Alkynes Mediated by Radical Pathways

Dissertation

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

By Stacy C. Fosu Graduate Program in Chemistry

The Ohio State University 2019

Dissertation Committee Prof. David Nagib, Advisor Prof. Dehua Pei Prof. Christo Sevov

Copyrighted by Stacy C. Fosu 2019

Abstract

Efficiently building molecular complexity has always been a long-standing problem in organic synthesis. To intricately stitch organic fragments together to construct valuable cores necessitates the appropriate handles. Classically, the synthesis of complex molecules such as natural products or pharmaceuticals usually requires utilizing pre-functionalized building blocks at the beginning of the synthesis to allow for later functional group manipulation to achieve the construction of the desired product. Diversifying complex organic molecules, such as natural products, becomes a slow and iterative process as the synthesis of new compounds relies heavily on functional group interconversion. Although carbon-hydrogen bonds are ubiquitous in organic molecules, due to their inert nature, these bonds are often not utilized as handles for functional group installation. With C-H bond functionalization, an otherwise inert C-H bond can be transformed into a C-X bond

(where X is a non-hydrogen atom). C-H bond functionalization strategies allows otherwise lengthy synthetic processes to be streamlined. Inspired by one of the earliest approaches to C- H bond functionalization, we sought to improve upon and develop other functionalization protocols which utilize the powerful nature of radicals. The research herein describes four novel methods to construct valuable cores through the functionalization of arenes, amines, alkenes, and alkynes using open-shell intermediates. The first method describes a convenient C-H functionalization methodology to install halides and pseudohalides on arenes and heteroarenes. The synthetic utility of nitrogen-centered radicals to afford selective amination and amino-functionalization will be outlined further. Coupling of aldehydes to π-systems to build unique atom-transfer products will also be discussed.

Dedication

I dedicate this to all who have helped me along the way.

Acknowledgments

I would like to acknowledge my family, friends, and labmates. I could not have done this without your continual support. First and foremost, I would like to thank my parents, Joseph and Regina for all the sacrifices that they have made for me. I know at times there were struggles, but you both always did what you thought was the best for your children, and what you thought was best for me. Thank you for making the trek all the way to America to give me the chance to have an education that might not have otherwise been possible. Thank you for leaving behind everything that you knew to give your children the opportunity to have a successful life. For all the sacrifices that you two have made that I cannot even imagine, I will always be forever grateful and will never take my degree for granted. I would also like to extend my gratitude to my Father Uncle Philip for always caring so much about me, for all the words of encouragement throughout the years, and for truly being a second father to me. I’m also appreciative of all my sisters and brothers, Getty, Joseph, Ronald, and Linda, for always looking out for their baby sister. Thank you to Christina for letting me call you at odd hours of the night and for the countless voicemail messages. Thank you, Abby, for letting me unleash my frustrations to you and for all your impromptu weekend visits to Columbus to cheer me up. Thank you, George, Hannah, and the kids for always making me feel at home. I can never get enough of your homecooked meals, Hannah. Thank you, Anthony, for always being a shoulder to lean on and for absolutely everything. I wish to acknowledge financial support that I have received throughout my PhD program. I am grateful for The Ohio State University Graduate School for my Graduate Enrichment Fellowship during my first year and for the Chemistry-Biology Interface Training Program for my fellowship during my second year. I am very grateful to the

iii

Howard Hughes Medical Institute for funding me for the last three years of my program through the Gilliam Fellowship. I am grateful for all the people that I have met through HHMI, all the places I have been able to go, and all the opportunities that HHMI has opened up for me. I would also like to take the opportunity to thank everyone that I had the pleasure of working with involving outreach activities. Thanks to Michelle for all her hard work with Scientific Thinkers. Thanks to all the kids at Innis and Mansion Day for making my Tuesdays and Thursdays a little bit brighter for the past four years. Thanks Angie, for being ‘the guy’ with all the stuff that I could ever need for outreach events. Thanks Marcela for being a champion for minorities in STEM. Thanks Jennifer for always having an answer or being able to point me in the right direction whenever I had a question. Thanks Susan for letting me knock on your door countless times and always having your chocolate dish stocked with goodies. I truly appreciate all the advice and support from Prof. Timothy Lash and for really being the first one to give me the opportunity to do organic chemistry research and showing me what it is like to truly love your career. Thank you, David for teaching me that it is okay to take chances sometimes. Thanks for your guidance and critiques to make me a better scientist. I would also like to thank all my labmates past and present. All of this work would not have been possible without the never-ending encouragement and advice of my labmates. Thanks Deyaa for being there with me from the beginning through the whole graduate school application process. Even though we went to different schools, it was still comforting to know we were going through the same obstacles even if we were in different locations. Mathieu, I will always appreciate ‘the wheel.’ May everyone always spin 100%. My dearest Avassaya, my TLC chamber is always waiting for you. Thank you for being my column conversation partner. Thank you Zuxiao for being a great example of working efficiently. Thanks Leah for being an awesome lifetime labmate. I have thoroughly enjoyed working alongside you teaching kiddos and starting organizations. I’m grateful to Q for being a great hood neighbor. You were always there with a good movie recommendation iv or some aqua regia. Thanks Joy for revealing your secret ability to sell anything, now I know who to call. I appreciate all our little talks Ray and will always treasure them. Thanks for being a trooper whenever we gave you a hard time. My dear Prusinowski, you may use my balance once I’m gone. James, I don’t care what other people say, you’re not a traitor to me. Melissa, thank you for being the best story-teller ever and making my first-year so enjoyable. Alyson, Ross, and Shania it was a pleasure to work with you all during my last year. I wish to thank various colleagues who I like to call dear friends that have worked tirelessly on multiple projects with me. Ethan, you were a great person to work with on our lab’s first paper. And thanks for being an awesome hood and desk neighbor in Evans and CBEC. Thanks for always being willing to talk through chemistry problems with me and your creative solutions. Thank you Kohki for your perseverance, hard work, and dedication. I’m always amazed by how hard and efficiently you work. And bless you. Thanks to Chido for her unwavering persistence and willpower. I appreciate your never- ending work ethic and determination to finish things. Thanks Andrew for all the computational work that you have done as well as our late-night “pep-talks.” To Lu, it has been truly incredible to know you, and thank you for all the hard work that you have done. I am truly privileged to have worked alongside you. In the same vein, I will always be grateful to Jeremy and Sean for all the hard work that they put into team ketyl. Jeremy, I will always treasure our Rhode Island Gordon and getting lost in San Francisco. Sean, I will always truly appreciate your honesty. Thank you for always having my back. I absolutely would not have been able to get through this all without the three remarkable scientists that I began this journey with. We have all been through a lot together and I could not imagine going through all five years of grad school with any other guys. Ethan, Kohki, and Jeremy-thank you. Once again, I am truly indebted to all who have supported me in one way or another throughout this process.

Vita

2011………………...... ……B.S. Chemistry, University of Illinois at Urbana-Champaign

2014…...... ……………………………….M.S. Chemistry, Illinois State University Thesis: “Synthesis of Benziporphyrin Analogs and Carbaporphyrinoid Systems”

2014 – 2015.……...…….………….……...…………………Graduate Enrichment Fellow Department of Chemistry and Biochemistry, The Ohio State University

2015 – 2016…………..…………….… Chemistry and Biology Interface Program Fellow Department of Chemistry and Biochemistry, The Ohio State University

2016 – present……..……….…….……Howard Hughes Medical Institute Gilliam Fellow Department of Chemistry and Biochemistry, The Ohio State University

Publications

Fosu, S. C.†; Hambira, C. M.†; Chen, A. D.; Fuchs, J. R.; Nagib, D. A. “In situ Iodane Activation Enables Site-Selective C-H Functionalization of (Hetero)arenes.” Chem, 2019, 5, 417 – 428

Fosu, S. C. “Streamlining Synthesis.” Chem, 2019, 5, 251 – 253

Wang, L.; Lear, J. M.; Rafferty, S. M.; Fosu, S. C.; Nagib, D. A. “Ketyl Radical Reactivity via Atom Transfer Catalysis.” Science, 2018, 362, 225 – 229

Nakafuku, K. M.†; Fosu, S. C.†; Nagib, D. A. “Catalytic Alkene Difunctionalization via Imidate Radicals.” J. Am. Chem. Soc., 2018, 140, 11202 – 11205

Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D. A. “Triiodide-Mediated δ-Amination of Secondary C-H Bonds.” Angew. Chem., Int. Ed. 2016, 55, 9974 – 9978

Fields of Study Major Field: Chemistry Division: Organic Chemistry

Table of Contents

Abstract ...... i Dedication ...... ii Acknowledgments...... iii Vita ...... vi Table of Contents ...... vii List of Tables ...... x List of Figures ...... xi Chapter 1 Introduction ...... 1 1.1 C-H Functionalization ...... 1 1.1.1 Concept of C-H Functionalization ...... 1 1.1.2 Challenges with C-H Functionalization ...... 2 1.1.3 Advantage of C-H Bond Functionalization ...... 4 1.2 Radicals in Synthetic Organic Chemistry ...... 4 1.2.1 Discovery of Persistent Radicals ...... 4 1.2.2 Radical Mechanism Basics ...... 5 1.2.3 Radical Initiation ...... 6 1.2.4 Radical Selectivity ...... 7 1.2.5 Radical Properties ...... 9 1.2.6 Synthetic Utility of Radicals ...... 10 1.3 Research Outline ...... 12 Chapter 2 C-H Functionalization of Arenes and Heteroarenes ...... 14 2.1 Importance of Arene Functionalization: Halide Incorporation ...... 14 2.2 Introduction to Hypervalent Iodine ...... 16 2.3 Reactivity of λ3 Hypervalent Iodine Reagents ...... 18 2.4 Development of C-H Functionalization Methodology ...... 20 2.4.1 Functionalization Strategy ...... 20 2.4.2 Results ...... 21 2.3.3. Mechanistic Studies ...... 28 2.5 Conclusions ...... 30 2.6 Experimental ...... 31 vii

2.6.1 General Information ...... 31 2.6.2 Substrate Synthesis and Characterization ...... 32 2.6.3 (Hetero)arene Halogenation and Oxygenation Synthesis and Characterization ...... 33 Chapter 3 Amination of Secondary C-H Bonds ...... 64 3.1 Background of the Hofmann-Löffler-Freytag Reaction ...... 64 3.2 Modifications to the HLF Reaction ...... 66 3.3 Strategy ...... 67 3.3.1 Limitations ...... 67 3.3.2 Acetyl Hypoiodite ...... 67 3.3.3 Triiodide ...... 68 3.4 Results ...... 69 3.4.1 Formation of Pyrrolidines ...... 69 3.4.2 Mechanistic Studies ...... 73 3.5 Conclusion ...... 75 3.6 Experimental ...... 76 3.6.1 General Information ...... 76 3.6.2 Substrate Synthesis ...... 78 3.6.3 Pyrrolidine Synthesis and Characterization ...... 89 3.6.4 Synthesis and Characterization of Intercepted Intermediates ...... 107 Chapter 4 Catalytic Difunctionalization ...... 109 4.1 Imidate Synthesis and Rearrangements ...... 109 4.2 1, 2-amino Alcohols ...... 111 4.3 Strategy ...... 112 4.4 Results ...... 114 4.4.1 Oxime Imidate ...... 114 4.4.2 Hydroamination ...... 115 4.4.3 Aminoalkylation ...... 117 4.4.4 Amino-arylation ...... 118 4.5 Mechanistic Studies ...... 120 4.6 Conclusion ...... 124 4.7 Experimental ...... 124 4.7.1 General Information ...... 124 viii

4.7.2 Synthesis of Imidoyl Chlorides ...... 128 4.7.3. Synthesis of Oxime Imidates ...... 130 4.7.4 Hydroamination of Allylic Alcohols ...... 140 4.7.5 Hydrolysis of Oxazolines ...... 149 4.7.6 Carboamination of Allylic Alcohols ...... 156 4.7.7 Aminoarylation of Allylic Alcohols ...... 162 Chapter 5 Ketyl Radical Reactivity ...... 166 5.1 Umpolung Chemistry ...... 166 5.2 Ketyl Radicals ...... 168 5.3 Ketyl Coupling ...... 169 5.4 Strategy ...... 169 5.5 Results ...... 170

5.5.1 Initiation with Et3B/O2 ...... 170 5.5.2 Catalytic Mn Coupling ...... 174 5.6 Mechanistic Studies ...... 179 5.7 Conclusion ...... 182 5.8 Experimental for Stoichiometric Reductant System ...... 182 5.8.1 General Information ...... 182 5.8.2 Synthesis of Acyl iodides...... 183 5.8.3 Alkyne Substrate Synthesis...... 184 5.8.4 Synthesis and Characterization of Vinyl Iodides ...... 185 5.9 Experimental for Catalytic Reductant System ...... 199 5.9.1 General Information ...... 199 5.9.2 Characterization of Vinyl Iodides ...... 201 References ...... 226

List of Tables

Table 2.1. Anion-mediated C-H functionalization of arenes...... 21 Table 2.2 Chloriation of Isoquinoline ...... 24 Table 2.3 Comparison of chlorination methods ...... 26 Table 2.4. Investigation of active oxidant in isoquinoline chlorination...... 28 Table 3.1. Optimization of triiodide-mediated amination...... 70 Table 5.1. Hyperconjugation effects on reduction potentials...... 170 Table 5.2. Investigation of catalytic ATRA methods...... 176 Table 5.3. Determination of Z-selectivity ...... 180

List of Figures

Figure 1.1. C-H bond dissociation energies of select organic compounds...... 3 Figure 1.2. Select examples of medal-mediated C-H functionalization...... 3 Figure 1.3. Basic radical mechanisms...... 6 Figure 1.4. Stereoelectronic, steric, and polar effects as a predictive model for radical reactivity...... 8 Figure 1.5. Kinetic vs. thermodynamic control over cyclization...... 8 Figure 1.6 Captodative effect...... 10 Figure 2.1. Examples of chlorine incorporation in pharmaceuticals...... 16 Figure 2.2. Examples of hypervalent iodanes...... 17 Figure 2.3. Select transformations using hypervalent iodine...... 19 Figure 2.4 Investigation of arene chlorination...... 23 Figure 2.5 Heteroarene C-H chlorination...... 25 Figure 2.6 Chlorination of pharmaceuticals and natural product derivatives...... 27 Figure 2.7 DFT calculations to predict arene selectivity...... 30 Figure 3.1 Hofmann-Löffler-Freytag reaction mechanism...... 66 Figure 3.2 Comparison of light and heat conditions for ester derived pyrrolidine...... 71 Figure 3.3 Functionalized pyrrolidines derived from triiodide-mediated cyclization...... 72 - Figure 3.4 UV-Vis spectroscopy observation of I3 ...... 74 Figure 3.5 Monitoring of reaction efficiency by 1H NMR spectra ...... 74 Figure 4.1 1,2 amino alcohols in pharmaceuticals...... 112 Figure 4.2 Difunctionalization strategy...... 113 Figure 4.3 Investigation of hydroamination strategy...... 117 Figure 4.4 Investigation of π-electrophile traps...... 118 Figure 4.5 Benzonitrile mediated arylations...... 119 Figure 4.6 Aminoarylation using electron deficient benzonitriles...... 120 Figure 4.7 Exploration of chaperone modularity effects on reactivity...... 121 Figure 4.8 Comparison of benzonitrile substitution in arylation reactivity...... 124

Figure 5.1 Synthetic utility of ketyl radical coupling...... 172 Figure 5.2 Proposed mechanism for Mn catalyzed ketyl radical coupling...... 177 Figure 5.3 Scope of Mn-catalyzed coupling...... 178 Figure 5.4 Synthetic utility of vinyl iodides...... 182

xii

Chapter 1 Introduction

1.1 C-H Functionalization

1.1.1 Concept of C-H Functionalization

The manifestation of many synthetically useful transformations relies heavily on preinstalled reactive functional groups. These reactive functional groups either have atoms with either empty low energy orbitals, or filled orbitals that are high in energy, to make them sufficiently reactive. These synthetic handles can include heteroatoms, halogens, or sites of unsaturation.1 However, C-H bonds, have neither empty low energy orbitals, or filled high energy orbitals - making them unreactive species with a high bond dissociation energy.2 Although hydrocarbons are typically unreactive, under high pressure and temperature these organic molecules can undergo a cracking phenomenon to produce more valuable materials, such as alkenes. However, these strategies rely on high pressures and temperatures to afford manipulation of these strong bonds.3 With the advent C-H bond functionalization, otherwise inert bonds can be broken to install a C-X bond (where X is a non-hydrogen atom) under much milder conditions. This allows for the use of commodity feedstock chemicals such as hydrocarbons to be quickly derivatized without the need for pre-functionalization.1 One of the first examples of C-H bond functionalization is the Hofmann-Löffler- Freytag (HLF) reaction. The HLF reaction is a powerful reaction that allows for the δ-C-H amination of amines to form pyrrolidines.4,5 This reaction has spring-boarded our quest to develop other radical-mediated C-H functionalization strategies. The details of this reaction will be discussed further in Chapter 3.

1.1.2 Challenges with C-H Functionalization

Since C-H functionalization involves the breaking of C-H bonds, understanding the energetics of C-H bonds are crucial to afford reliable C-H bond functionalization methodologies. Typical covalent bonds are very strong, making homolysis to the corresponding open-shell units quite difficult. Under high temperature and pressures this can be accomplished; however, not in the most convenient manner.6 There are three basic modes to determine the energetics of a bond to be susceptible to C-H functionalization: 7 bond dissociation energy (BDE), acid equilibrium (pKa), and hydride affinity (∆Hhydride). BDE represents the enthalpy change for homolysis of a C-H bond. Due to the inherent high BDE of C-H bonds, it makes them very difficult to break, illustrating a major challenge of C-H bond functionalization. Due to the ubiquity of C-H bonds in organic molecules and only slight differentiations in their bond strengths, as shown in Figure 1.1, site selectivity tends to be an inherent challenge with C-H bond functionalization.1 Simple alkyl bonds tend to have the highest C-H bond dissociation energy with methane having a BDE of 105 kcal/mol.7 The BDE of a C-H bond correlates to the stability of the carbon radical after homolysis of the C-H bond. Radicals can be stabilized through resonance when in conjugation with π systems. Due to this, benzylic and allylic C-H bonds have weaker BDEs. Radicals can also be stabilized by adjacent lone pairs, leading to decreased BDEs for C-H bonds next to heteroatoms. Since electrons in s atomic orbitals have a stronger attraction to the nucleus, carbons with more s-character hybridization have stronger C-H bonds. For instance, a sp3C-H bond is weaker than a spC-H bond. To compensate for smaller bond angles in smaller cyclic systems, carbon atoms adopt more p-character to aid in orbital overlap, this in turn makes C-H bonds in these systems weaker. An example of this difference is showcased with cyclohexane versus cyclopentane, where cyclohexane has stronger C-H bonds (96 vs 100 kcal/mol).7

Figure 1.1. C-H bond dissociation energies of select organic compounds.

To overcome these strong bonds to afford functionalization, there have been many advances in the realm of transition metal-mediated pathways for C-H bond activation. The White group has shown that Fe complexes can be used for the selective oxidation of tertiary C-H bonds to enable late stage C-H functionalization.8 Other synthetic transformations of C-H bonds such as olefination,9 arylation,10 and alkylation11 can also be accomplished through the use of transition metals (Figure 1.2).

Figure 1.2. Select examples of medal-mediated C-H functionalization.

1.1.3 Advantage of C-H Bond Functionalization

In most cases, several synthetic transformations are needed to incorporate desired functional groups in a final molecule of interest. In this manner, diversifying organic molecules becomes a slow and arduous process as the synthesis of new compounds depends on iterative synthetic routes. The development of new pharmaceuticals requires the synthesis and screening of multiple libraries of small molecules, leading to a time- consuming process. The development of novel C-H functionalization methods would allow for rapid synthesis of medicinally relevant cores to create a larger library of potential drug candidates, therefore, streamlining the drug discovery process.12 Late-stage functionalization of drug candidates would allow for a synthetically simple approach to quickly change the properties of the drug including, but not limited to potency, solubility, protein binding ability, and membrane permeability.

1.2 Radicals in Synthetic Organic Chemistry

1.2.1 Discovery of Persistent Radicals

Radicals, simply put, are atoms or molecules that have an unpaired electron. Moses Gomberg reported the first synthesis of a persistent radical in 1900.13 Gomberg, in the quest to synthesize hexaphenyl ethane from triphenylchloromethane observed something other than his desired product through combustion analysis. After reduction of triphenylchloromethane I-1 with zinc in air, he observed peroxide adducts to a triphenylmethyl group. Under an atmosphere of carbon dioxide, void of oxygen, he was able to observe a trivalent carbon species, the triphenylmethyl radical I-2, also in equilibrium with the dimer I-3 (Scheme 1.1).14–16 A few decades later, Paneth and coworkers discovered that alkyl radicals such as methyl and ethyl radicals could be generated through the decomposition of tetra-alkyl lead species under a stream of hydrogen.17,18 Although the chemical properties of radicals were still not fully understood at this time, this sparked a whole new field of organic chemistry.

Scheme 1.1. First observation of organic radicals.

As previously mentioned, one of the first examples of C-H functionalization was the HLF reaction, of which there was limited understanding of its mechanism (or even product formation) at the time of discovery.4 It was not until the mid-20th century, about 60 years after Hoffman’s discovery, that a radical mechanism was unveiled to be responsible for the derivatization of C-H bonds in the HLF reaction.19,20 Radicals were known and used to explain the mechanisms of many well-known reactions21 such as the HLF reaction,19,20 Barton22, and Minisici23 chemistry. However, a deeper understanding of radical kinetics24 and selectivity helped fuel the broad utility of radical intermediates in organic chemistry. Before elegant demonstrations of radical chemistry were well understood, it was often viewed that these open-shell intermediates were “messy, unpredictable, unpromising, and essentially mysterious” as described by Walling.25 Yet, throughout the years, quite the contrary has been demonstrated.

1.2.2 Radical Mechanism Basics

Many radical reactions tend to be reversible. There are four basic radical mechanisms shown in Figure 1.3. They are as follows: (1) homolysis of a covalent bond to - create two independent radical species; (2) radical substitution reactions (SH2) akin to 2e

SN2 reactions; (3) addition into π-systems and its reverse, β-fission; (4) single-electron transfer to furnish the corresponding anion (in a reductive manifold) or cation (in an oxidative manifold). The redox manifold is not considered chain propagative, unlike the previously mentioned radical mechanisms.26

Figure 1.3. Basic radical mechanisms.

The three elementary steps of a radical chain reaction are initiation, propagation, and termination. In initiation, a select radical precursor forms the first radical. In the case of azobisisobutyronitrile (AIBN)/Bu3SnH, AIBN thermally decomposes to give off molecular nitrogen and two alkyl radicals. Each alkyl radical abstracts hydrogen from the 27 weak Sn-H bond (78 kcal/mol) of Bu3SnH to afford Bu3Sn· driven by the formation of a stronger C-H bond. The Sn-centered radical then undergoes propagation to furnish more radicals. The last step of a radical chain reaction is termination in which the active radical combines with another radical to form a closed-shell species.

1.2.3 Radical Initiation

Radicals are often generated through thermolysis, photolysis, or radiation (such as x-rays or γ-rays).6 Taking advantage of weak bonds, such as those of azo compounds and peroxides, these bonds (with a bond dissociation energy <30-40 kcal/mol) can be easily homolyzed to generate radical species.6 In the presence of heat, peroxides homolyze to produce alkoxy and acyloxy radicals. Radicals can also be formed through initiators such as diazocompounds (e.g AIBN), boranes (e.g triethylborane or 9- Borabicyclo[3.3.1]nonane (9-BBN)), silanes (e.g. tris(trimethylsilyl)silane), and various metals. Diazocompounds are attractive radical initiators due to the exothermic loss of nitrogen, making the reverse reaction essentially impossible. Tin hydride reagents were often used in early radical chemistry; however, due to its high toxicity, use of Sn reagents is discouraged.28 Other initiators such as triethylborane/oxygen enable radical initiation at

29 much lower temperatures as compared AIBN/Bu3SnH. Germanium hydrides can also be used in place of tin reagents, albeit at reduced reactivity. Organophosphorus compounds, thiols, indium, titanium, copper, cobalt, manganese, cerium, and organozinc compounds are also known to initiate radical reactions.30

1.2.4 Radical Selectivity

Kharasch, one of the pioneers in the field of radical chemistry, elucidated some of the basic reaction mechanisms of radical reactivity. A major discovery in radical selectivity, deciphered by Kharasch, was anti-Markovnikov selectivity with radical addition across alkenes. Reacting allyl bromide with hydrobromic acid in the presence of peroxides led to primarily 1,3 dibromoethane. With radical inhibitors, 1,2 dibromoethane could be isolated only after a very sluggish reaction. He coined this inverted regioselectivity as the “peroxide effect.”31 Once more was revealed about the physical properties of these chemical species, it became easier to predict chemoselectivity, regioselectivity, and diastereoselectivity. Some of the more important factors governing these effects include steroelectronic, polar, and steric effects as depicted in Figure 1.4.26 Orbital overlap plays a key role in defining selectivity, as seen in Figure 1.4. The singly occupied molecular orbital (SOMO) can readily overlap the with the σ* of radical intermediate I-4 to generate the thermodynamically less stable primary radical of cyclopentene product I-5. However, poor orbital overlap does not allow for the thermodynamically favored secondary radical (within a seven-membered ring) I-6. This is an example of steroelectronic effects.26 Hydride delivery to the sterically unencumbered face of the bicycle I-7 to give I-8 instead of I-9 shows how sterics can play a role in diastereoselectivity of radical reactions. Rates of radical additions can be profoundly dependent on polar effects as shown by Giese. An alkene with an electron withdrawing group can help facilitate the rate of radical addition by making it faster due to the stabilizing effect of the electron-withdrawing group. For example, the rate of cyclohexyl radical I-10 addition into an alkene was substantially faster for alkenes with electron-withdrawing groups. For example, the relative rate of addition 7 into acrylonitrile to give I-11 was 6,000 times faster as compared to 1-hexene to give I- 12.32

Figure 1.4. Stereoelectronic, steric, and polar effects as a predictive model for radical reactivity.

However, there are some cases, in which a combination of kinetic control as well as steroelectronic effects dictate the outcome of a radical reaction (Figure 1.5). In this case, it has been extensively studied that 5-exo-trig cyclization of I-13 to render I-14 is much faster than the 6-endo-trig cyclization to produce I-15.33,34 Although kinetic control is often cited as being the main factor for the selectivity of this cyclization, better orbital overlap to produce the 5-membered ring also helps to facilitate this.26

Figure 1.5. Kinetic vs. thermodynamic control over cyclization.

1.2.5 Radical Properties

The stability of radicals plays an important role in reactivity as does its electronic effects. Common radical stability can be seen through substituent effects. Generally, the number of substituents on a carbon radical is proportional to the radical’s stability (e.g. primarydouble bond can overlap with the SOMO of the radical center. A portion of radical reactivity can be attributed to radical lifetimes. There are persistent and transient radicals. Most radicals tend to be transient, in that they cannot be observed on a reasonable timescale. Persistent radicals are radicals stable enough to be observed spectroscopically. For instance, persistent radicals include the first radical isolated by Gomberg, radical inhibitors such as 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO), or galvinoxyl, and oxygen diradical. Persistent radicals often exist due to steric effects. Such as in the example of triphenylmethane, the sterics of the three phenyl groups hinders the termination of the radical with another radical trap. Other examples of persistent radicals that depend on sterics to afford radical stability are di- and tri-substituted tert-butyl radicals. The captodative effect can also afford persistent radicals. This effect was first observed by Stella and coworkers.35 With this, a carbon-centered radical is substituted with an electron-withdrawing group and an electron-donating group. The electron-withdrawing group is known as the “captor,” in that it pulls electron density away from the radical. The electron-donating group is dative and releases electron density to the carbon-centered radical. Through resonance stabilization, this allows for a more stable radical center by delocalization. Stella and coworkers observed this effect when a captodative alkene I-16 was reacted with 2-azoisobutyronitrile. Upon heating, the isobutyronitirle radical I-17 9 selectively adds to the alkene to render the captodative radical I-18. Due to the stability of the radical, polymerization of the alkene does not occur, only termination by another isobutyronitrile radical (I-19) or homodimerization (I-20) (Figure 1.7).35,36

Figure 1.6 Captodative effect. Radicals can also be thought of as electrophilic or nucleophilic. Electrophiles are species that need to gain electrons, while nucleophiles are electron-rich and willing to donate electrons. The same philosophy can stand in terms of radical-philicity. This can be determined by the stability of the corresponding anions and cations. Take for example nitrogen-centered radicals: reduction of the nitrogen-centered radical would lead to a nitrogen anion which is favored compared to oxidation of the nitrogen radical to the cation. If the anion is more stable, such as is the case for the nitrogen-centered radical, then the radical is known to be electrophilic in nature as it is more susceptible to gaining an electron. The opposite is true for nucleophilic radicals. Nucleophilic radicals are often stabilized by lone pair electrons such as that of alpha-oxy radicals. This carbon-centered radical is more susceptible to losing an electron to generate a carbocation, therefore it is nucleophilic in nature.37 As in the case of ionic chemistry that electrophiles react with nucleophiles, the same parallels are drawn in radical chemistry in that nucleophilic radicals will more readily react with electrophilic radicals. Matching radical polarity can help determine selectivity.

1.2.6 Synthetic Utility of Radicals

Since the 1980’s, radicals have been found to be quite synthetically useful for the synthesis of many natural products. Although it had been realized well before the 1980s that radical cyclization could be an efficient means of forming carbon-carbon bonds, it was not used to its full potential.38

For instance, Hart and co-workers were one of the first to show that these one- electron intermediates can elegantly control selectivity needed for the synthesis of complex natural products. With AIBN/Bu3SnH as a radical initiator and I-21 as the radical precursor, an α-acylamino radical was generated to perform the required carbocyclization to afford the pyrrolizidinone cores I-22 and I-23 needed for the synthesis of supinidine I- 24 and heliotridine I-25. Further manipulation of the pyrrolizidine to append the alcohol finished the synthesis of heliotridine and supinidine (Scheme 1.2).39 Although these were not the most efficient syntheses of these natural products, it broke ground for others to see that radical chemistry could be employed to build complex natural products.40,16,41

Scheme 1.2 . Synthesis of Supinidine and Heliotridine.

A seminal example of a radical cascade sequence in total synthesis was reported by Curran and Rakiewicz in the synthesis of ±Hirsutene. This strategy took advantage of the fact that radical cyclization of hex-5-enyl compounds kinetically favor forming cyclopentane units. Hexyenyl cyclizations of this type to form carbocycles had been extensively studied by Julia;38 however, had not been previously exploited in polyolefinic cyclizations to produce condensed ring systems. Starting with an alkyl iodide I-26, the corresponding alkyl radical was generated in the presence of AIBN/Bu3SnH to produce a primary alkyl radical. This primary alkyl radical was then able to readily cyclize to form the corresponding tertiary alkyl radical intermediate I-27 to perform another radical cyclization to afford the natural product I-28 (Scheme 1.3).42,43

Scheme 1.3. Synthesis of ±Hirsutene.

From there, many labs have also used the predictability and tunability of radicals to afford complex transformations.16,41,44 One unique example from the Boger lab used iron as radical catalyst to couple catharanthine I-29 and vindoline I-30 to produce the natural product, vinblastine I-31 (Scheme 1.4a).45 A key step in the synthesis of maoecrystal Z from the Reisman lab was a tandem cyclization of I-32 to I-33 which relied on SmI2 initiation (Scheme 1.4b).46 Further manipulation of the cyclized product led to I-34. These are only a few examples of radicals in total synthesis and the list only continues to grow.

Scheme 1.4. Radical mediated natural product syntheses. 1.3 Research Outline

There are limited robust methods for selective radical mediated protocols for C-H bond functionalization. The research herein will merge the application of radical chemistry

12 to the challenge of C-H functionalization. Taking advantage of the unique reactivity of radicals, this work will outline strategies to utilize radicals to achieve C-H functionalization in a site-selective manner. In the second chapter, a methodology development for the C-H functionalization of arenes and heteroarenes will be discussed with the use of hypervalent iodine reagents. This method allowed for the streamlined derivatization of medicinal cores to achieve halogenation and oxygenation of these important motifs. The third chapter will delve into a new method for the construction of pyrrolidines which have found a significant place in pharmaceuticals as well. Utilizing an approach to mildly generate active oxidants in situ has allowed for diversity in scope of pyrrolidine synthesis via an HLF strategy. Expanding upon the reactivity of nitrogen-centered radicals, the photocatalytic generation of imidate radicals will be shown in the fourth chapter to allow for the difunctionalization of allylic alcohols via three different modes of reactivity. Lastly, the fifth chapter outlines a novel generation of ketyl radicals to allow for the robust synthesis of vinyl iodides. Through these research endeavors, the importance of C-H functionalization and radical chemistry will be highlighted to show how the synergistic combination of these two concepts can achieve useful synthetic transformations.

Chapter 2 C-H Functionalization of Arenes and Heteroarenes

Portions of this chapter are adapted from:

Fosu, S. C.†; Hambira, C. M.†; Fuchs, J. R.; Chen, A. D.; Nagib, D. A. “In situ Iodane Activation Enables Site-Selective C-H Functionalization of (Hetero)arenes.” Chem, 2019, 5, 417 – 428

2.1 Importance of Arene Functionalization: Halide Incorporation

The development of new pharmaceuticals requires screening multiple libraries of small molecules. In this process, divergent synthetic routes with iterative functional group manipulations are often employed to modify pharmacological properties. Due to the lengthy process of synthesizing complex molecules, creating large libraries of potential drug candidates creates a bottleneck in the drug discovery process.47,48 Aromatics are privileged scaffolds in medicines.49 Creating a simple method for the post-synthetic modification of aryl moieties could allow for faster synthetic routes to new testable compounds. Incorporation of halides on aromatics not only offers another structural analog, but also provides a synthetic handle further modifications.47,50 Replacing C-H bonds with other functional groups such as oxysulfonates would also provide similar advantages.51 In the earlier years of drug discovery, there were often no guidelines as to how to derivatize arenes of active pharmaceutical ingredients in terms of which functional group should be installed and at which position to increase efficacy. In the 1960’s Hansch and Fujita devised a mathematical algorithm to relate the activity of a molecule with its structure. This aided in observing lipophilicity, sterics, and electronics in a quantifiable manner.52 Later on in 1972, Topliss correlated these mathematical algorithms to the well-

14 known Topliss tree. This diagram gives chemists a quick guideline for arene functionalization when improving potential drugs with aryl substituents. According to the Topliss tree, the first aryl modification should be replacing the hydrogen atom at the 4- position with a chlorine atom. The main reason behind this first substitution strategy is to increase solubility.53 Halogen incorporation has been shown to increase solubility and prevent premature oxidation of pharmaceuticals. Paramount factors for evaluating a medicine’s efficacy is its absorption, distribution, metabolism, and excretion (ADME) properties. Halogens tend to make compounds more lipophilic. A higher lipophilicity is correlated to better activity through enhanced membrane permeability. Enhanced membrane permeability allows for better absorption, distribution, and desired bioavailability of a drug of interest. However, the opposite can also be true if a compound is too lipophilic; this can hinder excretion from the biological system.54 Attractive interactions between a halogen and a Lewis basic site in the same molecule is known as halogen bonding.55 Halogens can act as Lewis acids due to their associated electron deficiency. This act of halogen bonding can lead to better binding specificity to a select enzyme pocket leading to less off-target effects. Also due to their electron deficiency, they can also inhibit premature metabolism. Arenes, especially at the 4-position, are prone to oxidation (such as hydroxylation) by Cytochrome P450 enzymes. Once an arene is hydroxylated it can quickly undergo glucuronidation. This tag signals the body to excrete the compound. However, if this oxidation occurs prematurely, the compound is metabolized before it has a chance to make any biological improvements. The two most common halides in pharmaceuticals, mainly due to their stability in biological systems, are chlorine and fluorine. Examples of chlorinated FDA approved pharmaceuticals include the sedative Lunesta® and the antipsychotic Abilify® among many others (Figure 2.1).

Figure 2.1. Examples of chlorine incorporation in pharmaceuticals.

2.2 Introduction to Hypervalent Iodine

Hypervalent iodine reagents have been used for decades in organic synthesis as oxidants for a variety of transformations and have sparked a niche field of chemistry due to their likeness to transition metals. These compounds are termed ‘hypervalent’ because the iodine atom has more than 8 valence electrons. The 3-centered 4-electron bond of hypervalent iodanes helps to give it unique reactivity similar to transition metals. Two classes of hypervalent iodine reagents are trivalent (λ3) or pentavalent (λ5). Examples of these different iodanes are shown in Figure 2.2. λ3 iodanes have a trigonal bipyramidal geometry (II-1-II-3). With this geometry, the more electronegative atoms are in the axial position, while the ligands that are the least electronegative are in the equatorial position along with the lone pair atoms. In the case of λ3 iodanes which are classified as iodonium salts (II-2), they take on a T-shaped geometry with a loosely coordinated counterion. One of the first λ3 iodanes synthesized was iodobenzene dichloride, in the late 19th century by Willgerodt.56 Willgerodt was also a pioneer in the field of new hypervalent

16 iodine reagents by synthesizing iodylarenes and many other λ5 iodanes. Other λ3 iodanes include Zhadankin’s reagent57 and Togni’s reagent58 which are used for azidation and trifluoromethylation of organic compounds respectively. Diaryliodonium salts were first synthesized by Hartmann and Meyer through the reaction of PhIO and PhIO2 with silver oxide.59,60 There have been many advances in the synthesis of iodonium salts. One of the most common syntheses for diaryliodoniums include in-situ oxidation of an aryl iodide with 3-Chloroperbenzoic acid (MCPBA) followed by addition of another arene with triflic acid. Diaryliodoniums have been used quite extensively as aryl transfer reagents.61 λ5 iodanes take on square bipyramidal geometry.62 Some of the more well-known λ5 iodanes include 2-iodoxybenzoic acid (IBX) II-4 and Dess-Martin periodinane (DMP) II-5. IBX was first synthesized in 189363,64 and is mainly used as an oxidant to covert alcohols to carbonyls and can be easily accessed through oxidation of 2-iodoxybenzoic acid with potassium bromate. Reactions utilizing IBX are usually in DMSO or a mixture of DMSO/THF solvents owing to poor solubility in other organic solvents. However, due to the low solubility of IBX, DMP is often employed instead. DMP can be synthesized from heating IBX in a mixture of acetic acid and acetic anhydride.65

Figure 2.2. Examples of hypervalent iodanes.

2.3 Reactivity of λ3 Hypervalent Iodine Reagents

Commercially available hypervalent iodine reagents, iodobenzene diacetate and iodobenzene bis(trifluoroacetate) are known to readily and reversibly exchange ligands - - - with various anions such as trimethylsilyl nucleophiles (CN , AcO , N3 ). With this ligand exchange reactivity, Kita and coworkers have shown that by simply changing the nucleophile in the presence of iodobenzene bis(trifluoroacetate), oxidants formed in situ can successfully functionalize electron rich arenes such as II-6 to 2-cyanopyrolle II-7 or anisole II-8 to the azide analog II-9 (Scheme 2.1). Kita and coworkers propose that first, these nucleophiles are undergoing a ligand exchange with one of the trifluoroacetate groups on the hypervalent iodine. After which the hypervalent iodine interacts with the arene of interest through a charge transfer complex II-10 to create a radical cation II-11. The radical cation is sufficiently electrophilic enough to be attacked by the nucleophile in solution to give II-12. Subsequent oxidation and rearomatization then affords the desired functionalized arene II-13.66,67

Scheme 2.1. Mechanism for arene functionalization proposed by Kita and coworkers.

Another example of this ligand exchange was demonstrated with the first preparation of PhI(OH)OTs (Koser’s reagent) by mixing iodobenzene diacetate with tosic acid. It has also been reported that pre-formed hypervalent iodine derivatives such as Koser’s reagent and PhI(OH)OMs are able to successfully oxygenate polycyclic 18 aromatics.68,69 Other non-symmetric λ3 iodanes aside from Koser’s reagent have also shown unique reactivity. Muñiz and coworkers demonstrated that styrene derivatives such as II-14 could undergo allylic oxidation with iodane PhI(OAc)NTs2 II-15 and excess bistosylimide to get to II-16 (Figure 2.3a).70 Sharma and Hartwig reported a selective azidation of tertiary C-H bonds (II-17) using Zhdankin’s reagent II-18 along with iron to access alkyl azides (II-19).71 Other cross coupling reactions such as alkynylation are operative with BF3K salts (II-20) and benziodoxole reagents (II-21) under photocatalytic conditions to render alkynylated products (II-22).72 The Suna lab also reported aminations of heteroarenes utilizing amines (II-23) and electron rich hybrid iodanes (II-24) with copper to get to cross coupling products (II-25).73

Figure 2.3. Select transformations using hypervalent iodine. (a) allylic amination; (b) azidation; (c) alkynylation; (d) aryl amination.

2.4 Development of C-H Functionalization Methodology

2.4.1 Functionalization Strategy

Our inspiration for creating a streamlined method to derivatize arenes originated from the unique reactivity of hypervalent iodine reagents. We envisioned that in-situ activation of a hypervalent iodine could allow for the oxidation of arenes and heteroarenes to create C-O and C-X bonds. Many organic transformations utilizing hypervalent iodine reagents rely on the 74 activation of these iodanes with Lewis acids (e.g BF3·Et2O). Shafir and co-workers wanted to probe the nature of hypervalent iodane oxidants under Lewis acid activation and were able to isolate a crystal of a PhI(OAc)2 -BF3 adduct. The coordination of the Lewis acid elongates the I-O bond, making the oxidant non-symmetric, more cationic in nature, and more reactive.75 Using acid activation to our advantage, we postulated that if any Brønsted acid more acidic than AcOH reacts with PhI(OAc)2, a ligand exchange shall occur (Scheme 2.2), which would allow for the formation of an activated oxidant that could essentially exchange the hydrogen atom of an arene with the counterion of the acid. It was conceived that this method could allow for the functionalization of arenes in one simple step without the need to pre-form the desired oxidant. This system could then allow for the quick derivatization of arenes with a commercially available oxidant and common mineral acids. Other methods have used hypervalent iodine species to perform halogenation and oxygenation of arenes, albeit with limited substrate scope.76–79 The use of inexpensive mineral acids to functionalize arenes has also been underutilized.80

Scheme 2.2. Functionalization strategy. 20

2.4.2 Results

To test our hypothesis, we first reacted PhI(OAc)2 and 2-methyl pivanilide II-26 with various Brønsted acids (Table 2.1). At room temperature, there was low conversion towards a chlorinated arene using 1M HCl. However, reaction efficiency improved once the temperature was raised to 50 °C, and 4-chloro-2-methyl pivanilide II-27 was isolated in excellent yields. Encouraged by successful chlorination, we also investigated the bromination and iodination of this substrate with HBr and HI. We were able to obtain good yields of the brominated product with HBr (II-28). However, we were only able to achieve iodination of the anilide in low yields. Oxygenation of II-26 in reasonable yields was also possible with methanesulfonic acid (II-29), para-toluenesulfonic acid (II-30), and trifluoromethanesulfonic acid (II-27).

Table 2.1 Anion-mediated C-H functionalization of arenes.

Upon addition of the oxytriflate source (trimethylsilyltriflate or triflic acid), consumption of the starting anilide was rapid. The best results were observed at room temperature, with no improvement at colder temperatures down to -78 °C. It is possible that instead of a clean ligand exchange with the anion, Zefirov’s reagent was actually being formed. This reagent, although unstable, has been shown to be reactive towards alkenes to produce oxyvinyl iodoniums.81 It has also been reported that reactions with iodonium

21 triflate derivatives occur much fast than the tosylate derivatives-also explaining enhanced reactivity/instability of the triflate versus the tosylate and mesylate.82 Encouraged by the successful chlorination outcome, we decided to pursue this result further due to the importance of chlorinated (hetero)arenes in pharmaceutical cores, agrochemicals, and synthetic building blocks. Despite their significance in organic synthesis, efficient and reliable means to generate aryl chloride bonds has been a long- standing problem. Several existing chlorination methods suffer from harsh reaction conditions, poor regioselectivity, expensive metals, or unstable chlorinating reagents. With this chlorination strategy in hand, we went to investigate the substrate tolerance of this method as shown in Figure 2.4. We were pleased to note that we were able to chlorinate anilide and anisole derivates bearing halides (II-32-II-33), esters (II-34), and ketones (II-35) in moderate to high yields. These reaction conditions also allowed for the chlorination of a variety of nitrogen-containing aromatics (II-36-II-41). Dichlorination could also be achieved through adjusting reagent stoichiometry (II-42-II-43).

Figure 2.4 Investigation of arene chlorination.

Expanding the scope of this reaction method, we turned to heteroarenes such as isoquinoline. Unsurprisingly, under these acidic reaction conditions we only observed protonation of isoquinoline. Cognizant of other nucleophiles undergoing ligand exchange with iodobenzene diacetate, we explored if alternative chloride sources could be used for this chlorination strategy (Table 2.2). Even though trimethylsilyl chloride has been reported to undergo ligand exchange with iodobenzene diacetate to chlorinate 1,4 dimethoxynapthalenes,76 this combination only led to a 28% yield of the chlorinated isoquinoline (II-44). Koser also reported that using his reagent, chlorination of mesitylene with NaCl could be achieved. However, under our conditions using NaCl was not fruitful.69 Investigating other chloride sources, we found that acetyl chloride was able to efficiently react with isoquinoline to form 4-chloro isoquinoline II-44. Changing the acid chloride source to ethyl chloroformate, we were able to increase the yield to 92%. Using

23 pentafluorobenzoyl chloride, efficient chlorination of quinoline at the 3-position was also achieved.

Table 2.2 Chlorination of isoquinoline.

Now that we were able to attain chlorination of isoquinoline, we wanted to explore which other heteroarenes could be functionalized using our method (Figure 2.5). We were pleased to see that we could chlorinate five-membered heterocycles, indole (II-45-II-46) and pyrazole (II-47). Bromination could also be achieved for isoquinoline using HBr (II- 48). Other isoquinoline derivatives (II-49-II-50) and quinoline (II-51) and quinoxaline (II- 52) also fared well in our chlorination conditions. Pyridine derivatives (II-53-II-56) could also be chlorinated.

Figure 2.5 Heteroarene C-H chlorination.

Nitrogenous bases such as isoquinoline, quinoline, and pyridine are electron deficient species. Various synthetic routes to functionalize electron deficient heteroarenes such as isoquinoline, rely on nucleophilic attack on the heterocycles, therefore rendering functionalization of C-H bonds on electron deficient carbons of the heterocyclic ring. Several methods have been developed to functionalize the 2- and 4- positions of quinoline, many of which require the formation of N-oxides. Manipulation of C-H bonds on electron rich carbons of these basic systems difficult,83 and there are very few methods to functionalize the 4-position of isoquinoline84–88 and the 3-position of quinoline.89 Methods to functionalize these electron-rich positions heavily rely on functional group manipulation such as the Sandmeyer reaction or decarboxylation from a preformed oxime. This method for accessing chlorinated heteroarenes allows for further derivatization at these positions including arylation which could only previously be achieved using metal catalysts such as Pd.85 25

We were also pleased to note that our chlorination method for the synthesis of 4- chloroisoquinoline and 3-chloroquinoline were superior to well-known chlorination protocols using reagents such as Palau-chlor90 and 1-chloro-1,2-benziodoxol-3-one.91 There was observation of 20 % of the 4-chloroisoquinoline product with other unidentified products using tBuOCl (Table 2.3).

Table 2.3 Comparison of chlorination methods.

Interested in the potential medicinal chemistry application towards post-synthetic functionalization, we investigated halogenation of some biologically relevant molecules (Figure 2.7). Using our acid mediated conditions, we were able to chlorinate (II-57) and brominate (II-58) naproxen methyl ester and chlorination of lidocaine (II-59) could be accomplished even in the presence of a tertiary amine. Halogenation of dimethyl uracil (II- 60-II-61), caffeine (II-62), and papaverine (II-63- II-64) could be achieved up to 99% yield using this strategy. 2’-acetyl-phyllanthusmin D, a derivative of a natural product isolated in 2014,92 has a comparable diphyllin core structure to etoposide, a topoisomerase II inhibitor. Studies have shown that although 2’-acetyl-phyllanthusmin D is not a topoisomerase II inhibitor, (like structurally similar etoposide) it does have some activity against colon cancer cell lines.92,93 To expand upon the structure activity relationship map of the phyllanthusmins, in order to aid in the elucidation of the mechanism of action, we embarked on using our method to produce more derivatives of this compound. Chlorination of 2’-acetyl- 26 phyllanthusmin D using 1M HCl was unsuccessful and led to isolation of the aglycone. Due this de-glycosylation, we knew we needed to avoid acidic reagents. Referring to our solution for (iso)quinoline functionalization, we investigated other chloride sources. We found that we were able to attain selective chlorination of the napthyl ring using Bu4NCl (II-65) and LiBr produced 99% of brominated product (II-66) with high phenyl selectivity (Figure 2.6).

Figure 2.6 Chlorination of pharmaceuticals and natural product derivatives.

2.3.3. Mechanistic Studies

We first decided to investigate the ligand exchange between PhI(OAc)2 and 1M HCl. We were pleased to observe successful ligand exchange with various concentrations of acid. We also observed what we concluded to be a mixed iodane species, with one acetate ligand and one chlorine ligand.94,95 Therefore, the reaction is undergoing sequential ligand exchange. We also wanted to investigate the active oxidant and possible intermediates that could allow for the chlorination of the heteroarenes with acyl chloride. 1 Under H NMR analysis, we found that PhI(OAc)2 and acetyl chloride form PhICl2 as well as the mixed iodane. Curious if the dichloride was the active oxidant, we prepared the dichloride reagent independently from literature procedures96 and subjected it to reaction conditions with isoquinoline as the substrate. We found that with iodobenzene dichloride we saw drastically low yields (Table 2.4). With the thought that excess acid could still be the issue since HCl is used in the synthesis of iodobenzene dichloride, the reagent was vigorously dried, yet only gave a maximum of 30% yield of II-44, with the average yield being much lower. Since water was not compatible with heteroarene chlorination as it led to protonation, we investigated using hydrochloric acid in organic solvents. Low yields were also still obtained with using hydrochloric acid in organic solvents. Next, we wanted to probe the possibility of a mixed iodane being the active reagent instead the dichloride.

Using PhI(OAc)2 with either silver acetate or acetic anhydride we saw recapitulation of reactivity, leading us to conclude that the dichloride was not the active oxidant for heteroarene chlorination. However, our best yields were still with using acyl chlorides (Table 2.4).

Table 2.4 Investigation of active oxidant in isoquinoline chlorination. 28

From this switch in reactivity, based on the chloride source, we were intrigued to see if we would be able to observe arene vs. heteroarene selectivity depending on the chloride source used. We found that in a competition experiment between isoquinoline and 2-iodoanisole, we only observed formation 4-chloroisoquinoline II-44 using ethyl chloroformate, with recovery of unreacted 2-iodoansiole. Using 1M HCl as the chloride source, as expected, the isoquinoline is protonated and therefore deactivated, so only chlorination of 2-iodoansole to give II-67 was observed (Scheme 2.3).

Scheme 2.3 Chlorination competition experiments between isoquinoline and 2-iodoanisole.

Fukui index values and electron density map DFT calculations were performed to help predict selectivity (Figure 2.7). Fukui values can also be correlated to hard-soft acid base theory, in that the larger the Fukui value, the softer the atom and vice versa.97 The Fukui values were calculated by first determining the population analysis of each arene and the population analysis of its N-1 ionization state. The difference between the N-1 ionization state and ground state afforded the calculated value. The Fukui values correctly predicted the site of chlorination for piv-anilide and papaverine. However, we did find that

29 in many other cases, an electron density map was sufficient for predicting selectivity as seen with quinoline and isoquinoline.

Figure 2.7 DFT calculations to predict arene selectivity.

2.5 Conclusions

In this work, we have demonstrated an effective protocol for the C-H halogenation and oxygenation of arenes, which can also be applied to complex natural products. With this reagent-based chlorination selectivity, heteroarenes such as 4-chloroisoquinoline and 3-chloroquinoline can be quickly accessed from inexpensive starting materials. Creating this reactive oxidant in situ from bench stable reagents, eliminates the need for preformation of this oxidant, in turn making this protocol user friendly.

2.6 Experimental

2.6.1 General Information

All chemicals and reagents were purchased from Sigma-Aldrich, Alfa Aesar, Acros, TCI, or ChemImplex. Silicycle F60 (230-400 mesh) silica gel was used for column chromatography unless otherwise stated. Thin layer chromatography (TLC) analyses were performed using Merck silica gel 60 F254 plates and visualized under UV, KMNO4 or iodine stain. Melting points were determined using a Thermo Scientific Mel-Temp or a Thomas Hoover Uni-melt capillary melting point apparatus. 1H, 19F, 13C NMR spectra were recorded using a Bruker AVIII 400 MHz, AVIII 600 MHz, or AVIII 700 MHz NMR spectrometer. 1H NMR and 13C NMR chemical shifts are reported in parts per million and 1 13 referenced with respect to CDCl3 ( H: residual CHCl3 at δ 7.26, C: CDCl3 triplet at δ 77.16). 1H NMR data are reported as chemical shifts (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), relative integral. 13C and 19F NMR data are reported as chemical shifts (δ ppm). High resolution mass spectra were obtained using Bruker MicrOTOF (ESI) or Thermo LTQ Orbitrap. IR spectra were recorded using a Thermo Fisher Nicolet iS10 FT-IR or Thermo Scientific Nicolet 6700 FT- IR and are reported in terms of frequency of absorption (cm–1). Unless otherwise indicated, all hydrochloric acid solutions are in water. General Procedure for Amine Protection (GP1): Trimethylacetyl chloride (1 equiv) was added to a solution of arene (1 equiv.) and triethylamine (1.1 eq) in dichloromethane (1 M) at 0 °C. The solution was warmed to room temperature and stirred for 16 hours. The solution was washed with water and extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by recrystallization from dichloromethane and hexanes. General Procedure for Chlorination of Arenes (GP2): To an 8 mL dram vial was added iodobenzene diacetate (0.6 mmol, 1.5 equiv), arene (0.4 mmol, 1 eq.), dichloroethane (2 mL), then 1 M hydrochloric acid (2 mL, 5 equiv). The solution was allowed to stir (1000 rpm) at 50 °C for the indicated amount of time. After which the solution was washed with

31 saturated sodium bicarbonate, followed by saturated sodium thiosulfate and concentrated. The crude mixture was then purified by column chromatography. General Procedure for Chlorination of Heteroarenes (GP3): To an 8 mL dram vial was added iodobenzene diacetate (0.6 mmol, 1.5 equiv), and heteroarene (0.4 mmol, 1 eq.), anhydrous dichloroethane (1 mL), then chloride source (5 equiv). The solution was allowed to stir (1000 rpm) at 50 °C for the indicated amount of time. After which the solution was washed with saturated sodium bicarbonate, followed by saturated sodium thiosulfate and concentrated. The crude mixture was then purified by column chromatography.

2.6.2 Substrate Synthesis and Characterization

methyl 2-pivalamidobenzoate (SII-1). Prepared according to GP1. Methyl 2- aminobenzoateaniline (1.30 mL, 10 mmol) was reacted with triethylamine (1.70 mL, 12 mmol) and trimethylacetyl chloride (1.40 mL, 11 mmol) in dichloromethane (30 mL). Crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield SII-1 in quantitative yield as low melting solid.

Rf: 0.24 (5% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 11.31 (s, 1H), 8.78 (dd, J = 8.6, 1.1 Hz, 1H), 8.04 (dd, J = 8.0, 1.1 Hz, 1H), 7.58 – 7.49 (m, 1H), 7.11 – 7.02 (m, 1H), 3.93 (s, 3H), 1.35 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 178.1, 169.0, 142.2, 134.8, 131.0, 122.3, 120.5, 115.1, 52.5, 40.5, 27.8.

2-methyl-8,9-dihydro-2,9a-diazabenzo[cd]azulene-1,6(2H,7H)-dione (SII-2). 8,9- dihydro-2,9a-diazabenzo[cd]azulene-1,6(2H,7H)-dione (1.50 g, 7.4 mmol) was dissolved 32 in DMF (10 mL). Potassium tert-butoxide (1.25 g, 11.1 mmol) was added and allowed to stir for 30 minutes. After which iodomethane (691 µL, 11.1 mmol) was added and allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The product was purified by column chromatography eluting with 2% methanol/dichloromethane to yield SII-2 (628 mg, 39%) as a light-yellow solid.

Rf: 0.19 (2% methanol/dichloromethane). mp: 150.8 – 152.9 ºC. 1 H NMR (400 MHz, CDCl3): δ = 7.84 – 7.78 (m, 1H), 7.18 – 7.13 (m, 2H), 4.15 – 4.11 (m, 2H), 3.47 (s, 3H), 3.10 – 3.04 (m, 2H), 2.27 – 2.21 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ = 197.3, 154.0, 131.3, 129.1, 122.8, 120.8, 118.8, 111.8, 45.6, 44.7, 27.5, 20.5. + HRMS (ESI-TOF) m/z: calc’d for C12H12N2NaO2 [M+Na] 239.0796, found 239.0802. IR (film) cm–1: 2949, 2929, 1709, 1664, 1616, 1489, 1458, 1433, 1157, 1014, 796, 742, 592.

2.6.3 (Hetero)arene Halogenation and Oxygenation Synthesis and Characterization

N-(4-chloro-2-methylphenyl)pivalamide (II-27). Prepared according to GP2. N-(o- tolyl)pivalamide (50 mg, 0.26 mmol) was reacted with iodobenzene diacetate (126.1 mg, 0.39 mmol) and 1 M HCl (1.31 mL, 1.31 mmol) in dichloroethane (1 mL) for 4 hours. The crude product was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-27 (51.8 mg, 88%) as a white solid.

Rf: 0.65 (10% ethyl acetate/hexanes). mp: 112 ºC. 1 H NMR (600 MHz, CDCl3): δ 7.77 – 7.72 (m, 1H), 7.21 (s, 1H), 7.17 – 7.12 (m, J = 7.0, 2.4 Hz, 2H), 2.20 (s, 3H), 1.32 (s, 9H).

13 C NMR (151 MHz, CDCl3): δ 176.6, 134.6, 131.0, 130.2, 130.0, 126.8, 124.4, 39.8, 27.8, 17.6. + HRMS (ESI-TOF) m/z: calc’d for C12H16ClNO [M+H] 226.0993, found 226.0991. IR (film) cm–1: 3314, 1646, 1505, 811.

N-(4-bromo-2-methylphenyl)pivalamide (II-28). To an 8 mL dram vial was added iodobenzene diacetate (142 mg, 0.44 mmol, 1.1 equiv), N-(o-tolyl)pivalamide (76.5 mg, 0.4 mmol) dichloroethane (2 mL), and 48% hydrobromic acid (226 µL, 2 mmol). The solution was allowed to stir at 1000 rpm at 50 °C for 2 hours. After which the solution was washed with saturated sodium bicarbonate, followed by saturated sodium thiosulfate and concentrated. The crude mixture was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-28 (105 mg, 97%) as white crystals.

Rf: 0.22 (10% ethyl acetate/hexanes). mp: 120.0 – 121.6 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 9.2 Hz, 1H), 7.31 – 7.28 (m, 2H), 7.21 (s, 1H), 2.20 (s, 3H), 1.32 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 176.6, 135.1, 133.1, 131.0, 129.8, 124.5, 117.7, 39.9, 27.6, 17.5. + HRMS (ESI-TOF) m/z: calc’d for C12H16BrNONa [M+Na] 292.0313, found 292.0303. IR (film) cm–1: 3334, 2976, 2927, 2918, 2870, 1647, 1504, 1477, 1250, 1182, 874, 802, 607. Spectral data consistent with literature.98

3-methyl-4-pivalamidophenyl methanesulfonate (II-29). To an 8 mL dram vial was added methanesulfonic acid (78 µL, 1.2 mmol) to iodobenzene diacetate (193 mg, 0.6 mmol) in dichloromethane (1 mL) at room temperature. N-(o-tolyl)pivalamide (76.5 mg, 0.4 mmol) in dichloromethane (1 mL) added dropwise to solution and allowed to stir at 1000 rpm at room temperature for 45 minutes. After which the solution was washed with saturated sodium bicarbonate, followed by saturated sodium thiosulfate, and concentrated. The crude mixture was purified by column chromatography eluting with 30% ethyl acetate/hexanes to yield II-29 (75.5 mg, 66%) as a light-yellow solid.

Rf: 0.09 (30% ethyl acetate/hexanes). mp: 93.9 – 96.2 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.7 Hz, 1H) 7.25 (s, 1H), 7.14 – 7.08 (m, 2H), 3.10 (s, 3H), 2.26 (s, 3H), 1.33 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 176.7, 145.7, 135.3, 131.1, 124.2, 123.9, 120.1, 39.9, 37.3, 27.8, 17.8. + HRMS (ESI-TOF) m/z: calc’d for C13H19NO4SNa [M+Na] 308.0932, found 308.0930. IR (film) cm–1: 3286, 2973, 2929, 1649, 1512, 1358, 1178, 1132, 945, 827, 514.

3-methyl-4-pivalamidophenyl 4-methylbenzenesulfonate (II-30). To an 8 mL dram vial was added iodobenzene diacetate (193 mg, 0.6 mmol, 1.5 equiv), N-(o-tolyl)pivalamide (76.5 mg, 0.4 mmol) dichloroethane (2 mL), and p-toluenesulfonic acid monohydrate (114 mg, 0.6 mmol). The solution was allowed to stir at 1000 rpm at 50 °C for 1 hour. After which the solution was washed with saturated sodium bicarbonate, followed by saturated

35 sodium thiosulfate, and concentrated. The crude mixture was then purified by column chromatography eluting with 20% ethyl acetate/hexanes to yield II-30 (94.7 mg, 65%) as a light brown solid.

Rf: 0.08 (20% ethyl acetate/hexanes). mp: 135.1 – 137.2 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.20 (s, 1H), 6.93 (d, J = 2.7 Hz, 1H), 6.66 (dd, J = 8.8, 2.7 Hz, 1H), 2.44 (s, 3H), 2.19 (s, 3H), 1.31 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 176.6, 146.1, 145.4, 135.0, 132.7, 130.3, 129.9, 128.7, 124.4, 123.5, 120.4, 40.0, 27.8, 21.8, 17.8. + HRMS (ESI-TOF) m/z: calc’d for C19H24NO4S [M+H] 362.1426, found 362.1403. IR (film) cm–1: 3282, 2970, 2929, 1645, 1523, 1371, 1346, 1173, 941, 806, 548.

3-methyl-4-pivalamidophenyl trifluoromethanesulfonate (II-31). To an 8 mL dram vial was added triflic acid (71 µL, 0.8 mmol) to iodobenzene diacetate (258 mg, 0.8 mmol) in dichloromethane (1 mL) at room temperature. N-(o-tolyl)pivalamide (76.5 mg, 0.4 mmol) in dichloromethane (1 mL) added dropwise to the solution and allowed to stir at 1000 rpm at room temperature for 45 minutes. After which the solution was washed with saturated sodium bicarbonate, followed by saturated sodium thiosulfate, and concentrated. The crude mixture was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-31 (54.9 mg, 40%, isolated; 53% by crude 19F NMR using trifluorotoluene as in internal standard) as a light-yellow solid.

Rf: 0.14 (10% ethyl acetate/hexanes). mp: 105.9 – 107.1 °C. 1 H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.5 Hz, 1H), 7.27 (s, 1H), 7.15 – 7.10 (m, 2H), 2.29 (s, 3H), 1.34 (s, 1H). 36

13 C NMR (101 MHz, CDCl3): δ = 176.7, 145.7, 136.2, 130.8, 124.0, 123.1, 120.5, 119.6, 40.0, 27.8, 17.9. 19 F NMR (377 MHz, CDCl3): -72.83. + HRMS (ESI-TOF) m/z: calc’d for C13H17F3NO4S [M+H] 340.0830, found 340.0819. IR (film) cm–1: 3296, 2972, 2929, 1651, 1491, 1419, 1207, 1130, 941, 876, 814, 602.

N-(2,4-dichlorophenyl)pivalamide (II-32). Prepared according to GP2. N-(2- chlorophenyl)pivalamide (84.7 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 22 hours. The crude product was purified by column chromatography eluting with 3% ethyl acetate/hexanes to yield II-32 (75.6 mg, 77%) as white crystals.

Rf: 0.20 (3% ethyl acetate/hexanes). mp: 57.2 – 58.2 °C. 1 H NMR (400 MHz, CDCl3): δ = 8.38 (d, J = 8.9 Hz, 1H), 7.94 (s, 1H), 7.37 (d, J =2.4 Hz, 1H), 7.24 (dd, J =8.9, 2.4 Hz, 1H), 1.33 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 176.6, 133.7, 128.9, 128.7, 128.0, 123.5, 122.2, 40.3, 27.7. + HRMS (ESI-TOF) m/z: calc’d for C11H13Cl2NONa [M+Na] 268.0272, found 268.0278. IR (film) cm–1: 2977, 2952, 1655, 1576, 1504, 1474, 1383, 1171, 1099, 1056, 865, 806, 744, 585, 554. Spectral data consistent with literature.99

N-(2-bromo-4-chlorophenyl)pivalamide (II-33). Prepared according to GP2. N-(2- bromophenyl)pivalamide (102 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 4.5 hours. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield II-33 (90.4 mg, 78%) as colorless crystals.

Rf: 0.31 (5% ethyl acetate/hexanes). mp: 66.2 – 68.1 °C. 1 H NMR (600 MHz, CDCl3): δ = 8.36 (d, J = 8.9 Hz, 1H), 7.95 (bs, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.9, 2.4 Hz, 1H), 1.34 (s, 9H). 13 C NMR (151 MHz, CDCl3): δ = 176.8, 134.8, 131.7, 129.3, 128.6, 122.4, 113.8, 40.4, 27.7. + HRMS (ESI-TOF) m/z: calc’d for C11H14BrClNO [M+H] 289.9947, found 289.9927. IR (film) cm–1: 3292, 2974, 1653, 1502, 1471, 1369, 1167, 804. Spectral data consistent with literature.100

methyl 5-chloro-2-pivalamidobenzoate (II-34). Prepared according to GP2. Anilide SII-

1 (94.1 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 13 hours. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield II-34 (66.1 mg, 61%) as an off white solid.

Rf: 0.28 (5% ethyl acetate/hexanes). mp: 84.4 – 86.8 °C.

1 H NMR (400 MHz, CDCl3): δ = 11.23 (bs, 1H), 8.76 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 2.6 Hz, 1H) 7.47 (dd, J = 9.1, 2.6 Hz, 1H) 3.93 (s, 3H), 1.33 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 178.0, 167.9, 140.7, 134.6, 130.5, 127.3, 121.9, 116.3, 52.7, 40.5, 27.7. + HRMS (ESI-TOF) m/z: calc’d for C13H16ClNO3Na [M+Na] 292.0716, found 292.0700. IR (film) cm–1: 1303, 3129, 2956, 2912, 1689, 1583, 1510, 1428, 1394, 1284, 1240, 1146, 960, 920, 832, 785, 694, 534.

1-(5-chloro-2-methoxyphenyl)ethan-1-one (II-35). Prepared according to GP2. 1-(2- methoxyphenyl)ethan-1-one (57 µL, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 4.5 hours. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield II-35 (53.5 mg, 72%) as a yellow oil.

Rf: 0.17 (5% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 2.7 Hz, 1H), 7.38 (dd, J = 8.6, 2.8 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H), 2.59 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 198.4, 157.6, 133.3, 130.1, 129.4, 126.1, 113.2, 56.0, 31.8. + HRMS (ESI-TOF) m/z: calc’d for C11H13Cl2NONa [M+Na] 207.0189, found 207.0185. IR (film) cm–1: 3001, 2939, 2835, 1664, 1591, 1398, 1217, 1180, 1142, 1022, 814, 580. Spectral data consistent with literature.101

1-(5-chloroindolin-1-yl)-2,2-dimethylpropan-1-one (II-36). Prepared according to GP2. 1-(indolin-1-yl)-2,2-dimethylpropan-1-one (81.3 mg, 0.4 mmol) was reacted with iodobenzene diacetate (155 mg, 0.48 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 2 hours. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield II-36 (80.6 mg, 85%) as a colorless oil.

Rf: 0.11 (5% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 8.18 – 8.12 (m, 1H), 7.16 – 7.11 (m, 2H), 4.23 (d, J = 8.2 Hz, 2H), 3.11 (t, J = 8.2 Hz, 2H), 1.36 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 176.7, 143.5, 132.8, 128.5, 127.3, 124.5, 119.3, 49.7, 40.3, 29.2, 27.8. + HRMS (ESI-TOF) m/z: calc’d for C13H16ClNONa [M+Na] 260.0818, found 260.0802. IR (film) cm–1: 2964, 1641, 1589, 1465, 1354, 1327, 818.

5-chloro-1-methylindolin-2-one (II-37). Prepared according to GP2. Oxindole (58.9 mg,

0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (1 mL) for 45 minutes. The crude product was purified by column chromatography eluting with 15% ethyl acetate/hexanes to yield II-37 (51.2 mg, 70%) as pink crystals.

Rf: 0.09 (15% ethyl acetate/hexanes). mp: 99.7 – 101.1 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.28 – 7.24 (m, 1H), 7.23 – 7.22 (m, 1H), 6.73 (d, J = 8.2 Hz, 1H), 3.51 (s, 2H), 3.20 (s, 3H).

13 C NMR (101 MHz, CDCl3): δ = 174.5, 143.9, 127.9, 127.8, 126.2, 124.9, 109.0, 35.7, 26.4. + HRMS (ESI-TOF) m/z: calc’d for C9H8ClNONa [M+ Na] 204.0192, found 204.0192.. IR (film) cm–1: 2939, 2920, 2853, 1697, 1607, 1490, 1337, 1272, 1098, 1062, 869, 815, 664, 545, 523. Spectral data consistent with literature.102

5-chloro-1-methylindoline-2,3-dione (II-38). Prepared according to GP2. 1- methylindoline-2,3-dione (58.7 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 4 hours. The crude product was purified by column chromatography eluting with 20% ethyl acetate/hexanes to yield II-38 (48.8 mg, 63%) as orange needles.

Rf: 0.09 (20% ethyl acetate/hexanes). mp: 175.1 – 176.9 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.59 – 7.55 (m, 2H), 6.88 – 6.84 (m, 1H), 3.25 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 182.4, 157.8, 149.8, 137.9, 129.8, 125.4, 118.4, 111.3, 26.5. + HRMS (ESI-TOF) m/z: calc’d for C9H6ClNO2Na [M+ Na] 217.9985, found 217.9995. IR (film) cm–1: 3048, 1723, 1604, 1444, 1326, 1174, 1107, 1068, 906, 825, 726, 598, 527 Spectral data consistent with literature.103

6-chloro-3-methylbenzo[d]oxazol-2(3H)-one (II-39). Prepared according to GP2. 3- methylbenzo[d]oxazol-2(3H)-one (59.7 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 4 hours. The crude product was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-39 (54.5 mg, 74%) as a white powder.

Rf: 0.11 (10% ethyl acetate/hexanes). mp: 105.7 – 106.7 °C. 1 H NMR (600 MHz, CDCl3): δ = 7.22 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.3 Hz, 1.9 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.39 (s, 3H). 13 C NMR (151 MHz, CDCl3): δ = 154.5, 143.0, 130.6, 128.1, 124.1, 111.0, 108.7, 28.4. + HRMS (ESI-TOF) m/z: calc’d for C8H6ClNO2Na [M+Na] 205.9985, found 205.9981. IR (film) cm–1: 1743, 1616, 1748, 1380, 1356, 1281, 1244, 1078, 1051, 910, 823, 742, 585. Spectral data consistent with literature.104

5-chloro-2-methyl-1H-benzo[d]imidazole (II-40). Prepared according to GP2. 2- methylbenzimidazole (50.0 mg, 0.38 mmol), and tetrabutylammonium chloride (526 mg, 1.89 mmol). After 1.5 hours, the reaction mixture was purified by chromatography eluting with 5% methanol/dichloromethane to provide the II-40 (45.6 mg, 72% yield) as a white amorphous solid.

Rf: 0.3 (5% methanol/dichloromethane). 1 H NMR (400 MHz, CDCl3): δ 7.61 (s, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.5, 2.0 Hz, 1H), 2.63 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 152.2, 128.2, 123.1, 115.4, 114.7, 15.1. 42

+ HRMS (ESI-TOF) m/z: calc’d for C8H7ClN2 [M+H] m/z 167.0371, found 167.0369. IR (film) cm–1: 3315, 1647, 1506, 811. Spectral data consistent with literature.105

5-chloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (II-41). Prepared according to GP2. Benzoxindolidinone (64.9 mg, 0.4 mmol) was reacted with iodobenzene diacetate (142 mg, 0.44 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 1 hour to give 81% of 16 (by crude 1H NMR). An analytical sample was purified by preparatory thin layer chromatography eluting with 2% methanol/dichloromethane to yield II-41 as a white solid.

Rf: 0.16 (2% methanol/dichloromethane). mp: 160.8 – 162.5°C. 1 H NMR (600 MHz, CDCl3): δ = 7.07 (dd, J = 8.3, 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.41 (s, 3H), 3.40 (s, 3H). 13 C NMR (151 MHz, CDCl3): δ = 154.8, 131.1, 128.8, 127.0, 121.2, 108.1, 108.0, 27.4. + HRMS (ESI-TOF) m/z: calc’d for C9H9ClN2NaO [M+Na] 219.0301, found 219.0305. IR (film) cm–1: 1703, 1655, 1446, 1394, 1342, 1228, 912, 744.

5,6-dichloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (II-42). Prepared according to GP2. Benzoxindolidinone (64.9 mg, 0.4 mmol) was reacted with iodobenzene diacetate (322 mg, 1 mmol) and 1 M HCl (4 mL, 4 mmol) in dichloroethane

(2 mL) for 2 hours. The crude product was purified by column chromatography eluting with 1% methanol/dichloromethane to yield II-42 (70.0 mg, 70%) as white needles.

Rf: 0.24 (1% methanol/dichloromethane). mp: 233.1 – 236.0 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.00 (s, 2H), 3.37 (s, 6H). 13 C NMR (151 MHz, CDCl3): δ = 154.8, 129.7, 125.0, 109.0, 27.5. + HRMS (ESI-TOF) m/z: calc’d for C9H8Cl2N2ONa [M+Na] 252.9911, found 252.9904. IR (film) cm–1: 1716, 1679, 1621, 1484, 1463, 1431, 1378, 1258, 1023, 927, 747, 579. Spectral data consistent with literature.106

4,5-dichloro-2-methyl-8,9-dihydro-2,9a-diazabenzo[cd]azulene-1,6(2H,7H)-dione (II- 43). Prepared according to GP2, Benzoxindolidinone SII-2 (43.2 mg, 0.2 mmol) was reacted with iodobenzene diacetate (161 mg, 0.5 mmol) and 1 M HCl (4 mL, 4 mmol) in dichloroethane (2 mL) for 2 hours. The crude product was purified by column chromatography eluting with 1% methanol/dichloromethane to yield II-43 (48.0 mg, 84%) as a white powder.

Rf: 0.5 (5% methanol/dichloromethane). mp: 202.7 – 205.1°C. 1 H NMR (400 MHz, CDCl3): δ = 7.13 (s, 1H), 4.06 – 4.00 (m, 2H), 3.41 (s, 3H), 3.07 (t, J = 6.8 Hz, 2H), 2.24 – 2.34 (m, 2H). 13 C NMR (151 MHz, CDCl3): δ = 154.2, 129.9, 128.2, 127.5, 123.2, 121.7, 110.9, 45.5, 27.6, 23.8. + HRMS (ESI-TOF) m/z: calc’d for C24H20Cl4N4NaO4 [2M+Na] 593.0107, found 593.0119. IR (film) cm–1: 2918, 1712, 1672, 1620, 1485, 1431, 1379, 1155, 1022, 924, 847, 739, 673. 44

4-chloroisoquinoline (II-44). Prepared according to GP3. Isoquinoline (51.7 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and ethylchloroformate (191 µL, 2 mmol) for 3 hours. The reaction mixture was purified by column chromatography eluting with 0.5% methanol/dichloromethane to yield II-44 (60.5 mg, 92% yield) as a clear oil.

Rf: 0.05 (0.5% methanol/dichloromethane). 1 H NMR (400 MHz, CDCl3): δ = 9.13 (s, 1H), 8.56 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ = 151.2, 142.0, 133.6, 131.5, 129.5, 128.6, 128.3, 127.8, 123.4. + HRMS (ESI-TOF) m/z: calc’d for C9H6ClN [M+H] 164.0262, found 164.0260. IR (film) cm–1: 1572, 1379, 1254, 979, 888, 794. Spectral data consistent with literature.107

1-(3-chloro-1H-indol-1-yl)-2,2-dimethylpropan-1-one (II-45). Prepared according to GP2. 1-(1H-indol-1-yl)-2,2-dimethylpropan-1-one (80.5 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 1M HCl (2 mL, 2.0 mmol) for 55 minutes. The reaction mixture was purified by column chromatography with 5% ethyl acetate/hexanes to yield II-45 (66.7 mg, 71%) as a clear oil.

Rf: 0.65 (5% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 1.52 (s, 9H), 7.38 – 7.33 (m, 1H), 7.44 – 7.39 (m, 1H), 7.59 (dd, J = 7.8, 0.6 Hz, 1H), 7.73 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H).

13 C NMR (101 MHz, CDCl3): δ = 28.8, 41.4, 113.3, 117.6, 118.3, 122.1, 124.2, 126.6, 127.2, 136.1, 176.6. + HRMS (ESI-TOF) m/z: calc’d for C13H15ClNO [M+H] 236.0842, found 236.0841. IR (film) cm–1: 3167, 2985, 2935, 1689, 1446, 1306, 1178, 1151, 985, 895, 746. Spectral data consistent with literature.91

1-(5-bromo-3-chloro-1H-indol-1-yl)-2,2-dimethylpropan-1-one (II-46). Prepared according to GP2. 1-(5-bromo-1H-indol-1-yl)-2,2-dimethylpropan-1-one (62.9 mg, 0.2 mmol) was reacted with iodobenzene diacetate (77.0 mg, 0.24 mmol) for 1 hour. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield II-46 (55.8 mg, 87%) as white needles.

Rf: 0.42 (5% ethyl acetate/hexanes). mp: 170.1 – 171.0 °C. 1 H NMR (400 MHz, CDCl3): δ = 8.38 (d, J = 8.9 Hz, 1H), 7.73 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.9, 2.0 Hz, 1H), 1.51 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ = 176.4, 134.7, 129.4, 128.9, 123.1, 121.0, 119.1, 117.6, 112.2, 41.4, 28.7. + HRMS (ESI-TOF) m/z: calc’d for C13H13BrClNONa [M+Na] 335.9767, found 335.9758. IR (film) cm–1: 3178, 2993, 2976, 2931, 1697, 1441, 1300, 1174, 987, 901, 781, 600.

4-chloro-3,5-dimethyl-1H-pyrazole (II-47). Prepared according to GP3. 3,5- Dimethylpyrazole (50.0 mg, 0.52 mmol) was reacted with tetrabutylammonium chloride 46

(723 mg, 2.6 mmol), and iodobenzene diacetate (503 mg, 1.56 mmol) for 2 hours. The crude product was purified by column chromatography eluting with 50% ethyl acetate/hexanes to yield II-47 (46.5 mg, 69%) as a white solid.

Rf: 0.9 (2% methanol/dichloromethane). mp: 88.2 – 90.0 °C. 1 H NMR (600 MHz, CDCl3): δ = 9.45 (s, 1H), 2.22 – 2.67 (m, 6H). 13 C NMR (151 MHz, CDCl3): δ = 141.2, 108.1, 10.5. + HRMS (ESI-TOF) m/z: calc’d for C5H8ClN2 [M+H] 131.0376, found 131.0376. IR (film) cm–1: 3201, 3122, 3059, 1654, 1597, 1479, 1122, 1041, 912, 829, 742. Spectral data consistent with literature.108

4-bromoisoquinoline (II-48): Prepared according to GP3. Isoquinoline (51.7 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and dried fine KBr powder (238 mg, 2 mmol). After 14 hours, the reaction mixture was purified by column chromatography eluting with 0.5% methanol/dichloromethane to yield II-48 (58.3 mg, 70% yield) as a brown oil.

Rf: 0.2 (0.25% methanol/dichloromethane). 1 H NMR (600 MHz, CDCl3): δ 9.18 (s, 1H), 8.72 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.84 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.65 – 7.74 (m, 1H). 13 C NMR (151 MHz, CDCl3): δ 151.7, 144.4, 135.1, 132.0, 129.9, 128.1, 128.5, 126.1, 119.9. + HRMS (ESI-TOF) m/z: calc’d for C9H6BrN [M+H] 207.9756, found 207.9747. IR (film) cm–1: 1375, 1215, 958, 772. Spectral data consistent with literature.107

4-chloro-1-phenylisoquinoline (II-49). Prepared according to GP3 with modifications, 1- phenylisoquinoline (82.1 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and pentafluorobenzoyl chloride (288 µL, 2 mmol) in dichloroethane (1 mL) at 70 °C for 12 hours. The solution was stirred with saturated sodium bicarbonate for 1 hour and extracted with dichloromethane and concentrated. The product was purified by column chromatography eluting with 3% ethyl acetate/hexanes to yield II-49 (56.4 mg, 59%) as a white solid.

Rf: 0.15 (3% ethyl acetate/hexanes). mp: 124.3 – 126.2 °C. 1 H NMR (400 MHz, CDCl3): δ = 8.67 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.84 – 7.79 (m, 1H), 7.69 – 7.65 (m, 2H), 7.63 – 7.58 (m, 1H), 7.57 – 7.50 (m, 3H). 13 C NMR (151 MHz, CDCl3): δ =159.8, 141.2, 139.1, 134.4, 131.1, 130.1, 130.0, 128.6, 128.2, 128.0, 127.7, 127.5, 123.8. + HRMS (ESI-TOF) m/z: calc’d for C15H10ClNNa [M+Na] 240.0589 found, 240.0587. IR (film) cm–1: 3356, 3300, 2974, 2935, 1651, 1491, 1419, 1207, 1130, 943, 876, 814, 602. Spectral data consistent with literature.85

6-bromo-4-chloroisoquinoline (II-50). Prepared according to GP3. 6-bromo-4- chloroisoquinoline (21.0 mg, 0.1 mmol) was reacted with iodobenzene diacetate (97.0 mg, 0.3 mmol) and acetyl chloride (71 µL, 1 mmol) in dichloroethane (1 mL) at 50 °C for 13

48 hours. The product was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-50 (16.2 mg, 67%) as a white solid.

Rf: 0.12 (10% ethyl acetate/hexanes). mp: 117.8 – 120.6 °C. 1 H NMR (400 MHz, CDCl3): δ = 9.13 (s, 1H), 8.62 (s, 1H), 8.42 – 8.37(m, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 1.8 Hz, 1H). 13 C NMR (151 MHz, CDCl3): δ = 151.0, 142.9, 134.7, 126.0, 132.1, 129.5, 127.9, 127.4, 12.9. + HRMS (ESI-TOF) m/z: calc’d for C9H6BrClN [M+H] 241.9372, found 241.9365. IR (film) cm–1: 1608, 1342, 1227, 1065, 983, 912, 746.

3-chloroquinoline (II-51): Prepared according to GP3. Quinoline (47 µL, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and pentafluorobenzoyl chloride (288 µL, 2.0 mmol) in anhydrous dichloroethane (0.5 ml, 0.8 M) for 17 hours. The reaction mixture was quenched with saturated sodium bicarbonate and extracted using dichloromethane. The organic layer was further washed with 1M sodium hydroxide followed by saturated sodium thiosulfate, then concentrated. The crude mixture was purified by column chromatography eluting with 100% dichloromethane to yield II-51 (41.2 mg, 63% yield) as a clear oil.

Rf: 0.3 (100% dichloromethane). 1 H NMR (600 MHz, CDCl3): δ = 8.83 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.5, 0.4 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.72 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.58 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H). 13 C NMR (151 MHz, CDCl3): δ = 149.8, 146.9, 146.4, 134.1, 129.8, 129.6, 128.6, 127.9, 127.2. + HRMS (ESI-TOF) m/z: calc’d for C9H7ClN [M+H] 164.0267, found 164.0265. 49

IR (film) cm–1: 2919, 2850, 2359, 953, 751.

5,7-dichloroquinoxaline (II-52). Prepared according to GP3. Quinoxaline (52.1 mg, 0.4 mmol) was reacted with iodobenzene diacetate (322 mg, 1 mmol) and pentafluorobenzoyl chloride (288 µL, 2.0 mmol) for 4 hours. The crude product was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-52 (38.8 mg, 49%) as a white solid.

Rf: 0.18 (10% ethyl acetate/hexanes). mp: 148.2 – 150.1°C. 1 H NMR (600 MHz, CDCl3): δ = 8.95 (d, J = 1.8 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H). 13 C NMR (151 MHz, CDCl3): δ = 146.6, 145.3, 144.1, 138.7, 135.7, 134.5, 131.1, 127.8. + HRMS (ESI-TOF) m/z: calc’d for C8H5Cl2N2 [M+H] 198.9830, found 198.9835. IR (film) cm–1: 1655, 1030, 984, 912, 885, 746.

5-chloro-N,N-dimethylpyrimidin-2-amine (II-53). Prepared according to GP3. N,N- dimethylpyrimidin-2-amine (49.3 µL, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and acetyl chloride (2 mmol) for 1.5 hours. The crude product was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield to yield II-53 (35.8 mg, 57%) as a yellow oil.

Rf: 0.25 (5% ethyl acetate/hexanes).

H NMR (400 MHz, CDCl3): δ = 8.21 (s, 2H), 3.15 (s, 6H).

13 C NMR (151 MHz, CDCl3): δ = 160.7, 155.8, 117.7, 37.5. + HRMS (ESI-TOF) m/z: calc’d for C6H9ClN3 [M+H] 158.0485 found 158.0500. IR (film) cm–1: 2252, 1587, 1531, 1412, 1377. Spectral data consistent with literature.109

Prepared according to GP3. N,N-dimethylpyridin-2-amine (50 µL, 0.4 mmol) was reacted with iodobenzene diacetate (116 mg, 0.9 mmol) and pentafluorobenzoyl chloride (144 µL, 2 mmol) for 1 hour. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield II-54 (59%, 3.2:1 para:ortho by 1H NMR using mesitylene as an internal standard) as a colorless oil. 5-chloro-N,N-dimethylpyridin-2-amine (p- II-54).

Rf: 0.19 (5% ethyl acetate/hexanes). 1 H NMR (600 MHz, CDCl3): δ = 8.08 (d, J = 2.7 Hz, 1H), 7.37 (dd, J = 9.1, 2.7 Hz, 1H), 6.43 (d, J = 9.1 Hz, 1H). 13 C NMR (151 MHz, CDCl3): δ = 157.8, 146.3, 136.9, 118.7, 106.6, 38.4. + HRMS (ESI-TOF) m/z: calc’d for C7H10ClN2 [M+H] 157.0533, found 157.0552. IR (film) cm–1: 1706, 1657, 1595, 1496, 1442, 1390, 912, 742. 3-chloro-N,N-dimethylpyridin-2-amine (o- II-54).

Rf: 0.19 (5% ethyl acetate/hexanes). 1 H NMR (600 MHz, CDCl3): δ = 8.14 (dd, J = 4.8, 1.6 Hz, 1H), 7.54 (dd, J = 7.7, 1.6 Hz, 1H), 6.75 (dd, J = 7.7, 4.8 Hz, 1H). 13 C NMR (151 MHz, CDCl3): δ = 159.23, 145.56, 138.95, 121.26, 116.82, 41.55. + HRMS (ESI-TOF) m/z: calc’d for C7H10ClN2 [M+H] 157.0533, found 157.0552.

N-(5-chloro-6-methylpyridin-2-yl)pivalamide (II-55). Prepared according to GP3. N- (6-methylpyridin-2-yl)pivalamide (38.0 mg, 0.2 mmol) was reacted with iodobenzene diacetate (96.6 mg, 0.3 mmol) and pentafluorobenzoyl chloride (144 µL, 1 mmol) for 12 hours. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield II-55 (33.2 mg, 74%) as a yellow oil.

Rf: 0.08 (5% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 8.05 (dd, J = 8.7, 0.4 Hz, 1H), 7.94 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 2.51 (s, 3H), 1.32 (s, 9H). 13 C NMR (151 MHz, CDCl3): δ = 177.1, 154.1, 149.3, 138.7, 125.8, 112.4, 40.0, 27.6, 22.2. + HRMS (ESI-TOF) m/z: calc’d for C11H16ClN2O [M+H] 227.0951, found 227.0948. IR (film) cm–1: 2962, 2871, 1685, 1504, 1429, 1358, 1300, 1132, 1047, 833.

N,N'-(3,5-dichloropyridine-2,6-diyl)bis(2,2-dimethylpropanamide) (II-56). Prepared according to GP3, N,N'-(pyridine-2,6-diyl)bis(2,2-dimethylpropanamide) (111 mg, 0.4 mmol) was reacted with iodobenzene diacetate (322 mg, 1 mmol) and acetyl chloride (285 µL, 4 mmol) in dichloroethane (2 mL) for 12 hours. The crude product was purified by column chromatography eluting with 2% methanol/dichloromethane to yield II-56 (84.5 mg, 62%) as a white solid.

Rf: 0.21 (2% methanol/dichloromethane). mp: >250 °C. 1 H NMR (600 MHz, CDCl3): δ = 7.96 (s, 2H), 7.77 (s, 1H), 1.32 (s, 18H). 13 C NMR (151 MHz, CDCl3): δ = 176.1, 145.1, 139.7, 120.6, 40.1, 27.6.

+ HRMS (ESI-TOF) m/z: calc’d for C15H21Cl2N3O2Na [M+Na] 368.0909, found 368.0892. IR (film) cm–1: 3222, 2968, 1674, 1510, 1421, 1369, 1174, 943.

methyl 2-(5-chloro-6-methoxynaphthalen-2-yl)propanoate (II-57). Naproxen methyl ester (36.6 mg, 0.15 mmol) was reacted with iodobenzene diacetate (74 mg, 0.23 mmol) and 1M hydrochloric acid (750 µL, 0.75 mmol) in dichloroethane (1 mL) for 1.5 hours. The crude product was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-57 (30.7 mg, 73%) as a white solid.

Rf: 0.14 (5% ethyl acetate/hexanes). mp: 106.3 – 108.0 °C. 1 H NMR (600 MHz, CDCl3): δ = 8.18 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.53 (dd, J = 8.8, 1.7 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 4.03 (s, 3H), 3.88 (q, J = 7.2 Hz, 1H), 3.68 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3): δ = 175.0, 152.8, 136.7, 131.3, 129.7, 128.0, 127.6, 126.3, 124.2, 117.1, 114.3, 57.2, 52.2, 45.4, 18.6. + HRMS (ESI-TOF) m/z: calc’d for C15H15ClO3Na [M+Na] 301.0607, found 301.0592. IR (film) cm–1: 2976, 2954,1736, 1599, 1331, 1273, 1151, 1066, 881, 798, 526. 1H NMR Spectral data consistent with literature.110

methyl 2-(5-chloro-6-methoxynaphthalen-2-yl)propanoate (II-58). Naproxen methyl ester (36.6 mg, 0.15 mmol) was reacted with iodobenzene diacetate (74.1 mg, 0.23 mmol) and 48% hydrobromic acid (102 µL, 0.75 mmol) in dichloroethane (1 mL) for 1.5 hours. The crude product was purified by column chromatography eluting with 10% ethyl acetate/hexanes to yield II-58 (32.8 mg, 68%) as a white solid.

Rf: 0.06 (5% ethyl acetate/hexanes). mp: 92.7 – 94.3°C. 1 H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.52 (dd, J = 9.0, 1.8 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 4.03 (s, 3H), 3.87 (q, J = 7.2 Hz, 1H), 3.67 (s, 3H), 1.59 (d, J = 7.2 Hz, 1H). 13 C NMR (151 MHz, CDCl3): δ = 175.0, 153.9, 136.7, 132.5, 130.0, 129.0, 127.8, 126.9, 126.3, 114.1, 108.7, 57.2, 52.3, 45.3, 18.6. + HRMS (ESI-TOF) m/z: calc’d for C15H15BrNaO3 [M+Na] 345.0102, found 345.0072 IR (film) cm–1: 904, 727, 650. Spectral data consistent with literature.111

N-(3-chloro-2,6-dimethylphenyl)-2-(diethylamino)acetamide (II-59). Prepared according to GP2. Lidocaine (27.1 mg, 0.1 mmol) was reacted with iodobenzene diacetate (48.3 mg, 0.15 mmol) and 1M hydrochloric acid (500 µL, 0.5 mmol) in dichloroethane (1 mL) for 2 hours. The reaction was allowed to cool to room temperature then diluted with 1M hydrochloric acid (10 mL). The aqueous layer was basified with 10% NaOH and 54 extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. Crude product was purified by column chromatography on grade I basic alumina eluting with 10% ethyl acetate/hexanes to yield II-59 (16.0 mg, 60%) as a white solid.

Rf: 0.34 (2% methanol/dichloromethane). mp: 51.1 – 53.6 °C. 1 H NMR (400 MHz, CDCl3): δ = 8.98 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.23 (s, 2H), 2.70 (q, J = 7.1 Hz, 4H), 2.27 (s, 3H), 2.20 (s, 3H), 1.14 (t, J = 7.1 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ = 170.5, 135.3, 134.0, 133.6, 132.6, 128.6, 128.0, 57.6, 49.1, 18.6, 15.9, 12.8. + HRMS (ESI-TOF) m/z: calc’d for C14H21ClN2O [M+H] 269.1421, found 269.1402. IR (film) cm–1: 3240, 2964, 2927, 2804, 160, 1493, 1448, 1207, 1011, 818.

5-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (II-60). Prepared according to GP2. 1,3-dimethyluracil (56.1 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and 2M HCl in diethyl ether (1.0 ml, 2.0 mmol) for 40 minutes. The reaction mixture was purified by chromatography eluting with 1% methanol/dichloromethane to yield II-60 (59.8 mg, 86%) as a white amorphous solid.

Rf: 0.3 (2% methanol/dichloromethane). mp: 142 ºC. 1 H NMR (400 MHz, CDCl3): δ = 7.42 (s, 1H), 3.41 (s, 3H), 3.38 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 159.6, 151.0, 140.0, 108.1, 37.4, 29.1. + HRMS (ESI-TOF) m/z: calc’d for C6H7ClN2O2Na [M+Na] 197.0088, found 197.0077. IR (film) cm–1: 1717, 1661, 1445, 1340, 757. Spectral data consistent with literature.112 55

5-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (II-61). Prepared according to GP2. 1,3-dimethyluracil (29.2 mg, 0.21 mmol) was reacted with iodobenzene diacetate (74.1 mg, 0.23 mmol) and 48% hydrobromic acid (2.2 mL) for 1.5 hours. The reaction mixture was purified by column chromatography eluting with 100% ethyl acetate to yield II-61 (32.6 mg 71%) as a white solid.

Rf: 0.62 (100% ethyl acetate). mp: 183.4 – 184.8 °C. 1 H NMR (600 MHz, CDCl3): δ = 7.53 (s, 1H), 3.42 (s, 3H), 3.40 (s, 3H). 13 C NMR (151 MHz, CDCl3): δ = 159.6, 151.2, 142.5, 95.9, 37.4, 29.3. + HRMS (ESI-TOF) m/z: calc’d for C6H7BrN2O2Na [M+Na] 240.9589, found 240.9585. IR (film) cm–1: 2252, 1712, 1655, 1448, 1333, 1331, 1227, 912, 742, 650. 13C NMR Spectral data consistent with literature.113

8-chloro-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (II-62). Prepared according to GP3. Caffeine (77.7 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and pentafluorobenzoyl chloride (288 µL, 2.0 mmol) for 4 hours. The reaction mixture was quenched with saturated sodium bicarbonate and extracted using dichloromethane. The organic layer was further washed with 1M sodium hydroxide followed by saturated sodium thiosulfate, then concentrated. The reaction mixture was purified by column chromatography eluting with 1% methanol/dichloromethane to yield II-62 (60.1 g, 65%) as a white solid.

Rf: 0.5 (3% methanol/dichloromethane). mp: 188 ºC. 1 H NMR (400 MHz, CDCl3): δ = 3.95 (s, 3H), 3.55 (s, 3H), 3.40 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 154.7, 151.4, 147.3, 139.1, 108.4, 32.8, 29.9, 28.1. + HRMS (ESI-TOF) m/z: calc’d for C8H9ClN4O2 [M+H] m/z 229.0487, found 229.0474. IR (film) cm–1: 1707, 1664, 1369, 755. Spectral data consistent with literature.114

1-(2-chloro-4,5-dimethoxybenzyl)-6,7-dimethoxyisoquinoline (II-63). Prepared according to GP2 using HCl (67.9 mg, 2 mmol). After 4 hours, the reaction mixture was purified by column chromatography eluting with 1% methanol/dichloromethane to yield II-63 (70.4 g, 94% yield) as an off-white foamy solid.

Rf: 0.5 (1% methanol/dichloromethane). 1 H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.36 (s, 1H), 7.03 (s, 1H), 6.87 (s, 1H), 6.69 (s, 1H), 4.63 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.82 (s, 3H), 3.61 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 157.5, 152.8, 150.2, 148.3, 148.2, 140.7, 133.5, 129.0, 123.9, 123.0, 119.0, 113.0, 112.2, 105.3, 104.2, 56.3, 56.2, 56.1, 56.0, 38.5, 29.8. + HRMS (ESI-TOF) m/z: calc’d for C20H20ClNO4 [M+H] 374.1154, found 374.1129. IR (film) cm–1: 2360, 1508, 1272, 1235, 1160, 858. Spectral data consistent with literature90

1-(2-bromo-4,5-dimethoxybenzyl)-6,7-dimethoxyisoquinoline (II-64). Prepared according to GP2 using 48.8% aqueous HBr (111 µL, 2 mmol). After 2.5 hours, the reaction mixture was purified by column chromatography eluting with 1.5% methanol/dichloromethane to yield II-64 (82.8 g, 99%) as a foamy brown solid.

Rf: 0.5 (100% dichloromethane). 1 H NMR (600 MHz, CDCl3): δ 8.37 (d, J = 5.6 Hz, 1H), 7.43 (d, J = 5.6 Hz, 1H), 7.33 (s, 1H), 7.04 (d, J = 1.1 Hz, 2H), 6.66 (s, 1H), 4.64 (s, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 3.83 (s, 3H), 3.59 (s, 3H). 13 C NMR (151 MHz, CDCl3): δ 157.6, 152.8, 150.3, 148.8, 148.5, 141.0, 133.5, 131.2, 123.2, 119.0, 115.3, 113.8, 113.2, 105.4, 104.5, 56.5, 56.3, 56.1, 56.0, 41.6. + HRMS (ESI-TOF) m/z: calc’d for C20H20BrNO4 [M+H] 418.0648, found 418.0627 IR (film) cm–1: 1508, 1235, 1159, 1030, 857, 731. Spectral data consistent with literature.115

6-Chloro-2”-acetyl phyllanthusmin D (II-65). Synthesis of II-65 began from a known natural product derivative 2”-acetyl phyllanthusmin D92 prepared according to literature

58 procedures.93,116To an 8 mL dram vial was added iodobenzene diacetate (96.6 mg, 0.3 mmol), 2”-acetyl phyllanthusmin D (65.6 mg, 0.1 mmol), dichloroethane (1 mL), and tetrabutylammonium chloride (139.0 mg, 0.5 mmol). The solution was allowed to stir at 1000 rpm at room temperature for 48 hours. After which the solution was washed with saturated sodium bicarbonate, followed by saturated sodium thiosulfate and concentrated. The crude mixture was purified by column chromatography eluting with 10% acetonitrile in toluene, followed by 20% acetone in hexanes to yield II-65 (30.1 mg, 45%) as a white solid.

Rf: 0.3 (10% acetonitrile/90% toluene). 1 H NMR (700 MHz, CDCl3): δ = 7.13 (d, J = 0.9 Hz, 1H), 6.96 (dd, J = 8.1, 1.9 Hz, 1H), 6.81 – 6.74 (m, 2H), 6.11 – 6.05 (m, 2H), 5.62 (dd, J = 9.9, 7.3 Hz, 1H), 5.53 (dd, J = 14.9, 4.2 Hz, 1H), 5.45 (dd, J = 14.9, 2.6 Hz, 1H), 5.30 (d, J = 0.9 Hz, 1H), 5.21 (dd, J = 7.3, 2.3 Hz, 1H), 5.16 (dd, J = 9.8, 3.4 Hz, 1H), 4.00 – 3.98 (m, 1H), 3.98 (s, 3H), 3.77 (d, J = 0.6 Hz, 3H), 3.54 (d, J = 13.4 Hz, 1H), 2.22 (s, 3H), 2.14 (d, J = 0.5 Hz, 3H), 2.07 (s, 3H). Doubling and splitting of specific peaks has been previously and independently reported in structurally similar compounds by the Charlton42 and Kinghorn41 groups. This effect is attributed to the hindered rotation about the C1’-C7’ bond. In the characterization data below major peaks are listed (with all signals observed in parentheses). 13 C NMR (176 MHz, CDCl3): δ =170.4, 170.3, 169.7 (169.64, 169.65), 169.3, 152.5, 149.3, 147.9, 147.8, 143.6 (143.56, 143.57), 137.1, 134.7 (134.61, 134.68), 134.1, 128.1, 124.1, 123.8, 123.6, 122.00, 121.95, 121.4, 110.8 (110.75, 110.76), 110.6 (110.56, 110.58), 108.5, 107.3 (107.24, 107.25, 107.26), 102.2 (102.14, 102.15), 101.5, 70.4, 69.7, 68.1 (68.12, 68.14), 67.8, 64.5, 60.9, 55.9 (55.93, 55.95), 31.7, 29.9, 21.1 (21.08, 21.09, 21.11, 21.13), 20.8 (20.81, 20.82). + HRMS (ESI-TOF) m/z: calc’d for C32H29ClNaO14 [M+Na] 695.11380 found 695.11267. IR (film) cm–1: 2921, 2850, 1749, 1488, 1457, 1417, 1224, 1068, 1037.

6’-Bromo-2”-acetyl phyllanthusmin D (II-66). Synthesis of II-66 began from a known natural product derivative 2”-acetyl phyllanthusmin D92 prepared according to literature procedures.93,116 To an 8 mL dram vial was added iodobenzene diacetate (24.2 mg, 0.075 mmol), 2”-acetyl phyllanthusmin D (34.5 mg, 0.05 mmol), dichloroethane (1 mL), and lithium bromide (23.5 mg, 0.27 mmol). The solution was allowed to stir at 1000 rpm at room temperature for 1 hour. After which the solution was washed with saturated sodium bicarbonate, followed by saturated sodium thiosulfate and concentrated. The crude mixture was purified by column chromatography eluting with 50% acetone in hexanes to yield II- 66 (35.6 mg, 99%) as an orange solid.

Rf: 0.5 (50% acetone/50% hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 6.83 (s, 1H), 6.71 (d, J = 9.8 Hz, 1H), 6.10 (dd, J = 10.4, 9.2 Hz, 2H), 5.70 (dd, J = 9.5, 6.9 Hz, 1H), 5.47 (qd, J = 14.6, 7.9 Hz, 3H), 5.39 (dd, J = 3.4, 1.7 Hz, 1H), 5.19 (dd, J = 9.5, 3.5 Hz, 1H), 5.13 (dd, J = 13.7, 6.9 Hz, 1H), 4.21 (dt, J = 13.0, 2.9 Hz, 1H), 3.82 (s, 3H), 4.09 (s, 3H), 3.75 (ddd, J = 13.1, 7.7, 1.7 Hz, 1H), 2.11 (s, 3H), 2.22 (d, J = 0.7 Hz, 3H), 2.09 (d, J = 1.5 Hz, 3H). Doubling and splitting of specific peaks has been previously and independently reported in structurally similar compounds by the Charlton116 and Kinghorn92 groups. This effect is attributed to the hindered rotation about the C1’-C7’ bond. In the characterization data below major peaks are listed (with all signals observed in parentheses). 13 C NMR (101 MHz, CDCl3): δ = 170.3 (170.33, 170.34), 170.2 (170.19, 170.23), 169.7, 169.6, 169.2 (169.17, 169.20), 152.3 (152.23, 152.27), 151.0 (150.95, 150.96), 148.8 60

(148.75, 148.76), 147.6 (147.58, 147.62), 144.8 (144.78, 144.80), 134.5 (134.47, 134.57), 134.5 (134.47, 134.57), 130.3 (130.24, 130.32), 128.9 (128.90, 128.91), 127.1, 126.3, 126.2 (126.23, 126.25), 120.2 (120.17, 120.18), 114.8 (114.78, 114.80), 113.0 (112.94, 113.01), 111.1 (111.05, 111.16), 105.6 (105.63, 105.69), 102.2, 101.0 (100.83, 100.99, 101.21, 101.40), 77.4, 70.2 (70.17, 70.21), 69.5 (69.49, 69.54), 67.3 (67.31, 67.33, 67.36, 67.37), 64.0 (63.98, 64.10), 56.4 (56.40, 56.42), 56.1, 34.8, 34.7, 31.7, 29.2, 27.1, 25.4, 22.8, 21.1 (21.08, 21.10, 21.13), 20.8 (20.82, 20.83, 20.84). + HRMS (ESI-TOF) m/z: calc’d for C32H29ClNaO14 [M+Na] 717.08134 found 717.08371. IR (film) cm–1: 2922, 1749, 1506, 1488, 1475, 1433, 1217, 1031, 669.

4-chloro-2-iodo-1-methoxybenzene (SII-67). Prepared according to GP2. 2-iodoanisole (52 µL, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 1.5 eq) and 1 M HCl (2 mL, 5 equiv) in dichloroethane (2 mL) for 5 hours. Crude product was purified by column chromatography eluting with hexanes to yield SII-67 (79.1 mg, 74%) as colorless oil.

Rf: 0.32 (100% hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 8.8, 2.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 138.8, 129.4, 126.5, 111.5, 56.8. Spectral data consistent with literature.117

N-(4-chloro-2-(trifluoromethyl)phenyl)pivalamide (SII-3). Prepared according to GP2. N-(2-(trifluoromethyl)phenyl)pivalamide (98.1 mg, 0.4 mmol) was reacted with

61 iodobenzene diacetate (193 mg, 0.6 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 18 hours. Another 1.5 equivalents of iodobenzene diacetate (193 mg, 0.6 mmol) was added and allowed to stir further for 46 hours. The crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield SII-3 (55.5 mg, 50%) as a white solid.

Rf: 0.28 (5% ethyl acetate/hexanes). mp: 92.4 – 93.0 °C. 1 H NMR (600 MHz, CDCl3): δ = 8.23 (d, J = 8.9 Hz, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 1.32 – 1.30 (m, 9H). 13 3 C NMR (151 MHz, CDCl3): δ = 176.8, 134.5, 132.9, 129.6, 126.2 (q, JCF = 5.7 Hz), 1 2 125.6, 123.5 (q, JCF = 273.5 Hz), 121.2 (q, JCF = 30.3 Hz), 40.0, 27.4. 19 F NMR (376 MHz, CDCl3): δ = -61.33. + HRMS (ESI-TOF) m/z: calc’d for C12H13ClF3NNaO [M+Na] 302.0535, found 302.0514. IR (film) cm–1: 2974, 2931, 2875, 1658, 1491, 1456, 1317, 1273, 1157, 1113, 1055, 933, 773.

methyl 2-(5-chloro-6-methoxynaphthalen-2-yl)propanoate (SII-4). Under an atmosphere of nitrogen, Si(Me)3OTf (42 µL, 0.23 mmol) was added dropwise to a solution of iodobenzene diacetate (74.1 mg, 0.23 mmol) in dichloromethane (1 mL). A solution of naproxen methyl ester (36.6 mg, 0.15 mmol) in dichloromethane (1 mL) was added to the solution of Si(Me)3OTf and iodobenzene diacetate dropwise over 5 minutes. The solution stirred at room temperature for 30 minutes. The crude product was purified by column chromatography eluting with 20% ethyl acetate/hexanes yield SII-4 (17% by 19F NMR using trifluorotoluene as an internal standard) as a yellow oil.

Rf: 0.21 (20% ethyl acetate/hexanes).

1 H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.56 (dd, J = 8.8, 1.8 Hz, 1H), 7.35 (d, J = 9.1 Hz, 1H), 4.03 (s, 3H), 3.88 (q, J = 7.2 Hz, 1H), 3.68 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ = 174.8, 148.5, 137.3, 132.5, 129.4, 129.3, 128.5, 126.8, 126.3, 120.5, 120.5, 114.2, 52.3, 45.4, 29.8, 18.6. 19 F NMR (377 MHz, CDCl3): δ = -73.06. + HRMS (ESI-TOF) m/z: calc’d for C16H15F3NaO6S [M+Na] 415.0439, found 415.0416. IR (film) cm–1: 1707, 1655, 1448, 1342, 1223, 1074, 912, 742.

8-bromo-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (SII-5). Prepared according to GP3. Caffeine (77.7 mg, 0.4 mmol) was reacted with iodobenzene diacetate (193 mg, 0.6 mmol) and lithium bromide (173.7 mg, 2.0 mmol) for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate and extracted using dichloromethane. The organic layer was further washed with saturated sodium thiosulfate, then concentrated. The reaction mixture was purified by column chromatography eluting with 1% methanol/dichloromethane to yield SII-5 (31.1 mg, 29%) as a white powder.

Rf: 0.2 (1% methanol/dichloromethane). mp: 205.1 – 207.0 ºC. 1 H NMR (400 MHz, CDCl3): δ = 3.95 (s, 1H), 3.54 (s, 1H), 3.39 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 154.6, 151.4, 148.2, 128.3, 109.5, 34.1, 30.0, 28.2. + HRMS (ESI-TOF) m/z: calc’d for C8H10BrN4O2 [M+H] m/z 272.9987, found 272.9984. IR (film) cm–1: 1707, 1664, 1454, 1457, 1353, 743. Spectral data consistent with literature.114

Chapter 3 Amination of Secondary C-H Bonds

Portions of this chapter are adapted from:

Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D. A. “Triiodide-Mediated δ-Amination of Secondary C-H Bonds.” Angew. Chem., Int. Ed. 2016, 55, 9974 – 9978

3.1 Background of the Hofmann-Löffler-Freytag Reaction

Before modern chemical instrumentation, solving structures of organic compounds was usually accomplished through degradation studies or combustion analysis. The structures of many heteroarenes that we take for granted today were simply a mystery in the 1800s. In the attempts to solve the structure of piperidine (unknown at the time), Hofmann treated the organic compound with acid and halogenation conditions to give III- 1. In the process, he made a reaction occur; however, the only thing that could be concluded about the newly formed product at the time was that a tertiary amine was produced. Many years later, it was revealed that the mysterious compound formed was δ-coneceine III-2 (Scheme 3.1a). It not until the synthesis of nicotine presented by Löffler and Freytag that it was concluded haloamines III-3 could efficiently cyclize to produce pyrrolidine heterocycles III-4 (Scheme 3.1b).5,118 Wawzonek and Thelan were the first to propose a mechanism for the HLF reaction.20 They observed efficient cyclization of N-chloro-N-methylcyclooctylamine III- 5 in the preparation of N-methylgranatanine III-6 (Scheme 3.1c). During their study, they observed that the reaction could proceed in the presence of heat, ultraviolet radiation with or without chlorine, and hydrogen peroxide protected from light. From this they proposed that it was going through a radical chain mechanism. Although the HLF reaction typically

64 forms pyrrolidines, in this instance a piperidine ring was formed which is attributed to steric preference.19 Later on, Corey and Hertler through extensive mechanistic studies, proved that Wasonek and Thelan’s mechanism was correct.19

Scheme 3.1 Early contributions to understanding the HLF reaction.

Under traditional HLF reaction conditions, δ-amination first proceeds with protonation of the haloamine to produce an aminium III-7. The N-X bond of the aminium is homolytically cleaved through radical initiation (with light, heat, or peroxides) to reveal a nitrogen-centered radical III-8. The aminium cation is not necessary for homolytic cleavage to occur; however, protonation significantly increases the rate of the reaction. The radical on the nitrogen is then transferred to the δ position of the amine via a 1,5-hydrogen atom transfer (1,5-HAT).119 This 1,5-HAT (versus a 1,4 or 1,6) is preferred due to the chair- like transition state it assumes. The alkyl radical is then trapped by a halide either from X· or another haloamine in a propagative fashion to form an alkyl halide III-9. A basic workup

65 facilitates the subsequent nucleophilic attack by the amine to cyclize to yield pyrrolidine III-10 (Figure 3.1).

Figure 3.1 Hofmann-Löffler-Freytag reaction mechanism.

3.2 Modifications to the HLF Reaction

Although this is a robust means for the synthesis of pyrrolidines, there are some drawbacks to this methodology, the most significant being that it requires the use of preformed haloamines and harsh reaction conditions (strong acid).4,5,19 In 1976, Kimura and Ban reported that strong acid is not needed for the HLF reaction. They found that if they irradiated N- chloroamines under a 300W lamp, they could observe cyclization without the need of sulfuric 120 acid. However, this did require H· abstraction from weak C-H bonds α to heteroatoms. In the 1980s, Suárez and coworkers discovered that the use of acid and pre-formed haloamines could be circumvented by using an amine with an electron withdrawing group.

This allowed for the in situ oxidation of amines (with Hg(OAc)2 or PhI(OAc)2 and I2) to 121 generate haloamines. This led to the advantage of being able to use more convenient amine precursors. Martínez and Muñiz reported a system which employed a tailored oxidant and catalytic iodine to improve functional group tolerability. This approach is tolerant of sensitive motifs, 122 such as alkenes and anisoles, but still requires the need for weak (tertiary) C-H bonds. To solve the problem of primary amines being utilized in the HLF reaction Herrera and coworkers

66 reported that through sequential addition of PhI(OAc)2 and I2, amines with primary δ-C-H bonds are able to efficiently cyclize due to limiting the amount of active oxidant present in the 123 reaction mixture at any one time.

3.3 Strategy

3.3.1 Limitations

19,123–125 Although improvements have been made to the original HLF reaction, the amination of unbiased secondary C-H bonds has remained an unmet challenge through this strategy. This 100-yr. old transformation has been limited to the use of weak C-H bonds (benzylic, tertiary, α-hetero) or substrates with entropic bias.

3.3.2 Acetyl Hypoiodite

126 Acetyl hypoiodite is produced through the reaction of an acetate oxidant with I2. This reagent was first synthesized by mixing mercury acetate with iodine in acetic acid. Early examples also used silver acetate. It was later shown that through spectroscopic analysis, acetyl hypoiodite is also formed from the reaction of iodobenzene diacetate and iodine. Through 1H NMR, a new acetyl peak was observed that did not correspond to iodobenzene diacetate or acetic acid. The same peak was also present with the reaction with silver acetate and iodine. Through GC/MS studies, acetyl hypoiodite is quite unstable, however, the fragmentation of this intermediate to methyl iodide was observed which is consistent with an acetyl hypoiodite intermediate.127 This fragmentation event has also been described by many in the synthesis of alkyl halides. Borodine observed in 1861, that the combination of I2 with the silver salt of a carboxylic acid led to decomposition of the carboxylic acid to give an alkyl halide.128 These conditions were modified and made more general and is known as the Hunsdiecker reaction.129 Simonini also observed through doubling the stoichiometry of the silver salt, this led to an ester product.130 Kochi reported a variation of this decarboxylation event 131 using Pb(OAc)4 and lithium chloride with a silver salt carboxylate. 67

This reagent has been used for a variety of transformations.132 Acetyl hypoiodite can readily react with alkenes to produce vicinal diols as seen with the Prevost reaction.133,134 Fragmentation of alcohols with this reagent can also render carbonyls through β-fragmentation. Iodination of aromatic scaffolds can also be achieved with acetyl hypoiodite.135 Most relevant to this research work, however is that acetyl hypoiodite is the active oxidant in the HLF reaction. Due to these other transformations it can mediate, such as over-oxidation and fragmentation, this has deterred the broad use of the HLF reaction on unactivated C-H bonds.

3.3.3 Triiodide

In the iodine clock reaction, it has been shown that iodide salts in solution with oxidants, such as persulfates, form iodine.136 Iodine in solution with iodide salts form polyhalides such as triiodide. In an equilibrium of all three, triiodide is preferred (Scheme 3.2).137 Our amination strategy for unbiased secondary C-H bonds was to slowly generate the active oxidant, acetyl hypoiodite III-11 in situ. We proposed that if we were able to - oxidize iodide to make iodine in situ and trap it as I3 , this would reduce the concentration of iodine in the reaction, which is needed to form III-11 (Scheme 3.2). A lower concentration of the oxidant then, therefore, decreases the amount of undesired side products and unproductive reactive intermediates that prevent highly functionalized amines from being used in the HLF reaction.

Scheme 3.2 Strategy to limit active oxidant through triiodide formation.

3.4 Results

3.4.1 Formation of Pyrrolidines

Taking N-tosyl heptylamine III-12, with NaI and PhI(OAc)2 and irradiating under a CFL light, we observed that we were able to form the corresponding pyrrolidine III-13. In the presence of only iodine, we observed 33% of the target pyrrolidine (Table 3.1). Yields could be increased with I2 conditions with the addition of sodium iodide. The excess iodide in solution helped to push the equilibrium toward the triiodide species, in turn raising the yield of the target pyrrolidine due to less side reactivity. We found that with increasing equivalents of NaI to 4, we were able to reach optimal isolated yields of 74%.

Table 3.1 Optimization of triiodide-mediated amination.

Other salts could also afford cyclization; however, the best results were obtained with sodium iodide. Exploring counterion effects, other iodide salts such as potassium, lithium, and cesium iodide gave 35%, 47%, and 8% yield of product respectively. Presumably, once sodium iodide creates a triiodide species sodium acetate can be formed. The base formed can help with the final cyclization. Noting this, other bases were investigated, such as potassium phosphates; however, the addition of exogenous bases proved not to be advantageous. Initially, it was conceived that we would only need to employ light conditions to initiate the radical reaction. However, in the attempts of cyclizing amide III-14 under light initiation to ester pyrrolidine III-15, this led to yields which peaked only slightly above 40%. We then investigated heat to propagate the reaction. Heating III-14, oxidant, and sodium iodide at 50 ºC, we found a significant increase in yield of III-15 (75%), albeit at the expense of a decrease in diastereoselectivity as shown in Figure 3.2. The major diastereomer in all cases was the cis isomer, with trans being the minor isomer. We postulate that the thermodynamically more stable isomer is the trans isomer, which is formed in low yields, under the light conditions. However, there is an increase in production of the trans isomer upon heating.

Figure 3.2 Comparison of light and heat conditions for ester derived pyrrolidine.

With these two procedures in hand, we investigated the efficiency of this triiodide- mediated approach (Figure 3.3). This protocol was highly efficient for many amines bearing differing functionalities as shown in Figure 3.3. Our protocol was successful for simple aliphatic amines (III-13, III-16, III-18), as well as amines with activated C-H bonds (III-17). Ethers (III-19) as well as arenes with varying electronics (III-20-III-22) were well tolerated. Pyrrolidines bearing substituents at differing positions of the heterocycle (III-23-III-25) were also formed successfully. Esters (III-26), fluorine substituents (III-27) and incorporation of other heteroatoms in the ring (III-28) were tolerated. Weak α-carbonyl C-H bonds did not hinder reactivity (III-15, III-29) Although we knew electron withdrawing amine protecting groups are necessary to facilitate this reaction, we were pleased to observe that a variety of sulfonamide protecting groups (III-30-III-35) were well tolerated (e.g. Ns, Ms, SES). A SES protecting group, introduced by Weinreb is convenient, as it allows for facile deprotection through desilyation.138 The diastereoselectivity was mild in pyrrolidine formation, with the cis isomer preferred. The assignment of the major diastereomer was confirmed by x-ray analysis of the phenyl ketone pyrrolidine III-29. An exception to this was 2,4 dimethyl pyrrolidine (III-

18). Although the dr was close to 1:1, the trans isomer was slightly preferred under heating conditions, while under light conditions, the cis isomer was slightly preferred.

Figure 3.3 Functionalized pyrrolidines derived from triiodide-mediated cyclization.

As seen with this menthol derivative example (Scheme 3.3), amination of III-36 at the secondary position to give III-37 is still preferred over a weaker tertiary C-H bonds. However, 72 sterics can also play a role in product formation. As seen with the second menthol derivatization example, transannular H atom abstraction of the secondary C-H bond of III-38 is not preferred, and rather only exocyclic cyclization is observed to render the fused bicycle III-39.

Scheme 3.3 Intramolecular amination competition experiment.

3.4.2 Mechanistic Studies

To confirm that we were in fact generating a triiodide species in solution, we subjected varying concentrations of NaI to PhI(OAc)2 and monitored the reaction via UV- Vis spectroscopy. We found that with even one equivalent of sodium iodide and oxidant, we were able to see the appearance of a triiodide species under UV-Vis spectroscopy at an absorbance of λ = 360 nm136 (Figure 3.4). This helped to confirm that a triiodide species is being generated and attenuating the reactivity of iodine in solution by its sequestration.

- Figure 3.4 UV-Vis spectroscopy observation of I3 .

To illustrate the efficiency of our methodology, examining the crude proton NMRs of reactions carried out under our conditions, we observed high product yield and minimal byproduct formation as compared to Suárez conditions which led to several unidentifiable byproducts (Figure 3.5).

Figure 3.5 Monitoring of reaction efficiency by 1H NMR spectra: pure pyrrolidine product (a. green) and - crude reaction mixtures mediated by I3 (b. blue) or I2 (c. red).

The mechanism was also further confirmed by the isolation and characterization of proposed reaction intermediates by using different halide salts (Scheme 3.4). It was found that when tosylated pentylamine III-40 was heated with sodium chloride and PhI(OAc)2, the N-Cl intermediate III-41 could be isolated. Even though under photocatalytic conditions, there have

74 been examples of homolysis of an N-Cl bond to provide HLF reactivity,139 the mildness of our reaction did not allow for such reactivity. When the same substrate was subjected to NaBr and oxidant the alkyl bromide III-42 was isolated as the major product. There was some observed cyclized product along with a vicinal dibrominated alkyl amine as minor products. With an alkyl bromide, the C-Br bond is stronger than the C-I bond of the corresponding alkyl iodide, limiting the following ring closure. Efficient cyclization to III-43 is only observed using NaI. Decreased yields were also observed with addition of radical traps such as TEMPO and

Galvinoxyl or under an atmosphere of oxygen.

Scheme 3.4 Observation of HLF intermediates.

3.5 Conclusion

In summary, we have successfully demonstrated selective δ-amination of unbiased secondary C-H bonds through a triiodide mediated strategy. Our triiodide mediated approach efficiently curtailed the production of side products to allow for the formation of highly functionalized pyrrolidines. This method is a mild alternative to the generation of N- centered radicals for selective C-H amination protocols.

3.6 Experimental

3.6.1 General Information

All chemicals and reagents were purchased from Sigma-Aldrich, Alfa Aesar, Acros, TCI, or ChemImplex. Sodium iodide was dried under high vacuum before use. Acetonitrile and triethylamine were distilled over calcium hydride before use. Silicycle F60 (230-400 mesh) silica gel was used or a CombiFlash® Automated Flash Chromatograph for flash column chromatography. Thin layer chromatography (TLC) analyses were performed using Merck silica gel 60 F254 plates and visualized under UV, KMNO4, or iodine stain. Melting points were determined using a Thermo Scientific Mel-Temp. 1H, 19F, 13C NMR spectra were recorded using a Bruker AVIII 400 or AVIII 600 MHz NMR spectrometer. 1H NMR and 13C NMR chemical shifts are reported in parts per million and 1 13 referenced with respect to CDCl3 ( H: residual CHCl3 at δ 7.26, C: CDCl3 triplet at δ 77.16). 1H NMR data are reported as chemical shifts (δ ppm), multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, app t = apparent triplet, app q = apparent quartet), coupling constant (Hz), relative integral. 19F NMR data are reported as chemical shifts (δ ppm). High resolution mass spectra were obtained using Bruker MicrOTOF (ESI). IR spectra were recorded using a Thermo Fisher Nicolet iS10 FT-IR and are reported in terms of frequency of absorption (cm–1). GC analyses were performed with an Agilent 3890N gas chromatograph. UV-Vis absorbance spectra were recorded on a Cary 5000 UV-Vis/NIR spectrophotometer using an internal DRA. General Protection Procedure (GP1): Substrate (1 equiv.) was dissolved in methylene chloride and cooled to 0 °C. Triethylamine (1 – 3 equiv.) and dimethylaminopyridine (0.1 equiv.) were added. Finally, the sulfonyl or acyl chloride (1 – 2 equiv.) was added portionwise. The solution was slowly warmed to room temperature and stirred for an additional12 hours. Once complete, the reaction was quenched with 1 M hydrochloric acid. The aqueous layer was washed with methylene chloride, dried over magnesium sulfate, 76 concentrated in vacuo, and purified via flash column chromatography on silica gel with the indicated eluent. Any changes to this procedure will be specified for each substrate. General Tosylation of Amino Acids (GP2): The amino acid (1 equiv.) was dissolved in 1.5 M potassium hydroxide. ρ-toluenesulfonyl chloride (1.2 equiv.) was dissolved in diethyl ether and this solution was added to the solution containing the amino acid. The reaction was stirred 12 hours and was then acidified with 1 M hydrochloric acid to a pH of 2. This solution was washed with excess diethyl ether and the organic layer was dried over magnesium sulfate and then concentrated in vacuo. Any changes to this procedure will be specified for each substrate. General Procedure for the Synthesis of Aldimines (GP3): Aldimines were prepared according to literature.1 Aldehyde (28.0 mmol), p-toluenesulfonamide (4.80 g, 28.0 mmol), and sodium ptoluenesulfinate (5.00 g, 28.0 mmol) was stirred at room temperature in formic acid (45 mL) and water (45 mL) for 16 hrs. Precipitate was filtered and washed with water then pentanes. The precipitate was dissolved in dichloromethane (100 mL) and stirred with a solution of aqueous saturated sodium bicarbonate (100 mL) for 2 hours. The organic layer was extracted and dried over sodium bicarbonate. Solvent was removed under reduced pressure to yield aldimines. General Procedure for the Reduction of Nitriles (GP4): To an oven dried 100 mL round bottom flask equipped with a magnetic stir bar, was added dry THF (or diethyl ether) and LAH (2 – 2.5 equiv.) which was cooled to 0 °C. The nitrile (1 equiv.) in 10 mL of dry THF was added dropwise via an addition funnel over a 10 – 15 minute period. After the complete addition, the solution was warmed to room temperature and stirred 12 hours. The reaction was then cooled to 0 °C and the reaction was quenched using the Fieser workup (X mL

H2O, then X mL 15% NaOH, then 3X mL H2O where X equals the gram quantity of LAH used). The resulting mixture was warmed to room temperature and stirred for thirty minutes, then the solid was removed via vacuum filtration and the solution was concentrated in vacuo. General Procedure for Triiodide Reaction Conditions (light) (GP5): To an oven-dried 8-dram vial with a PTFE septa cap, was added a magnetic stir bar, substrate (0.2 mmol),

77 iodobenzene diacetate (0.8 mmol), and dry sodium iodide (0.8 mmol).* This vial was sealed and sequentially evacuated and backfilled with nitrogen three times. Separately, acetonitrile was degassed using a freeze-pump-thaw technique three times. Acetonitrile (2 mL) was added to the vial and the vial was irradiated using two 23 W compact fluorescent light bulbs. The reaction was run for 2 – 48 hours and monitored using a combination of thin-layer chromatography and gas chromatography. Upon completion, the reaction was diluted with diethyl ether, and washed with aqueous sodium thiosulfate (20% w/w). The aqueous layer was then extracted with diethyl ether and the combined organic fractions were dried magnesium sulfate then concentrated in vacuo to yield the crude material. This material was purified using flash column chromatography on silica gel with the indicated eluent. General Procedure for Triiodide Reaction Conditions (heat) (GP6): To an oven-dried 8-dram vial with a PTFE septa cap, was added a magnetic stir bar, substrate (0.2 mmol), iodobenzene diacetate (0.8 mmol), and dry sodium iodide (0.8 mmol). This vial was sealed and sequentially evacuated and backfilled with nitrogen three times. Separately, acetonitrile was degassed using a freeze-pump-thaw technique three times. Acetonitrile (2 mL) was added to the vial and the vial was heated at 50 °C in an aluminum block (8.9 x 6.4 x 4.4 cm). The reaction was run for 2 – 48 hours and monitored using a combination of thin-layer chromatography and gas chromatography. Upon completion, the reaction was cooled to room temperature, diluted with diethyl ether, and washed with aqueous sodium thiosulfate (20% w/w). The aqueous layer was then extracted with diethyl ether and the combined organic fractions were dried magnesium sulfate then concentrated in vacuo to yield the crude material. This material was purified using flash column chromatography on silica gel with the indicated eluent.

3.6.2 Substrate Synthesis

N-(1-(4-fluorophenyl)pentyl)-4-methylbenzenesulfonamide (SIII-1). Following GP3, 4-fluorobenzaldehyde (2.2 mL, 20.0 mmol) was reacted with p-toluenesulfonamide (3.42 g, 20.0 mmol), and sodium p-toluenesulfinate (3.56 g, 20.0 mmol) to yield an aldimine (1.20 g, 31%) as a white solid. n-Butyl lithium (1.6 M in hexanes, 1.5 mL, 1.8 mmol) was added to a stirred solution of the aldimine (500 mg, 1.80 mmol) in toluene (10 mL) at –78 °C for 4 hours. The solution was warmed to room temperature and stirred further at room temperature for 14 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and solvent was evaporated under reduced pressure. The resulting solid was purified via flash column chromatography (silica gel, 20% ethyl acetate/hexanes) to yield amide SIII-1 (319 mg, 53%) as a white solid.

Rf = 0.37 (20% ethyl acetate/hexanes). MP = 55.1 – 56.1 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.02 – 6.94 (m, 2H), 6.83 (app t, J = 8.7 Hz, 2H), 4.71 (d, J = 6.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 1H), 2.37 (s, 3H), 1.81 – 1.57 (m, 2H), 1.30 – 1.15 (m, 3H), 1.11 – 1.00 (m, 1H), 0.80 (t, J = 7.1 Hz, 3H). 13 4 C NMR (100 MHz, CDCl3): δ = 163.3, 160.8, 143.2, 137.9, 137.1 ( JCF = 3.2 Hz), 128.3 3 1 2 ( JCF = 8.1 Hz), 128.3 ( JCF = 223.5 Hz), 115.3 ( JCF = 21.4 Hz), 57.8, 37.5, 28.1, 22.3, 21.5, 13.9. 19 F NMR (376 MHz, CDCl3): δ = –115.1. + HRMS (ESI-TOF) m/z: calc’d for C18H22FNO2SNa [M+Na] 358.1253, found 358.1254. IR (film) cm–1: 3240, 2956, 2920, 2866, 1604, 1508, 1433, 1315, 1229, 1154, 1091, 1042, 907, 832, 807, 667.

N-(3,7-dimethyloctyl)-4-methylbenzenesulfonamide (SIII-2). PPh3 (0.91 g, 3.5 mmol) was dissolved in dry THF along with 3,7-dimethyloctan-1-ol140 (0.5 g, 3.2 mmol) and tert- butyl tosylcarbamate (1.01 g, 3.5 mmol). This was stirred for ten minutes then cooled to 0 °C. DIAD (0.7 g, 0.68 mL, 3.5 mmol) was added and the solution was allowed to warm to rt. The reaction was monitored by TLC until completion ca. 8 hours. Upon completion, the solution was concentrated and purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield Boc-protected amide which was carried forward to the deprotection. Boc-protected amide was dissolved in CH2Cl2 and TFA (1.8 g, 1.21 mL, 15.7 mmol) was added. The solution was stirred for three hours until starting material was consumed (monitored by TLC). Excess acid was quenched with saturated sodium bicarbonate. The organic phase was collected and the aqueous solution was washed with

CH2Cl2. The combined organic fractions were dried over magnesium sulfate and concentrated. The resultant crude material was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield amide SIII-2 (0.92 g, 94%) as a colorless oil.

Rf = 0.46 (20% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 3.02 – 2.89 (m, 2H), 2.42 (s, 3H), 1.53 – 1.37 (m, 3H), 1.29 – 1.00 (m, 7H), 0.84 (d, J = 6.5 Hz, 6H), 0.80 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.5, 137.2, 129.8, 127.3, 41.5, 39.3, 37.1, 36.8, 30.4, 28.1, 24.7, 22.8, 22.7, 21.6, 19.4. + HRMS (ESI-TOF) m/z: calc’d for C17H29NSO2Na [M+Na] 334.1817, found 334.1807. IR (film) cm–1: 3293, 2929, 2924, 2867, 1599, 1461, 1423, 1382, 1322, 1157, 1093, 813, 661.

N-(2-((tert-butyldimethylsilyl)oxy)hexyl)-4-methylbenzenesulfonamide (SIII-3). N- (2-hydroxyhexyl)-4-methylbenzenesulfonamide (0.5 g, 1.8 mmol) was dissolved in 25 mL of dimethylformamide to which imidazole (0.18 g, 2.6 mmol), dimethylaminopyridine (23 mg, 0.19 mmol), and tert-butyldimethylsilyl chloride (0.28 g, 1.8 mmol) were added sequentially. The reaction was allowed to stir 12 hours. Upon completion, the mixture was partitioned between equal volumes of water and diethyl ether (100 mL each) and then the aqueous layer was washed again with diethyl ether (2 x 50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated to yield a crude oil which was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield amide SIII-3 (0.53 g, 75%) as a low-melting white solid.

Rf = 0.59 (20% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.55 (t, J = 5.9 Hz, 1H), 3.74 – 3.68 (m, 1H), 2.98 – 2.93 (m, 1H), 2.90 – 2.84 (m, 1H), 2.43 (s, 3H), 1.45 – 1.39 (m, 2H), 1.29 – 1.11 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H), 0.83 (s, 9H), 0.01 (s, 3H), –0.03 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.5, 136.9, 129.8, 127.3, 71.0, 48.1, 34.7, 27.5, 25.9, 22.8, 21.6, 18.1, 14.1, –4.4, –4.6. + HRMS (ESI-TOF) m/z: calc’d for C19H35NSO3SiNa [M+Na] 408.2005, found 408.1996. IR (film) cm–1: 3295, 2954, 2929, 2856, 1598, 1462, 1330, 1256, 1161, 1093, 1053, 836, 776, 668, 580.

4-methyl-N-(2-methylpentyl)benzenesulfonamide (SIII-4). Diisopropyl azodicarboxylate (1.0 mL, 5.5 mmol) was added to a solution of 2-methylpentan-1-ol (500 µL, 4.04 mmol), triphenylphosphine (1.44 g, 5.5 mmol), and tert-butyl tosylcarbamate (1.6 g, 5.5 mmol) in THF (10 mL) at 0 °C. The solution was warmed to room temperature and stirred for 24 hours. The solution was concentrated and purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to provide tosyl-boc protected 81

amine. The amine was dissolved in dicholoromethane (10 mL), and trifluoroacetic acid added (2 mL) and stirred at room temperature for 2 hours. The solution was concentrated to yield amide S11 (906 mg, 87%) without further purification as a yellow oil.

Rf = 0.31 (15% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 4.42 (t, J = 6.3 Hz, 1H), 2.88 – 2.80 (m, 1H), 2.77 – 2.68 (m, 1H), 2.43 (s, 3H), 1.62 – 1.50 (m, 1H), 1.36 – 1.15 (m, 3H), 1.11 – 0.99 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H), 0.83 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.4, 137.3, 129.8, 127.2, 49.2, 36.3, 33.1, 21.7, 19.9, 17.6, 14.3. + HRMS (ESI-TOF) m/z: calc’d for C13H21NO2SNa [M+Na] 278.1191, found 278.1181. IR (film) cm-1: 3293, 2955, 2924, 2870, 1598, 1454, 1425, 1323, 1157, 1093, 812, 660.

4-methyl-N-(1,1,1-trifluorohexan-2-yl)benzenesulfonamide (SIII-5). Trifluoroacetic acid (250 µL, 1.9 mmol) was added to a stirred solution of 4-methyl-N-

pentylidenebenzenesulfonamide (359 mg, 1.5 mmol) and KHF2 (88.3 mg, 1.1 mmol) in acetonitrile (2 mL) and DMF (350 µL, 4.5 mmol) at 0 °C and stirred for 5 minutes at 0 °C.

TMSCF3 was added at 0 °C and the solution warmed to room temperature and stirred further for 4 hours. The reaction was quenched with saturated sodium carbonate, diluted with water, and extracted with a 1:1 diethyl ether/hexanes mixture. Organic extracts were combined and dried over sodium sulfate and concentrated. The product was purified via flash column chromatography (silica gel, 20% ethyl acetate/hexanes) to yield amide S1II- 5 (119 mg, 26%) as a white solid.

Rf = 0.41 (20% ethyl acetate/hexanes). MP = 79.9 – 82.5 °C.

1 H NMR (400 MHz, CDCl3): δ = 7.75 – 7.68 (m, 2H), 7.31 – 7.21 (m, 2H), 4.74 (d, J = 9.5 Hz, 1H), 3.93 – 3.74 (m, 1H), 2.40 (s, 3H), 1.80 – 1.65 (m, 1H), 1.49 – 1.16 (m, 5H), 0.82 (t, J = 6.1 Hz, 3H). 13 1 C NMR (100 MHz, CDCl3): δ = 143.9, 138.0, 129.8, 127.1, 55.4 (q, JCF = 30.6 Hz), 29.9, 29.0, 27.0, 22.2, 21.7, 13.8. 19 F NMR (376 MHz, CDCl3): δ = –75.7 (d, J = 6.8 Hz). + HRMS (ESI-TOF) m/z: calc’d for C13H18F3NO2SNa [M+Na] 332.0908, found 332.0889. IR (film) cm–1: 3266, 2957, 2929, 2873, 1598, 1463, 1435, 1329, 1270, 1163, 1136, 1093, 1060, 943, 884, 811, 663.

Synthesis of N-(2-ethoxyethyl)-4-methylbenzenesulfonamide (SIII-6). 1-tosylaziridine (50 mg, 0.25 mmol) was dissolved in 4 mL of ethanol along with ρ-toluenesulfonic acid monohydrate (40 mg, 0.25 mmol). The reaction was stirred for two hours, washed with water, and concentrated in vacuo. The crude material was purified via flash column chromatography (silica gel, 30% ethyl acetate/hexanes), yielding amide SIII-6 (39 mg, 63% yield) as a whitish yellow oil.

Rf = 0.20 (15% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.78 (d, J = 6.0 Hz, 1H), 3.45 – 3.38 (m, 4H), 3.11 (q, J = 5.2 Hz, 2H), 2.43 (s, 3H), 1.14 (t, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.2, 136.8, 129.5, 126.9, 68.2, 66.3, 42.9, 21.3, 14.8. + HRMS (ESI-TOF) m/z: calc’d for C11H17NO2SNa [M+Na] : 266.0827, found 266.0803. IR (film) cm–1: 3293, 2971, 2922, 2868, 1598, 1324, 1157, 1089, 958, 813, 659.

4-nitro-N-(4-phenylbutyl)benzenesulfonamide (SIII-7). Following GP1, 4- phenylbutylamine (0.5 mL, 3.2 mmol) was protected using p-nitrobenzenesulfonyl chloride (0.77 g, 3.5 mmol), triethylamine (0.87 mL, 6.3 mmol), and 4- dimethylaminopyridine (38.5 mg, 0.3 mmol). After workup, the crude material was purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to yield amide SIII-7 (0.36 g, 75%) as an off-white solid. The material was further purified by recrystallization from methylene chloride and hexanes to remove trace impurities.

Rf = 0.24 (20% ethyl acetate/hexanes). MP = 69.5 – 71.5 °C. 1 H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.28 – 7.24 (m, 2H), 7.20 – 7.16 (m, 1H), 7.11 – 7.09 (m, 2H), 4.43 (t, J = 6.1 Hz, 1H), 3.04 (q, J = 6.7 Hz, 2H), 2.58 (t, J = 7.4 Hz, 2H), 1.64 – 1.57 (m, 2H), 1.54 – 1.46 (m, 2H). 13 C NMR (150 MHz, CDCl3): δ = 150.2, 146.2, 141.6, 128.6, 128.5, 128.4, 126.2, 124.5, 43.5, 35.3, 29.3, 28.2. + HRMS (ESI-TOF) m/z: calc’d for C16H18N2SO4Na [M+Na] 357.0885, found 357.0858. IR (film) cm–1: 3271, 3098, 3027, 2936, 2858, 1606, 1530, 1416, 1347, 1308, 1158, 1088, 962, 849, 734.

N-heptyl-4-nitrobenzenesulfonamide (SIII-8). Following GP1, heptylamine (2.0 g, 2.6 mL, 17.5 mmol) was protected using triethylamine (3.5 g, 4.8 mL, 29 mmol), dimethylaminopyridine (0.2 g, 1.7 mmol), and p-nitrobenzenesulfonyl chloride (4.2 g, 19 mmol) to yield crude material that was purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) then recrystallized from methylene chloride/hexanes to yield amide SIII-8 (1.3 g, 25%) as a white solid.

Rf = 0.33 (20% ethyl acetate/hexanes). MP = 80.1 – 81.1 °C.

1 H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H), 4.44 (s, 1H), 3.02 (q, J = 6.8 Hz, 2H), 1.48 (t, J = 7.2, 2H), 1.30 – 1.18 (m, 8H), 0.86 (t, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 150.2, 146.3, 128.4, 124.5, 43.6, 31.7, 29.9, 28.8, 26.6, 22.6, 14.1. + HRMS (ESI-TOF) m/z: calc’d for C13H20N2SO4Na [M+Na] : 323.1041, found: 323.1066. IR (film) cm–1: 3260, 2955, 2919, 2852, 1435, 1301, 1139, 764.

N-(4-phenylbutyl)methanesulfonamide (SIII-9). Following GP1, 4-phenylbutylamine (0.5 mL, 3.2 mmol) was protected using methanesulfonyl chloride (0.24 g, 3.2 mmol), triethylamine (0.87 mL, 6.3 mmol), and 4-dimethylaminopyridine (38.5 mg, 0.3 mmol). After workup, the crude material was purified using an Isco CombiFlash (silica gel, 0 to 50 % ethyl acetate/hexanes over 15 minutes) to yield amide SIII-9 in quantitative yield as a clear oil.

Rf = 0.54 (20% ethyl acetate/hexanes). 1H NMR (400 MHz, CDCl3): δ = 7.30 – 7.27 (m, 2H), 7.21 – 7.16 (m, 3H), 4.20 (s, 1H), 3.13 (q, J= 6.7 Hz, 2H), 2.92 (s, 3H), 2.65 (t, J = 7.4 Hz, 2H), 1.74 – 1.66 (m, 2H), 1.64 – 1.55 (m, 2H). 13C NMR (150 MHz, CDCl3): δ = 141.9, 128.5 (2C), 126.0, 43.2, 40.3, 35.4, 29.7, 28.4. HRMS (ESI-TOF) m/z: calc’d for C11H17NSO2Na [M+Na]+ 250.0878, found 250.0872. IR (film) cm–1: 3293, 3023, 2931, 2858, 1603, 1495, 1453, 1409, 1309, 1143, 1080, 974, 747, 699.

N-(4-phenylbutyl)-2-(trimethylsilyl)ethane-1-sulfonamide (SIII-10). 4-phenyl butylamine (237 µL, 1.5 mmol) was dissolved in pyridine (10 mL) and cooled to 0 °C. 2(trimethylsilyl)ethanesulfonyl chloride was added dropwise and the solution was allowed to stir at room temperature for 20 hours. The solution was diluted with dichloromethane and washed repeatedly with 1M HCl. The organic extracts were combined and concentrated. The residue was purified via flash column chromatography (silica gel, 20% ethyl acetate/hexanes) to yield amide SIII-10 (262 mg, 56%) as an off-white solid.

Rf = 0.31 (20% ethyl acetate/hexanes). MP = 47.0 – 49.2 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.28 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.17 d, J = 7.5 Hz, 2H), 4.08 (t, J = 6.0 Hz, 1H), 3.12 (q, J = 6.8 Hz, 2H), 2.94 – 2.89 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H), 1.69 (p, J = 7.6 Hz, 2H), 1.59 (p, J = 7.4 Hz, 2H), 1.03 – 0.97 (m, 2H), 0.05 (s, 9H). 13 C NMR (150 MHz, CDCl3): δ = 141.9, 128.6, 128.5, 126.1, 49.0, 43.4, 35.5, 30.2, 28.4, 10.8, – 1.9. + HRMS (ESI-TOF) m/z: calc’d for C15H27NO2SSiNa [M+Na] 336.1429, found 336.1457. IR (film) cm–1: 3293, 3260, 2946, 2860, 1603, 1428, 1310, 1249, 1170, 1131, 1071, 860, 830, 742, 697.

N-heptyl-2-(trimethylsilyl)ethane-1-sulfonamide (SIII-11). Heptylamine (0.2 g, 0.3 mL, 2.1 mmol) was dissolved in 25 mL of pyridine and cooled to 0 °C. 2(Trimethylsilyl)ethanesulfonyl chloride (0.5 g, 0.5 mL, 2.6 mmol) was added slowly and the mixture was warmed to room temperature and stirred 12 hours. Once complete, the reaction was quenched with 1 M hydrochloric acid (2 x 50 mL). The aqueous layer was washed with methylene chloride (3 x 50 mL), dried over magnesium sulfate, concentrated in vacuo, and purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to yield amide SIII-11 (0.43 g, 71%) as a white solid. 86

Rf = 0.42 (20% ethyl acetate/hexanes). MP = 47 – 48 °C. 1 H NMR (400 MHz, CDCl3): δ = 4.04 (t, J = 6.0 Hz, 1H), 3.10 (d, J = 6.8 Hz, 2H), 2.93 (m, 2H), 1.55 (m, 2H), 1.36 – 1.25 (m, 8H), 1.04 – 0.99 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H), 0.06 (s, 9H). 13 C NMR (150 MHz, CDCl3): δ = 48.9, 43.6, 31.8, 30.6, 29.0, 26.7, 22.7, 14.2, 10.9, – 1.8. + HRMS (ESI-TOF) m/z: calc’d for C12H29NSO2SiNa [M+Na] 302.1586, found 302.1586. IR (film) cm–1: 3279, 2955, 2922, 2857, 1428, 1313, 1249, 1130, 864, 830.

N-((2-isopropyl-5-methylcyclohexyl)methyl)-4-methylbenzenesulfonamide (SIII-12). (2-isopropyl-5-methylcyclohexyl)methanamine (1.02 g, 6 mmol) was dissolved in pyridine. Dimethylaminopyridine (74 mg, 0.61 mmol) was added followed by p- toluenesulfonyl chloride (1.73 g, 9.1 mmol) and the reaction was allowed to stir 12 hours. Upon completion, the crude material was partitioned between 1M HCl and methylene chloride. The aqueous layer was washed with two more portions of methylene chloride and the combined organic solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield amide SIII-12 (1.38 g, 71%) as a white solid.

Rf = 0.43 (20% ethyl acetate/hexanes). MP = 105.3 – 106.2 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 4.19 (t, J = 6.1 Hz, 1H), 2.97 – 2.91 (m, 2H), 2.43 (s, 3H), 1.94 – 1.88 (m, 1H), 1.74 – 1.68 (m, 1H), 1.68 – 1.63 (m, 2H), 1.30 – 1.21 (m, 2H), 0.84 (d, J = 6.5 Hz, 3H), 0.98 – 0.81 (m, 4H), 0.78 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H).

13 C NMR (100 MHz, CDCl3): δ = 143.5, 137.2, 129.8, 127.3, 47.0, 40.2, 36.7, 35.7, 35.6, 29.5, 26.1, 25.5, 22.7, 21.8, 21.7, 20.7. + HRMS (ESI-TOF) m/z: calc’d for C18H29NSO2Na [M+Na] 346.1817, found 346.1810. IR (film) cm–1: 3279, 2924, 2915, 2872, 2840, 1599, 1447, 1409, 1323, 1302, 1149, 1093, 1064, 978, 865, 817, 812, 706, 660.

N-tosyl-neomenthylamine (SIII-13). Menthylamine (0.43 g, 2.8 mmol) was dissolved in 25 mL of pyridine. Dimethylaminopyridine (34 mg, 0.28 mmol) was added followed by p- toluenesulfonyl chloride (0.79 g, 4.1 mmol) and the reaction was allowed to stir 12 hours. Upon completion, the crude material was partitioned between 1M HCl and methylene chloride. The aqueous layer was washed with two more portions of methylene chloride and the combined organic solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield amide SIII-13 (0.22 g, 26%) as a white solid.

Rf = 0.46 (20% ethyl acetate/hexanes). MP = 189.3 – 190.4 °C. 1 H NMR (600 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.42 (d, J = 8.4 Hz, 1H), 3.69 – 3.67 (m, 1H), 2.42 (s, 3H), 1.76 – 1.72 (m, 1H), 1.70 – 1.66 (m, 1H), 1.59 (dq, J = 13.6, 3.0 Hz, 1H), 1.45 – 1.35 (m, 2H), 0.99 – 0.89 (m, 2H), 0.82 (d, J = 6.7 Hz, 3H), 0.86 – 0.78 (m, 2H), 0.70 (t, J = 6.9 Hz, 6H). 13 C NMR (100 MHz, CDCl3): δ = 143.2, 138.8, 129.7, 127.2, 51.2, 47.7, 39.8, 34.7, 28.8, 26.1, 24.8, 22.1, 21.6, 20.9, 20.6. + HRMS (ESI-TOF) m/z: calc’d for C17H27NSO2Na [M+Na] 322.1660, found 322.1655.

IR (film) cm–1: 3293, 2954, 2915, 2870, 1595, 1451, 1428, 1329, 1311, 1150, 1091, 1036, 978, 919, 812, 705, 674.

N-(2-isopropoxyethyl)-4-methylbenzenesulfonamide (SIII-14). 1-tosylaziridine (0.2 g, 1.02 mmol) was dissolved in isopropanol at room temperature with p-toluenesulfonic acid monohydrate (0.062 g, 0.51 mmol). The reaction was stirred for two hours, washed with water, and concentrated in vacuo. The crude material was purified via flash column chromatography (silica gel, 30% ethyl acetate/hexanes), yielding amide SIII-14 (0.17 g, 87% yield) as a clear yellow oil.

Rf = 0.22 (20% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.80 (t, J = 6.0 Hz, 1H), 3.51 – 3.45 (m, 1H), 3.42 (t, J = 4.9 Hz, 2H), 3.09 (t, J = 5.2 Hz, 2H), 2.43 (s, 3H), 1.09 (d, J = 6.3 Hz, 6H). 13 C NMR (100 MHz, CDCl3): δ = 143.6, 137.2, 129.8, 127.3, 72.1, 66.1, 43.4, 21.7, 20.1. + HRMS (ESI-TOF) m/z: calc’d for C12H19NO3SNa [M+Na] : 280.0983, found 280.0978. IR (film) cm–1: 3053, 2975, 2867, 2328, 1598, 1398, 1323, 1264, 1160, 1085, 976, 894, 814, 731.

3.6.3 Pyrrolidine Synthesis and Characterization

2-propyl-1-tosylpyrrolidine (III-13). Following GP5, N-heptyl-4-

methylbenzenesulfonamide (53.9 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (2.5% ethyl acetate/hexanes)

to yield pyrrolidine III-13 (39.4 mg, 74%) as an oil that solidified upon standing at room temperature.

Rf = 0.44 (20% ethyl acetate/hexanes). MP = 57 – 59 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.62 – 3.56 (m, 1H), 3.38 – 3.32 (m, 1H), 3.20 – 3.14 (m, 1H), 2.41 (s, 3H), 1.84 – 1.72 (m, 2H), 1.58 – 1.29 (m, 6H), 0.92 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.4, 135.4, 129.9, 127.8, 60.7, 49.1, 39.0, 31.0, 24.4, 21.8, 19.7, 14.3. + HRMS (ESI-TOF) m/z: calc’d for C14H21NSO2Na [M+Na] : 290.1191, found: 290.1177. IR (film) cm–1: 2956, 2928, 2869, 1598, 1453, 1338, 1156, 1090, 814, 661.

2-methyl-1-tosylpyrrolidine (III-16). Following GP5, 4-methyl-N-

pentylbenzenesulfonamide (48.3 mg, 0.2 mmol) was reacted with PhI(OAc)2 (258 mg, 0.8 mmol), and NaI (120 mg, 0.8 mmol) in acetonitrile (2 mL) for 23 hours. Product was purified via flash column chromatography (silica gel, 20% ethyl acetate/hexanes) to yield pyrrolidine III-16 (33.4 mg, 70%) as an off white solid.

Rf = 0.40 (20% ethyl acetate/hexanes). MP = 89.5 – 91.6 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.75 – 3.67 (m, 1H), 3.47 – 3.39 (m, 1H), 3.19 – 3.10 (m, 1H), 2.42 (s, 3H), 1.87 – 1.77 (m, 1H), 1.73 – 1.63 (m, 1H), 1.59 – 1.44 (m, 2H), 1.31 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.3, 135.2, 129.7, 127.6, 56.2, 49.2, 33.6, 24.1, 23.0, 21.6. + HRMS (ESI-TOF) m/z: calc’d for C12H17NO2SNa [M+Na] 262.0878, found 262.0865. IR (film) cm-1: 2967, 2870, 1596, 1457, 1330, 1329, 1155, 1090, 1040, 815, 716, 660. 90

2-phenyl-1-tosylpyrrolidine (III-17). Following GP5, 4-methyl-N-(4-

phenylbutyl)benzenesulfonamide (60.7 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to yield pyrrolidine III-17 (56.3 mg, 93%) as a white solid.

Rf = 0.29 (20% ethyl acetate/hexanes). MP = 88.0 – 88.5 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 8.6 Hz, 2H), 7.26 – 7.16 (m, 7H), 4.75 (dd, J = 8.3 Hz, 3.9 Hz, 1H), 3.60 – 3.54 (m, 1H), 3.41 – 3.35 (m, 1H), 2.38 (s, 3H), 1.97 – 1.90 (m, 1H), 1.84 – 1.73 (m, 2H), 1.64 – 1.60 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ = 143.4, 143.2, 135.3, 129.7, 128.4, 127.6, 127.1, 126.3, 63.4, 49.5, 35.9, 24.1, 21.6. + HRMS (ESI-TOF) m/z: calc’d for C17H19NSO2Na [M+Na] 324.1034, found 324.1017. IR (film) cm–1: 3051, 2979, 2872, 1599, 1494, 1449, 1343, 1265, 1158, 730.

2,5-dimethyl-1-tosylpyrrolidine (III-18). Following GP6, N-(hexan-2-yl)-4-

methylbenzenesulfonamide (51.1 mg, 0.2 mmol) was reacted with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in acetonitrile (2 mL) for 24 hours. Product was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield pyrrolidine III-18 (41.2 mg, 80%, d.r. 1:1.2) as an off white solid.

Rf = 0.08 (5% ethyl acetate/hexanes).

1 H NMR (400 MHz, CDCl3): Major diastereomer (cis): δ = 7.71 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 3.71 – 3.63 (m, 2H), 2.41 (s, 3H), 2.14 – 2.08 (m, 1H), 1.62 – 1.46 (m, 3H), 1.33 (d, J = 6.4 Hz, 6H). Minor diastereomer (trans): δ = 7.73 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 4.01 (p, J = 6.5 Hz, 2H), 2.14 – 2.08 (m, 1H), 1.62 – 1.46 (m, 3H), 1.19 (d, J = 6.3 Hz, 6H). 13 C NMR (100 MHz, CDCl3): δ = 143.2, 142.7, 139.9, 135.4, 129.7, 129.5, 127.6, 127.1, 57.7, 56.3, 32.2, 31.3, 23.8, 21.6, 21.6, 21.4.

HRMS (ESI-TOF) m/z: calc’d for C13H19NO2SNa [M+Na]+ 276.1034, found 276.1029. IR (film) cm-1: 2967, 2866, 1323, 1153, 659.

(5-methyl-1-tosylpyrrolidin-2-yl)methyl acetate (III-19). Following GP5, 2-((4- methylphenyl)sulfonamido)hexyl acetate (62.6 mg, 0.2 mmol) was cyclized with

PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup the crude material was purified via flash column chromatography (silica gel, 20% ethyl acetate/hexanes), yielding pyrrolidine III-19 (47.4 mg, 75%, d.r. 1.2:1) as an off-white crystalline solid.

Rf = 0.30 (15% ethyl acetate/hexanes). MP = 82.8 – 84.2 °C. Relative stereochemistry determined by nOe analysis. 1 H NMR (600 MHz, CDCl3): Major diastereomer (cis): δ = 7.72 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.20 – 4.11 (m, 2H), 3.90 – 3.86 (m, 1H), 3.67 (q, J = 6.4 Hz, 1H), 2.42 (s, 3H), 2.07 (s, 3H), 1.69 – 1.64 (m, 2H), 1.53 – 1.48 (m, 2H), 1.34 (d, J = 6.2 Hz, 3H). Minor diastereomer (trans): δ = 7.74 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 4.29 – 4.25 (m, 1H), 4.08 – 4.04 (m, 3H), 2.41 (s, 3H), 2.14 – 2.02 (m, 2H), 1.94 (s, 3H), 1.82 – 1.79 (m, 1H), 1.53 – 1.48 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H).

13C NMR (100 MHz, CDCl3): δ = 170.9, 170.6, 143.6, 143.1, 139.1, 134.8, 129.8, 129.7, 127.7, 127.1, 66.7, 65.1, 59.6, 58.0, 57.8, 57.1, 32.3, 31.5, 27.4, 27.0, 23.1, 21.6, 21.6, 21.1, 21.0, 20.9. + HRMS (ESI-TOF) m/z: calc’d for C15H21NSO4Na [M+Na] 334.1089, found 334.1063. IR (film) cm–1: 2959, 2922, 2851, 1738, 1343, 1230, 1158, 1091, 1039, 814, 663.

2-methyl-5-phenyl-1-tosylpyrrolidine (III-20). Following GP6, 4-methyl-N-(1-

phenylpentyl)benzenesulfonamide (63.5 mg, 0.2 mmol) was reacted with PhI(OAc)2 (258 mg, 0.8 mmol), and NaI (120 mg, 0.8 mmol) for 48 hours. Product was purified via flash column chromatography (silica gel, 20% ethyl acetate/hexanes) to yield pyrrolidine III-20 (43.6 mg, 69%, d.r. 1.2:1) as a yellow solid.

Rf = 0.32 (10% ethyl acetate/hexanes). MP = 111 – 114 °C. Relative stereochemistry determined by nOe analysis. 1 H NMR (400 MHz, CDCl3): Major diastereomer (cis): δ = 7.69 (d, J = 8.3 Hz, 2H), 7.43 – 7.00 (m, 7H), 4.73 (t, J = 6.7 Hz, 1H), 3.98 – 3.88 (m, 1H), 2.53 – 2.22 (m, 1H), 2.43 (s, 3H), 1.94 – 1.49 (m, 3 H), 1.47 (d, J = 6.4 Hz, 3H). Minor diastereomer (trans): δ = 7.43 – 7.00 (m, 9H), 4.98 (d, J = 8.6 Hz, 1H), 4.30 (p, J = 6.6 Hz, 1H), 2.53 – 2.22 (m, 1H), 2.35 (s, 3H), 1.94 – 1.49 (m, 3H), 1.39 (d, J = 6.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.4, 143.0, 142.7, 142.5, 139.1, 135.5, 129.7, 129.1, 128.4, 128.2, 127.8, 127.2, 127.1, 126.9, 126.7, 126.4, 65.1, 63.8, 58.0, 57.4, 34.6, 33.4, 32.3, 31.6, 22.9, 21.8, 21.7, 21.5. + HRMS (ESI-TOF) m/z: calc’d for C18H21NO2SNa [M+Na] 338.1191, found 338.1196. IR (film) cm-1: 2967, 2919, 2869, 1594, 1492, 1451, 1335, 1151, 1087, 1012, 816, 759, 701, 661, 598.

(5S)-2-(4-fluorophenyl)-5-methyl-1-tosylpyrrolidine (III-21). Following GP6, amide

SIII-1 (50.0 mg, 0.15 mmol) was reacted with PhI(OAc)2 (193 mg, 0.6 mmol), and NaI (89.9 mg, 0.6 mmol) in acetonitrile (2 mL) for 48 hours. Product was purified via flash column chromatography (silica gel, 15% ethyl acetate/hexanes) to yield pyrrolidine III-21 (30.4 mg, 60%, d.r. 1.3:1) as a yellow solid.

Rf = 0.28 (15% ethyl acetate/hexanes). MP = 108.8 – 115.1 °C. Relative stereochemistry determined by nOe analysis. 1 H NMR (600 MHz, CDCl3): Major diastereomer (cis): δ = 7.68 (d, J = 8.2 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.01 – 6.97 (m, 2H), 4.69 (t, J = 6.6 Hz, 1H), 3.96 – 3.89 (m, 1H), 2.43 (s, 3H), 1.93 – 1.79 (m, 2H), 1.76 – 1.68 (m, 1H), 1.64 – 1.47 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H). Minor diastereomer (trans): δ = 7.39 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 7.01 – 6.97 (m, 2H), 6.81 (t, J = 8.7 Hz, 2H), 4.95 (d, J = 8.5 Hz, 1H), 4.30 (p, J = 6.8 Hz, 1H), 2.52 – 2.44 (m, 1H), 2.36 (s, 3H), 2.28 (m, 1H), 1.76 – 1.68 (m, 1H), 1.64 -1.47 (m, 1H), 1.38 (d, J = 6.4 Hz, 3H). 13 1 1 C NMR (150 MHz, CDCl3): δ = 162.0 ( JCF = 245.4 Hz), 161.9 ( JCF = 245.4 Hz), 4 4 143.5, 142.7, 139.1, 138.7 ( JCF = 2.5 Hz), 138.5 ( JCF = 3.2 Hz), 135.3, 129.7, 129.2, 128.3 3 3 2 2 ( JCF = 7.8 Hz), 128.0 ( JCF = 8.4 Hz), 127.8, 127.1, 115.2 ( JCF = 21.8 Hz), 114.9 ( JCF = 21.4 Hz), 64.5, 63.0, 58.0, 57.5, 34.6, 33.5, 32.3, 31.5, 23.0, 21.7, 21.7, 21.5. 19 F NMR (376 MHz, CDCl3): δ = -116.1 – -116.1 (m), -116.2 – -116.3 (m). + HRMS (ESI-TOF) m/z: calc’d for C18H20FNO2SNa [M+Na] 356.1096, found 356.1120. IR (film) cm-1: 2975, 2948, 2924, 2869, 1600, 1508, 1444, 1333, 1222, 1152, 1093, 815, 663.

2-(4-methoxyphenyl)-5-methyl-1-tosylpyrrolidine (III-22). Following GP6, N-(1-(4- methoxyphenyl)pentyl)-4-methylbenzenesulfonamide (69.4 mg, 0.2 mmol) was reacted with PhI(OAc)2 (258 mg, 0.8 mmol), and NaI (120 mg, 0.8 mmol) in acetonitrile (4 mL) for 24 hours. Product was purified via flash column chromatography (silica gel, 20% ethyl acetate/hexanes) to yield pyrrolidine III-22 (46.5 mg, 67%, d.r. 1.1:1) as a yellow solid.

Rf = 0.24 (20% ethyl acetate/hexanes). MP = 75.0 – 89.6 °C. Relative stereochemistry determined by nOe analysis. 1 H NMR (400 MHz, CDCl3): Major diastereomer (cis): δ = 7.68 (d, J = 8.4 Hz, 2H), 7.30 – 7.25 (m, 4H), 6.85 (d, J = 8.8 Hz, 2H), 4.67 (t, J = 6.6 Hz, 1H), 3.96 – 3.88 (m, 1H), 3.80 (s, 3H), 2.51 –2.21 (m, 1H), 2.42 (s, 3H), 1.88 – 1.48 (m, 3H), 1.45 (d, J = 6.4 Hz, 3H). Minor diastereomer (trans): δ = 7.37 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 9.0 Hz, 2H), 4.93 (d, J = 9.2 Hz, 1H), 4.28 (p, J = 6.7 Hz, 1H), 3.76 (s, 3H), 2.51 – 2.21 (m, 1H), 2.34 (s, 3H), 1.88 – 1.48 (m, 3H), 1.39 (d, J = 6.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 158.8, 158.7, 143.3, 142.3, 139.2, 135.6, 135.0, 134.8, 129.6, 129.0, 127.9, 127.8, 127.6, 127.1, 113.8, 113.5, 64.6, 63.2, 57.9, 57.4, 55.4, 55.4, 34.5, 33.4, 32.3, 31.7, 23.0, 21.9, 21.6, 21.5. + HRMS (ESI-TOF) m/z: calc’d for C19H23NO3SNa [M+Na] 368.1296, found 368.1275. IR (film) cm-1: 2959, 2925, 2869, 2834, 1611, 1508, 1332, 1243, 1154, 1100, 1033, 810, 664.

2-isopentyl-3-methyl-1-tosylpyrrolidine (III-23). Following GP5, amide SIII-2 (61.6

mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (silica gel, 2.5% ethyl acetate/hexanes) to yield pyrrolidine III-23 (56.8 mg, 93%, d.r. 1:1) as a low-melting white solid.

Rf = 0.56 (20% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.2, 2H), 7.29 (d, J = 8.5 Hz, 2H), 3.59 – 3.11 (m, 3H), 3.59 – 3.11 (m, 3H), 2.42 (s, 3H), 2.42 (s, 3H), 2.00 – 1.11 (m, 8H), 2.00 – 1.11 (m, 8H), 0.90 – 0.88 (m, 9H), 0.90 – 0.88 (m, 6H), 0.54 (d, J = 6.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.2 (2C), 135.4, 135.1, 129.7, 129.6, 127.7, 127.6, 67.9, 63.9, 47.6, 47.4, 37.7, 36.7, 35.5, 34.9, 34.1, 31.8, 31.7, 28.5, 28.4, 28.3. + HRMS (ESI-TOF) m/z: calc’d for C17H27NSO2Na [M+Na] 332.1660, found 332.1662. IR (film) cm–1: 2954, 2903, 2869, 1598, 1461, 1345, 1161, 1093, 1042, 815, 662.

4-((tert-butyldimethylsilyl)oxy)-2-ethyl-1-tosylpyrrolidine (III-24). Following GP5,

amide SIII-3 (77.2 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude product was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield pyrrolidine III-24 (66.7 mg, 87%, d.r. 1.2:1) as a yellow oil.

Rf = 0.59 (20% ethyl acetate/hexanes). Relative stereochemistry determined by nOe analysis.

1H NMR (400 MHz, CDCl3): Major diastereomer (cis): δ = 7.70 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.83 (m, 1H), 3.62 – 3.58 (m, 1H), 3.44 (dd, J = 11.3, 5.8 Hz, 1H), 3.16 (dd, J = 11.3, 5.3 Hz, 1H), 2.42 (s, 3H), 2.03 – 1.53 (m, 4H), 0.89 (t, J = 7.5 Hz, 3H), 0.81 (s, 9H), –0.04 (s, 3H), –0.05 (s, 3H). Minor diastereomer (trans): δ = 7.71 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.25 (m, 1H), 3.57 (dd, J = 10.9, 4.7 Hz, 1H), 3.59 – 3.54 (m, 1H), 3.12 (m, 1H), 2.40 (s, 3H), 2.03 – 1.53 (m, 4H), 0.89 (t, J = 7.4 Hz, 3H), 0.73 (s, 9H), –0.08 (s, 3H), –0.09 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 143.4, 143.2, 135.7, 134.8, 129.8, 129.6, 127.9, 127.4, 70.6, 69.9, 61.3, 60.3, 57.5, 55.9, 40.3, 38.9, 29.5, 28.7, 25.8, 21.6, 18.1, 18.0, 10.4, 9.8, – 4.8, –4.9 (3C). + HRMS (ESI-TOF) m/z: calc’d for C19H33NSO3SiNa [M+Na] 406.1848, found 406.1825. IR (film) cm–1: 2955, 2928, 2854, 1598, 1463, 1332, 1257, 1159, 1133, 1066, 1065, 1014, 918, 830, 778.

(2S)-2,4-dimethyl-1-tosylpyrrolidine (III-25). Following GP5, amide SIII-4 (51.1 mg,

0.2 mmol) was reacted with PhI(OAc)2 (258 mg, 0.8 mmol), and NaI (120 mg, 0.8 mmol) in acetonitrile (2 mL) for 3 hours. Product was purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to yield pyrrolidine III-25 (43.2 mg, 85%, d.r. 1.2:1) as a colorless oil.

Rf = 0.21 (10% ethyl acetate/hexanes). Relative stereochemistry determined by nOe analysis. 1 H NMR (600 MHz, CDCl3): Major diastereomer (trans): δ = 7.71 (d, J = 8.2 Hz, 2H), 7.32 – 7.28 (m, 2H), 3.80 – 3.73 (m, 1H), 3.63 – 3.49 (m, 1H), 2.58 (t, J = 9.3 Hz, 1H), 2.42 (s, 3H), 2.38 – 2.30 (1H, m), 1.62 – 1.53 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.29 – 1.25 (m, 1H), 0.83 (d, J = 6.6 Hz, 3H). Minor diastereomer (cis): δ = 7.71 (d, J = 8.2 Hz, 2H), 7.32 – 7.28 (m, 2H), 3.63 – 3.49 (m, 2H), 2.90 (t, J = 10.7 Hz, 1H), 2.42 (s, 3H), 2.09 -2.03 97

(m, 1H), 1.62 – 1.53 (m, 1H), 1.39 (d, J = 6.2 Hz, 3H), 1.17 – 1.09 (m, 1H), 0.91 (d, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, CDCl3): δ = 143.2, 143.2, 135.6, 134.8, 129.7, 129.6, 127.7, 127.6, 57.3, 56.1 (2C), 56.0, 43.4, 41.5, 32.7, 31.5, 23.5, 23.0, 21.6 (2C), 17.2, 17.0. + HRMS (ESI-TOF) m/z: calc’d for C13H19NHO2S [M+H] 254.1215, found 254.1204. IR (film) cm–1: 2960, 2923, 2869, 1597, 1455, 1336, 1153, 1091, 1031, 814, 730, 659.

Methyl 5-methyl-1-tosylpyrrolidine-2-carboxylate (III-26). Following GP5, methyl 2- ((4-methylphenyl)sulfonamido)hexanoate (59.5 mg, 0.2 mmol) was cyclized with

PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via preparatory TLC (5% ethyl acetate/hexanes) to yield pyrrolidine III-26 (38.1 mg, 65%, d.r. 1.5:1) as a colorless oil.

Rf = 0.24 (20% ethyl acetate/hexanes). Relative stereochemistry determined by nOe analysis. 1 H NMR (400 MHz, CDCl3): Major diastereomer (cis): δ = 7.75 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.26 (dd, J = 7.9, 5.5 Hz, 1H), 3.81 (q, J = 6.3 Hz, 1H), 3.74 (s, 3H), 2.42 (s, 3H), 2.03 – 1.73 (m, 2H), 1.63 – 1.56 (m, 2H), 1.34 (d, J = 6.2 Hz, 3H). Minor diastereomer (trans): δ = 7.75 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 4.43 (d, J = 7.0 Hz, 1H), 4.09 (m, 1H), 3.64 (s, 3H), 2.41 (s, 3H), 2.29 – 2.26 (m, 2H), 2.03 – 1.73 (m, 1H), 1.63 – 1.56 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 173.0, 172.9, 143.7, 143.3, 138.2, 135.7, 129.8, 129.5, 127.7, 127.6, 62.0, 61.2, 57.7, 56.2, 52.6, 52.3, 32.9, 32.1, 29.5, 28.8, 22.2, 21.6 (2C), 21.4. + HRMS (ESI-TOF) m/z: calc’d for C14H19NSO4Na [M+Na] 320.0932, found 320.0927. IR (film) cm–1: 3049, 2971, 1736, 1265, 1157, 907, 729.

(2S)-2-methyl-1-tosyl-5-(trifluoromethyl)pyrrolidine (III-27). Following GP6, amide

SIII-5 (21.8 mg, 0.07 mmol) was reacted with PhI(OAc)2 (90.2 mg, 0.28 mmol), and NaI (42.1 mg, 0.28 mmol) in acetonitrile (1 mL) for 6 hours. Reaction mixture was washed with saturated sodium thiosulfate and extracted with ethyl acetate. The organic layers were combined and concentrated. The reaction mixture was resubjected under GP6 conditions using PhI(OAc)2 (90.2 mg, 0.28 mmol), and sodium iodide (42.0 mg, 0.28 mmol) in acetonitrile (1.0 mL) for 6 hours. Product was purified by preparatory TLC (silica gel, 10% ethyl acetate/hexanes) to yield pyrrolidine III-27 (9.6 mg, 45%, d.r. 1.6:1) as a white solid. Crude 19F NMR yield was 53% using ethyl trifluoroacetate as an internal standard.

Rf = 0.21 (10% ethyl acetate/hexanes). MP = 63.9 – 77.0 °C. Relative stereochemistry determined by nOe analysis. 1H NMR (400 MHz, CDCl3): Major diastereomer (cis): δ = 7.74 (app t, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 4.39 – 4.28 (m, 1H), 3.90 – 3.80 (m, 1H), 2.44 (s, 3H), 2.12 – 1.91 (m, 2H), 1.76 – 1.56 (m, 2H), 1.31 (d, J = 6.4 Hz, 3H), Minor diastereomer (trans): δ = 7.74 (app t, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 4.53 (p, J = 7.5 Hz, 1H), 4.06 – 3.96 (m, 1H), 2.42 (s, 3H), 2.30 – 2.14 (m, 2H), 2.12 – 1.91 (m, 1H), 1.76 – 1.56 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H). 13 C NMR (150 MHz, CDCl3): δ = 144.2, 143.4, 138.9, 135.6, 130.0, 129.6, 127.9, 127.1, 126.1, 124.3, 61.2 (q, J = 32.3 Hz), 60.3 (q, J = 31.5 Hz), 58.6, 58.4, 32.8, 32.7, 26.0, 24.9, 22.1, 21.7, 21.7, 21.5. 19 F NMR (376 MHz, CDCl3): δ = –72.1 (d, J = 7.5 Hz), –74.6 (d, J = 7.5 Hz). + HRMS (ESI-TOF) m/z: calc’d for C13H16F3NO2SNa [M+Na] 330.0752, found 330.0732. IR (film) cm-1: 3250, 2960, 2920, 2870, 1598, 1467, 1390, 1327, 1269, 1156, 1139, 1093, 1017, 812, 703, 661.

2-Methyl-3-tosyloxazolidine (III-28). Following GP5, amide SIII-6 (48.7 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (129 mg, 0.4 mmol) and NaI (60 mg, 0.4 mmol) in degassed acetonitrile (2 mL). After workup the crude product was purified via flash column chromatography (silica gel, 1:1 petroleum ether/methylene chloride) to yield pyrrolidine III-28 (33 mg, 69%) as a white solid.

Rf = 0.26 (20% ethyl acetate/hexanes). MP = 126.1 – 127.2 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.17 (q, J = 5.5 Hz, 1H), 3.91 – 3.86 (m, 1H), 3.45 – 3.42 (m, 2H), 3.37 – 3.32 (m, 1H), 2.43 (s, 3H), 1.47 (d, J = 5.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 144.2, 143.4, 130.0, 127.9, 88.6, 65.3, 46.7, 22.2, 21.7. + HRMS (ESI-TOF) m/z: calc’d for C11H15NHSO3 [M+H] 242.0851, found 242.0837. IR (film) cm–1: 2986, 2930, 2884, 1597, 1344, 1164, 907, 728, 662.

Methyl 2-((5S)-5-methyl-1-tosylpyrrolidin-2-yl)acetate (III-15). Following GP6, methyl 3-((4-methylphenyl)sulfonamido)heptanoate (62.6 mg, 0.2 mmol) was reacted with

PhI(OAc)2 (258 mg, 0.8 mmol), and NaI (120 mg, 0.8 mmol) in acetonitrile (4 mL) for 24 hrs. Product was purified via flash column chromatography (silica gel, 15% ethyl acetate/hexanes) to yield pyrrolidine III-15 (47.9 mg, 75%, d.r. 1.2:1) as a yellow oil.

Rf = 0.18 (15% ethyl acetate/hexanes). Relative stereochemistry determined by nOe analysis. 1 H NMR (600 MHz, CDCl3): Major diastereomer (cis): δ = 7.74 (d, J = 6.4 Hz, 2H), 7.32 (d, J =8.3 Hz, 2H), 3.97 – 3.92 (m, 1H), 3.69 (s, 3H), 3.68 – 3.64 (m, 1H), 3.10 (dd, J = 100

15.8, 4.0 Hz, 1H), 2.50 (dd, J = 15.8, 9.7 Hz, 1H) 2.43 (s, 3H), 2.12 – 2.05 (m, 1H), 1.77 – 1.44 (m, 3H), 1.33 (d, J = 6.4 Hz, 3H). Minor diastereomer (trans): δ = 7.75 (d, J = 6.6 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 4.24 (m, 1H), 4.10 (p, J = 6.4 Hz, 1H), 3.67 (s, 3H), 3.20 (dd, J = 15.9, 3.3 Hz, 1H), 2.42 (s, 3H), 2.37 (dd, J = 16.1, 10.5 Hz, 1H), 2.12 – 2.05 (1H, m), 1.77 – 1.44 (m, 3H), 1.13 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 171.9, 171.8, 143.6, 143.1, 139.2, 134.7, 129.8, 129.7, 127.7, 127.1, 58.2, 57.7, 56.7, 56.6, 51.7, 51.7, 42.2, 39.7, 31.9, 30.9, 30.3, 29.4, 23.5, 21.6, 21.6, 20.6. + HRMS (ESI-TOF) m/z: calc’d for C15H21NO4SNa [M+Na] 334.1089, found 334.1105. IR (film) cm–1: 2952, 2869, 1733, 1598, 1436, 1336, 1304, 1155, 1092, 1041, 1009, 815, 661.

2-(5-methyl-1-tosylpyrrolidin-2-yl)-1-phenylethan-1-one (III-29). Following GP6, 4- methyl-N-(1-oxo-1-phenylheptan-3-yl)benzenesulfonamide (71.9 mg, 0.2 mmol) was reacted with PhI(OAc)2 (258 mg, 0.8 mmol), and NaI (120 mg, 0.8 mmol) in acetonitrile (4 mL) for 24 hours. Product was purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to yield pyrrolidine III-29 (46.0 mg, 65%, d.r. 1.5:1) as a yellow solid.

Rf = 0.24 (10% ethyl acetate/hexanes). MP = 86.7 – 90.5 °C. Relative stereochemistry determined by nOe analysis. 1 H NMR (400 MHz, CDCl3): Major diastereomer (cis): δ = 8.07 – 7.97 (m, 2H), 7.80 – 7.71 (m, 2H), 7.63 – 7.54 (m, 1H), 7.53 – 7.45 (m, 2H), 7.37 – 7.26 (m, 2H), 4.23 – 4.06 (m, 1H), 4.00 – 3.88 (m, 1H), 3.73 – 3.62 (m, 1H), 3.13 (dd, J = 17.1 Hz, 10.6 Hz, 1H), 2.43 (s, 3H), 2.18 – 2.10 (m, 1H), 1.88 – 1.45 (m, 3H), 1.38 (d, J = 6.4 Hz, 3H). Minor

101

diastereomer (trans): δ = 8.07 – 7.97 (m, 2H), 7.80 – 7.71 (m, 2H), 7.63 – 7.54 (m, 1H), 7.53 – 7.45 (m, 2H), 7.37 – 7.26 (m, 2H), 4.48 – 4.38 (m, 1H), 4.23 – 4.06 (m, 1H), 4.00 – 3.88 (m, 1H), 3.00 (dd, J = 16.7, 10.6 Hz, 1H), 2.42 (s, 3H), 1.88 – 1.45 (m, 4H), 1.12 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 198.9, 198.7, 143.6, 143.1, 136.8, 136.8, 134.5, 133.5, 129.9, 129.7, 128.8, 128.3, 127.7, 127.2, 58.4, 57.6, 56.7, 47.3, 46.0, 44.5, 32.0, 31.0, 30.5, 29.5, 29.2, 26.8, 23.5, 22.1, 21.7, 21.6, 20.5, 13.9. + HRMS (ESI-TOF) m/z: calc’d for C20H23NO3SNa [M+Na] 380.1296, found 380.1278. IR (film) cm–1: 2961, 2923, 2854, 1682, 1595, 1447, 1337, 1302, 1211, 1152, 1090, 1042, 812, 755, 665.

1-((4-nitrophenyl)sulfonyl)-2-phenylpyrrolidine (III-30). Following GP5, amide SIII-

7 (66.7 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (silica gel, 10 % ethyl acetate/hexanes) to yield pyrrolidine III-30 (57.6 mg, 87%) as a white solid.

Rf = 0.29 (20% ethyl acetate/hexanes). MP = 129.2 – 131.6 °C. 1 H NMR (400 MHz, CDCl3): δ = 8.23 – 8.21 (d, J = 8.8 Hz, 2H), 7.80 – 7.77 (d, J = 8.8 Hz, 2H), 7.26 – 7.22 (m, 3H), 7.17 – 7.14 (m, 2H), 4.87 (dd, J = 7.8, 4.3 Hz, 1H), 3.63 (t, J = 6.6 Hz, 2H), 2.22 – 2.13 (m, 1H), 2.04 – 1.80 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ = 149.9, 144.8, 141.9, 128.5, 128.4, 127.6, 126.5, 124.1, 63.8, 49.5, 36.1, 24.4. + HRMS (ESI-TOF) m/z: calc’d for C16H16N2SO4Na [M+Na] 355.0728, found 355.0720. IR (film) cm–1: 3110, 2978, 2898, 2857, 1719, 1602, 1521, 1454, 1347, 1313, 1192, 1161, 1087, 1050, 994, 853, 743, 704. 102

1-((4-nitrophenyl)sulfonyl)-2-propylpyrrolidine (III-31). Following GP5, amide SIII-8

(60.1 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (silica gel, 3% ethyl acetate/hexanes), yielding pyrrolidine III-31 (38.6 mg, 65%) as a clear oil.

Rf = 0.40 (15% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 3.70 – 3.62 (m, 1H), 3.47 – 3.39 (m, 1H), 3.26 – 3.17 (m, 1H), 1.90 – 1.76 (m, 2H), 1.66 – 1.59 (m, 2H), 1.59 – 1.40 (m, 2H), 1.39 – 1.27 (m, 2H), 1.33 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 150.1, 144.3, 128.7, 124.4, 61.0, 49.0, 38.5, 30.8, 24.3, 19.5, 14.1. + HRMS (ESI-TOF) m/z: calc’d for C13H18N2O4SNa [M+Na] 321.0885, found 321.0886. IR (film) cm–1: 2959, 2928, 2868, 1681, 1596, 1448, 1336, 1301, 1211, 1154, 1092, 812, 755, 666.

1-(methylsulfonyl)-2-phenylpyrrolidine (III-32). Following GP5, amide SIII-9 (45.4 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to yield pyrrolidine III-32 (41.2 mg, 92%) as a white solid.

Rf = 0.43 (20% ethyl acetate/hexanes). MP = 103.2 – 105.6 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.30 – 7.17 (m, 5H), 4.82 (dd, J = 8.4, 4.3 Hz, 1H), 3.64 – 3.49 (m, 2H), 2.61 (s, 3H), 2.36 – 2.27 (m, 1H), 2.00 – 1.84 (m, 3H). 103

13 C NMR (100 MHz, CDCl3): δ = 142.9, 128.7, 127.6, 126.4, 63.2, 49.2, 38.4, 36.3, 24.6. + HRMS (ESI-TOF) m/z: calc’d for C11H15NSO2Na [M+Na] 248.0721, found 248.0706. IR (film) cm–1: 2969, 2929, 2857, 1603, 1522, 1494, 1453, 1323, 1166, 1141, 1087, 1051, 999, 972, 854, 779, 754.

1-(methylsulfonyl)-2-propylpyrrolidine (III-33). Following GP5, N- heptylmethanesulfonamide (58 mg, 0.3 mmol) was cyclized with PhI(OAc)2 (387 mg, 1.2 mmol) and NaI (180 mg, 1.2 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes), yielding pyrrolidine III-33 (31.1 mg, 54%) as a clear oil.

Rf = 0.30 (15% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 3.72 – 3.63 (m, 1H), 3.41 – 3.28 (m, 2H), 2.79 (s, 3H), 2.02 –1.89 (m, 2H), 1.81 – 1.66 (m, 2H), 1.47 – 1.21 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 60.3, 48.6, 38.3, 35.5, 30.9, 24.5, 19.3, 13.9. + HRMS (ESI-TOF) m/z: calc’d for C8H17NO2SH [M+H] 192.1058, found 192.1070. IR (film) cm–1: 2960, 2928, 2872, 1711, 1420, 1359, 1330, 1220, 1152, 734.

(R)-2-phenyl-1-((2-(trimethylsilyl)ethyl)sulfonyl)pyrrolidine (III-34). Following GP5, amide SIII-10 (62.6 mg, 0.2 mmol) was reacted with PhI(OAc)2 (258 mg, 0.8 mmol), and NaI (120 mg, 0.8 mmol) in acetonitrile (2 mL) for 3 hours. Product was purified via flash column chromatography (silica gel, 15% ethyl acetate/hexanes) to yield pyrrolidine III-34 (50.4 mg, 81%) as a white solid.

Rf = 0.33 (15% ethyl acetate/hexanes). 104

MP = 33.3 – 35.0 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.29 – 7.24 (m, 4H), 7.23 – 7.17 (m, 1H), 4.90 – 4.82 (m, 1H), 3.82 – 3.72 (m, 1H), 3.53 – 3.43 (m, 1H), 2.59 – 2.31 (m, 3H), 2.05 – 1.83 (m, 3H), 0.92 – 0.74 (m, 2H), -0.16 (s, 9H). 13 C NMR (150 MHz, CDCl3): δ = 143.2, 128.7, 127.7, 126.7, 63.2, 49.8, 49.1, 36.6, 25.2, 10.1, – 2.0. + HRMS (ESI-TOF) m/z: calc’d for C15H25NO2SSiNa [M+Na] 334.1273, found 334.1254. IR (film) cm–1: 2950, 2897, 1602, 1494, 1455, 1325, 1245, 1167, 1135, 1074, 835, 750, 696.

2-propyl-1-((2-(trimethylsilyl)ethyl)sulfonyl)pyrrolidine (III-35). Following GP5,

amide SIII-11 (55.9 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude material was purified via flash column chromatography (silica gel, 2% ethyl acetate/hexanes) to yield pyrrolidine III-35 (37.4 mg, 68%) as an off-white solid.

Rf = 0.43 (20% ethyl acetate/hexanes). MP = 40.9 – 41.7 °C. 1H NMR (400 MHz, CDCl3): δ = 3.86 – 3.80 (m, 1H), 3.47 – 3.42 (m, 1H), 3.30 – 3.24 (m, 1H), 2.86 (m, 2H), 2.02 – 1.82 (m, 3H), 1.77 – 1.65 (m, 2H), 1.43 – 1.25 (m, 3H), 1.08 – 0.99 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H), 0.04 (s, 9H). 13 C NMR (100 MHz, CDCl3): δ = 60.1, 48.6, 47.0, 38.6, 31.2, 25.0, 19.5, 14.1, 10.3, – 1.9. + HRMS (ESI-TOF) m/z: calc’d for C12H27NSO2SiNa [M+Na] 300.1429, found 300.1421. IR (film) cm–1: 2956, 2927, 2874, 2871, 1448, 1405, 1327, 1246, 1171, 1138, 1040, 986, 892, 844, 760, 697.

105

8-isopropyl-3-methyl-6-tosyl-6-azabicyclo[3.2.1]octane (III-37). Following GP5,

amide SIII-12 (64.1 mg, 0.2 mmol), was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup, the crude product was purified via flash column chromatography (silica gel, 4% ethyl acetate/hexanes) to yield pyrrolidine III-37 (50.4 mg 79%) as a white solid.

Rf = 0.58 (20% ethyl acetate/hexanes). MP = 102.2 – 103.6 °C. 1 H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 3.50 (t, J = 8.8 Hz, 1H), 3.19 (dd, J = 11.7, 9.1 Hz 1H), 2.65 – 2.58 (m, 1H), 2.40 (s, 3H), 1.52 – 1.66 (m, 4H), 1.38 (d, J = 11.7 Hz, 6H), 1.17 – 1.09 (m, 1H), 1.00 – 0.89 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H), 0.80 – 0.70 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ = 142.5, 139.3, 129.5, 127.0, 68.9, 50.7, 49.7, 34.3, 33.7, 33.7, 29.6, 26.9, 24.0, 23.6, 22.4, 21.6. + HRMS (ESI-TOF) m/z: calc’d for C18H27NSO2Na [M+Na] 344.1660, found 344.1630. IR (film) cm–1: 2955, 2912, 2867, 1597, 1452, 1328, 1304, 1153, 1111, 1092, 1043, 991, 976, 820, 713, 662.

(3S,3aS,6R,7aS)-3,6-dimethyl-1-tosyloctahydro-1H-indole + ent. (III-39). Following

GP5, amide SIII-13 (62.4 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup the crude product was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield pyrrolidine III-39 (24.7 mg, 40%, d.r. = 8:1) as a white solid. 106

Following GP6, amide SIII-13 (62.3 mg, 0.2 mmol) was cyclized with PhI(OAc)2 (258 mg, 0.8 mmol) and NaI (120 mg, 0.8 mmol) in degassed acetonitrile (2 mL). After workup the crude product was purified via flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to yield pyrrolidine III-39 (45.7 mg, 74%, d.r. = 2:1) as a white solid.

Rf = 0.53 (20% ethyl acetate/hexanes). MP = 130.5 – 131.5 °C. Relative stereochemistry determined by nOe analysis. 1 H NMR (400 MHz, CDCl3): Major diastereomer (depicted above): δ = 7.70 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.65 (dd, J = 10.5, 6.8 Hz, 1H), 3.51 (app. q, J = 5.1 Hz, 1H), 2.87 (dd, J = 10.5, 4.1 Hz, 1H), 2.42 (s, 3H), 2.26 (m, 1H), 1.91 – 1.84 (m, 1H), 1.79 – 1.25 (m, 7H), 0.89 (d, J = 6.8 Hz, 3H), 0.54 (d, J = 6.9 Hz, 3H) Minor diastereomer: δ = 7.69 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.48 (dd, J = 10.9, 8.4 Hz, 1H), 3.35 (app. q, J = 3.3 Hz, 1H), 3.09 (app. t, J = 10.9 Hz, 1H), 2.56 (m, 1H), 2.42 (s, 3H), 1.79 – 0.88 (m, 8H), 0.86 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 143.2, 134.5, 129.8, 129.6 (2C), 127.7 (3C), 62.1, 57.8, 55.2, 54.5, 45.4, 42.4, 37.2, 36.4, 36.3, 35.3, 34.8, 33.4, 31.2, 26.5, 26.4, 25.6, 22.5, 22.2, 21.6, 20.7, 18.1, 12.1. + HRMS (ESI-TOF) m/z: calc’d for C17H25NSO2Na [M+Na] 330.1504, found 330.1502. IR (film) cm–1: 2947, 2924, 2865, 1598, 1456, 1454, 1338, 1299, 1214, 1160, 1089, 1037), 1010, 937, 824, 744, 670.

3.6.4 Synthesis and Characterization of Intercepted Intermediates

N-chloro-4-methyl-N-pentylbenzenesulfonamide (III-41). Following GP6, 4-methyl-

N-pentylbenzenesulfonamide (48.3 mg, 0.2 mmol) was reacted with PhI(OAc)2 (515 mg, 1.6 mmol) and NaCl (93.5 mg, 1.6 mmol) in acetonitrile (2 mL) for 18 hours. Product was

107

purified via flash column chromatography (silica gel, 10% ethyl acetate/hexanes) to yield haloamine III-41 as a colorless oil.

Rf = 0.42 (10% ethyl acetate/hexanes).

1 H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 3.22 (t, J = 6.9 Hz, 2H), 2.47 (s, 3H), 1.62 – 1.47 (m, 2H), 1.39 – 1.30 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ = 145.4, 130.1, 129.8, 129.7, 56.8, 28.3, 26.9, 22.3, 21.8, 14.0. + HRMS (ESI-TOF) m/z: calc’d for C12H18ClNO2SNa [M+Na] 298.0644, found 298.0617.

N-(4-bromopentyl)-4-methylbenzenesulfonamide (III-42). Following GP5, 4-methyl-

N-pentylbenzenesulfonamide (48.9 mg, 0.2 mmol) was reacted with PhI(OAc)2 (64.4 mg, 0.2 mmol) and NaBr (20.6 mg, 0.2 mmol) in acetonitrile (2 mL) for 2 hours. Product was purified by preparatory TLC (silica gel, 15% ethyl acetate/hexanes) to yield alkyl bromide III-42 as a colorless oil.

Rf = 0.15 (15% ethyl acetate/hexanes). 1 H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 4.40 (t, J = 6.6 Hz, 1H), 4.10 – 4.01 (m, 1H), 2.97 (q, J = 6.6 Hz, 2H), 2.43 (s, 3H), 1.83 – 1.70 (m, 3H), 1.67 (d, J = 6.6 Hz, 3H), 1.64 – 1.55 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ = 143.7, 137.1, 129.9, 127.2, 50.7, 42.7, 37.9, 28.0, 26.6, 21.7. + HRMS (ESI-TOF) m/z: calc’d for C12H18BrNO2SNa [M+Na] 342.0139, found 342.0122.

108

Chapter 4 Catalytic Difunctionalization

Portions of this chapter are adapted from:

Nakafuku, K. M.†; Fosu, S. C.†; Nagib, D. A. “Catalytic Alkene Difunctionalization via Imidate Radicals.” J. Am. Chem. Soc., 2018, 140, 11202 – 11205

4.1 Imidate Synthesis and Rearrangements

Imidates, which are adducts of nitriles and alcohols are also known as imino ethers or imido esters. Imidate hydrochlorides were first synthesized by Pinner in 1877.141 Pinner discovered that alcohols could add into nitriles with the aid of HCl gas to form imidate hydrochloride salts. These reaction conditions, however are not viable for all imidate syntheses. A base catalyzed imidate synthesis was first utilized by Nef and coworkers,142 then made more applicable for the synthesis of aliphatic imidates at a later date.143 Roberts and coworkers found that by using methyl or ethyl N-phenylformimidate, they were able to introduce bulkier secondary alcohols, such as isopropanol through transesterificiation.144 Other efficient imidate transesterification protocols use trifluro or tribromo ethylimidates as precursors.145 Additional starting materials for imidate syntheses include amides and imino chlorides. Amides can be reacted with ethyl chloroformate146 or undergo O- alkylation147 to furnish N-substituted imidates. Imidates can also be formed from reacting imino chorides with alcohols.148 Free-based imidates tend to be quite unstable and can readily decompose to the nitrile and alcohol.149 However, upon heating, it has been reported several times that imidates can undergo rearrangements. Mumm and coworkers reported in 1915 that heating

109

N-phenyl benzimidate IV-1 formed an N,N diphenyl benzamide IV-2, which is known as the Chapman rearrangement (Scheme 4.1a). Imidates are also known to undergo 3,3 sigmatropic rearrangements. The first observed cyclization of imidates was in 1937 by a thermal rearrangement of a benzimidate.150 One of the most famous imidate rearrangements however, is the Overman rearrangement discovered in the 1970s, in which a trichloroacetimidate (IV-3) is converted to an allylic amine (IV-4) (Scheme 4.1b).

Scheme

4.1 Representative examples of imidate rearrangements.

Overman first discovered that allylic alcohol motifs (IV-5) such as cyclohexanol could be appended to chloral to give acetal IV-6 and after treatment with mercury trifluoroacetate followed by sodium borohydride reduction, diol IV-7 could be generated.151 With this as a blueprint, Overman proposed that the same strategy could be used for the synthesis of 1,2 amino alcohols. He devised that this could be accomplished by appending the alcohol to trichloroacetonitrile to form an imidate (IV-8). However, under the same reaction conditions he used to synthesize the 1,2 diol motifs, Overman only observed trace amounts of the desired 1,2 amino alcohol IV-9 (Scheme 4.2). The major product in this case ended up being the sigmatropic rearrangement to the allylic amine.152,153 This formation of an allylic amine spurred an efficient synthesis154 of this motif which has been used extensively in organic synthesis.

110

Scheme 4.2 Desired reactivity of allyl imidates to form 1, 2 amino alcohols.

4.2 1, 2-amino Alcohols

1,2-amino alcohols are privileged motifs prevalent in biologically active compounds such Taxol, vancomycin, and quinine (Figure 4.3). These medicines are used as chemotherapeutics for breast cancer, antibiotics, and antimalarials, respectively. These scaffolds are also commonly found in beta-blockers. This functional group is widely found in chiral auxiliaries such as Evan’s oxazolidinone and bis(oxazolines) to afford asymmetric reactions. Owing to the importance of this motif, developing new methods to synthesize 1,2 amino alcohols from a variety of strategies is quite significant. Current methods to synthesize amino alcohols include aminohydroxylation of alkenes, of which the enantioselective variant was introduced by Sharpless using an Os catalyst. Other synthetic routes include ring opening of epoxides or aziridines and azapinacol couplings.

111

Figure 4.1 1,2 amino alcohols in pharmaceuticals.

4.3 Strategy

It has been previously reported that imidates have privileged reactivity and if subjected to our triiodide conditions discussed in chapter 3,155 these imidates can form oxazolines through a selective 1,5-HAT. Hydrolysis of these oxazolines can then generate free 1,2 amino alcohols.156 These conditions for transforming saturated alcohols to amino alcohols is quite robust, but not amenable for the functionalization of allylic alcohols. Under Lewis acidic conditions or heat, allylic imidates readily undergo the Overman rearrangement to produce allylic amines as previously discussed (Figure 4.4).152,154,157 Although it has been extensively explored by Overman that these allylic imidates can readily rearrange, we envisioned that we could bypass this 2e- rearrangement by going through a 1e- mechanism. We hypothesized that this could be accomplished through a radical-relay chaperone strategy. We proposed that single-electron reduction of an oxime imidate would provide an N-centered radical through photocatalysis. This strategy of reducing an N-XR bond through photocatalysis has been previously explored with iminyl ethers,158 thioethers,159 112 and esters160 to provide iminyl radicals. Amidyl radicals have also been explored through scission of an N-XR bond.161 However, there are other means for providing amidyl radicals, such as through a proton-coupled electron transfer (PCET) mechanism.162 Excitation of a photocatalyst by light, followed by reduction of the excited photocatalyst by a sacrificial reductant, would generate a photo-reductant capable of performing a single electron reduction of an oxime imidate IV-10. Mesolytic cleavage would then leave the N-centered radical IV-11 with a phenoxide anion. Subsequent 5-exo- trig cyclization to the appended alkene would generate a carbon centered radical IV-12. This radical could then be terminated with the appropriate radical trap to give a difunctionalized product IV-13. SH2 would lead to a hydroamination product, while trapping with a π-electrophile or aryl radical would lead to C-C bond formation. Hydrolysis of the oxazoline product could then furnish a 1,2 amino alcohol IV-14.

Figure 4.2 Difunctionalization strategy.

113

4.4 Results

4.4.1 Oxime Imidate

Although a triiodide-mediated approach can generate imidate radicals, under an oxidative manifold,156 alkene functional groups would break down to give alkene rearrangement, oxygenation,163 or amino iodination164 of the alkene. This would not allow for a diverse difunctionalization strategy. Other methods of generating imidate radicals include thermolysis; however, under extremely high temperatures, fragmentation and dimerization of the N-centered radicals is quite proficient.148 Photolysis of the N-Cl bond of trimethylsilyl N-chloro imidates also allows for the formation of imidate radicals,165 but this method does not allow for the facile synthesis of an imidate chaperone precursor. Knowing our strategy required a simple and reliable generation of an N-centered radical under reductive conditions, we concluded that an imidate with a weak N-X (either N-O or N-halide) bond, could be easily reduced to reveal a nitrogen-centered radical needed for the desired transformation. Since there are several photocatalytic methods to generate N-centered radicals through cleavage of an N-O bond,166,167 we decided to approach synthesizing an imidoyl chloride as our radical-relay chaperone. This would allow for a chaperone that could handle the addition of an alcohol to produce an imidate. In the first-generation synthesis of the imidoyl chloride IV-15, we took hydroxylamine IV-16, which could be easily acylated with the appropriate acyl chloride and deprotonated to give the hydroxamic acid potassium salt IV-17. Arylation using a diaryliodonium afforded the amide IV-18. This amide could then undergo dehydration using PCl5 to give the imidoyl chloride chaperone IV-15 (Scheme 4.3). Addition of an alkoxide allowed for the isolation of the starting oxime imidates. However, arylation of IV-17 to IV-18 via a diaryliodonium proved to be inefficient. In our second generation strategy, we could easily arylate N-hydroxyphthalamide IV-19 using Chan-Lam coupling168,169 conditions followed by phthalmide deprotection and acylation of IV-20 to afford the same amide intermediate IV-18 but in significantly higher and more reproducible yields. The introduction of the aryl boronic acid in the Chan-Lam coupling 114 also allowed for a potentially modular synthesis of the chaperone. Modularity could also be achieved by using different acyl chlorides besides benzoyl chloride. However, if there was an acyl group on the oxygen of the imidoyl chloride, alcohol addition became quite difficult as it often led to decomposition of the chaperone to yield a free OH. To circumvent this problem, generation of the oxime imidate could bypass the chaperone synthesis through a Mitsunobu reaction170 of the amide IV-18. However, there was usually poor chemoselectivity between the nitrogen and oxygen nucleophiles. Our second-generation strategy proved to be the most modular and efficient and was used throughout this imidate radical reactivity investigation.

Scheme 4.3 Synthesis of oxime imidate.

a.) BzCl,K2CO3, EtOAc/H2O; b.) KOH, EtOH; c.) PCl5, CCl4 or CHCl3; d.) NaH, ROH; e.) PhB(OH)2, CuCl, air, DCE; N2H4 H2O, 10% MeOH/CHCl3; 4M HCl in dioxanes; f.) DEAD, PPh3, ROH, THF

4.4.2 Hydroamination

Once the appropriate chaperone was in hand through combination of an allylic alcohol with imidoyl chloride IV-15, this oxime imidate was subjected to reductive photocatalytic conditions. Hünig’s base was used as the sacrificial reductant with 1,4 cyclohexadiene as the H-atom source under blue LED irradiation. Through initial reduction of the N-O bond under photocatalytic conditions, the N-centered radical was formed, which selectively underwent a 5-exo-trig cyclization. The subsequently generated alkyl radical was then capped with a hydrogen atom donor, affording 1,2- amino alcohol motifs. Hünig’s base could serve as the sacrificial reductant as well a hydrogen atom source for the reaction. 115

Once the conditions were optimized, we investigated the tolerance of our reaction conditions (Figure 4.3). Investigating the utility of this method, we explored a range of allylic alcohols. 5- exo-trig cyclization was preferentially kinetically favored with a range of radical intermediates with varying stability, such as primary (IV-21), secondary (IV-22), benzylic (IV-23), and tertiary (IV-24) radicals. Hydroamination of internal and terminal olefins as well as trisubstituted olefins (IV-25) were also tolerated. Unfortunately, tetra-substituted olefins did lead to an Overman rearrangement product. However, substitution on the alkene that would thermodynamically favor a 6-membered ring (IV-25) still gave 5-exo-trig cyclization. Chloro-(IV-26) and silyl-(IV-27) substituted olefins both survived reaction conditions. Natural product derivatives (IV-28-30) were amenable to reaction conditions. Acyclic (IV-31) and cyclic (IV-32) secondary alcohols also afforded hydroamination products with primarily syn-diastereoselectivity. Even with homoallylic (IV-33) or benzyl (IV-34) C-H bonds, competitive 1,5 hydrogen atom abstraction is not a viable pathway. Our method also allowed for hydroamination of complex natural products such as gibberellic acid methyl ester IV-35 leaving the free tertiary alcohol untouched, leading to orthogonal reactivity compared to other hydroamination methods.171 Hydrolysis of the formed oxazoline product can be hydrolyzed using HCl in THF to afford a N-Bz protected amino alcohol. In some cases, however, migration did occur to give an OBz product such as in IV-29.

116

Figure 4.3 Investigation of hydroamination strategy.

4.4.3 Aminoalkylation

Since we proposed that we were going through an alkyl radical intermediate IV-12 in our mechanism, we were interested in investigating whether this alkyl radical intermediate could be trapped by a carbon radical trap. Aware of Giese-type radical additions,32 we first tried Michael acceptors such as acrylates. With this, we were able to trap the carbon radical to afford aminoalkylated products (IV-36-38) with acrylates as shown in Figure 4.4. Excess radical trap was needed for efficient trapping as these radical traps are prone to polymerization. Some Michael acceptors were not as efficient at trapping the carbon radical. This included acrylonitrile and methyl vinyl ketone. However, 1,2 disubstituted cyclic olefins proved to be superior to their acyclic counterparts in terms of 117 isolation due to inseparable polymers formed from the acrylates. Other π-electrophiles, such as styrenes (IV-39-41) also gave amino-alkylation. Vinylpyridines (IV-42-43) were also competent radical traps. Although tertiary radicals were more efficient in trapping the π- electrophile, primary (IV-40) and secondary radicals could also be trapped with diphenylethylene.

Figure 4.4 Investigation of π-electrophile traps.

4.4.4 Amino-arylation

It has been previously reported that benzonitriles with strong electron withdrawing groups under the appropriate conditions can form radical anions.172 These aryl radicals can then couple with other motifs to created arylated organic molecules. Arnold showed that irradiating 1,4 dicyanobenzene with 1,1 dimethyl ethylene in acetonitrile, ipso substitution at the CN group of the benzonitrile followed by incorporation of a solvent molecule afforded the cyclized product IV-44.173 MacMillan and coworkers expanded upon this reactivity even further with photoredox chemistry. They found that these benzonitriles with 118 electron withdrawing groups could be easily reduced by an iridium photocatalyst to afford the radical anion. In the presence of alkyl amines, α-amino arylation occurred to afford IV- 45.174 In the presence of an amine catalyst, β-arylation of aldehydes and carbonyls could also produce IV-46 under photocatalysis.175 Inoue and coworkers showed that by using benzophenone as a photosensitizer, benzylic arylation of toluene to render IV-47 could be accomplished using these precursors176 (Figure 4.5).

Figure 4.5 Benzonitrile mediated arylations.

With these precedents in mind, we proposed that if these aryl radicals could be formed through reduction of an iridium photocatalyst, then we should be able to simultaneously generate the alkyl radical and the aryl radical. With these two radicals in solution, they could synergistically combine to give an arylated product. On the outset, the reaction did not work very efficiently. However, by changing the solvent from acetonitrile

119 to a 1:1 mixture of methanol/acetonitrile and decreasing the concentration to help solubilize the benzonitrile and stabilize the radical intermediate, we were able to afford good yields of the amino-arylated product (Figure 4.6). Benzonitriles with a CN group at the 2 (IV-48) and 4 (IV-49) position were well tolerated. 1,2 dicyanobenzene gave poorer yields most likely due to steric hindrance. Other electron deficient benzonitriles such as pentafluorocyanobenzene (IV-50), cyanopyridine (IV-51), and a para ester derivative (IV- 52) were all well tolerated.

Figure 4.6 Aminoarylation using electron deficient benzonitriles.

4.5 Mechanistic Studies

As previously discussed, due to the modular synthesis of the oxime imidate chaperones, we tested a few different imidate radical precursors to investigate how electronics would impact reactivity (Figure 4.7). The N-OMe bond of imidate IV-53 could not be sufficiently reduced as it has a large reduction potential, outside of the window of the photocatalysts explored. This was not surprising considering that the methoxy group is quite electron-rich. Only 10% of oxazoline IV-55 could be isolated which upon hydrolysis would give the amino alcohol IV-21. The N-OPh oxime imidate IV-54 gave the best results and was further used for exploration of this imidate reactivity.

120

Figure 4.7 Exploration of chaperone modularity effects on reactivity.

A note to be made about these imidate precursors is that although they are less prone to spontaneous rearrangement like the corresponding free NH imidates, rearrangement can still occur. Under Pd catalysis, rearrangement of the oxime imidate can occur through a 2e- pathway. However, under our conditions, the 1e- pathway allows for hydroamination (Scheme 4.4).

Scheme 4.4 Overman rearrangement of oxime imidates.

Other N-centered radical precursors have been shown to afford hydroamination reactivity under different reaction conditions.161,171 Our method provides a complimentary way to access these products from different starting materials. We subjected imidate IV- 58, imine IV-59, and amide IV-60, (precursors derived from alcohols, ketones, and acid

121 chlorides respectively) and we only observed cyclization to oxazoline IV-61 from imidate IV-58. There was no clear observation of dihydropyrrole IV-62 or lactam IV-63 which would have been produced through the cyclization of imine IV-59 and amide IV-60 (Scheme 4.5).

Scheme 4.5 Competition experiment between different radical precursors.

To investigate relative rates of radical trapping, we synthesized 1,6 diene IV-64 as a radical clock. Once a nitrogen-centered radical was generated, it quickly underwent a 5- exo-trig cyclization to give alkyl radical intermediate IV-65. In the presence of 1,4 CHD, cyclization of IV-65 to IV-66 rapidly occurred to furnish alkyl radical intermediate IV-66. This intermediate was then capped with a hydrogen atom to yield cyclized product IV-67. However, once methyl methacrylate is added to the reaction, cyclization of IV-65 to IV- 66 is not observed and trapping of radical intermediate IV-65 to form trapped product IV- 122

68 is isolated. Acrylate trapping of IV-66 is also not seen. From this study, it is found that radical trapping with methyl methacrylate is faster than the rate of the second cyclization of IV-65 to IV-66 and trapping the alkyl radical intermediates is slower than the rate of that same cyclization (Scheme 4.6).

Scheme 4.6 Radical trapping competition.

Probing the feasibility of radical-radical coupling, we noticed that 1,4 dicyanobenzene, 1,2 dicyanobenzene, and 1,3 dicyanobenzene, all have different reduction potentials (Figure 4.8). 1,3 dicyanobenzene has the highest reduction potential which is outside of the reduction potential window of our photocatalyst and we saw no reactivity. We only isolated appreciable yields of arylated oxazoline from 1,4 dicyanobenzene. Some product was isolated with 1,2 dicyanobenzene, however yields were low mainly due to steric hinderance of the radical-radical coupling step.

123

Figure 4.8 Comparison of benzonitrile substitution in arylation reactivity.

4.6 Conclusion

Our radical-relay chaperone strategy successfully demonstrates generation of imidate radicals from oxime imidates. This curtails rearrangement byproducts (allylic amines), conducive to two-electron chemistry observed with allylic imidates to allow for the difunctionalization of allylic alcohols. We were pleased to see that our method allowed for a broad range of difunctionalization of allylic alcohols. We were able to terminate alkyl radical intermediates with a hydrogen atom to afford hydroamination products and with carbon radical traps to afford carboamination products. Various radical traps such as acrylates, styrenes, and aryl nitriles were viable to afford different mechanisms of reactivity.

4.7 Experimental

4.7.1 General Information

All chemicals and reagents were purchased from Sigma-Aldrich, Alfa Aesar, Acros, TCI, Combi-Blocks, or ChemImplex. MeCN was distilled over calcium hydride before use. CH2Cl2, THF, Et2O and DMF were dried and degassed with nitrogen using an Innovative Technology solvent system. For flash column chromatography, Silicycle F60 (230-400 mesh) silica gel or a CombiFlash Automated Flash Chromatograph was used. For preparative thin-layer chromatography (PTLC) and thin layer chromatography (TLC) analyses, Merck silica gel 60 F254 plates were used and visualized under UV (254 nm) and 1 19 KMnO4. Melting points were determined using an Electrotherman IA9000. H, F, and

124

13C NMR spectra were recorded using a Bruker AVIII 400 MHz, AVIII 600 MHz, or AVIII 700 MHz NMR spectrometer. 1H NMR and 13C NMR chemical shifts are referenced with 1 13 1 respect to CDCl3 ( H: residual CHCl3 at δ 7.26, C: CDCl3 triplet at δ 77.16), CD2Cl2 ( H: 13 1 residual CH2Cl2 at δ 5.32, C: CD2Cl2 quintet at δ 53.84), CD3OD ( H: residual CH3OH 13 1 13 at δ 3.31, C: CD3OD septet at δ 49.00), or CD3CN ( H: residual CH3CN at δ 1.94, C: 1 CH3CN at δ 118.26). H NMR data are reported as chemical shifts (δ ppm), multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, app t = apparent triplet, app q = apparent quartet, app qd = apparent quartet of doublets), coupling constant (Hz), relative integral. 19F and 13C NMR data are reported as chemical shifts (δ ppm). High resolution mass spectra were obtained using Bruker MicrOTOF (ESI). IR spectra were recorded using a Thermo Fisher Nicolet iS10 FT-IR and are reported in terms of frequency of absorption (cm–1). The diastereomeric ratio of the hydroamination product was determined by 1H NMR analysis of the crude reaction mixture. Photochemical reactions were performed by placing reaction vessel approximately 10 cm away from one 90 W blue LED lamp (Kessil A360WE tuna blue) or two 45 W blue LED lamps (Kessil A160WE tuna blue). The temperature of the reaction was maintained at approximately 25 ºC via a fan.

General procedure for alcohol addition to imidoyl chloride (GP1)

To a flame-dried round bottom flask with a stir bar was added NaH (60% dispersion in mineral oil) (1.5 mmol, 1.5 equiv). The flask was evacuated and refilled with N2 three times. Dry THF (5 mL) was added via syringe. The reaction was cooled to 0 °C and then alcohol (1 mmol, 1 equiv) was added. The reaction mixture was allowed to stir for 3 hrs at room temperature. Then, the reaction was cooled to 0 °C and the imidoyl chloride (1.1

125 mmol, 1.1 equiv) in THF (5 mL) was added. The reaction was stirred at room temperature until full consumption of alcohol. Upon completion, the reaction was poured into a separatory funnel containing Et2O and H2O. The aqueous phase was extracted with Et2O.

The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude reaction mixture was loaded onto silica gel and purified to afford the oxime imidate.

General procedure for hydroamination of allylic alcohols (GP2)

To an oven-dried, 2-dram vial equipped with a stir bar was added oxime imidate (0.2 mmol, 1 equiv) and Ir photocatalyst (1 mol%). The vial was evacuated and backfilled with N2 three times. Dry acetonitrile (2 mL) was degassed using a freeze-pump-thaw i technique and added. Sequentially, Pr2NEt (174 µL, 1 mmol, 5 equiv) and 1,4- cylohexadiene (1,4-CHD) (38 µL, 0.4 mmol, 2 equiv) were added to the vial under N2. The reaction was irradiated with two 455 nm Blue LED lamps for 12 hrs and monitored by TLC. Upon completion, the reaction was concentrated and the crude oxazoline was loaded directly onto silica gel and purified to afford the oxazoline. (Note: In case oxazoline product co-elutes with phenol, dissolve the crude reaction mixture in CH2Cl2 and add 1M NaOH (5 equiv). Allow the mixture to stir at room temperature for 1 hr and extract the aqueous layer with CH2Cl2.) The combined organic phase was dried over MgSO4, concentrated, and loaded onto silica gel and purified to afford the pure oxazoline.

126

General procedure for hydrolysis of oxazolines (GP3)

The oxazoline (0.1 mmol) was dissolved in THF (1 mL) and 2M HCl (0.5 mL) was added and stirred at room temperature and monitored by TLC. Upon completion, saturated

NaHCO3 was added and the organic material was extracted with EtOAc. The combined organic phase was dried over MgSO4, concentrated, and loaded onto silica gel directly to afford the pure β-amido alcohol. Note: Hydrolysis of ester-containing products results in complex mixtures due to transesterification. Similarly, electron-poor arenes are prone to undesired nucleophilic aromatic substitution during acidic hydrolysis.

General procedure for aminoalkylation of allylic alcohols (GP4)

To an oven-dried, 2-dram vial equipped with a stir bar was added oxime imidate (0.1 mmol, 1 equiv) and Ir photocatalyst (1 mol%). The vial was evacuated and backfilled with N2 three times. Dry acetonitrile (4 mL), which was degassed using a freeze-pump- i thaw technique, was added. Sequentially, Pr2NEt (87 µL, 0.5 mmol, 5 equiv) and trap (1 mmol, 10 equiv) were added to the vial under N2. The reaction was irradiated with two 455 nm Blue LED lamps for 12 hrs and monitored by TLC. Upon completion, the 1H NMR of crude material was analyzed with 1,2-dichloroethane (0.1 mmol, 1 equiv) as an internal standard to determine yield. The crude oxazoline was loaded directly onto silica gel and

127 purified. The isolated material was then loaded on PTLC to afford the aminoalkylation product.

General procedure for aminoarylation of allylic alcohols (GP5)

To an oven-dried, 2-dram vial equipped with a stir bar was added oxime imidate (0.05 mmol, 1 equiv), Ir photocatalyst (2 mol%) and trap (0.25 mmol, 5 equiv). The vial was evacuated and backfilled with N2 three times. Dry acetonitrile (2.5 mL) and MeOH (2.5 mL), which were degassed using a freeze-pump-thaw technique, were added. Then, i Pr2NEt (17 µL, 0.1 mmol, 2 equiv) was added to the vial under N2. The reaction was irradiated with two 455 nm Blue LED lamps for the indicated amount of time and monitored by TLC. Upon completion, the reaction was concentrated and the 1H NMR of crude material was analyzed with 1,2-dichloroethane (0.05 mmol, 1 equiv) as an internal standard to determine yield. The crude oxazoline was loaded directly onto silica gel and purified to afford the aminoarylation product.

4.7.2 Synthesis of Imidoyl Chlorides

(Z)-N-methoxybenzimidoyl chloride (SIV-1). In a round-bottom flask containing a stir bar, O-methylhydroxylamine hydrochloride (1.8 g, 20 mmol, 1.1 equiv) and K2CO3 (5.5 g,

40 mmol, 2 equiv) were dissolved in a mixture of EtOAc (30 mL) and H2O (15 mL). The

128 mixture was cooled to 0 °C and acetyl chloride (2.3 mL, 20 mmol, 1 equiv) was added dropwise to the mixture. It was then allowed to stir at 0 °C for 2 hours. The reaction was then quenched with sat. NaHCO3 and more EtOAc was added. The organic layer was washed twice with sat. NaHCO3. It was then dried over MgSO4, filtered and concentrated. The crude material was used without further purification. The crude N-methoxybenzamide was dissolved in CCl4 or CHCl3 (68 mL) and cooled to 0 °C. PCl5 (4.6 g, 22 mmol, 1.1 equiv) was added and stirred under N2. After 6 hrs, the solvent was evaporated, and the residue was taken up in Et2O and washed twice with water. The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude material was loaded onto silica gel and purified by column chromatography (100% hexanes) to afford the imidoyl chloride SIV-1 as a liquid (1.5 g, 43%).

Rf: 0.83 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.87 – 7.84 (m, 2H), 7.46 – 7.37 (m, 3H), 4.11 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ: 137.3, 132.7, 130.6, 128.5, 127.3, 63.3. + HRMS (ESI): m/z calculated for C8H9ClNO [M+H] : 170.0373, found 170.0389. IR (neat): 3263, 1637, 1586, 1460, 1446, 1262, 1181, 1050, 967, 891.

(Z)-N-phenoxybenzimidoyl chloride (SIV-2). In a round-bottom flask containing a stir 177 bar, O-phenylhydroxylamine hydrochloride (1 equiv) and Na2CO3 (2 equiv) were dissolved in a mixture of EtOAc and H2O. The mixture was cooled to 0 °C and benzoyl chloride (1 equiv) was added dropwise to the mixture. It was then allowed to stir at 0 °C for 2 hours. The reaction was then quenched with sat. NaHCO3 and more EtOAc was added. The organic layer was washed twice with sat. NaHCO3. It was then dried over

MgSO4, filtered and concentrated. The crude material was used without further purification. (Note: the crude product can be recrystallized from EtOAc and hexanes to afford the pure product.). The N-phenoxybenzamide (11 mmol, 1 equiv) was dissolved in 129

CCl4 or CHCl3 (66 mL) and cooled to 0 °C. PCl5 (2.5 g, 12 mmol, 1.1 equiv) was added and stirred under N2. After 6 hrs, the solvent was evaporated, and the residue was taken up in Et2O and washed twice with water. The combined organic phases were dried over

MgSO4, filtered, and concentrated. The crude material was loaded onto silica gel and purified by column chromatography (100% hexanes) to afford the imidoyl chloride SIV-2 as a white solid (2.3 g, 91%).

Rf: 0.84 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 8.00 – 7.98 (m, 2H), 7.52 – 7.43 (m, 3H), 7.40 – 7.32 (m, 4H), 7.13 – 7.09 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ: 159.0, 141.6, 132.4, 131.3, 129.6, 128.7, 127.7, 123.4, 115.1. + HRMS (ESI): m/z calculated for C13H10ClNONa [M+Na] : 254.0349, 254.0348. IR (neat): 3056, 1589, 1560, 1475, 1456, 1446, 1306, 1261, 1197, 979, 949. MP: 36.7 – 37.4 °C.

4.7.3. Synthesis of Oxime Imidates

allyl (Z)-N-methoxybenzimidate (IV-53). Prepared following GP1 with the following changes, using prop-2-en-1-ol (68 µL, 1 mmol, 1 equiv), imidoyl chloride SIV-1 (187 mg, 1.1 mmol, 1.1 equiv), and NaH (60 mg, 1.5 mmol, 1.5 equiv), the product was obtained as a colorless oil (110 mg, 58%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.52 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.71 – 7.68 (m, 2H), 7.42 – 7.34 (m, 3H), 6.01 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.36 (dq, J = 17.0, 1.6 Hz, 1H), 5.25 (dq, J = 10.4, 1.3 Hz, 1H), 4.72 (dt, J = 5.8, 1.4 Hz, 2H), 3.92 (s, 3H).

130

13 C NMR (100 MHz, CDCl3) δ: 154.3, 133.3, 131.1, 130.1, 128.5, 127.3, 118.5, 72.5, 62.5.

HRMS (ESI): m/z calculated for C11H13NO2Na [M+Na]: 214.0844, found 214.0844. IR (neat): 2937, 2898, 2817, 1647, 1610, 1573, 1314, 1304, 1096, 1050.

allyl (Z)-N-phenoxybenzimidate (IV-54). Prepared following GP1 with the following changes, using prop-2-en-1-ol (213 µL, 2.1 mmol, 1 equiv), imidoyl chloride SIV-2 (579 mg, 2.5 mmol, 1.2 equiv), and NaH (126 mg, 3.15 mmol, 1.5 equiv), the product was obtained as a colorless oil (403 mg, 76%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.17 (2% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.88 – 7.81 (m, 2H), 7.48 – 7.39 (m, 3H), 7.36 – 7.28 (m, 4H) 7.06 – 7.00 (m,1H), 6.08 (ddt, J = 17.1, 10.4, 5.8 Hz, 1H), 5.41 (dq, J = 17.1, 1.5 Hz, 1H), 5.29 (dq, J = 10.5, 1.5 Hz, 1H), 4.93 (dt, J = 5.1, 1.3 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ: 159.6, 156.9, 133.3, 131.1, 130.9, 129.6, 128.8, 127.9, 122.4, 119.1, 114.8, 73.7.

HRMS (ESI): m/z calculated for C16H15NO2Na [M+Na]: 276.1000, found 276.0980. IR (neat): 3058, 2935, 2878, 1588, 1487, 1318, 1211, 1095, 932, 750, 689.

(E)-but-2-en-1-yl (Z)-N-phenoxybenzimidate (SIV-3). Prepared following GP1 with the following changes, using (E)-but-2-en-1-ol (180 µL, 2.1 mmol, 1 equiv), imidoyl chloride SIV-2 (579 mg, 2.5 mmol, 1.2 equiv), and NaH (126 mg, 3.15 mmol, 1.5 equiv). The product was obtained as a colorless oil (516 mg, 92%) after purification by flash column chromatography (2% EtOAc/hexanes).

131

Rf: 0.20 (5% EtOAc/hexanes) 1 H NMR (400 MHz, CDCl3) δ: 7.86 – 7.81 (m, 2H), 7.47 – 7.39 (m, 3H), 7.36 – 7.28 (m, 4H), 7.06 – 7.00 (m, 1H), 5.88 – 5.70 (m, 2H), 4.90 – 4.83 (m, 2H), 1.77 – 1.71 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ: 159.5, 156.9, 132.2, 131.2, 130.6, 129.4, 128.5, 127.7, 126.0, 122.2, 114.7, 73.6, 18.0. + HRMS (ESI): m/z calculated for C17H17NO2Na [M+Na] : 290.1157, found 290.1162. IR (neat): 2969, 2883, 1588, 1488, 1319, 1211, 1095, 963, 751, 689.

cinnamyl (Z)-N-phenoxybenzimidate (SIV-4). Prepared following GP1 using (E)-3- phenylprop-2-en-1-ol (134 mg, 1 mmol, 1 equiv), imidoyl chloride SIV-2 (254 mg, 1.1 mmol, 1.1 equiv), and NaH (60 mg, 1.5 mmol, 1.5 equiv). The product was obtained as a white solid (280 mg, 85%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.67 (20% EtOAc/hexanes) 1 H NMR (400 MHz, CDCl3) δ: 7.88 – 7.85 (m, 2H), 7.49 – 7.25 (m, 12H), 7.06 – 7.02 (m, 1H), 6.71 (dt, J = 15.8, 1.3 Hz, 1H), 6.44 (dt, J = 15.8, 6.4 Hz, 1H,), 5.10 (dd, J = 6.4, 1.3 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ: 159.5, 156.9, 136.3, 134.7, 131.0, 130.7, 129.5, 128.8, 128.6, 128.3, 127.7, 126.9, 124.0, 122.3, 114.7, 73.4. + HRMS (ESI): m/z calculated for C22H20NO2 [M+H] : 330.1494, found 330.1478. IR (neat): 3026, 1623, 1583, 1573, 1488, 1446, 1316, 1298, 1212, 1097. MP: 43.8 – 45.1 °C

132

3-methylbut-2-en-1-yl (Z)-N-phenoxybenzimidate (SIV-5). Prepared following GP1 with the following changes, using 3-methylbut-2-en-1-ol (213 uL, 2.1 mmol, 1 equiv), imidoyl chloride SIV-2 (579 mg, 2.5 mmol, 1.2 equiv), and NaH (126 mg, 3.15 mmol, 1.5 equiv). The product was obtained as a colorless oil (371 mg, 63%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.17 (2% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.86 – 7.81 (m, 2H), 7.47 – 7.39 (m, 3H), 7.37 – 7.29 (m, 4H), 7.05 – 7.00 (m, 1H), 5.57 – 5.51 (m, 1H), 4.93 (d, J = 7.3 Hz, 2H), 1.77 (s, 3H), 1.66 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 159.8, 157.5, 140.1, 131.5, 130.8, 129.6, 128.7, 127.9, 122.3, 119.8, 114.9, 69.6, 26.2, 18.5. + HRMS (ESI): m/z calculated for C18H19NO2Na [M+Na] : 304.1313, found 304.1287. IR (neat): 3060, 2972, 2911, 1588, 1488, 1297, 1211, 1091, 922, 750, 688.

. (E)-3-chlorooct-2-en-1-yl (Z)-N-phenoxybenzimidatephenoxybenzimidate (SIV-6). Prepared following GP1 using (E)-3-chlorooct-2-en-1-ol178 (163 mg, 1.0 mmol, 1 equiv), imidoyl chloride SIV-2 (254 mg, 1.1 mmol, 1.1 equiv), and NaH (60 mg, 1.5 mmol, 1.5 equiv). The product was obtained as a colorless oil (324 mg, 91%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.62 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.85 – 7.84 (m, 2H), 7.48 – 7.45 (m, 1H), 7.43 – 7.41 (m, 2H), 7.36 – 7.30 (m, 4H), 7.05 – 7.02 (m, 1H), 5.89 – 5.86 (m, 1H), 5.11 – 5.10 (m, 2H), 2.37 – 2.35 (m, 2H), 1.58 – 1.53 (m, 2H), 1.33 – 1.25 (m, 4H), 0.90 – 0.88 (m, 3H).

133

13 C NMR (100 MHz, CDCl3) δ: 159.4, 156.7, 139.8, 130.9, 130.7, 129.4, 128.6, 127.6, 122.3, 120.8, 114.6, 69.6, 39.6, 30.8, 26.9, 22.5, 14.1. + HRMS (ESI): m/z calculated for C21H24ClNO2Na [M+Na] : 380.1393, found 380.1374. IR (neat): 2955, 2930, 1624, 1588, 1488, 1466, 1320, 1299, 1211, 1158, 1098.

(E)-3-(triisopropylsilyl)allyl (Z)-N-phenoxybenzimidate (SIV-7). Prepared following GP1 using (E)-3-(triisopropylsilyl)prop-2-en-1-ol179 (231 mg, 1.0 mmol, 1.0 equiv), imidoyl chloride SIV-2 (254 mg, 1.1 mmol, 1.1 equiv), and NaH (60 mg, 1.5 mmol, 1.5 equiv). The product was obtained as a colorless oil (360 mg, 88%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.62 (10% EtOAc/hexanes) 1 H NMR (400 MHz, CDCl3) δ: 7.84 – 7.82 (m, 2H), 7.48 – 7.38 (m, 3H), 7.35 – 7.28 (m, 4H), 7.04 – 7.00 (m, 1H), 6.27 (dt, J = 19.0, 5.3 Hz, 1H), 5.94 (dt, J = 19.0, 1.5 Hz, 1H), 4.95 (dd, J = 5.3, 1.4 Hz, 2H), 1.12 – 1.00 (m, 21H). 13 C NMR (100 MHz, CDCl3) δ: 159.5, 157.0, 142.1, 131.0, 130.7, 129.4, 129.2, 128.5, 127.7, 122.2, 114.6, 75.5, 18.7, 10.9. + HRMS (ESI): m/z calculated for C25H35NO2SiNa [M+Na] : 432.2335, found 432.2319. IR (neat): 2939, 2861, 1637, 1588, 1487, 1463, 1339, 1208, 1109, 997, 918, 884.

(E)-3,7-dimethylocta-2,6-dien-1-yl (Z)-N-phenoxybenzimidate (SIV-8). Prepared following GP1 with the following changes, using geraniol (260 µL, 1.5 mmol, 1 equiv), imidoyl chloride SIV-2 (417 mg, 1.8 mmol, 1.2 equiv), and NaH (90 mg, 2.25 mmol, 1.5

134 equiv). The product was obtained as a colorless oil (233 mg, 44%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.20 (5% EtOAc/hexanes) 1 H NMR (400 MHz, CDCl3) δ: 7.79 – 7.81 (m, 2H), 7.47 – 7.38 (m, 3H), 7.36 – 7.28 (m, 4H), 7.05 – 6.99 (m, 1H), 5.53 (tq, J = 7.2, 1.3 Hz, 1H), 5.10 – 5.05 (m, 1H), 4.95 (d, J = 7.2 Hz, 2H), 2.12 – 2.01 (m, 4H), 1.66 (s, 3H), 1.64 (s, 3H), 1.59 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 159.6, 157.3, 143.2, 132.0, 131.3, 130.6, 129.4, 128.5, 127.7, 123.9, 122.1, 119.4, 114.7, 69.4, 39.7, 26.4, 25.8, 17.8, 16.7. + HRMS (ESI): m/z calculated for C23H27NO2Na [M+Na] : 372.1939, found 372.1917. IR (neat): 2980, 2912, 1588, 1488, 1212, 926, 751, 689.

(S)-(4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl (Z)-N-phenoxybenzimidate (SIV-9). Prepared following GP1 with the following changes, using (S)-perillyl alcohol (274 mg, 1.8 mmol, 1 equiv), imidoyl chloride SIV-2 (500 mg, 2.2 mmol, 1.2 equiv), and NaH (108 mg, 2.7 mmol, 1.5 equiv). The product was obtained as a colorless oil (408 mg, 65%) after purification by flash column chromatography (10% EtOAc/hexanes).

Rf: 0.20 (5% EtOAc/hexanes) 1 H NMR (400 MHz, CDCl3) δ: 7.89 – 7.85 (m, 2H), 7.50 – 7.42 (m, 3H), 7.40 – 7.32 (m, 4H), 7.09 – 7.03 (m, 1H), 5.85 – 5.79 (m, 1H), 4.81 (s, 2H), 4.79 – 4.73 (m, 2H), 2.37 – 2.14 (m, 4H), 2.08 – 1.95 (m, 1H), 1.95 – 1.86 (m, 1H), 1.77 (s, 3H), 1.61 – 1.47 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ: 159.6, 157.2, 149.7, 133.6, 131.1, 130.6, 129.4, 128.5, 127.7, 126.9, 122.1, 114.6, 109.0, 77.0, 40.9, 30.6, 27.5, 26.6, 20.9. + HRMS (ESI): m/z calculated for C23H25NO2Na [M+Na] : 370.1783, found 370.1791. IR (neat): 3061, 2917, 2835, 1588, 1489, 1317, 1212, 1095, 917, 886, 750, 689.

135

((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl (Z)-N-phenoxybenzimidate (SIV-10). Prepared following GP1 with the following changes, using (1R)-(-)myrtenol (482 mg, 3.12 mmol, 3.6 equiv), imidoyl chloride SIV-2 (200 mg, 0.86 mmol, 1 equiv), and NaH (91 mg, 3.78 mmol, 4.4 equiv). The product was obtained as a colorless oil (185 mg, 62%) after purification by flash column chromatography (3% EtOAc/hexanes).

Rf: 0.20 (5% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.93 – 7.87 (m, 2H), 7.52 – 7.42 (m, 3H), 7.42 – 7.34 (m, 4H), 7.10 – 7.05 (m, 1H), 5.71 – 5.65 (m, 1H), 4.95 – 4.80 (m, 2H), 2.50 – 2.43 (m, 1H), 2.43 – 2.30 (m, 3H), 2.20 – 2.11 (m, 1H), 1.35 (s, 3H), 1.26 (d, J = 8.7 Hz, 1H), 0.93 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 159.5, 157.1, 144.1, 131.1, 130.6, 129.4, 128.5, 127.7, 122.6, 122.1, 114.6, 75.7, 43.8, 40.8, 38.2, 31.7, 31.5, 26.3, 21.3. + HRMS (ESI): m/z calculated for C23H25NO2Na [M+Na] : 370.1783, found 370.1783. IR (neat): 2982, 2913, 1589, 1488, 1317, 1212, 1096, 920, 750, 689.

hex-1-en-3-yl (Z)-N-phenoxybenzimidate (SIV-11). Prepared following GP1 using hex- 1-en-3-ol (100 mg, 1 mmol, 1 equiv), imidoyl chloride SIV-2 (255 mg, 1.1 mmol, 1.1 equiv), and NaH (60 mg, 1.5 mmol, 1.5 equiv). The product was obtained as a colorless oil (288 mg, 98%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.66 (10% EtOAc/hexanes) 1 H NMR (400 MHz, CDCl3) δ: 7.83 – 7.81 (m, 2H), 7.47 – 7.38 (m, 3H), 7.36 – 7.28 (m, 4H), 7.04 – 7.01 (m, 1H), 5.91 – 5.82 (m, 1H), 5.21 – 5.15 (m, 3H), 1.99 – 1.90 (m,

136

1H), 1.77 – 1.68 (m, 1H), 1.58 – 1.45 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 159.5, 156.3, 136.8, 131.7, 130.5, 129.4, 128.5, 127.7, 122.1, 118.3, 114.7, 83.2, 37.5, 18.6, 14.1. + HRMS (ESI): m/z calculated for C19H21NO2Na [M+Na] : 318.1470, found 318.1463. IR (neat): 2958, 2929, 2872, 1653, 1589, 1521, 1488, 1339, 1236, 1158, 998.

cyclohex-2-en-1-yl (Z)-N-phenoxybenzimidate (SIV-12). Prepared following GP1 using cyclohex-2-en-1-ol (98 mg, 1 mmol, 1 equiv), imidoyl chloride SIV-2 (255 mg, 1.1 mmol, 1.1 equiv), and NaH (60 mg, 1.5 mmol, 1.5 equiv). The product was obtained as a colorless oil (214 mg, 73%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.59 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.90 – 7.89 (m, 2H), 7.49 – 7.41 (m, 3H), 7.37 – 7.31 (m, 4H), 7.06 – 7.03 (m, 1H), 6.05 – 5.98 (m, 2H), 5.34 – 5.33 (m, 1H), 2.21 – 1.91 (m, 5H), 1.71 – 1.66 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ: 159.6, 156.3, 133.2, 131.9, 130.5, 129.4, 128.5, 127.6, 126.1, 122.1, 114.6, 75.7, 29.4, 25.2, 18.8. + HRMS (ESI): m/z calculated for C19H19NO2Na [M+Na] : 316.1313, found 316.1297. IR (neat): 2980, 2971, 1594, 1588, 1488, 1322, 1212, 1158, 1097, 1072, 937.

hexa-1,5-dien-3-yl (Z)-N-phenoxybenzimidate (SIV-13). Prepared following GP1 using hexa-1,5-dien-3-ol (235 µL, 2.1 mmol, 1 equiv), imidoyl chloride SIV-2 (579 mg, 2.5 mmol, 1.2 equiv), and NaH (126 mg, 3.2 mmol, 1.5 equiv). The product was obtained as a

137 colorless oil (214 mg, 73%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.20 (5% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.86 – 7.80 (m, 2H), 7.47 – 7.38 (m, 3H), 7.36 – 7.27 (m, 4H), 7.05 – 7.00 (m, 1H), 5.99 – 5.84 (m, 2H), 5.28 – 5.12 (m, 5H), 2.74 – 2.65 (m, 1H), 2.61 – 2.52 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ: 159.5, 155.9, 136.1, 133.3, 131.5, 130.6, 129.4, 128.5, 127.7, 122.2, 118.6, 118.4, 114.7, 82.5, 40.0. + HRMS (ESI): m/z calculated for C19H19NO2Na [M+Na] : 316.1313, found 316.1296. IR (neat): 3073, 2982, 1588, 1488, 1297, 1210, 1092, 918, 750, 688.

1-phenylbut-3-en-2-yl (Z)-N-phenoxybenzimidate (SIV-14). Prepared following GP1 using 1-phenylbut-3-en-2-ol (148 mg, 1 mmol, 1 equiv), imidoyl chloride SIV-2 (255 mg, 1.1 mmol, 1.1 equiv), and NaH (60 mg, 1.5 mmol, 1.5 equiv). The product was obtained as a colorless oil (300 mg, 87%) after purification by flash column chromatography (2% EtOAc/hexanes).

Rf: 0.53 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.64 – 7.62 (m, 2H), 7.45 – 7.41 (m, 1H), 7.37 – 7.26 (m, 11H), 7.05 – 7.02 (m, 1H), 5.95 – 5.86 (m, 1H), 5.37 – 5.32 (m, 1H), 5.20 – 5.15 (m, 2H), 3.29 – 3.24 (m, 1H), 3.08 – 3.03 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ: 159.5, 156.2, 137.0, 136.0, 131.3, 130.5, 130.0, 129.4, 128.5, 128.4, 127.8, 126.8, 122.2, 118.7, 114.7, 83.6, 42.1. + HRMS (ESI): m/z calculated for C23H21NO2Na [M+Na] : 366.1470, found 366.1446. IR (neat): 3061, 3027, 1622, 1587, 1488, 1454, 1335, 1210, 1158, 1098, 1071.

138

C2-(Z)-N-phenoxybenzimidate of gibberellic acid methyl ester (SIV-15). To a flame- dried 50 mL round bottom flask with a stir bar were added gibberellic acid methyl ester180 (180 mg, 0.5 mmol, 1 equiv) and NaH (60 mg, 1.5 mmol, 3.0 equiv). The flask was evacuated and refilled with N2 three times. Dry THF (5 mL) was added via syringe. The reaction was stirred at 50 °C for 6 hrs. Imidoyl chloride SIV-2 (173 mg, 0.75 mmol, 1.5 equiv) in THF was added and stirred overnight at 50 °C. Upon completion, the reaction was poured into a separatory funnel containing EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated. The product was obtained as a white solid (63 mg, 23%, 20:1 dr) after purification by flash column chromatography (50% EtOAc/hexanes).

Rf: 0.20 (50% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 8.01 – 7.98 (m, 2H), 7.46 – 7.34 (m, 5H), 7.30 – 7.28 (m, 2H), 7.09 – 7.04 (m, 1H), 6.36 (dd, J = 9.4, 1.5 Hz, 1H), 6.19 (dd, J = 9.4, 2.5 Hz, 1H), 5.74 – 5.73 (m, 1H), 5.29 – 5.28 (m, 1H), 4.97 – 4.96 (m, 1H), 3.74 (s, 3H), 3.04 (d, J = 10.6 Hz, 1H), 2.83 (d, J = 10.5 Hz, 1H), 2.21 – 2.17 (m, 2H), 2.12 – 1.69 (m, 8H), 1.39 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 175.3, 172.5, 159.0, 156.8, 154.3, 132.8, 130.9, 130.6, 130.0, 129.6, 128.6, 127.4, 122.7, 114.5, 107.8, 89.0, 81.9, 78.3, 58.3, 54.3, 52.4, 51.2, 51.0, 50.3, 45.1, 43.2, 38.4, 17.2, 15.0. + HRMS (ESI): m/z calculated for C33H33NO7Na [M+Na] : 578.2155, found 578.2144. IR (neat): 3409, 2936, 1778, 1708, 1623, 1588, 1573, 1488, 1436, 1360, 1228.

139

4.7.4 Hydroamination of Allylic Alcohols

4-methyl-2-phenyl-4,5-dihydrooxazole (IV-21’). Prepared following GP2 with the following changes, using imidate IV-54 (51 mg, 0.2 mmol) and MeCN (1 mL). The product was obtained as a colorless oil (22 mg, 69%) after purification by flash column chromatography (5% EtOAc/hexanes).

Rf: 0.09 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.97 – 7.91 (m, 2H), 7.50 – 7.44 (m, 1H), 7.43 – 7.37 (m, 2H), 4.52 (dd, J = 9.5, 8.0 Hz, 1H), 4.43 – 4.32 (m, 1H), 3.95 (t, J = 7.9 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 163.8, 131.6, 128.6, 128.6, 128.2, 74.4, 62.4, 21.8. + HRMS (ESI): m/z calculated for C10H12NO [M+H] : 162.0919, found 162.0925. IR (neat): 2970, 2927, 2894, 1645, 1449, 1356, 1055, 1024, 968, 693.

4-ethyl-2-phenyl-4,5-dihydrooxazole (IV-22’). Prepared following GP2 with the following changes, using imidate SIV-3 (27 mg, 0.1 mmol) and MeCN (0.5 mL). The product was obtained as a colorless oil (14 mg, 80%) after purification by flash column chromatography (10% EtOAc/hexanes).

Rf: 0.14 (10% EtOAc/hexanes).

140

1 H NMR (400 MHz, CDCl3) δ: 7.97 – 7.91 (m, 2H), 7.49 – 7.42 (m, 1H), 7.42 – 7.35 (m, 2H), 4.46 (dd, J = 9.8, 8.1 Hz, 1H), 4.28 – 4.18 (m, 1H), 4.04 (t, J = 7.9 Hz, 1H), 1.82 – 1.71 (m, 1H), 1.66 – 1.55 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 163.6, 131.3, 128.4, 128.4, 128.1, 72.3, 68.1, 28.8, 10.1. + HRMS (ESI): m/z calculated for C11H14NO [M+H] : 176.1075, found 176.1081. IR (neat): 2980, 2887, 1265, 904, 726.

4-benzyl-2-phenyl-4,5-dihydrooxazole (IV-23’). Prepared following GP2 using imidate SIV-4 (66 mg, 0.2 mmol). The product was obtained as a colorless oil (29 mg, 62%) after purification by flash column chromatography (5% EtOAc/hexanes).

Rf: 0.41 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.95 (d, J = 7.3 Hz, 2H), 7.49 – 7.21 (m, 8H), 4.62 – 4.54 (m, 1H), 4.34 (t, J = 8.9 Hz, 1H), 4.14 (t, J = 7.9 Hz, 1H), 3.25 (dd, J = 13.7, 5.1 Hz, 1H), 2.73 (dd, J = 13.7, 8.9 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ: 164.1, 138.1, 131.5, 129.4, 128.7, 128.5, 128.4, 127.9, 126.6, 72.0, 68.0, 42.0. + HRMS (ESI): m/z calculated for C16H16NO [M+H] : 238.1232, found 238.1232. IR (neat): 3027, 2896, 1646, 1603, 1579, 1494, 1473, 1450, 1356, 1279.

4-isopropyl-2-phenyl-4,5-dihydrooxazole (IV-24’). Prepared following GP2 with the following changes, using imidate SIV-5 (56 mg, 0.2 mmol) and MeCN (1 mL). The

141 product was obtained as a colorless oil (23 mg, 61%) after purification by flash column chromatography (5% EtOAc/hexanes).

Rf: 0.40 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 8.00 – 7.91 (m, 2H), 7.49 – 7.43 (m, 1H), 7.42 – 7.37 (m, 2H), 4.45 – 4.35 (m, 1H), 4.17 – 4.07 (m, 2H), 1.92 – 1.81 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 163.5, 131.3, 128.4, 128.4, 128.1, 72.7, 70.2, 33.0, 19.1, 18.2. + HRMS (ESI): m/z calculated for C12H16NO [M+H] : 190.1232, found 190.1247. IR (neat): 2958, 2898, 2872, 1650, 1580, 1495, 1449, 1352, 1250, 1080, 1063.

4-(1-chlorohexyl)-2-phenyl-4,5-dihydrooxazole (IV-26’). Prepared following GP2 using imidate SIV-6 (72 mg, 0.2 mmol). The product was obtained as a colorless oil (48 mg, 91%, 1.3:1 dr) after purification by flash column chromatography (2% EtOAc/hexanes). Two diastereomers were isolated together for isolated yield. However, they were individually isolated for characterization. The relative stereochemistry was not determined.

Rf: 0.35 (Major), 0.27 (Minor) (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: (Major diastereomer) 7.96 – 7.94 (m, 2H), 7.51 – 7.47 (m, 1H), 7.43 – 7.39 (m, 2H), 4.53 – 4.41 (m, 3H), 4.02 – 3.97 (m, 1H), 2.13 – 2.04 (m, 1H), 1.81 – 1.70 (m, 1H), 1.69 – 1.63 (m, 1H), 1.51 – 1.41 (m, 1H), 1.38 – 1.31 (m, 4H), 0.93 – 0.89 (m, 3H). (Minor diastereomer) 7.97 – 7.95 (m, 2H), 7.52 – 7.47 (m, 1H), 7.43 – 7.38 (m, 2H), 4.67 (td, J = 8.5, 3.6 Hz, 1H), 4.47 – 4.45 (m, 2H), 4.14 – 4.10 (m, 1H), 1.83 – 1.77 (m, 2H), 1.69 – 1.59 (m, 1H), 1.48 – 1.38 (m, 1H), 1.35 – 1.26 (m, 4H), 0.90 – 0.87 (m, 3H).

142

13 C NMR (100 MHz, CDCl3) δ: (Major diastereomer) 165.3, 131.8, 128.6, 128.5, 127.6, 72.2, 70.5, 66.3, 35.5, 31.4, 26.1, 22.7, 14.2. (Minor diastereomer) 165.5, 131.8, 128.6, 128.5, 127.5, 71.4, 69.5, 64.7, 33.1, 31.4, 26.6, 22.7, 14.1. + HRMS (ESI): (Major diastereomer) m/z calculated for C15H21ClNO [M+H] : 266.1312, + found 266.1306. (Minor diastereomer) m/z calculated for C15H20ClNONa [M+Na] : 288.1131, found 288.1121. IR (neat): 2956, 2925, 2839, 1731, 1648, 1600, 1521, 1466, 1378, 1250, 1098.

2-phenyl-4-((triisopropylsilyl)methyl)-4,5-dihydrooxazole (IV-27’). Prepared following GP2 using imidate SIV-7 (82 mg, 0.2 mmol). The product was obtained as a colorless oil (46 mg, 73%) after purification by flash column chromatography (5% EtOAc/hexanes).

Rf: 0.80 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.95 – 7.93 (m, 2H), 7.47 – 7.44 (m, 1H), 7.41 – 7.38 (m, 2H), 4.53 (dd, J = 9.1, 7.8 Hz, 1H), 4.45 (app quint, J = 7.9 Hz, 1H), 3.97 (t, J = 7.7 Hz, 1H), 1.20 (dd, J = 14.6, 7.2 Hz, 1H), 1.16 – 1.09 (m, 21H), 0.93 (dd, J = 14.8, 7.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ: 162.6, 131.2, 128.4, 128.3, 128.3, 75.5, 64.1, 19.0, 18.1, 11.6. + HRMS (ESI): m/z calculated for C19H32NOSi [M+H] : 318.2253, found 318.2237. IR (neat): 2939, 2889, 2863, 1650, 1463, 1450, 1354, 1338, 1078, 1062, 881.

143

4-(6-methylhept-5-en-2-yl)-2-phenyl-4,5-dihydrooxazole (IV-28). Prepared following GP2 with the following changes, using imidate SIV-8 (70 mg, 0.2 mmol) and MeCN (1 mL). The product was obtained as a colorless oil (37 mg, 71%, 1.1:1 dr) after purification by flash column chromatography (5% EtOAc/hexanes).

Rf: 0.19 (5% EtOAc /hexanes). 1 H NMR (400 MHz, CDCl3) δ: (Mixture of two diastereomers) 7.99 – 7.92 (m, 4H), 7.50 – 7.43 (m, 2H), 7.43 – 7.36 (m, 4H), 5.20 – 5.05 (m, 2H), 4.48 – 4.32 (m, 2H), 4.30 – 4.07 (m, 4H), 2.17 – 1.93 (m, 4H), 1.92 – 1.78 (m, 1H), 1.75 – 1.65 (m, 7H) 1.63 – 1.59 (d, J = 4.7 Hz, 6H), 1.58 – 1.41 (m, 2H), 1.29 – 1.18 (m, 2H), 1.00 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: (Mixture of two diastereomers) 163.4 (2C), 131.7 (2C), 131.2 (2C), 128.4 (2C), 128.1 (2C), 124.6 (2C), 71.8, 71.5, 70.7, 69.5, 37.6, 36.9, 33.6, 33.0, 25.8 (2C), 25.7 (2C), 17.8 (2C), 15.7, 14.7. + HRMS (ESI): m/z calculated for C17H24NO [M+H] : 258.1858, found 258.1859. IR (neat): 2980, 2912, 1588, 1488, 1212, 926, 751, 689.

(5s,8s)-2-phenyl-8-(prop-1-en-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-ene (IV-29’). Prepared following GP2 with modifications using imidate SIV-9 (69 mg, 0.2 mmol) and MeCN (1 mL). The product was obtained as a colorless oil (42 mg, 82%, 4.1:1 dr) after purification by flash column chromatography (2 – 10% EtOAc/hexanes). Major diastereomer

Rf: 0.53 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 8.00 – 7.93 (m, 2H), 7.49 – 7.42 (m, 1H), 7.42 – 7.37 144

(m, 2H), 4.81 – 4.73 (m, 2H), 4.04 (s, 2H), 1.61 – 1.52 (m, 2H), 1.70 – 1.63 (m, 2H), 2.01 – 1.91 (m, 3H), 1.87 – 1.81 (m, 2H), 1.79 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 161.6, 150.4, 131.1, 128.7, 128.4, 128.3, 108.7, 79.1, 70.2, 45.0, 38.3, 27.8, 21.2. + HRMS (ESI): m/z calculated for C17H22NO [M+H] : 256.1701, found 256.1696. IR (neat): 2925, 1651, 1449, 1292, 1057, 694. Minor diastereomer

Rf: 0.25 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.97 – 7.91 (m, 2H), 7.49 – 7.43 (m, 1H), 7.42 – 7.36 (m, 2H), 4.74 – 4.69 (m, 2H), 4.20 (s, 2H), 1.99 – 1.84 (m, 5H), 1.77 – 1.72 (m, 5H), 1.78 – 1.27 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ: 162.2, 149.9, 131.3, 128.4, 128.7, 128.2, 108.7, 76.6, 71.5, 43.9, 37.4, 28.5, 21.3. + HRMS (ESI): m/z calculated for C17H22NO [M+H] : 256.1701, found 256.1696. IR (neat): 2980, 2888, 1647, 1380, 1264, 905, 727.

(1R,2S,5S)-6,6-dimethyl-2'-phenyl-5'H-spiro[bicyclo[3.1.1]heptane-2,4'-oxazole] (IV- 30’). Prepared following GP2 with the following changes, using imidate SIV-10 (69 mg, 0.2 mmol) and MeCN (1 mL). The product was obtained as a colorless oil (34 mg, 67%, 20:1 dr) after purification by flash column chromatography (5% EtOAc/hexanes).

Rf: 0.25 (5% EtOAc/hexanes). 1 H NMR (600 MHz, CDCl3) δ: 7.73 – 7.70 (m, 2H), 7.39 – 7.37 (m, 1H), 7.35 – 7.33 (m, 2H), 5.21 (d, J = 5.7 Hz, 1H), 5.14 (d, J = 5.7 Hz, 1H), 3.89 – 3.85 (m, 1H), 3.82 – 3.77 (m, 1H), 3.67 – 3.62 (m, 3H), 3.60 – 3.56 (m, 1H), 3.55 – 3.51 (m, 2H), 3.15 (s, 3H), 2.92 (s, 3H).

145

13 C NMR (100 MHz, CDCl3) δ: 161.2, 131.1, 128.4, 128.4, 128.3, 80.9, 75.4, 53.0, 40.2, 38.3, 31.5, 27.1, 24.6, 23.1. + HRMS (ESI): m/z calculated for C17H22NO [M+H] : 256.1701, found 256.1697. IR (neat): 2908, 2867, 1649, 1449, 1355, 1293, 1061, 975, 777, 693.

4-methyl-2-phenyl-5-propyl-4,5-dihydrooxazole (IV-31’). Prepared following GP2 using imidate SIV-11 (59 mg, 0.2 mmol). The product was obtained as a colorless oil (33 mg, 80%, 20:1 dr) after purification by flash column chromatography (10% EtOAc/hexanes).

Rf: 0.38 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.96 – 7.93 (m, 2H), 7.48 – 7.44 (m, 1H), 7.42 – 7.37 (m, 2H), 4.21 – 4.16 (m, 1H), 3.90 (quint, J = 6.8 Hz, 1H), 1.77 – 1.45 (m, 4H), 1.34 (d, J = 6.7 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 162.9, 131.3, 128.4, 128.4, 128.3, 86.9, 67.4, 37.2, 21.7, 18.7, 14.1. + HRMS (ESI): m/z calculated for C13H18NO [M+H] : 204.1388, found 204.1402. IR (neat): 2960, 2928, 2872, 1646, 1603, 1580, 1495, 1450, 1373, 1111, 1078.

2-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole (IV-32’). Prepared following GP2 using imidate SIV-12 (59 mg, 0.2 mmol). The product was obtained as a colorless oil (33 mg, 83%, 20:1 dr) after purification by flash column chromatography (5% EtOAc/hexanes). 146

Rf: 0.28 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.98 – 7.95 (m, 2H), 7.49 – 7.45 (m, 1H), 7.43 – 7.38 (m, 2H), 4.68 (dt, J = 8.2, 7.9 Hz, 1H), 4.13 (dt, J = 8.0, 6.3 Hz, 1H), 1.96 – 1.81 (m, 3H), 1.69 – 1.35 (m, 5H). 13 C NMR (100 MHz, CDCl3) δ: 164.4, 131.3, 128.6, 128.4, 128.3, 79.0, 63.8, 27.9, 26.4, 20.0, 19.3. + HRMS (ESI): m/z calculated for C13H16NO [M+H] : 202.1232, found 202.1241. IR (neat): 2935, 2860, 1636, 1579, 1495, 1449, 1347, 1082, 1064, 906.

5-allyl-4-methyl-2-phenyl-4,5-dihydrooxazole (IV-33’). Prepared following GP2 using imidate SIV-13 (29 mg, 0.1 mmol). The product was obtained as a colorless oil (14 mg, 67%, 20:1 dr) after purification by flash column chromatography (10% EtOAc/hexanes).

Rf: 0.14 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.99 – 7.91 (m, 2H), 7.50 – 7.43 (m, 1H), 7.43 – 7.37 (m, 2H), 5.90 – 5.77 (m, 1H), 5.23 – 5.12 (m, 2H), 4.25 (q, J = 6.4 Hz, 1H), 3.97 (quint, J = 6.7 Hz, 1H), 2.56 – 2.34 (m, 2H), 1.33 (d, J = 6.7 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 162.8, 132.8, 131.3, 128.4, 128.3, 128.2, 118.5, 85.7, 66.7, 39.1, 21.6. + HRMS (ESI): m/z calculated for C13H16NO [M+H] : 202.1232, found 202.1246. IR (neat): 3072, 2963, 2923, 1645, 1450, 1342, 1060, 917, 780, 693.

147

5-benzyl-4-methyl-2-phenyl-4,5-dihydrooxazole (IV-34’). Prepared following GP2 using imidate SIV-14 (69 mg, 0.2 mmol). The product was obtained as a colorless oil (34 mg, 67%, 20:1 dr) after purification by flash column chromatography (10% EtOAc/hexanes).

Rf: 0.36 (20 % EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.95 – 7.93 (m, 2H), 7.50 – 7.45 (m, 1H), 7.42 – 7.38 (m, 2H), 7.36 – 7.32 (m, 2H), 7.28 – 7.24 (m, 3H), 4.42 (app quart, J = 6.7 Hz, 1H), 4.02 (app quint, J = 6.7 Hz, 1H), 3.13 (dd, J = 13.9, 7.2 Hz, 1H), 2.89 (dd, J = 13.9, 6.1 Hz, 1H), 1.22 (d, J = 6.7 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 162.7, 137.0, 131.4, 129.5, 128.7, 128.5, 128.4, 128.2, 126.9, 87.2, 67.0, 41.2, 21.6. + HRMS (ESI): m/z calculated for C17H18NO [M+H] : 252.1388, found 252.1378. IR (neat): 3062, 3028, 2925, 1645, 1603, 1494, 1449, 1343, 1091, 1060, 977.

Oxazoline of gibberellic acid methyl ester (IV-35’). Prepared following GP2 using imidate SIV-15 (56 mg, 0.1 mmol). The product was obtained as a colorless oil (30 mg, 65%, 20:1 dr) after purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes).

Rf: 0.21 (60% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.90 – 7.88 (m, 2H), 7.48 – 7.44 (m, 1H), 7.40 – 7.36 (m, 2H), 5.25 – 5.24 (m, 1H), 4.50 (m, 1H), 4.74 – 4.71 (m, 1H), 4.64 – 4.61 (m, 1H), 3.74 (s, 3H), 2.98 – 2.94 (m, 1H), 2.78 – 2.70 (m, 2H), 2.24 – 1.62 (m, 11H), 1.30 (s, 3H). 148

13 C NMR (100 MHz, CDCl3) δ: 175.6, 173.0, 156.3, 131.8, 128.6, 128.5, 127.2, 107.7, 92.0, 84.1, 78.3, 63.2, 55.0, 53.3, 52.4, 50.8, 50.5, 49.8, 45.9, 43.0, 38.4, 35.6, 29.8, 17.8, 14.6. + HRMS (ESI): m/z calculated for C27H30NO6 [M+H] : 464.2073, found 464.2055. IR (neat): 2979, 1772, 1733, 1652, 1558, 1506, 1456, 1338, 1196.

4.7.5 Hydrolysis of Oxazolines

N-(1-hydroxypropan-2-yl)benzamide (IV-21). Oxazoline IV-21’ (21 mg, 0.13 mmol) was dissolved in THF (1 mL) and 3M HCl (250 µL) was added. The reaction was allowed to stir at room temperature for 24 hrs. H2O (10 mL) added and extracted with CHCl3 (25 mL x5). 6M NaOH (10 mL) was added to the aqueous layer and allowed stir at room temperature for 1 hr. The aqueous layer was then extracted with CHCl3 (25 mL x5). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The product was obtained as a white solid (16 mg, 69%) without further purification.

Rf: 0.31 (5% MeOH/CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ: 7.81 – 7.72 (m, 2H), 7.53 – 7.46 (m, 1H), 7.45 – 7.38 (m, 2H), 6.41 (bs, 1H), 4.35 – 4.20 (m, 1H), 3.77 (dd, J = 11.0, 3.7 Hz, 1H), 3.64 (dd, J = 11.0, 5.7 Hz, 1H), 2.98 (s, 1H), 1.28 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 168.2, 134.5, 131.8, 128.7 127.1, 67.3, 48.3, 17.3. + HRMS (ESI): m/z calculated for C10H13NO2Na [M+Na] : 202.0844, found 202.0849. IR (neat): 2980, 2883, 1646, 1382, 903, 724, 649.

N-(1-hydroxybutan-2-yl)benzamide (IV-22). Oxazoline IV-22’ (46 mg, 0.26 mmol) was dissolved in THF (2 mL) and 3M HCl (0.5 mL) was added. The reaction was allowed to 149 stir at room temperature for 24 hrs. H2O (10 mL) added and extracted with CHCl3 (25 mL x5). 6M NaOH (20 mL) was added to the aqueous layer and allowed stir at room temperature for 1 hr. The aqueous layer was then extracted with CHCl3 (25 mL x5). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The product was obtained as a white solid (43 mg, 85%) without further purification.

Rf: 0.36 (5% MeOH/CH2Cl2). 1 H NMR (600 MHz, CDCl3) δ: 7.80 – 7.73 (m, 2H), 7.51 – 7.46 (m,1H), 7.42 – 7.37 (m, 2H), 6.47 (d, J = 7.1 Hz, 1H), 4.09 – 4.09 (m, 1H), 3.76 (dd, J = 11.0, 3.6 Hz, 1H), 3.68 (dd, J = 11.0, 5.3 Hz, 1H), 3.12 (s, 1H), 1.73 – 1.65 (m, 1H), 1.65 – 1.57 (m, 1H), 0.98 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 168.4, 134.6, 131.8, 128.8, 127.1, 65.6, 54.0, 24.5, 10.8. + HRMS (ESI): m/z calculated for C11H15NO2Na [M+Na] : 216.1000, found 216.1008. IR (neat): 2980, 2881, 1381, 904, 727, 649.

N-(1-hydroxy-3-phenylpropan-2-yl)benzamide (IV-23). Prepared following GP3 using oxazoline IV-23’ (24 mg, 0.1 mmol). The product was obtained as a white solid (23 mg,

91%) after purification by flash column chromatography (100% CH2Cl2 to 2%

MeOH/CH2Cl2).

Rf: 0.38 (10% MeOH/CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ: 7.69 – 7.66 (m, 2H), 7.52 – 7.47 (m, 1H), 7.43 – 7.39 (m, 2H), 7.35 – 7.30 (m, 2H), 7.28 – 7.23 (m, 3H), 6.34 (bs, 1H), 4.41 – 4.33 (m, 1H), 3.81 (dd, J = 11.1, 3.5 Hz, 1H), 3.72 (dd, J = 11.1, 3.5 Hz, 1H), 3.01 (dd, J = 5.1, 3.7 Hz, 2H), 2.61 (bs, 1H). 13 C NMR (100 MHz, CDCl3) δ: 168.2, 137.7, 134.4, 131.8, 129.4, 128.9, 128.8, 127.1, 127.0, 64.6, 53.5, 37.2.

150

+ HRMS (ESI): m/z calculated for C16H17NO2Na [M+Na] : 278.1157, found 278.1145. IR (neat): 3308, 3029, 2957, 2360, 1637, 1602, 1532, 1489, 1449, 1331, 1283, 1248. MP: 147.9 – 148.8 °C.

N-(1-hydroxy-3-methylbutan-2-yl)benzamide (IV-24). Prepared following GP3 using oxazoline IV-24’ (19 mg, 0.1 mmol). The product was obtained as a colorless oil (16 mg, 79%) after purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes).

Rf: 0.18 (50% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.79 – 7.77 (m, 2H), 7.52 – 7.49 (m, 1H), 7.46 – 7.42 (m, 2H), 6.34 (bs, 1H), 3.98 – 3.92 (m, 1H), 3.84 – 3.76 (m, 2H), 2.59 (bs, 1H), 2.06 – 1.98 (m, 1H), 1.03 (app t, J = 6.8 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ: 168.6, 134.7, 131.8, 128.8, 127.1, 64.3, 57.7, 29.4, 19.8, 19.1. + HRMS (ESI): m/z calculated for C12H17NO2Na [M+Na] : 230.1157, found 230.1164. IR (neat): 3301, 2956, 2922, 2849, 1636, 1577, 1544, 1489, 1465, 1441.

N-(3-chloro-1-hydroxyoctan-2-yl)benzamide (IV-26). Prepared following GP3 using oxazoline IV-26’ (27 mg, 0.1 mmol) with following changes. Upon completion, sat.

NaHCO3 was added and extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated, and the white solid was triturated with hexanes to isolate the product (22 mg, 77%, 1:1 dr). Diastereomers identified from 1H COSY.

Rf: 0.38 (10% MeOH/CH2Cl2). 151

1 H NMR (400 MHz, CDCl3) δ: (first diastereomer) 8.14 – 8.10 (m, 2H), 7.68 – 7.63 (m, 1H), 7.54 – 7.50 (m, 2H), 4.77 – 4.73 (m, 1H), 4.62 – 4.55 (m, 2H), 4.06 – 4.02 (m, 1H), 2.02 – 1.93 (m, 2H), 1.72 – 1.63 (m, 2H), 1.40 – 1.34 (m, 4H), 0.95 – 0.90 (m, 3H). (second diastereomer) 8.14 – 8.10 (m, 2H), 7.68 – 7.63 (m, 1H), 7.54 – 7.50 (m, 2H), 4.64 – 4.62 (m, 1H), 4.42 – 4.34 (m, 2H), 3.94 – 3.90 (m, 1H), 1.92 – 1.81 (m, 2H), 1.56 – 1.46 (m, 2H), 1.40 – 1.34 (m, 4H), 0.95 – 0.90 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ: (Mixture of two diastereomers) 167.4, 167.2, 134.8, 134.8, 130.9, 130.9, 130.4, 130.4, 129.7, 129.7, 64.1, 62.6, 62.5, 61.6, 56.2, 55.3, 35.5, 35.5, 32.1, 32.0, 27.5, 26.9, 23.4, 23.4, 14.3, 14.3. + HRMS (ESI): m/z calculated for C15H23ClNO2 [M+H] : 284.1417, found 284.1410. IR (neat): 3059, 2862, 1729, 1599, 1520, 1454, 1387, 1251, 1099, 1027. MP: 189.2 – 191.4 °C.

N-(1-hydroxy-3-(triisopropylsilyl)propan-2-yl)benzamide (IV-27). Prepared following GP3 using oxazoline IV-27’ (32 mg, 0.1 mmol). The product was obtained as a white solid

(18 mg, 53%, 1.3:1) after purification by flash column chromatography (100% CH2Cl2 to

2% MeOH/CH2Cl2).

Rf: 0.50 (10% MeOH/CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ: 7.76 – 7.52 (m, 2H), 7.53 – 7.49 (m, 1H), 7.46 – 7.42 (m, 2H), 6.18 (bs, 1H), 4.47 – 4.39 (m, 1H), 3.80 (dd, J = 10.9, 3.3 Hz, 1H), 3.62 (dd, J = 10.8, 6.2 Hz, 1H), 2.71 (m, 1H), 1.57 (bs, 1H), 1.12 – 1.03 (m, 21H). 13 C NMR (100 MHz, CDCl3) δ: 168.0, 134.3, 131.8, 128.8, 127.0, 69.3, 49.8, 19.0, 19.0, 11.4. + HRMS (ESI): m/z calculated for C19H33NO2SiNa [M+Na] : 358.2178, found 358.2163. IR (neat): 3279, 2938, 2863, 1631, 1538, 1491, 1462, 1346, 1323, 1058.

152

((1s,4s)-1-amino-4-(prop-1-en-2-yl)cyclohexyl)methyl benzoate (IV-29). Oxazoline IV-29’ (major diastereomer, 34 mg, 0.13 mmol) was dissolved in THF (1 mL) and 3M HCl

(250 µL) was added. The reaction was allowed to stir at room temperature for 24 hrs. H2O

(10 mL) added and extracted with CHCl3 (25 mL x4). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The product was obtained as a white solid (34 mg, 96%, 20:1 dr) without further purification.

Rf: 0.47 (5% MeOH/CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ: 8.94 (s, 2H), 8.33 – 8.26 (m, 2H), 7.54 – 7.49 (m, 1H), 7.43 – 7.35 (m, 2H), 4.75 (s, 1H), 4.69 (t, J = 1.6 Hz, 1H), 4.38 (s, 2H), 2.09 (m, 2H), 1.96 – 1.78 (m, 3H), 1.71 (s, 3H), 1.54 – 1.37 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ: 166.1, 148.9, 133.4, 130.7, 129.1, 128.4, 110.1, 69.5, 56.1, 45.0, 31.5, 25.3, 20.9. + HRMS (ESI): m/z calculated for C17H24NO2 [M+H] : 274.1807, found 274.1796. IR (neat): 3328, 3260, 3065, 2926, 1633, 1550, 1435, 1303, 1051, 876, 708, 688, 663, 608, 522.

N-(3-hydroxyhexan-2-yl)benzamide (IV-31). Prepared following GP3 using oxazoline IV-31’ (20 mg, 0.1 mmol). The product was obtained as a white solid (21 mg, 96%, 20:1 dr) after purification by flash column chromatography.

Rf: 0.38 (10% MeOH/CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ: 7.79 – 7.76 (m, 2H), 7.51 – 7.47 (m, 1H), 7.44 – 7.40 (m, 2H), 6.45 (bs, 1H), 4.24 – 4.16 (m, 1H), 3.68 – 3.64 (m, 1H), 2.25 (bs, 1H), 1.53 – 1.39 (m, 4H), 1.31 – 1.29 (m, 3H), 0.94 – 0.86 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ: 167.6, 134.8, 131.6, 128.7, 127.1, 74.7, 49.4, 36.9, 19.0, 18.6, 14.2. 153

+ HRMS (ESI): m/z calculated for C13H19NO2Na [M+Na] : 244.1313, found 244.1322. IR (neat): 2982, 1737, 1652, 1522, 1447, 1372, 1235, 1097, 1044, 936.

N-(2-hydroxycyclohexyl)benzamide (IV-32). Prepared following GP3 using oxazoline IV-32’ (20 mg, 0.1 mmol). The product was obtained as a white solid (18.2 mg, 83%, 20:1) after purification by flash column chromatography.

Rf: 0.38 (10% MeOH/CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ: 7.80 – 7.77 (m, 2H), 7.51 – 7.47 (m, 1H), 7.44 – 7.40 (m, 2H), 6.53 (bs, 1H), 4.17 – 4.10 (m, 1H), 4.05 (m, 1H), 1.96 (bs, 1H), 1.84 – 1.78 (m, 2H), 1.72 – 1.63 (m, 3H), 1.61 – 1.53 (m, 1H), 1.50 – 1.39 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ: 167.3, 134.9, 131.6, 128.7, 127.1, 69.3, 51.3, 32.2, 27.3, 24.0, 19.8. + HRMS (ESI): m/z calculated for C13H17NO2Na [M+Na] : 242.1157, found 242.1163. IR (neat): 3304, 2962, 2911, 2846, 1624, 1577, 1528, 1490, 1448, 1424, 1355, 1279.

N-(3-hydroxyhex-5-en-2-yl)benzamide (IV-33). Oxazoline IV-33’ (14 mg, 0.07 mmol). was dissolved in THF (1 mL) and 3M HCl (250 µL) was added. The reaction was allowed to stir at room temperature for 24 hrs. H2O (10 mL) added and extracted with CHCl3 (25 mL x5). 6M NaOH (10 mL) was added to the aqueous layer and allowed stir at room temperature for 1 hr. The aqueous layer was then extracted with CHCl3 (25 mL x5). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The product was obtained as a white solid (8.3 mg, 56%, 20:1 dr) without further purification.

Rf: 0.42 (5% MeOH/CH2Cl2). 154

1 H NMR (400 MHz, CDCl3) δ: 7.81 – 7.77 (m, 2H), 7.53 – 7.48 (m, 1H), 7.47 – 7.41 (m, 2H), 6.43 (d, J = 7.9 Hz, 1H), 5.93 – 5.79 (m, 1H), 5.20 – 5.17 (m, 1H), 5.17 – 5.11 (m, 1H), 4.29 – 4.20 (m, 1H), 3.76 – 3.67 (m, 1H), 2.43 – 2.33 (m, 1H), 2.29 – 2.16 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 167.5, 134.8, 134.3, 131.6, 128.7, 127.1, 118.9, 73.6, 49.0, 39.6, 18.7. + HRMS (ESI): m/z calculated for C13H17NO2Na [M+Na] : 242.1157, found 242.1159. IR (neat): 3326, 2927, 1636, 1527, 989, 914, 712, 692.

N-(3-hydroxy-4-phenylbutan-2-yl)benzamide (IV-34). Prepared following GP3 using oxazoline IV-34’ (25 mg, 0.1 mmol). The product was obtained as a white solid (21 mg, 79%, 20:1 dr) after purification by flash column chromatography.

Rf: 0.54 (10% MeOH/CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ: 7.82 – 7.79 (m, 2H), 7.54 – 7.50 (m, 1H), 7.47 – 7.43 (m, 2H), 7.34 – 7.30 (m, 2H), 7.25 – 7.22 (m, 3H), 6.51 (bs, 1H), 4.35 – 4.27 (m, 1H), 3.91 – 3.89 (ddd, J = 8.9, 4.6, 2.4 Hz, 1H), 2.90 (dd, J = 13.7, 4.5 Hz, 1H), 2.75 (dd, J = 11.6, 6.8 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 167.4, 138.0, 134.8, 131.6, 129.5, 128.9, 128.7, 127.1, 126.9, 75.5, 48.9, 41.5, 18.8. + HRMS (ESI): m/z calculated for C17H20NO2 [M+H] : 270.1494, found 270.1493. IR (neat): 3341, 2924, 2853, 1716, 1636, 1522, 1487, 1452, 1271. MP: 141.9 – 142.3 °C.

155

4.7.6 Carboamination of Allylic Alcohols

methyl 4-methyl-4-(2-phenyl-4,5-dihydrooxazol-4-yl)pentanoate (IV-36). Prepared following GP4 using imidate SIV-5 (28 mg, 0.1 mmol). The product was obtained as a colorless oil after purification by flash column chromatography (hexanes to 10% EtOAc/hexanes) and preparative thin layer chromatography (20% EtOAc/hexanes). Yield: 72% (1H NMR)

Rf: 0.32 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.96 – 7.93 (m, 2H), 7.49 – 7.36 (m, 3H), 4.35 (dd, J = 10.2, 8.7 Hz, 1H), 4.25 (t, J = 8.3 Hz, 1H), 4.10 (dd, J = 10.2, 8.7 Hz, 1H), 3.67 (s, 3H), 2.42 – 2.38 (m, 2H), 1.76 – 1.67 (m, 2H), 0.93 (s, 3H), 0.89 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 174.8, 163.6, 131.3, 128.4, 128.4, 128.0, 75.4, 68.6, 51.8, 36.5, 34.3, 29.4, 22.8, 22.5. + HRMS (ESI): m/z calculated for C16H22NO3 [M+H] : 276.1600, found 276.1596. IR (neat): 2958, 1736, 1652, 1579, 1450, 1358, 1260, 1167, 1086, 1025, 965.

4-(2-(2-phenyl-4,5-dihydrooxazol-4-yl)propan-2-yl)dihydrofuran-2(3H)-one (IV-37). Prepared following GP4 using imidate SIV-5 (28 mg, 0.1 mmol). The product was obtained as a colorless oil after purification by flash column chromatography eluting with 35% ethyl acetate/hexanes. Yield: 66%, 1.1:1 dr (1H NMR)

Rf: 0.24 (35% EtOAc/hexanes). 156

1 H NMR (600 MHz, CDCl3) δ: (Mixture of two diastereomers) 7.96 – 7.90 (m, 4H), 7.51 – 7.47 (m, 2H), 7.44 – 7.39 (m, 4H), 4.56 (dd, J = 9.3, 8.2 Hz, 1H), 4.23 (dd, J = 9.3, 8.2 Hz, 1H), 4.38 (dd, J = 10.1, 8.8 Hz, 2H), 4.30 – 4.20 (m, 4H), 4.16 – 4.09 (m, 2H), 2.95 – 2.88 (m, 2H), 2.60 – 2.47 (m, 4H), 0.94 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H), 0.83 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ: (Mixture of two diastereomers) 177.3, 177.2, 164.1, 163.9, 131.7, 131.7, 131.7, 128.5, 128.5, 128.4, 128.4, 127.6, 74.8, 74.3, 70.2, 69.9, 68.5, 68.4, 44.2, 43.1, 37.8, 37.7, 30.5, 30.4, 29.8, 22.1, 20.9, 19.5. + HRMS (ESI): m/z calculated for C16H20NO3 [M+H] : 274.1443, found 274.1424. IR (neat): 2960, 2912, 1770, 1649, 1359, 1172, 1024, 963, 694.

methyl 2,4-dimethyl-4-(2-phenyl-4,5-dihydrooxazol-4-yl)pentanoate (IV-38). Prepared following GP4 with following changes. To an oven-dried a 2-dram vial equipped with a stir bar was added the oxime imidate SIV-5 (0.1 mmol, 1 equiv) and Ir photocatalyst

(2 mol%). The vial was evacuated and backfilled with N2 three times. Dry acetonitrile (0.5 mL), which was degassed using a freeze-pump-thaw technique, was added. Sequentially, i Pr2NEt (8 equiv) and trap (5 equiv) were added to the vial under N2. The reaction was irradiated with two 455 nm Blue LED for 12 hours and monitored using TLC. Upon completion, the 1H NMR of crude material was analyzed with 1,2-dichloroethane (0.1 mmol, 1 equiv) as an internal standard to determine yield. The product was obtained as a colorless oil after purification by flash column chromatography and preparative thin-layer chromatography. Yield: 81%, 1.3:1 dr (1H NMR)

Rf: 0.47 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: (Major diastereomer): 7.96 – 7.93 (m, 2H), 7.48 – 7.44 (m, 1H), 7.42 – 7.37 (m, 2H), 4.37 – 4.22 (m, 2H), 4.11 – 4.07 (m, 1H), 3.65 (s, 3H), 2.72 – 2.62 (m, 1H), 1.41 (dd, J = 14.2, 3.0 Hz, 1H), 1.31 (dd, J = 14.2, 2.8 Hz, 1H), 1.20 (d, J 157

= 7.0 Hz, 3H), 0.95 (s, 3H), 0.80 (s, 3H). (Minor diastereomer): 7.96 – 7.93 (m, 2H), 7.48 – 7.44 (m, 1H), 7.42 – 7.37 (m, 2H), 4.37 – 4.22 (m, 2H), 4.11 – 4.07 (m, 1H), 3.67 (s, 3H), 2.72 – 2.62 (m, 1H), 2.00 – 1.91 (m, 2H), 1.19 (d, J = 5.1 Hz, 3H), 0.89 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ: (Mixture of two diastereomers) 178.4, 178.3, 163.5, 163.5, 131.3, 131.3, 128.4, 128.4, 128.4, 128.4, 128.1, 128.1, 76.1, 75.2, 68.7, 68.6, 51.8, 43.6, 43.2, 37.2, 37.0, 35.6, 35.6, 23.4, 22.9, 22.6, 22.4, 20.7, 20.6. + HRMS (ESI): m/z calculated for C17H24NO3 [M+H] : 290.1756, found 290.1754. IR (neat): 2965, 2875, 1733, 1652, 1603, 1580, 1450, 1357, 1265, 1195, 1163.

4-(2-methyl-4-phenylbutan-2-yl)-2-phenyl-4,5-dihydrooxazole (IV-39). Prepared following GP4 using imidate SIV-5 (28 mg, 0.1 mmol). The product was obtained as a colorless oil after purification by flash column chromatography and preparative thin layer chromatography eluting twice with 5% EtOAc/hexanes. Yield: 88% (1H NMR)

Rf: 0.16 (5% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.99 – 7.94 (m, 2H), 7.49 – 7.44 (m, 1H), 7.44 – 7.37 (m, 2H), 7.31 – 7.27 (m, 2H), 7.23 – 7.15 (m, 3H), 4.35 (dd, J = 9.6, 8.5 Hz, 1H), 4.27 (app t, J = 8.1 Hz, 1H), 4.18 (dd, J = 9.6, 7.8 Hz, 1H), 2.76 – 2.58 (m, 2H), 1.68 – 1.59 (m, 2H), 1.04 (s, 3H), 0.97 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 163.4, 143.3, 131.3, 128.5, 128.5, 128.4, 128.4, 128.1, 125.8, 75.6, 68.6, 41.7, 37.0, 30.6, 23.2, 22.9. + HRMS (ESI): m/z calculated for C20H24NO [M+H] : 294.1858, found 294.1846. IR (neat): 2966, 2902, 1651, 1495, 1451, 1355, 1084, 1024, 964, 693.

158

4-(3,3-diphenylpropyl)-2-phenyl-4,5-dihydrooxazole (IV-40). Prepared following GP4 using imidate IV-54 (25 mg, 0.1 mmol). The product was obtained as a colorless oil after purification by chromatography on silica eluting with 10 – 15% EtOAc hexanes. Diluted with CH2Cl2 and stirred with 1M NaOH (1 mL) for 30 minutes, extracted with CH2Cl2, dried over Na2SO4 and concentrated. The product was obtained after preparative thin layer chromatography on silica, eluting with 10% EtOAc/hexanes. Yield: 57% (1H NMR)

Rf: 0.17 (10% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.95 – 7.89 (m, 2H), 7.48 – 7.44 (m, 1H), 7.42 – 7.36 (m, 2H), 7.28 – 7.24 (m, 8H), 7.20 – 7.13 (m, 2H), 4.46 (dd, J = 9.7, 8.1 Hz, 1H), 4.35 – 4.23 (m, 1H), 4.03 – 3.90 (m, 2H), 2.36 – 2.24 (m, 1H), 2.20 – 2.07 (m, 1H), 1.78 – 1.65 (m, 1H), 1.58 – 1.49 (m, 1H). 13 C NMR (150 MHz, CDCl3) δ: 163.6, 145.0, 144.9, 131.4, 128.6, 128.4, 128.4, 128.0, 126.3, 72.6, 66.9, 51.6, 34.7, 32.1. + HRMS (ESI): m/z calculated for C24H24NO [M+H] : 342.1858, found 342.1844. IR (neat): 2980, 2884, 1380, 1152, 903, 726, 649.

4-(2-methyl-4,4-diphenylbutan-2-yl)-2-phenyl-4,5-dihydrooxazole (IV-41). Prepared following GP4 using imidate SIV-5 (28 mg, 0.1 mmol). The product was obtained as a colorless oil after purification by flash column chromatography and preparative thin layer chromatography. Yield: 88% (1H NMR)

Rf: 0.31 (10% EtOAc/hexanes). 159

1 H NMR (400 MHz, CDCl3) δ: 7.96 – 7.90 (m, 2H), 7.49 – 7.43 (m, 1H), 7.43 – 7.36 (m, 2H), 7.34 – 7.23 (m, 8H), 7.18 – 7.10 (m, 2H), 4.24 – 4.13 (m, 2H), 4.12 – 4.00 (m, 2H), 2.31 (dd, J = 14.1, 7.7 Hz, 1H), 2.17 (dd, J = 14.1, 5.7 Hz, 1H), 0.96 (s, 3H), 0.77 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 163.3, 146.8, 146.4, 131.4, 131.2, 128.7, 128.6, 128.4, 128.1, 128.1, 127.8, 126.3, 126.1, 75.5, 68.6, 47.7, 45.4, 37.8, 23.9, 23.6. + HRMS (ESI): m/z calculated for C26H28NO [M+H] : 370.2171, found 370.2160. IR (neat): 2980, 2888, 1381, 1151, 1072, 952. MP: 129.4 – 130.4 °C.

4-(2-methyl-4-(pyridin-4-yl)butan-2-yl)-2-phenyl-4,5-dihydrooxazole (IV-42). Prepared following GP4 using imidate SIV-5 (14 mg, 0.05 mmol) with a 36 hour reaction time. The product was obtained as a colorless oil after purification by flash column chromatography and preparative thin layer chromatography (35% EtOAc/hexanes). Yield: 76% (1H NMR)

Rf: 0.09 (35% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 8.50 (m, 2H), 7.98 – 7.92 (m, 2H), 7.50 – 7.44 (m, 1H), 7.44 – 7.36 (m, 2H), 7.15 (d, J = 4.0 Hz, 2H), 4.37 (dd, J = 10.4, 8.6 Hz, 1H), 4.27 (app t, J = 8.1 Hz, 1H), 4.18 (dd, J = 10.4, 7.7 Hz, 1H), 2.76 – 2.58 (m, 2H), 1.70 – 1.64 (m, 2H), 0.99 (d, J = 3.0 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ: 163.6, 152.3, 149.8, 131.4, 128.4, 128.4, 128.0, 75.4, 68.5, 40.5, 37.0, 30.1, 29.9, 23.2, 22.6. + HRMS (ESI): m/z calculated for C19H23N2O [M+H] : 295.1810, found 295.1802. IR (neat): 2963, 2922, 1647, 1603, 1101, 700.

160

4-(2-methyl-4-(pyridin-2-yl)butan-2-yl)-2-phenyl-4,5-dihydrooxazole (IV-43). Prepared following GP4 using imidate SIV-5 (14 mg, 0.05 mmol). The product was obtained as a colorless oil after purification by flash column chromatography (35% EtOAc/ hexanes, then 50% EtOAc/hexanes). Yield: 72% (1H NMR)

Rf: 0.21 (35% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 8.54 – 8.50 (m, 1H), 7.98 – 7.93 (m, 2H), 7.58 (td, J = 7.7, 1.9 Hz, 1H), 7.48 – 7.43 (m, 1H), 7.42 – 7.37 (m, 2H), 7.20 – 7.16 (m, 1H), 7.11 – 7.07 (m, 1H), 4.36 (dd, J = 10.0, 8.6 Hz, 1H), 4.32 – 4.27 (m, 1H), 4.19 (dd, J = 10.0, 7.8 Hz, 1H), 2.92 – 2.77 (m, 2H), 1.80 – 1.73 (m, 2H), 1.05 (s, 3H), 0.97 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 163.5, 162.8, 149.4, 136.5, 131.3, 128.4, 128.4, 128.1, 122.9, 121.1, 75.5, 68.6, 39.8, 37.0, 33.2, 23.0, 22.8. + HRMS (ESI): m/z calculated for C19H23N2O [M+H] : 295.1810, found 295.1810. IR (neat): 2980, 2888, 1652, 1264, 964, 733, 694.

tert-butyl 3,4-dimethyl-4-(2-phenyl-4,5-dihydrooxazol-4-yl)pentanoate (SIV-16). Prepared following GP4 using imidate SIV-5 (28 mg, 0.1 mmol). The product was obtained as a colorless oil after purification by flash column chromatography and preparative thin layer chromatography. Yield: 34%, 1.5:1 dr (1H NMR)

Rf: 0.14 (10% EtOAc/hexanes) 1 H NMR (400 MHz, CDCl3) δ: (Mixture of two diastereomers) 7.98 – 7.92 (m, 4H), 7.49 – 7.44 (m, 2H), 7.42 – 7.37 (m, 4H), 4.39 – 4.23 (m, 6H), 4.19 – 4.10 (m, 4H), 2.65 (dd, J 161

= 14.8, 3.0 Hz, 1H), 2.57 (dd, J = 14.8, 3.0 Hz, 1H), 2.20 – 2.10 (m, 2H), 2.10 – 2.02 (m, 2H), 1.29 – 1.25 (m, 7H), 1.02 (d, J = 6.8 Hz, 3H), 0.97 – 0.91 (m, 8H), 0.80 (s, 3H), 0.77 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: (Mixture of two diastereomers) 174.2, 174.0, 163.3, 163.3, 131.3, 131.3, 128.4, 128.4, 128.4, 128.4, 128.1, 128.1, 73.3, 73.1, 68.7, 68.6, 60.5, 60.4, 39.2, 39.1, 37.5, 37.4, 36.8, 36.8, 20.3, 20.0, 19.7, 19.5, 15.1, 14.9, 14.4, 14.4. + HRMS (ESI): m/z calculated for C18H26NO3 [M+H] : 304.1913, found 304.1898. IR (neat): 2969, 2936, 1730, 1652, 1256, 1178, 1025, 965, 693.

4.7.7 Aminoarylation of Allylic Alcohols

4-(2-(2-phenyl-4,5-dihydrooxazol-4-yl)propan-2-yl)benzonitrile (IV-49). Prepared following GP5 using imidate SIV-5 (14 mg, 0.05 mmol). The product was obtained as an off-white solid after purification by flash column chromatography (eluted twice with 15% EtOAc/ hexanes). Yield: 85% (1H NMR yield)

Rf: 0.18 (15% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.94 – 7.88 (m, 2H), 7.62 – 7.56 (m, 2H), 7.54 – 7.46 (m, 3H), 7.43 – 7.37 (m, 2H), 4.53 (dd, J = 10.2, 7.6 Hz, 1H), 4.22 (dd, J = 10.2, 9.0 Hz, 1H), 3.94 (dd, J = 9.0, 7.6 Hz, 1H),1.46 (s, 3H), 1.38 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 164.5, 152.1, 132.0, 131.6, 128.5, 128.4, 127.8, 127.6, 119.1, 110.3, 75.9, 69.2, 42.1, 26.3, 23.5. + HRMS (ESI): m/z calculated for C19H19N2O [M+H] : 291.1497, found 291.1478. IR (neat): 2979, 2920, 2231, 1648, 1359, 1086, 843, 699, 559. MP: 74.2 – 76.4 °C.

162

2-(2-(2-phenyl-4,5-dihydrooxazol-4-yl)propan-2-yl)benzonitrile (IV-48). Prepared following GP5 using imidate SIV-5 (28 mg, 0.1 mmol). The product was obtained as a colorless oil (10 mg, 34%) after purification by flash column chromatography.

Rf: 0.36 (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.94 – 7.92 (m, 2H), 7.73 – 7.71 (m, 1H), 7.57 – 7.51 (m, 2H), 7.49 – 7.45 (m, 1H), 7.41 – 7.38 (m, 2H), 7.35 – 7.31 (m, 1H), 5.23 (dd, J = 10.0, 7.5 Hz, 1H), 4.28 (t, J = 9.5 Hz, 1H), 4.02 (dd, J = 8.8, 7.7 Hz, 1H), 1.66 (s, 3H), 1.43 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 164.3, 150.4, 136.3, 132.8, 131.5, 128.5, 128.4, 128.2, 127.8, 126.9, 120.4, 111.1, 73.5, 69.2, 42.7, 24.9, 22.8. + HRMS (ESI): m/z calculated for C19H19N2O [M+H] : 291.1497, found 291.1492. IR (neat): 2964, 2924, 1712, 1648, 1596, 1580, 1480, 1450, 1353, 1259, 1086.

2,3,5,6-tetrafluoro-4-(2-(2-phenyl-4,5-dihydrooxazol-4-yl)propan-2-yl)benzonitrile (IV-50). Prepared following GP5 with the following changes: To an oven-dried, 2-dram vial equipped with a stir bar was added oxime imidate SIV-5 (0.05 mmol, 1 equiv) and Ir photocatalyst (2 mol%). The vial was evacuated and backfilled with N2 three times. Dry acetonitrile (2.5 mL) and MeOH (2.5 mL), which were degassed using a freeze-pump-thaw i technique, were added. Sequentially, Pr2NEt (0.10 mmol, 2 equiv) and trap (0.25 mmol, 5 equiv) were added to the vial under N2. The reaction was irradiated with two 455 nm Blue LED lamps for 48 hrs and monitored by TLC. Upon completion, the reaction was

163 concentrated and the crude oxazoline was loaded directly onto silica gel and the product was obtained as a colorless oil after purification by flash column chromatography (first with 10% acetone/hexanes, then 20% EtOAc/hexanes). Yield: 78% (1H NMR)

Rf: 0.56 (20% Acetone/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 7.83 – 7.80 (m, 2H), 7.42 – 7.38 (m, 1H), 7.34 – 7.29 (m, 2H), 4.78 (dd, J = 9.9, 6.6 Hz, 1H), 4.29 (t, J = 9.6 Hz, 1H), 4.18 (dd, J = 9.2, 6.6 Hz, 1H), 1.46 (app t, J = 3.0 Hz, 3H), 1.39 (app t, J = 2.7 Hz, 3H). 13 C NMR (175 MHz, CDCl3) δ: 165.0, 148.7 – 147.0 (m), 145.7 – 145.6 (m), 132.5 (t, J = 12.2 Hz), 131.9, 128.5, 128.5, 127.3, 107.6 (t, J = 3.5 Hz), 92.7 (t, J = 17.3 Hz), 73.4, 68.8, 45.0, 29.8, 23.8 – 23.7 (m). 19 F NMR (376 MHz, CDCl3) δ: –132.7 – –132.8 (m, 2F), –132.9 – –133.0 (m, 2F). + HRMS (ESI): m/z calculated for C19H15F4N2O [M+H] : 363.1121, found 363.1103. IR (neat): 3007, 2946, 1647, 1473, 1459, 1296, 1257, 1085, 975, 907.

2-phenyl-4-(2-(pyridin-4-yl)propan-2-yl)-4,5-dihydrooxazole (IV-51). Prepared following GP5 using imidate SIV-5 (14 mg, 0.05 mmol), The product was obtained as a colorless oil after purification by flash column chromatography (35%EtOAc/hexanes). Yield: 62% (1H NMR)

Rf: 0.09 (35% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3) δ: 8.53 (m, 2H), 7.95 – 7.89 (m, 2H), 7.51 – 7.46 (m, 1H), 7.43 – 7.37 (m, 2H), 7.32 (d, J = 4.5 Hz, 2H), 4.54 (dd, J = 10.1, 7.6 Hz, 1H), 4.23 (dd, J = 10.1, 9.1 Hz, 1H), 3.96 (dd, J = 9.1, 7.6 Hz, 1H), 1.45 (s, 3H), 1.35 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ: 164.4, 155.6, 149.7, 131.4, 128.3, 128.3, 127.5, 122.1, 75.5, 69.0, 41.5, 26.0, 22.6.

164

+ HRMS (ESI): m/z calculated for C17H19N2O [M+H] : 267.1497, found 267.1497. IR (neat): 2965, 2928, 1645, 1409, 1355, 1261, 1089, 966, 824, 695, 572.

165

Chapter 5 Ketyl Radical Reactivity

Portions of this chapter are adapted from:

Wang, L..; Lear, J. M.; Rafferty, S. M.; Fosu, S. C.; Nagib, D. A. “Ketyl Radical Reactivity via Atom Transfer Catalysis.” Science, 2018, 362, 225 – 229

5.1 Umpolung Chemistry

The term “umpolung” (which means ‘reversal’ in German) was first introduced by Seebach and Kolb to describe the unique synthetic strategy in organic synthesis of reversing the normal polarity of functional groups.181 Before the coinage of this term to label this chemical phenomenon, polarity reversal was also known as “symmetrisation, dipole inversion, or charge affinity inversion” in organic synthesis.181 With umpolung reactivity, centers that are traditionally one polarity are reversed, allowing for diverse ways to construct carbon-carbon bonds and the availability of exceptional transformations.182,183 With traditional polarity reactivity, it is not possible to have an even number of carbon centers between two heteroatom groups; however, with umpolung chemistry this becomes feasible.183 Early examples of umpolung chemistry are depicted in Scheme 5.1. One seminal example is the benzoin condensation which was first reported by Wohler and Liebig in 1832184 and the mechanism of the reaction was later elucidated by Lapworth.185 In this reaction, two benzaldehyde units V-1 are condensed together to create benzoin V-2. The aldehydes by themselves do not react considering they are both electrophilic species, but in the presence of a cyanide anion, the anion can add into the carbonyl. This leaves the adjacent proton quite acidic, so it can be easily deprotonated generating a nucleophilic carbonyl through a nitrile enolate V-3. 166

Other illustrations of cyanide anions reversing the polarity of carbonyls is demonstrated with the Stetter reaction. In this reaction, the first step is the same as in the benzoin condensation in that a cyanide anion attacks an aldehyde and after deprotonation creates V-3. However, once this nucleophilic carbon radical is generated, it adds into unsaturated carbonyls to produce V-4.186 This reaction is more robust than the previously mentioned benzoin condensation because the benzoin condensation is reversible. However, the compounds formed in the Stetter reaction are more stable, making reversibility more of a challenge, funneling the benzoin products into the desired compounds. Umpolung reactivity is also demonstrated in biology, where thiamine can catalyze these polarity reversal reactions, such as the decarboxylation of pyruvate. Using thiazolium salts as catalysts for umpolung chemistry has also been employed in the benzoin condensation and Stetter reaction through a Breslow intermediate V-5.187 Carbenes are organic molecules with shared and unshared pairs of electrons. N- heterocyclic carbenes (NHC) are often used in a similar manner to cyanide anions and thiazolium salts, in that they can reverse the polarity of carbonyl compounds.188 Observation of carbenes can be quite difficult due to its high reactivity as they are prone to dimerization. Due to strength of metal carbon bonds, seminal reports of carbene observation include the isolation of chromium and mercury carbene-metal complexes.189,190 Arduengo found that making a carbene center sterically encumbered prevents dimerization and allows for the observation of a free carbene. This was done by decorating a carbene with two bulky adamanyl groups.191 The Corey-Seebach reaction allows for carbonyls V-6 to be precursors for carbonyl adducts V-7. This takes advantage of the fact that α-protons can become quite acidic if they are next to a divalent sulfur. Corey and Seebach found that dithianes can be easily generated from aldehydes or acetals and subsequently deprotonated to generate an acyllithium species V-8 as an acyl anion equivalent. This species can then react with electrophiles to produce acylated compounds.192

167

Scheme 5.1 Examples of Umpolung reactivity.

5.2 Ketyl Radicals

Another method to render carbonyls nucleophilic is through the generation of ketyl radicals. However, the generation of these radicals usually requires strong metal reductants (Li, Na, Sn, and Sm).193 Various reagents are more equipped to allow for single electron transfer to give ketyl radicals such as titanium. TiCl3 has been used in conjunction with

LiAlH4 for the reductive coupling of ketones and aldehydes to render alkenes through McMurry coupling.194,195 This coupling strategy can also be accomplished with the use of other reductants such as zinc196 and magnesium.197 This deoxygenation approach of carbonyls was first reported by Sharpless with tungsten halides.198 Samarium diiodide or Kagan’s reagent is also often used as a single electron reductant to afford ketyl radical reactivity for organic transformations. HMPA is often used with this reagent to break up aggregates to lower the reduction potential of the reductant.199

168

Due to the versatility of this reagent it has been employed extensively in natural product syntheses.200

5.3 Ketyl Coupling

Early examples of intramolecular ketyl radical coupling include cyclization to cyclopentanones. This could be accomplished with reduction of carbonyls to the corresponding ketyls with a combination of sodium and liquid ammonia201 or with sodium naphthalide as a reductant.202 Corey et al also found that efficient cyclization of ketones to alkenes and alkynes could be accomplished by using TMSCl and Zn.203 Aside from using metals, these transformations can happen through photochemical204 and electrochemical205 initiation.

5.4 Strategy

Strong metal reductants which are often needed to form ketyls primarily go through reductive pathways. Aryl aldehydes are often employed as coupling partners due to a lower reduction potential versus aliphatic aldehydes, which have reduction potentials of -1.9 V and -2.2 V vs. SCE respectively.206 We hypothesized that if we would be able to pre- activate aliphatic aldehydes to lower their reduction potential, we would be able to use much milder reductants. As shown in Table 5.1, the reduction potential of cyclohexyl bromide V-9 is higher than that of cyclohexyl iodide V-10 (-1.7 V vs. -1.5 V respectively). Since iodide is a much bigger atom than bromide, steric repulsion elongates the C-I bond, making it weaker and easier to reduce. Due to hyperconjugation of the lone pair on the oxygen atom of the of cyclohexyl bromide sugar derivative V-11, this compound has an even lower reduction potential (-1.3 V). Noticing that hyperconjugation could allow for lower reduction potential of cyclic halides, we proposed that an α-oxy iodide should have an even lower reduction potential than all three cyclic halides. If we could have a protected carbonyl

169 halide system, a carbonyl radical could be generated (from reduction of the carbon-halide bond) which could add into π systems.

Table 5.1 Hyperconjugation effects on reduction potentials.

5.5 Results

5.5.1 Initiation with Et3B/O2

We synthesized our α-oxy iodide intermediates from an adaptation of a procedure reported by French and Adams to get α-oxy halides.207 Acyl iodide can be generated in situ through a Finkelstein reaction of acyl chloride and sodium iodide. Once the acyl iodide was generated, the simple aliphatic aldehyde pentanal was added to the system. The initial reduction potential of the aliphatic aldehyde V-12 is high, and our hypothesis was proven correct that this strategy could lower the carbonyl reduction potential. The measured reduction potential of the α-oxy iodide V-13 was -1.1 V (Scheme 5.2).

Scheme 5.2 Generation of α-oxy iodide.

We subjected these α-oxy iodides to Et3B/O2 to produce ketyl radicals. In the presence of alkyne electrophiles, we were able to observe the coupling of these radicals to

170

π-traps. The vinyl radical could then be trapped with iodide to lead to a redox neutral atom transfer radical addition (ATRA) product V-14, or subsequent reduction of the vinyl iodide to the alkene. This allows for more control over the reactivity as compared to strong metal reductants because it allows for a redox neutral pathway. Depending on the radical trap introduced to the system, both reaction manifolds can be accessed.

Since initiation with Et3B/O2, forms ethyl radicals, we hypothesized that an alkyl radical precursor additive could help radical chain propagation in the reaction. With ethyl iodide, we saw an increase in yield from 50% to 60% of V-15 (Scheme 5.3). (Me3Si)3SiH was found to be the most efficient H atom source to render the reductive coupling product

V-16. Ph3SiH was inferior to (Me3Si)3SiH due to the difference in the strength of the Si-H bond.

Scheme 5.3 Optimization of ketyl radical trapping.

Upon investigation of the reaction scope (Figure 5.1), we saw that various acyl iodides were amenable to reaction conditions. The Z-isomer is slightly favored in this reaction. Sterically larger acyl iodides helped to improve this selectivity as is shown with the comparison of V-15 with V-17 which gives 1:1 vs 1.3:1 diastereoselectivity. Increasing the size of the protecting group even more to a Piv group (V-18) increased the

171 diastereoselectivity to 1.5:1. Aliphatic aldehydes of different sterics nBu (V-15), iPr (V- 19), tBu (V-20) all gave moderate yields. Ethers (V-21), aromatics (V-22), halides (V-23), ketones (V-24), and esters (V-25) all survived reaction conditions. It is worth noting that aryl ketones and halides are often reduced under harsher reductive protocols.

Figure 5.1 Synthetic utility of ketyl radical coupling.

172

The alkynes that could be used in this method included electron deficient alkynes with benzyl (V-26), aryl (V-28), and thioester (V-29) substituents. The Z-selectivity of the reaction is improved upon addition of an alkyne trap with a silyl substituent (V-29-V-30), i with Si Pr3 (V-31) giving almost exclusive Z-selective vinyl iodides. This increased selectivity could be attributed to α-silyl stabilization. Interestingly, higher Z- selectivity was observed under reductive conditions, so we wanted to gain some mechanistic insight into the selectivity (Scheme 5.4). Under our atom transfer conditions, we got a 1.1:1 mixture of the vinyl iodides V-15; however when we subjected the vinyl iodide mixture to silane we observed a 4:1 mixture of Z:E alkenes V- 16, which is the same ratio observed when coupling straight from the aldehyde and alkyne under the reductive atom transfer manifold. The isomerization is not occurring in the presence of just Et3B/O2 as subjecting the mixture of vinyl iodides V-15 to ATRA conditions led to no isomerization.

Scheme 5.4 Investigation of diastereoselectivity.

173

5.5.2 Catalytic Mn Coupling

Although we were able to successfully obtain atom transfer radical addition

(ATRA) under stoichiometric Et3B/O2 initiation, over reduction of the vinyl iodides was still an issue. The synthesis of vinyl halides is not trivial. These precursors can be used as intermediates for the synthesis of many other complex natural products. One method to make vinyl halides includes cross metathesis.208 Sub-stoichiometric amounts of radical initiator led to significantly decreased yields. To combat this problem, we developed milder, photocatalytic conditions. Udding and coworkers reported a copper-catalyzed ATRA reaction of 209 chloroacetates V-32 to tetrahydrofurans V-33. As previously discussed, SmI2 is a powerful reagent for reductive coupling.210,211 It is often used stoichiometrically, however Corey and coworkers have shown that it can be used catalytically to reduce alkyl iodides V-34 to the corresponding alkyl radicals which can add into alkynes to generate vinyl cyclopentanes V-35. However, this method does require using a mercury-zinc amalgum.212 Ruthenium and Iridium photocatalysts have also been shown to produce ketyl radicals to add into π-systems.213 As shown in Scheme 5.5c, a Ru photocatalyst was used to generate a ketyl radical from substrate V-36 which underwent an intramolecular cyclization to give V-37. Two electron pathways to couple aldehydes and alkynes have been extensively studied by Montogomery and Jamison with nickel catalysis towards natural product synthesis.214–219 Under nickel catalysis, V-38 and V-39 can undergo an intermolecular coupling to produce V-40. In many ketyl radical couplings, (for example those shown in Scheme 5.5b-c) overreduction still occurs. There have however been recent examples where organic photocatalysts can employ ATRA mechanisms effectively.220

174

Scheme 5.5 Catalytic ATRA and ketyl radical coupling.

We later found that adding Zn(OTf)2 as a Lewis acid catalyst helps give better yields of AcI. Combining AcI with aldehyde V-41 to generate the α-oxy iodide, we investigated several photocatalysts to see if one would be able to couple the α-oxy iodide with alkyne V-42 to produce either V-29 or V-43 (Table 5.2). These catalysts included iron, ruthenium, iridium, and manganese. We were pleased to note that Mn2CO10 gave the best yields with high Z-selectivity. The reactivity of Mn2CO10 has not been extensively applied to organic synthesis methodolgy,221 as this catalyst is mainly used for polymerization chemistry.222

175

Table 5.2 Investigation of catalytic ATRA methods.

The proposed mechanism for this coupling strategy is shown in Figure 5.2. The photocatalyst, Mn2CO10, is homolytically cleaved by blue LED irradiation to give two 17 e- Mn· radicals (V-44). The Mn· then abstracts I· from the α-oxy iodide to generate the ketyl radical V-45 and MnI V-46. This ketyl radical then combines with π-electrophile V- 47. The resulting vinyl radical V-48 then abstracts I· from Mn-I to give the vinyl iodide V- 49 while regenerating the photocatalyst. Under these mild ATRA reaction conditions, overreduction to alkene V-50 does not occur which classical happens with reductive coupling.

176

Figure 5.2 Proposed mechanism for Mn catalyzed ketyl radical coupling.

We were able to achieve carbonyl-alkyne couplings of various aldehydes and ketones with pi electrophiles with high functional group tolerability (Figure 5.3). Many of these coupling partners could not be employed using our first generation Et3B/O2 conditions. Investigating the synthetic utility, we found that using this manganese system, pentanal was able to couple with a variety of alkynes. Interestingly, through the α-oxy iodide intermediate, pentanal was able to couple to triethylsilylacetylene (V-30) and a boronate (V-51), which gives the produced compound more synthetic handles for further derivatization. Aryl groups (V-52) were tolerated and diene products (V-53) could be generated. Multiple functional groups remained untouched in the reaction conditions including esters (V-15), thioesters (V-54), weak α-oxy C-H bonds (V-55), alkynes (V-56), alcohols (V-57), and ketones (V-58-V-59).

177

Figure 5.3 Scope of Mn-catalyzed coupling.

178

We also investigated the tolerability of different aldehyde coupling partners. Simple formaldehyde (V-60) as well as other simple aliphatic aldehydes (V-61) proved successful. Aryl groups with varying electronics were also tolerated (V-62-V-64). Other functional groups that were viable on the aldehydes included ethers (V-65-V-66), amides (V-67-V-69), and halides (V-70-V-71). Knowing that the reaction protocol was quite successful for coupling aldehydes, we wanted to explore how this strategy faired for ketones. We were pleased that we could couple trifluoroacetone to silyl acetylene to incorporate a fluorine pharmacophore (V-72). Alkenes could also be coupled with aldehydes and ketones (V-73-V-74). A vitamin E derivative also proved to be viable with this coupling strategy.

5.6 Mechanistic Studies

Again, we were curious about the origin of the diastereoselectivity. We found that the reaction is complete within 15 minutes; however, when the reaction is halted prematurely the diastereoselectivity suffers (Table 5.3). Running the reaction for 2 hours was able to increase the diastereoselectivity up to >20:1 without a significant loss in yield. Since it appeared the two diastereomers were being funneled to the Z-vinyl iodide, we probed this a little further by subjecting a 1:1 mixture of the vinyl iodides to 20 mol%

Mn2CO10 and this increased the Z:E ratio from 1:1 to >20:1. Therefore the Mn catalyst is responsible for the diastereoselectivity through epimerization.

179

Table 5.3 Determination of Z-selectivity.

We then investigated the relative rate of atom transfer with radical clocks V-76 and V-78 (Scheme 5.6). We found that the atom transfer event is faster than the rate of cyclization,223 as the cyclized product V-79 was not observed and only ATRA product V- 80 and V-82 were isolated. We then probed how the identity of the ensuing carbon radical affects the outcome of product formation with intramolecular alkyne and alkene traps. We saw that aldehyde V-83 only cyclized to give the ATRA product V-84 and no trapping of the vinyl iodide with an alkyne occurred. However, using aldehyde V-85 to generate an sp3 carbon-centered radical, allowed for a radical that was long lived enough to allow for trapping of the alkyne and subsequent trapping of the iodide to form three bonds in one step (V-86).

180

Scheme 5.6 Kinetics of ATRA reaction.

The geminal vinyl iodide and silane are orthogonal cross coupling partners, further demonstrating the synthetic utility of this method. As shown in Figure 5.4, the vinyl iodide can be used as a synthetic handle for alkylation (V-87), vinylation (V-88), and arylation (V-89-V-91). The vinyl silicate can be used as an arylation precursor (V-92). This can be done by converting the silane to an iodide using NIS and Suzuki cross coupling with

PhB(OH)2.

181

Figure 5.4 Synthetic utility of vinyl iodides.

5.7 Conclusion

We have developed methods to mildly generate ketyl radicals to employ polarity- reversal reactivity. First, lowering the reduction potential of the carbonyl by transforming it into an α-oxy iodide, allows for milder reduction conditions by effectively lowering the reduction potential of the carbonyl. These nucleophilic carbonyls can add into alkynes to produce (Z)-vinyl iodides, and upon further reduction, the corresponding (Z)-alkene can also be obtained. We have successfully shown that α-oxy radicals can be mildly generated

using Et3O2/O2 as well as photocatalytic Mn conditions to give Z-vinyl iodides. This catalytic variant allowed for an expanded substrate scope with extensive functional group tolerability with high diastereoselectivity.

5.8 Experimental for Stoichiometric Reductant System

5.8.1 General Information

Unless noted, all commercial reagents were used as purchased without further purification, and all reactions were carried out under nitrogen. Silicycle F60 (230-400

182 mesh) silica gel or a CombiFlash® Automated Flash Chromatograph was used for flash column chromatography. Thin layer chromatography (TLC) analyses were performed using Merck silica gel 60 F254 plates and visualized under UV or phosphomolybdic acid stain. 1H and 13C NMR spectra were recorded using a Bruker AVIII 400 or AVIII 600 MHz NMR spectrometer and are reported as chemical shifts (δ ppm), multiplicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), relative integral. 1H NMR spectra were referenced with respect 13 to CDCl3 (δ = 7.26 ppm) as an internal reference and C NMR spectra were referenced with respect to CDCl3 (δ = 77.00 ppm) as an internal reference. High resolution mass spectra were obtained using Bruker MicrOTOF (ESI). IR spectra were recorded using a Thermo Fisher Nicolet iS10 FT-IR and are reported in terms of frequency of absorption (cm–1).

5.8.2 Synthesis of Acyl iodides

General procedure for the synthesis of acyl iodides (GP1): To a round bottom flask was added sodium iodide (1.05 eq) and the corresponding acyl chloride (1.0 eq) at 0 °C. Then the reaction was warmed up to room temperature and stirred further for 2 hours, after which the reaction mixture was filtered to remove sodium chloride. The crude product was purified by distillation.

Acetyl iodide (SV-1). Prepared according to GP1. Distillation at 140 ºC under 1 atm afforded the title product in 51% yield as a yellow liquid. 1 H NMR (CDCl3, 600 MHz): δ 2.97 (s, 3H) 13 C NMR (CDCl3, 150 MHz): δ 47.24, 156.07

183

Phenylacetyl iodide (SV-2). Prepared according to GP1. Distillation at 140 ºC under 20 Torr afforded the title product in 58% yield as a red liquid. 1 H NMR (CDCl3, 600 MHz): δ 4.33 (s, 2H), 7.26-7.27 (m, 2H), 7.38-7.39 (m, 3H) 13 C NMR (CDCl3, 150 MHz): δ 65.52, 128.31, 129.05, 129.78, 130.97, 159.81.

5.8.3 Alkyne Substrate Synthesis

General procedure for the synthesis of alkynes (GP2): To the solution of alcohol (1.0 º eq) in CH2Cl2 was added propiolic acid (1.02 eq) and DCC (1.02 eq) at -50 C. The reaction was warmed up to 0 ºC and stirred at 0 ºC for 2 hours and then the reaction mixture was filtered. Then the solvent was removed under vacuum and the crude product was purified by column chromatography on silica gel.

S-(4-methoxyphenyl) prop-2-ynethioate (SV-3). Prepared according to GP2. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) afforded the title product in 62% yield as a pale-yellow oil.

Rf = 0.3 (9% ethyl acetate/91% hexanes). 1 H NMR (CDCl3, 400 MHz): δ 3.39 (s, 1H), 3.84 (s, 3H), 6.95-6.98 (m, 2H), 7.35-7.39 (m, 2H).

13 C NMR (CDCl3, 100 MHz): δ 55.36, 78.87, 81.13, 115.12, 116.64, 136.24, 161.29, 176.17.

+ HRMS (ESI) for C10H8O2SNa [M+Na] : calcd 215.0143, found 215.0149.

184

4-Methoxybenzyl propiolate (SV-4). Prepared according to GP2. Extra 0.5% DMAP was used as a catalyst. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) afforded the title product in 74% yield as a colorless oil.

Rf = 0.3 (9% ethyl acetate/91% hexanes).

1 H NMR (CDCl3, 400 MHz): δ 2.87 (s, 1H), 3.81 (s, 3H), 5.16 (s, 2H), 6.88-6.92 (m, 2H), 7.30-7.34 (m, 2H).

13 C NMR (CDCl3, 100 MHz): δ 55.25, 67.76, 74.61, 74.81, 114.02, 126.63, 130.49, 152.57, 159.97.

+ HRMS (ESI) for C11H10O3Na [M+Na] : calcd 213.0528, found 213.0525.

5.8.4 Synthesis and Characterization of Vinyl Iodides

General procedure for the synthesis of vinyl iodides with Et3B (GP3): To an 8 mL vial was added aldehyde (0.5 mmol) and phenylacetyl iodide (0.6 mmol). The mixture was

stirred at 0 ºC for 10 min. To this mixture was added CH2Cl2 (0.5 mL), alkyne (1.0 mmol),

iodoethane (201 µL, 2.5 mmol) and BEt3 (0.6 mL, 0.6 mmol, 1.0 M in hexanes) at 0 ºC.

Then O2 (11.2 mL, 0.5 mmol) was bubbled through the solution via syringe pump (12 mL/h) at 0 ºC. After the addition was finished, the reaction was warmed up to room temperature and stirred for another 2 hours. Then the solvent was removed under vacuum and the crude product was purified by column chromatography on silica gel. Z:E ratios were determined using purified products via 1H NMR.

185

(E)-Methyl 4-acetoxy-2-iodooct-2-enoate (V-15). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) afforded the title product and the isomer in 59% yield as a colorless oil. E:Z ratio: 1:1.1.

Rf = 0.3 (9% ethyl acetate/91% hexanes). 1 H NMR (CDCl3, 400 MHz): δ 0.88 (t, J = 7.6 Hz, 3H), 1.27-1.36 (m, 4H), 1.58-1.70 (m, 2 H), 2.02 (s, 3H), 3.80 (s, 3H), 5.78-5.84 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.83, 20.91, 22.30, 26.96, 33.16, 53.28, 73.19, 86.41, 153.30, 163.54, 170.11. + HRMS (ESI) for C11H17IO4Na [M+Na] : calcd 363.0069, found 363.0032. IR (film): 2954, 2860, 1716, 1608, 1433, 1221, 1143, 882, 783 cm-1. 1 (Z)-Methyl 4-acetoxy-2-iodooct-2-enoate (V-15). H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.31-1.39 (m, 4H), 1.63-1.75 (m, 2H), 2.06 (s, 3H), 3.82 (s, 3H), 5.38- 5.42 (m, 1H), 7.16 (d, J = 7.2 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.84, 20.88, 22.41, 26.87, 32.27, 53.71, 77.64, 93.78, 150.48, 162.93, 170.19. IR (film): 2954, 2861, 1726, 1618, 1433, 1225, 1020, 893, 745 cm-1. + HRMS (ESI) for C11H17IO4Na [M+Na] : calcd 363.0069, found 363.0047.

Rf = 0.25 (9% ethyl acetate/91% hexanes).

(E)-Methyl 2-iodo-4-(2-phenylacetoxy)oct-2-enoate (V-17). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) afforded the title product and the isomer in 70% yield as a colorless oil. E:Z ratio: 1:1.3.

Rf = 0.4 (9% ethyl acetate/91% hexanes).

186

1 H NMR (CDCl3, 600 MHz): δ 0.86 (t, J = 7.2 Hz, 3H), 1.21-1.32 (m, 4H), 1.59-1.70 (m, 2 H), 3.61 (s, 2H), 3.79 (s, 3H), 5.84-5.88 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 7.25- 7.28 (m, 3H), 7.31-7.34 (m, 2H). 13 C NMR (CDCl3, 150 MHz): δ 13.82, 22.26, 26.89, 33.16, 41.34, 53.33, 73.67, 86.61, 127.11, 128.54, 129.19, 133.77, 153.35, 163.48, 170.72. IR (film): 2954, 2861, 1731, 1604, 1454, 1224, 1142, 989, 881, 566 cm-1. + HRMS (ESI) for C17H21IO4Na [M+Na] : calcd 439.0382, found 439.0367. 1 (Z)-Methyl 2-iodo-4-(2-phenylacetoxy)oct-2-enoate (V-17). H NMR (CDCl3, 600 MHz): δ 0.87 (t, J = 7.2 Hz, 3H), 1.24-1.34 (m, 4H), 1.59-1.75 (m, 2H), 3.64 (s, 2H), 3.82 (s, 3H), 5.40-5.43 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.25-7.28 (m, 3H), 7.31-7.34 (m, 2H). 13 C NMR (CDCl3, 150 MHz): δ 13.81, 22.32, 26.77, 32.20, 41.23, 53.71, 78.13, 93.91, 127.15, 128.56, 129.24, 133.66, 150.25, 162.90, 170.82. IR(film): 2954, 2862, 1724, 1619, 1455, 1244, 1139, 979, 695 cm-1. + HRMS (ESI) for C17H21IO4Na [M+Na] : calcd 439.0382, found 439.0360.

Rf = 0.35 (9% ethyl acetate/91% hexanes).

(E)-Methyl 2-iodo-4-(pivaloyloxy)oct-2-enoate (V-18). To an 8 mL vial was added trimethylacetyl chloride (74 µL, 0.6 mmol) and sodium iodide (112.4 mg, 0.75 mmol). The reaction was stirred at room temperature for 2 hours. Then the reaction was cooled down to 0 ºC and pentanal (53 µL, 0.5 mmol) was added. The mixture was stirred at room

temperature for 2 hours. To this mixture was added CH2Cl2 (0.5 mL), alkyne (89 µL, 1.0

mmol), iodoethane (201 µL, 2.5 mmol) and BEt3 (0.6 mL, 0.6 mmol, 1.0 M in hexanes) at

0 ºC. Then O2 (11.2 mL, 0.5 mmol) was bubbled through the solution via syringe pump (12 mL/h) at 0 ºC. After the addition was finished, the reaction was warmed up to room temperature and stirred for another 2 hours. Then the solvent was removed under vacuum

187

and the crude product was purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 100:1-50:1) to afford the title product and the isomer in 68% yield as a colorless oil. E:Z ratio: 1:1.5. 1 H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.19 (s, 9H), 1.30-1.36 (m, 4H), 1.64-1.71 (m, 2H), 3.82 (s, 3H), 5.80-5.84 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H).

13 C NMR (CDCl3, 150 MHz): δ 13.88, 22.29, 27.03, 27.07, 33.18, 38.73, 53.33, 73.08, 86.20, 154.27, 163.45, 177.64. IR (film): 2956, 2931, 2871, 1726, 1607, 1479, 1224, 1147, 975, 878 cm-1. + HRMS (ESI) for C14H23IO4Na [M+Na] : calcd 405.0539, found 405.0508.

Rf = 0.5 (9% ethyl acetate/91% hexanes).

1 (Z)-Methyl 2-iodo-4-(pivaloyloxy)oct-2-enoate (V-18). H NMR (CDCl3, 600 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.21 (s, 9H), 1.31-1.41 (m, 4H), 1.64-1.76 (m, 2H), 3.82 (s, 3H), 5.34-5.37 (m, 1H), 7.13 (d, J = 7.8 Hz, 1H).

13 C NMR (CDCl3, 150 MHz): δ 13.86, 22.34, 26.91, 27.10, 32.13, 38.80, 53.70, 77.55, 93.61, 150.74, 162.95, 177.80. IR (film): 2956, 2872, 1728, 1618, 1479, 1248, 1146, 970, 892 cm-1. + HRMS (ESI) for C14H23IO4Na [M+Na] : calcd 405.0539, found 405.0513.

Rf = 0.45 (9% ethyl acetate/91% hexanes).

(E)-Methyl 2-iodo-5-methyl-4-(2-phenylacetoxy)hex-2-enoate (IV-19). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) afforded the title product and the isomer in 53% yield as a colorless oil. E:Z ratio: 1:1.1. 1 H NMR (CDCl3, 600 MHz,): δ 0.88 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 1.92- 1.98 (m, 1H), 3.62 (s, 2H), 3.80 (s, 3H), 5.69 (dd, J = 6.6, 8.4 Hz, 1H), 6.69 (d, J = 9.0 Hz, 1H), 7.25-7.27 (m, 3H), 7.31-7.34 (m, 2H).

188

13 C NMR (CDCl3, 150 MHz): δ 17.44, 18.22, 32.10, 41.41, 53.29, 77.28, 87.64, 127.11, 128.55, 129.24, 133.82, 151.47, 163.62, 170.66. IR (film): 2967, 1720, 1264, 1221, 1126, 984, 734, 704 cm–1. + HRMS (ESI) for C16H19IO4Na [M+Na] : calcd 425.0226, found 425.0211.

Rf = 0.18 (5% ethyl acetate/95% hexanes). (Z)-Methyl 2-iodo-5-methyl-4-(2-phenylacetoxy)hex-2-enoate (IV-19). 1H NMR

(CDCl3, 400 MHz,): δ 0.93 (d, J = 7.2 Hz, 6H), 2.02-2.10 (m, 1H), 3.65 (s, 2H), 3.83 (s, 3H), 5.28 (dd, J = 5.6, 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.25-7.35 (m, 5H) 13 C NMR (CDCl3, 100 MHz): δ 17.40, 18.38, 31.91, 41.31, 53.73, 81.92, 95.47, 127.16, 128.57, 129.30, 133.73, 148.96, 162.97, 170.77. IR (film): 2980, 1264, 906, 730, 705, 649 cm–1. + HRMS (ESI) for C16H19IO4Na [M+Na] : calcd 425.0226, found 425.0203.

Rf = 0.15 (5% ethyl acetate/95% hexanes).

(E)-Methyl 2-iodo-5,5-dimethyl-4-(2-phenylacetoxy)hex-2-enoate (V-20). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) afforded the title product and the isomer in 64% yield as a colorless oil. E:Z ratio: 1:1.

1 H NMR (CDCl3, 400 MHz): δ 0.88 (s, 9H), 3.62 (s, 2H), 3.81 (s, 3H), 5.66 (d, J = 9.6 Hz, 1H), 6.63 (d, J = 10.0 Hz, 1H), 7.24-7.28 (m, 3H), 7.30-7.34 (m, 2H).

13 C NMR (CDCl3, 100 MHz): δ 25.49, 34.77, 41.49, 53.20, 78.60, 89.13, 127.07, 128.52, 129.25, 133.82, 148.14, 163.80, 170.42. IR (film): 2955, 1719, 1603, 1431, 1364, 1297, 1222, 1141, 978 cm–1.

+ HRMS (ESI) for C17H21IO4Na [M+Na] : calcd 439.0382, found 439.0380.

Rf = 0.20 (5% Ethyl acetate/95% hexanes).

189

(Z)-Methyl 2-iodo-5,5-dimethyl-4-(2-phenylacetoxy)hex-2-enoate (V-20). 1H NMR

(CDCl3, 400 MHz,): δ 0.93 (s, 9H), 3.64 (s, 2H), 3.83 (s, 3H), 5.24 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 7.24-7.34 (m, 5H). 13 C NMR (CDCl3, 100 MHz): δ 25.81, 36.13, 41.38, 53.74, 83.93, 97.77, 127.12, 128.54, 129.33, 133.73, 147.01, 163.13, 170.51. IR (film): 2959, 1718, 1433, 1366, 1237, 1140, 980, 906, 728 cm–1. + HRMS (ESI) for C17H21IO4Na [M+Na] : calcd 439.0382, found 439.0378.

Rf = 0.15 (5% ethyl acetate/95% hexanes).

(E)-Methyl 8-((tert-butyldiphenylsilyl)oxy)-2-iodo-4-(pivaloyloxy)oct-2-enoate (V- 21). To an 8 mL vial was added trimethylacetyl chloride (74 µL, 0.6 mmol) and sodium iodide (112.4 mg, 0.75 mmol). The reaction was stirred at room temperature for 2 hours. Then the reaction was cooled down to 0 Cº and 5-((tert-butyldiphenylsilyl)oxy)pentanal (170 mg, 0.5 mmol) and dichloromethane (0.5 mL) was added and the mixture was stirred at 0 ºC for 30 minutes. To this mixture was added methyl propiolate (89 µL, 1.0 mmol), iodoethane (201 µL, 2.5 mmol) and BEt3 (1.0 mL, 1.0 mmol, 1.0 M in hexanes) at 0 Cº.

Then O2 (11.2 mL, 0.5 mmol) was bubbled through the solution via syringe pump (12 mL/h) at 0 Cº . After the addition was finished, the reaction was warmed up to room temperature and stirred for another 2 hours. The reaction mixture was washed with water, and then the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1) afforded the title product and the isomer in 62% yield as a colorless oil. E:Z ratio: 1:1.4.

1 H NMR (CDCl3, 600 MHz): δ 1.04 (s, 9H), 1.19 (s, 9H), 1.40-1.75 (m, 6H), 3.66 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 5.80-5.86 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 7.36-7.44 (m, 6H), 7.64-7.67 (m, 4H).

190

13 C NMR (CDCl3, 150 MHz): δ 19.22, 21.41, 26.89, 27.10, 32.20, 33.36, 38.75, 53.31, 63.55, 73.10, 86.34, 127.61, 129.54, 134.05, 135.57, 154.13, 163.43, 177.63. IR (film): 2958, 2931, 2860, 1729, 1427, 1225, 1150, 1111, 702. + HRMS (ESI) for C30H41IO5SiNa [M+Na] : calcd for 659.1666, found 659.1644.

Rf: 0.45 (9% ethyl acetate/91% hexanes). (Z)-Methyl 8-((tert-butyldiphenylsilyl)oxy)-2-iodo-4-(pivaloyloxy)oct-2-enoate (V- 1 21). H NMR (CDCl3, 600 MHz): δ 1.04 (s, 9H), 1.21 (s, 9H), 1.44-1.78 (m, 6H), 3.67 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 5.34-5.37 (m, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.36-7.43 (m, 6H), 7.65-7.67 (m, 4H). 13 C NMR (CDCl3, 150 MHz): δ 19.22, 21.30, 26.88, 27.13, 32.20, 32.31, 38.82, 53.68, 63.45, 77.58, 93.74, 127.62, 129.56, 134.00, 135.58, 150.60, 162.93, 177.77. IR (film): 2956, 2936, 2860, 1730, 1428, 1255, 1150, 1110, 943, 910, 703. + HRMS (ESI) for C30H41IO5SiNa [M+Na] : calcd for 659.1666, found 659.1650.

Rf: 0.40 (9% ethyl acetate/91% hexanes).

(E)-Methyl 2-iodo-6-phenyl-4-(2-phenylacetoxy)hex-2-enoate (V-22). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) afforded the title product and the isomer in 50% yield as a colorless oil. E:Z ratio: 1:1.2. 1 H NMR (CDCl3, 400 MHz,): δ 1.91-2.06 (m, 2H), 2.55-2.64 (m, 2H), 3.62 (s, 2H), 3.71 (s, 3H), 5.84-5.89 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 7.06-7.08 (m, 2H), 7.16-7.20 (m, 1H), 7.24-7.37 (m, 7H). 13 C NMR (CDCl3, 100 MHz): δ 31.15, 35.03, 41.38, 53.31, 73.32, 87.18, 126.06, 127.23, 128.35, 128.42, 128.63, 129.24, 133.72, 140.82, 153.01, 163.42, 170.66. IR (film): 2941, 2290, 2252, 2105, 1729, 1434, 1374, 1035, 917, 750, 700 cm–1. + HRMS (ESI) for C21H21IO4Na [M+Na] : calcd 487.0382, found 487.0361.

191

Rf = 0.13 (5% ethyl acetate/95% hexanes). 1 (Z)-Methyl 2-iodo-6-phenyl-4-(2-phenylacetoxy)hex-2-enoate. H NMR (CDCl3, 600 MHz,): δ 1.93-1.99 (m, 1H), 2.02-2.08 (m, 1H), 2.58-2.69 (m, 2H), 3.65 (s, 2H), 3.81 (s, 3H), 5.38-5.41 (m, 1H), 7.07-7.09 (m, 2H), 7.17-7.20 (m, 2H), 7.25-7.36 (m, 6H). 13 C NMR (CDCl3, 100 MHz): δ 31.05, 33.96, 41.28, 53.74, 77.71, 94.02, 126.17, 127.28, 128.38, 128.47, 128.66, 129.30, 133.63, 149.99, 162.81, 170.77. IR (film): 2941, 2290, 2252, 2104, 1724, 1434, 1374, 1245, 1034, 917, 734 cm–1. + HRMS (ESI) for C21H21IO4Na [M+Na] : calcd 487.0382, found 487.0376.

Rf = 0.08 (5% ethyl acetate/95% hexanes).

(E)-Methyl 6-(4-chlorophenyl)-2-iodo-4-(2-phenylacetoxy)hex-2-enoate (V-23). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1-10:1) afforded the title product and the isomer in 62% yield as a colorless oil. E:Z ratio: 1:1.4. 1 H NMR (CDCl3, 600 MHz): δ 1.90-2.01 (m, 2H), 2.50-2.60 (m, 2H), 3.62 (s, 2H), 3.73 (s, 3H), 5.83-5.86 (m, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.97-6.99 (m, 2H), 7.21-7.23 (m, 2H), 7.27-7.30 (m, 3H), 7.34-7.36 (m, 2H). 13 C NMR (CDCl3, 150 MHz): δ 30.51, 34.87, 41.41, 53.32, 73.15, 87.08, 127.26, 128.51, 128.65, 129.23, 129.69, 131.85, 133.71, 139.24, 152.78, 163.41, 170.56. IR (film): 3028, 2950, 2916, 1728, 1492, 1433, 1226, 1147, 1092, 910, 725 cm–1. + HRMS (ESI) for C21H20ClIO4Na [M+Na] : calcd 520.9992, found 520.9960.

Rf = 0.40 (9% ethyl acetate/91% hexanes). (Z)-Methyl 6-(4-chlorophenyl)-2-iodo-4-(2-phenylacetoxy)hex-2-enoate. 1H NMR

(CDCl3, 400 MHz,): δ 1.88-2.07 (m, 1H), 2.52-2.66 (m, 1H), 3.65 (s, 2H), 3.82 (s, 3H), 5.34-5.39 (m, 1H), 6.96-7.00 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.20-7.23 (m, 2H), 7.27- 7.38 (m, 5H).

192

13 C NMR (CDCl3, 150 MHz): δ 30.32, 33.77, 41.29, 53.71, 77.41, 94.15, 127.27, 128.54, 128.64, 129.24, 129.70, 131.94, 133.59, 138.91, 149.69, 162.70, 170.60. IR (film): 2977, 2247, 1721, 1620, 1453, 1389, 1245, 1181, 1015, 924, 724 cm–1. + HRMS (ESI) for C21H20ClIO4Na [M+Na] : calcd 520.9992, found 520.9968.

Rf = 0.35 (9% ethyl acetate/91% hexanes).

(E)-Methyl 6-(4-acetylphenyl)-2-iodo-4-(2-phenylacetoxy)hex-2-enoate (V-24). 1.5 eq. BEt3 was used. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1-5:1) afforded the title product and the isomer in 51% yield as a colorless oil. E:Z ratio: 1:1.3. 1 H NMR (CDCl3, 600 MHz,): δ 1.97-2.03 (m, 2H), 2.57 (s, 3H), 2.57-2.68 (m, 2H), 3.62 (s, 2H), 3.73 (s, 3H), 5.85-5.88 (m, 1H), 6.74 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.28-7.30 (m, 3H), 7.34-7.36 (m, 2H), 7.85-7.86 (m, 2H). 13 C NMR (CDCl3, 150 MHz): δ 26.51, 31.17, 34.56, 41.42, 53.35, 73.16, 87.11, 127.30, 128.57, 128.59, 128.67, 129.24, 133.70, 135.38, 146.57, 152.79, 163.40, 170.57, 197.64. IR (film): 3028, 2947, 2920, 1731, 1679, 1605, 1267, 1227, 1146, 1028, 696 cm–1. + HRMS (ESI) for C23H23IO5Na [M+Na] : calcd 529.0488, found 529.0477.

Rf = 0.33 (20% ethyl acetate/80% hexanes). (Z)-Methyl 6-(4-acetylphenyl)-2-iodo-4-(2-phenylacetoxy)hex-2-enoate (V-24). 1H

NMR (CDCl3, 600 MHz,): δ 1.93-2.11 (m, 2H), 2.58 (s, 3 H), 2.62-2.74 (m, 2H), 3.65 (s, 2H), 3.81 (s, 3H), 5.35-5.40 (m, 1H), 7.13-7.16 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.28- 7.38 (m, 5H), 7.84-7.87 (m, 2H). 13 C NMR (CDCl3, 150 MHz): δ 26.50, 31.01, 33.52, 41.33, 53.76, 77.42, 94.30, 127.34, 128.61, 128.63, 128.70, 129.28, 133.60, 135.47, 146.19, 149.60, 162.73, 170.65, 197.62. IR (film): 3030, 2947, 2918, 1722, 1679, 1606, 1432, 1246, 1146, 1017, 696 cm–1. + HRMS (ESI) for C23H23IO5Na [M+Na] : calcd 529.0488, found 529.0476.

193

Rf = 0.30 (20% ethyl acetate/80% hexanes).

(E)-Ethyl 4-(5-iodo-6-methoxy-6-oxo-3-(2-phenylacetoxy)hex-4-en-1-yl)benzoate (V-

25). 1.5 eq. BEt3 was used. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) afforded the title product and the isomer in 58% yield as a colorless oil. E:Z ratio: 1:1.4. 1 H NMR (CDCl3, 600 MHz,): δ 1.38 (t, J = 7.2 Hz, 3H), 1.94-2.04 (m, 2H), 2.59-2.67 (m, 2H), 3.61 (s, 2H), 3.73 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H), 5.84-5.88 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.11-7.13 (m, 2H), 7.27-7.30 (m, 3H), 7.33-7.36 (m, 2H), 7.92-7.94 (m, 2H). 13 C NMR (CDCl3, 150 MHz): δ 14.32, 31.19, 34.60, 41.39, 53.33, 60.79, 73.18, 87.15, 127.27, 128.32, 128.51, 128.65, 129.22, 129.73, 133.69, 146.15, 152.77, 163.39, 166.50, 170.56. IR (film): 2979, 2952, 2930, 1711, 1609, 1274, 1226, 1104, 1022, 705 cm–1. + HRMS (ESI) for C24H25IO6Na [M+Na] : calcd 559.0594 found 559.0606.

Rf = 0.30 (20% ethyl acetate/80% hexanes). (Z)-Ethyl 4-(5-iodo-6-methoxy-6-oxo-3-(2-phenylacetoxy)hex-4-en-1-yl)benzoate. 1 H NMR (CDCl3, 400 MHz,): δ 1.39 (t, J = 7.2 Hz, 1H), 1.92-2.10 (m, 2H), 2.60-2.74 (m, 2H), 3.64 (s, 2H), 3.81 (s, 3H), 4.36 (q, J = 7.2 Hz, 1H), 5.35-5.40 (m, 1H), 7.11-7.13 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.27-7.38 (m, 5H), 7.92-7.95 (m, 2H).

13 C NMR (CDCl3, 150 MHz): δ 14.32, 31.02, 33.55, 41.31, 53.73, 60.81, 77.45, 94.25, 127.32, 128.37, 128.63, 128.68, 129.27, 129.78, 133.60, 145.79, 149.66, 162.73, 166.47, 170.63. IR (film): 2979, 2952, 2927, 1712, 1610, 1433, 1273, 1245, 1105, 1020, 744 cm–1. + HRMS (ESI) for C24H25IO6Na [M+Na] : calcd 559.0594 found 559.0604.

Rf = 0.25 (20% ethyl acetate/80% hexanes). 194

(E)-Benzyl 2-iodo-4-(2-phenylacetoxy)oct-2-enoate (V-26). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 70:1-50:1) afforded the title product and the isomer in 62% yield as a colorless oil. E:Z ratio: 1:1.1. 1 H NMR (CDCl3, 600 MHz): δ 0.80 (t, 3H), 1.11-1.21 (m, 4H), 1.54-1.65 (m, 2H), 3.60 (s, 2H), 5.22 (abq, J = 12.0 Hz, 2H), 5.85-5.88 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 7.25- 13 7.28 (m, 3H), 7.31-7.40 (m, 7H); C NMR (CDCl3, 150 MHz): δ 13.80, 22.24, 26.88, 33.19, 41.31, 68.32, 73.73, 87.04, 127.10, 128.24, 128.41, 128.54, 128.56, 129.20, 133.78 134.94, 153.35, 162.81, 170.65. IR (film): 2954, 2860, 1720, 1603, 1454, 1197, 1143, 981 cm-1. + HRMS (ESI) for C23H25IO4Na [M+Na] : calcd 515.0695, found 515.0679.

Rf = 0.4 (9% ethyl acetate/91% hexanes). 1 (Z)-Benzyl 2-iodo-4-(2-phenylacetoxy)oct-2-enoate (V-26). H NMR (CDCl3, 600 MHz): δ 0.86 (t, 3H), 1.25-1.32 (m, 4H), 1.62-1.72 (m, 2H), 3.63 (s, 2H), 5.23 (s, 2H), 5.41-5.44 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.24-7.27 (m, 3H), 7.29-7.39 (m, 7H). 13 C NMR (CDCl3, 150 MHz): δ 13.80, 22.29, 26.78, 32.18, 41.22, 68.52, 78.11, 94.27, 127.13, 128.19, 128.42, 128.54, 128.59, 129.20, 133.65 135.19, 150.36, 162.19, 170.79. IR (film): 2955, 2860, 1717, 1618, 1454, 1225, 1139, 977 cm-1. + HRMS (ESI) for C23H25IO4Na [M+Na] : calcd 515.0695, found 515.0670.

Rf = 0.35 (9% ethyl acetate/91% hexanes).

(E)-Phenyl 2-iodo-4-(2-phenylacetoxy)oct-2-enoate (V-27). Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 70:1-50:1-30:1) afforded the title product and the isomer in 63% yield as a colorless oil. E:Z ratio: 1:1.1.

195

1 H NMR (CDCl3, 600 MHz): δ 0.83 (t, J = 7.2 Hz, 3H), 1.23-1.30 (m, 4H), 1.65-1.73 (m, 2H), 3.63 (s, 2H), 5.90-5.93 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.15-7.18 (m, 2H), 7.24-7.28 (m, 4H), 7.31-7.34 (m, 2H), 7.38-7.41 (m, 2H). 13 C NMR (CDCl3, 150 MHz): δ 13.81, 22.27, 26.90, 33.05, 41.33, 73.69, 85.67, 121.27, 126.30, 127.12, 128.56, 129.18, 129.49, 133.73, 150.50, 154.19, 161.73, 170.73. IR (film): 2954, 2862, 1732, 1590, 1492, 1187, 1085, 978 cm-1. + HRMS (ESI) for C22H23IO4Na [M+Na] : calcd 501.0539, found 501.0525.

Rf = 0.4 (9% ethyl acetate/91% hexanes). 1 (Z)-Phenyl 2-iodo-4-(2-phenylacetoxy)oct-2-enoate (V-27). H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.28-1.38 (m, 4H), 1.69-1.79 (m, 2H), 3.67 (s, 2H), 5.46- 5.50 (m, 1H), 7.11-7.13 (m, 2H), 7.24-7.41 (m, 8H). 13 C NMR (CDCl3, 150 MHz): δ 13.82, 22.33, 26.85, 32.15, 41.24, 78.24, 93.35, 121.24, 126.20, 127.19, 128.59, 129.24, 129.47, 133.61, 150.98, 151.82, 160.93, 170.93. IR (film): 2955, 2862, 1733, 1616, 1492, 1217, 1187, 987 cm-1. + HRMS (ESI) for C22H23IO4Na [M+Na] : calcd 501.0539, found 501.0522.

Rf = 0.35 (9% ethyl acetate/91% hexanes).

(E)-2-Iodo-1-oxo-1-(phenylthio)oct-2-en-4-yl 2-phenylacetate. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 100:1-70:1-50:1) afforded the title product and the isomer in 58% yield as a colorless oil. E:Z ratio: 1:2. 1 H NMR (CDCl3, 600 MHz): δ 0.82 (t, J = 7.2 Hz, 3H), 1.19-1.27 (m, 4H), 1.57-1.68 (m, 2H), 3.61 (s, 2H), 5.71-5.75 (m, 1H), 6.53 (d, J = 8.4 Hz, 1H), 7.25-7.27 (m, 3H), 7.31- 7.33 (m, 2H), 7.42-7.45 (m, 5H). 13 C NMR (CDCl3, 150 MHz): δ 13.82, 22.35, 26.85, 33.33, 41.34, 73.89, 92.56, 127.11, 128.35, 128.55, 129.21, 129.36, 129.83, 133.78, 134.62, 149.85, 170.55, 188.68. IR (film): 2955, 2860, 1734, 1662, 1454, 1248, 1139, 998 cm-1. 196

+ HRMS (ESI) for C22H23ISO3Na [M+Na] : calcd 517.0310, found 517.0294.

Rf = 0.4 (9% ethyl acetate/91% hexanes). 1 (Z)-2-Iodo-1-oxo-1-(phenylthio)oct-2-en-4-yl 2-phenylacetate. H NMR (CDCl3, 600 MHz): δ 0.89 (t, J = 7.2 Hz, 3H), 1.29-1.34 (m, 4H), 1.68-1.78 (m, 2H), 3.67 (s, 2H), 5.49-5.52 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.26-7.35 (m, 5H), 7.42-7.45 (m, 5H). 13 C NMR (CDCl3, 150 MHz): δ 13.80, 22.30, 26.78, 32.26, 41.23, 78.00, 102.56, 127.17, 127.75, 128.58, 129.18, 129.29, 129.81, 133.60, 134.70, 147.61, 170.78, 186.20. IR (film): 2956, 2860, 1738, 1684, 1455, 1248, 1147, 982 cm-1. + HRMS (ESI) for C22H23ISO3Na [M+Na] : calcd 517.0310, found 517.0288.

Rf = 0.35 (9% ethyl acetate/91% hexanes).

(E)-1-Iodo-1-(trimethylsilyl)hept-1-en-3-yl acetate (V-29). 20 eq. of alkyne was used. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 200:1-150:1) afforded the title product and the isomer in 70% yield as a colorless oil. E:Z ratio: 1:7. 1 H NMR (CDCl3, 600 MHz): δ 0.32 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H), 1.23-1.36 (m, 4H), 1.46-1.52 (m, 1H), 1.62-1.68 (m, 1H), 2.04 (s, 3H), 5.32-5.35 (m, 1H), 7.01 (d, J = 9.6 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 0.89, 13.89, 21.13, 22.48, 27.08, 34.09, 74.40, 113.46, 153.09, 170.10. IR (film): 2957, 2932, 2861, 1739, 1370, 1231, 1018, 843 cm-1. + HRMS (ESI) for C12H23IO2SiNa [M+Na] : calcd 377.0410, found 377.0394.

Rf = 0.6 (9% ethyl acetate/91% hexanes). 1 (Z)-1-Iodo-1-(trimethylsilyl)hept-1-en-3-yl acetate. H NMR (CDCl3, 600 MHz): δ 0.18 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H), 1.31-1.37 (m, 4H), 1.60-1.69 (m, 2H), 2.06 (s, 3H), 5.46-5.50 (m, 1H), 6.16 (d, J = 7.2 Hz, 1H).

197

13 C NMR (CDCl3, 150 MHz): δ -1.58, 13.92, 21.13, 22.50, 26.95, 32.88, 79.72, 113.52, 145.52, 170.05. IR (film): 2956, 2861, 1738, 1369, 1227, 1018, 839 cm-1 + HRMS (ESI) for C12H23IO2SiNa [M+Na] : calcd 377.0410, found 377.0393.

Rf = 0.55 (9% ethyl acetate/91% hexanes).

(E)-1-Iodo-1-(triethylsilyl)hept-1-en-3-yl acetate (V-30). 20 eq. of alkyne was used. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 200:1- 150:1) afforded the title product and the isomer in 71% yield as a colorless oil. E:Z ratio: 1:6.

1 H NMR (CDCl3, 400 MHz): δ 0.76-0.93 (m, 9H), 0.98 (t, J = 8.0 Hz, 9H), 1.23-1.36 (m, 4H), 1.44-1.53 (m, 1H), 1.61-1.70 (m, 1H), 2.03 (s, 3H), 5.22-5.28 (m, 1H), 7.16 (d, J = 10.0 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 4.63, 7.29, 13.90, 21.11, 22.53, 27.13, 34.50, 74.70, 111.46, 155.16, 170.03. IR (film): 2955, 2933, 2874, 1740, 1369, 1230, 1017, 1002 cm-1. + HRMS (ESI) for C15H29IO2SiNa [M+Na] : calcd 419.0879, found 419.0865.

Rf = 0.6 (9% ethyl acetate/91% hexanes). 1 (Z)-1-Iodo-1-(triethylsilyl)hept-1-en-3-yl acetate (V-30). H NMR (CDCl3, 600 MHz): δ 0.69 (q, J = 8.4 Hz, 6H), 0.89 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.8 Hz, 9H), 1.30-1.37 (m, 4H), 1.59-1.71 (m, 2H), 2.04 (s, 3H), 5.46-5.50 (m, 1H), 6.16 (d, J = 6.6 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 2.89, 6.99, 13.91, 21.08, 22.51, 26.91, 32.85, 79.90, 110.00, 147.24, 169.95. IR (film): 2954, 2873, 1740, 1368, 1227, 1004, 965, 824 cm-1. + HRMS (ESI) for C15H29IO2SiNa [M+Na] : calcd 419.0879, found 419.0857.

Rf = 0.55 (9% ethyl acetate/91% hexanes).

198

(Z)-1-iodo-1-(triisopropylsilyl)hept-1-en-3-yl acetate (V-31). 20 eq. of alkyne was used. Column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 200:1-150:1) afforded the title product in 50% yield as a colorless oil. 1 H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.10 (d, J = 7.2 Hz, 9H), 1.11 (d, J = 7.2 Hz, 9H), 1.30-1.39 (m, 7H), 1.64-1.72 (m, 2H), 2.05 (s, 3H), 5.49-5.52 (m, 1H), 6.21 (d, J = 6.6 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 11.62, 13.95, 18.32, 18.36, 21.07, 22.54, 26.96, 32.76, 80.41, 107.16, 148.67, 170.02. IR (film): 2942, 2864, 1741, 1368, 1227, 1017, 881, 816, 678, 507 cm-1. + HRMS (ESI) for C18H35IO2SiNa [M+Na] : calcd 461.1349, found 461.1323.

Rf = 0.55 (9% ethyl acetate/91% hexanes).

5.9 Experimental for Catalytic Reductant System

5.9.1 General Information

General procedure for triethylsilyl acetylene or trimethylsilyl acetylene coupling partners (GP4): To an 8 mL vial was added CH2Cl2 (0.5 mL), AcI (0.6 mmol), Zn(OTf)2 (0.025 mmol) and aldehyde (0.5 mmol) consecutively at 0 ºC. The mixture was stirred at the same temperature for 15 min. To this mixture was added DIPEA (0.25 mmol) at 0 ºC, then the mixture was stirred for another 15 min. After that triethylsilyl acetylene (2.5 mmol) and Mn2(CO)10 (0.025 mmol) were added to the mixture. The reaction mixture was degassed by chill-pump-thaw for 20 min, then irradiated with one 90 W blue LED lamp (Kessil A360WE tuna blue) or two 45 W blue LED lamps (Kessil A160WE tuna blue) at approximately 5 cm away from the light source. The reaction temperature was around 40 ºC. After 2 h, the solvent was removed under vacuum and the crude product was purified

199 by column chromatography on silica gel. Z:E ratios were determined using purified products via 1H NMR. *Note: 1) The quality of AcI is crucial for the reaction since HI generated from impure

AcI would destroy Mn2(CO)10 to yield poor yield and selectivity. 2) Zn(OTf)2 was used to eliminate side product (<10%) formation in α-acetoxy iodide generation. 3) The concentration of the reaction is crucial for the selectivity as lower concentration affords poor selectivity. 4) Peak absorbance of the light: 458 nm. General procedure for other alkyne coupling partners (GP5): To an 8 mL vial was added CH2Cl2 (1.0 mL), AcI (0.6 mmol), Zn(OTf)2 (0.025 mmol) and aldehyde (0.5 mmol) consecutively at 0 ºC. The mixture was stirred at the same temperature for 15 min. To this mixture was added 4Å MS (25 mg) and KOAc (0.5 mmol) at 0 ºC, then the mixture was stirred for another 15 min. After that alkyne (1.0 mmol) and Mn2(CO)10 (0.1 mmol) were added to the mixture. The reaction mixture was degassed by chill-pump- thaw for 20 min, then irradiated with one 90 W blue LED lamp (Kessil A360WE tuna blue) or two 45 W blue LED lamps (Kessil A160WE tuna blue) at approximately 5 cm away from the light source. The reaction temperature was around 40 ºC. After 2 h, the solvent was removed under vacuum and the crude product was purified by column chromatography on silica gel. Z:E ratios were determined using purified products via 1H NMR. *Note: 1) The quality of AcI is crucial for the reaction since HI generated from impure

200

5.9.2 Characterization of Vinyl Iodides

(Z)-1-Iodo-1-(trimethylsilyl)hept-1-en-3-yl acetate (V-29). 10% Mn2(CO)10 catalyst was used. Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 100:1) afforded the title product in 78% yield as a colorless oil. Z:E ratio: >20:1. 1 H NMR (CDCl3, 600 MHz): δ 0.18 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H), 1.31-1.37 (m, 4H), 1.60-1.69 (m, 2H), 2.06 (s, 3H), 5.46-5.50 (m, 1H), 6.16 (d, J = 7.2 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ -1.58, 13.92, 21.13, 22.50, 26.95, 32.88, 79.72, 113.52, 145.52, 170.05. IR (film): 2956, 2861, 1738, 1369, 1227, 1018, 839 cm-1. + HRMS (ESI) for C12H23IO2SiNa [M+Na] : calcd 377.0410, found 377.0393.

Rf = 0.35 (5% ethyl acetate/95% hexanes). 1 (E)-1-Iodo-1-(trimethylsilyl)hept-1-en-3-yl acetate (V-29). H NMR (CDCl3, 600 MHz): δ 0.32 (s, 9H), 0.90(t, J = 7.2 Hz, 3H), 1.23-1.36 (m, 4H), 1.46-1.52 (m, 1H), 1.62- 1.68 (m, 1H), 2.04 (s, 3H), 5.32-5.35 (m, 1H), 7.01 (d, J = 9.6 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 0.89, 13.89, 21.13, 22.48, 27.08, 34.09, 74.40, 113.46, 153.09, 170.10. IR (film): 2957, 2932, 2861, 1739, 1370, 1231, 1018, 843 cm-1. + HRMS (ESI) for C12H23IO2SiNa [M+Na] : calcd 377.0410, found 377.0394.

Rf = 0.38 (5% ethyl acetate/95% hexanes).

(Z)-1-Iodo-1-(triethylsilyl)hept-1-en-3-yl acetate (V-30). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 100:1) afforded the title product in 78% yield as a colorless oil. Z:E ratio: >20:1. 201

1 H NMR (CDCl3, 600 MHz): δ 0.69 (q, J = 8.4 Hz, 6H), 0.89 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.8 Hz, 9H), 1.30-1.37 (m, 4H), 1.59-1.71 (m, 2H), 2.04 (s, 3H), 5.46-5.50 (m, 1H), 6.16 (d, J = 6.6 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 2.89, 6.99, 13.91, 21.08, 22.51, 26.91, 32.85, 79.90, 110.00, 147.24, 169.95. IR (film): 2954, 2873, 1740, 1368, 1227, 1004, 965, 824 cm-1. + HRMS (ESI) for C15H29IO2SiNa [M+Na] : calcd 419.0879, found 419.0857.

Rf = 0.35 (5% ethyl acetate/95% hexanes). 1 (E)-1-Iodo-1-(triethylsilyl)hept-1-en-3-yl acetate (V-30). H NMR (CDCl3, 400 MHz): δ 0.76-0.93 (m, 9H), 0.98 (t, J = 8.0 Hz, 9H), 1.23-1.36 (m, 4H), 1.44-1.53 (m, 1H), 1.61- 1.70 (m, 1H), 2.03 (s, 3H), 5.22-5.28 (m, 1H), 7.16 (d, J = 10.0 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 4.63, 7.29, 13.90, 21.11, 22.53, 27.13, 34.50, 74.70, 111.46, 155.16, 170.03. IR (film): 2955, 2933, 2874, 1740, 1369, 1230, 1017, 1002 cm-1. + HRMS (ESI) for C15H29IO2SiNa [M+Na] : calcd 419.0879, found 419.0865.

Rf = 0.38 (5% ethyl acetate/95% hexanes).

(Z)-1-Iodo-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hept-1-en-3-yl acetate (V- 51). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1-20:1- 8:1) afforded the title product and the isomer in 52% yield as a colorless oil. Z:E ratio: 6:1.

1 H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 6.6 Hz, 3H), 1.24-1.35 (m, 16H), 1.64-1.68 (m, 2H), 2.05 (s, 3H), 5.44-5.48 (m, 1H), 6.79 (d, J = 7.2 Hz, 1H)

13 C NMR (CDCl3, 100 MHz): δ 13.91, 21.04, 22.48, 24.72, 24.75, 26.97, 32.41, 78.92, 85.00, 152.39, 170.20. 202

IR (film): 2955, 2928, 1738, 1371, 1326, 1230, 1141, 1019, 849 cm-1. + HRMS (ESI) for C15H26IO4BNa [M+Na] : calcd 431.0867, found 431.0675.

Rf = 0.1 (9% ethyl acetate/91% hexanes). (E)-1-Iodo-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hept-1-en-3-yl acetate (V- 1 51). H NMR (CDCl3, 600 MHz): δ 0.89 (t, J = 7.2 Hz, 3H), 1.22-1.35 (m, 16H), 1.51- 1.68 (m, 2H), 2.02 (s, 3H), 5.61-5.65 (m, 1H), 6.96 (d, J = 9.0 Hz, 1H) 13 C NMR (CDCl3, 150 MHz): δ 13.88, 21.13, 22.26, 24.58, 24.73, 26.91, 33.74, 74.82, 85.00, 155.37, 169.96. IR (film): 2931, 2858, 1738, 1371, 1323, 1230, 1141, 1017, 967, 847 cm-1. + HRMS (ESI) for C15H26IO4BNa [M+Na] : calcd 431.0867, found 431.0692.

Rf = 0.30 (9% ethyl acetate/91% hexanes).

(Z)-1-Iodo-1-(4-methoxyphenyl)hept-1-en-3-yl acetate (V-52). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1) afforded the title product and the isomer in 56% yield as a colorless oil. Z:E ratio: 7:1. 1 H NMR (CDCl3, 600 MHz): δ Z isomer (major): 0.92 (t, J = 7.2 Hz, 3H), 1.35-1.41 (m, 4H), 1.67-1.79 (m, 2H), 2.07 (s, 3H), 3.82 (s, 3H), 5.51-5.54 (m, 1H), 5.87 (d, J = 7.8 Hz, 1H), 6.81-6.84 (m, 2H), 7.40-7.42 (m, 2H); E isomer (minor): 0.84 (t, J = 7.2 Hz, 3H), 1.19-1.23 (m, 4H), 1.47-1.63 (m, 2H), 2.01 (s, 3H), 3.81 (s, 3H), 5.10-5.14 (m, 1H), 6.35 (d, J = 9.0 Hz, 1H), 6.84-6.85 (m, 2H), 7.26-7.27 (m, 2H). 13 C NMR (CDCl3, 100 MHz): δ Z isomer (major): 13.93, 21.11, 22.56, 27.03, 33.58, 55.37, 79.37, 106.01, 113.50, 129.79, 135.05, 135.33, 160.04, 170.09; E isomer (minor): 13.80, 21.05, 22.31, 26.90, 33.96, 55.26, 72.78, 100.45, 113.61, 129.58, 133.94, 140.77, 159.54, 169.85. IR (film): 2952, 2858, 1734, 1603, 1506, 1369, 1230, 1176, 1030, 961, 826 cm-1. + HRMS (ESI) for C16H21IO3Na [M+Na] : calcd 411.0433, found 411.0414. 203

Rf = 0.25 (9% ethyl acetate/91% hexanes).

(Z)-1-(Cyclohex-1-en-1-yl)-1-iodohept-1-en-3-yl acetate (V-53). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 100:1) afforded the title product and the isomer in 50% yield as a colorless oil. Z:E ratio: 2.2:1.

1 H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.31-1.36 (m, 4H), 1.55-1.59 (m, 3H), 1.63-1.69 (m, 3H), 2.05 (s, 3H), 2.15-2.16 (m, 2H), 2.24-2.33 (m, 2H), 5.55- 5.58 (m, 1H), 5.75 (d, J = 7.2 Hz, 1H), 6.18 (d, J = 4.2 Hz, 1H).

13 C NMR (CDCl3, 100 MHz): δ 13.95, 21.17, 22.15, 22.56, 22.84, 26.13, 27.02, 27.76, 33.66, 79.54, 112.75, 132.04, 134.07, 136.78, 170.15. IR (film): 2928, 2861, 1736, 1369, 1228, 1017, 957, 957, 799 cm-1.

+ HRMS (ESI) for C15H23IO2Na [M+Na] : calcd 385.0640, found 385.0645.

Rf = 0.35 (5% ethyl acetate/95% hexanes).

1 (E)-1-(Cyclohex-1-en-1-yl)-1-iodohept-1-en-3-yl acetate (V-53). H NMR (CDCl3, 600 MHz): δ 0.89 (t, J = 7.2 Hz, 3H), 1.23-1.34 (m, 4H), 1.46-1.52 (m, 1H), 1.56-1.64 (m, 3H), 1.65-1.73 (m, 2H), 2.00-2.04 (m, 2H), 2.01 (s, 3H), 2.14-2.18 (m, 2H), 5.36- 5.40 (m, 1H), 5.73-5.75 (m, 1H), 6.03 (d, J = 9.6 Hz, 1H).

13 C NMR (CDCl3, 100 MHz): δ 13.85, 21.16, 21.74, 22.21, 22.36, 25.22, 27.11, 27.86, 34.13, 72.33, 107.77, 127.18, 138.59, 138.79, 169.90. IR (film): 2929, 2834, 1738, 1435, 1368, 1228, 1015, 957, 922, 725 cm-1.

+ HRMS (ESI) for C15H23IO2Na [M+Na] : calcd 385.0640, found 385.0618.

Rf = 0.40 (5% ethyl acetate/95% hexanes).

204

(Z)-Methyl 4-acetoxy-2-iodooct-2-enoate (V-15). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1) afforded the title product and the isomer in 65% yield as a colorless oil. Z:E ratio: 14:1. 1 H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.31-1.39 (m, 4H), 1.63-1.75 (m, 2H), 2.06 (s, 3H), 3.82 (s, 3H), 5.38-5.42 (m, 1H), 7.16 (d, J = 7.2 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.84, 20.88, 22.41, 26.87, 32.27, 53.71, 77.64, 93.78, 150.48, 162.93, 170.19. IR (film): 2954, 2861, 1726, 1618, 1433, 1225, 1020, 893, 745 cm-1. + HRMS (ESI) for C11H17IO4Na [M+Na] : calcd 363.0069, found 363.0047.

Rf = 0.25 (9% ethyl acetate/91% hexanes). 1 (E)-Methyl 4-acetoxy-2-iodooct-2-enoate. H NMR (CDCl3, 400 MHz): δ 0.88 (t, J = 7.6 Hz, 3H), 1.27-1.36 (m, 4H), 1.58-1.70 (m, 2 H), 2.02 (s, 3H), 3.80 (s, 3H), 5.78-5.84 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.83, 20.91, 22.30, 26.96, 33.16, 53.28, 73.19, 86.41, 153.30, 163.54, 170.11. IR (film): 2954, 2860, 1716, 1608, 1433, 1221, 1143, 882, 783 cm-1. + HRMS (ESI) for C11H17IO4Na [M+Na] : calcd 363.0069, found 363.0032.

Rf = 0.3 (9% ethyl acetate/91% hexanes).

(Z)-2-Iodo-1-oxo-1-(phenylthio)oct-2-en-4-yl acetate (V-54). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 50:1 to 30:1) afforded the title product in 57% yield as a colorless oil. Z:E ratio: >20:1. 1 H NMR (CDCl3, 600 MHz): δ 0.93 (t, J = 7.2 Hz, 3H), 1.34-1.43 (m, 4H), 1.69-1.81

205

(m, 2H), 2.10 (s, 3H), 5.49-5.52 (m, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.41-7.46 (m, 5H). 13 C NMR (CDCl3, 100 MHz): δ 13.83, 20.87, 22.42, 26.92, 32.43, 77.58, 102.48, 127.81, 129.30, 129.82, 134.73, 147.87, 170.11, 186.22. IR (film): 2957, 2858, 1739, 1682, 1440, 1369, 1226, 1060, 1022, 745 cm-1. + HRMS (ESI) for C16H19IO3SNa [M+Na] : calcd 440.9997, found 440.9972.

Rf = 0.30 (9% ethyl acetate/91% hexanes).

(Z)-4-Acetoxy-2-iodooct-2-en-1-yl 2-methoxyacetate (V-55). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 10:1-7:1) afforded the title product and the isomer in 54% yield as a colorless oil. Z:E ratio: 3:1. 1 H NMR (CDCl3, 600 MHz): δ 0.89 (t, J = 7.2 Hz, 3H), 1.27-1.36 (m, 4H), 1.57-1.69 (m, 2H), 2.04 (s, 3H), 3.46 (s, 3H), 4.09 (s, 2H), 4.81 (dd, J = 13.2, 1.2 Hz, 1H), 4.85 (d, J = 13.2, 1.2 Hz, 1H), 5.34-5.38 (m, 1H), 5.98 (dt, J = 7.8, 1.2 Hz, 1H) 13 C NMR (CDCl3, 150 MHz): δ 13.83, 20.97, 22.42, 26.84, 31.14, 59.44, 69.67, 71.30, 77.47, 99.96, 137.59, 169.25, 169.99. IR (film): 2957, 2856, 1735, 1370, 1229, 1176, 1124, 1019, 961, 933 cm-1. + HRMS (ESI) for C13H21IO5Na [M+Na] : calcd 407.0331, found 407.0310.

Rf = 0.20 (9% ethyl acetate/91% hexanes). 1 (E)-4-Acetoxy-2-iodooct-2-en-1-yl 2-methoxyacetate (V-55). H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.22-1.36 (m, 4H), 1.52-1.69 (m, 2H), 2.04 (s, 3H), 3.47 (s, 3H), 4.11 (s, 2H), 4.78 (d, J = 13.2 Hz, 1H), 5.16 (d, J = 12.6 Hz, 1H), 5.44-5.48 (m, 1H), 6.31 (d, J = 9.6 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ13.85, 20.99, 22.36, 26.95, 33.68, 59.48, 66.37, 69.76, 71.45, 98.70, 143.95, 169.46, 170.15. IR (film): 2931, 2862, 1737, 1370, 1230, 1178, 1126, 1018, 968, 932 cm-1. + HRMS (ESI) for C13H21IO5Na [M+Na] : calcd 407.0331, found 407.0314. 206

Rf = 0.25 (9% ethyl acetate/91% hexanes).

(Z)-But-3-yn-1-yl 4-acetoxy-2-iodooct-2-enoate (V-56). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1) afforded the title product and the isomer in 50% yield as a colorless oil. Z:E ratio: 8:1.

1 H NMR (CDCl3, 600 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.31-1.40 (m, 4H), 1.63-1.76 (m, 2H), 2.02 (t, J = 3.0 Hz, 1H), 2.07 (s, 3H), 2.60 (dt, J = 7.2, 3.0 Hz, 2H), 4.28-4.34 (m, 2H), 5.39-5.43 (m, 1H), 7.19 (d, J = 7.8 Hz, 1H).

13 C NMR (CDCl3, 150 MHz): δ 13.83, 18.88, 20.88, 22.42, 26.92, 32.31, 64.39, 70.22, 77.66, 79.45, 93.80, 150.76, 162.15, 170.16. IR (film): 3291, 2957, 2858, 1722, 1371, 1223, 1020, 745 cm-1.

+ HRMS (ESI) for C14H19IO4Na [M+Na] : calcd 401.0226, found 401.0203.

Rf = 0.25 (9% ethyl acetate/91% hexanes).

1 (E)-But-3-yn-1-yl 4-acetoxy-2-iodooct-2-enoate (V-56). H NMR (CDCl3, 600 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.29-1.36 (m, 4H), 1.61-1.70 (m, 2H), 2.02 (t, J = 2.4 Hz, 1H), 2.04 (s, 3H), 2.56-2.65 (m, 2H), 4.28-4.35 (m, 2H), 5.82-5.86 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.85, 18.79, 20.93, 22.41, 26.99, 33.28, 64.18, 70.31, 73.22, 79.46, 86.70, 153.18, 162.87, 170.04. IR (film): 2955, 2861, 1724, 1370, 1225, 1018, 647 cm-1. + HRMS (ESI) for C14H19IO4Na [M+Na] : calcd 401.0226, found 401.0200.

Rf = 0.30 (9% ethyl acetate/91% hexanes).

207

(Z)-3-Hydroxybutyl 4-acetoxy-2-iodooct-2-enoate (V-57). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 7:1 to 4:1) afforded the title product in 55% yield as a colorless oil. Z:E ratio: >20:1. 1 H NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.21 (s, 9H), 1.25 (d, J = 6.0 Hz, 3H), 1.32-1.41 (m, 4H), 1.62-1.91 (m, 5H), 3.91-3.98 (m, 1H), 4.26-4.32 (m, 1H), 4.40-4.46 (m, 1H), 5.33-5.38 (m, 1H), 7.14 (dd, J = 7.6, 0.8 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.83, 22.32, 23.61, 26.92, 27.08, 32.12, 37.76, 38.80, 64.29, 64.96, 64.97, 77.50, 93.50, 93.51, 150.79, 162.60, 162.62, 177.80. IR (film): 3350, 2959, 2871, 1713, 1479, 1245, 1146, 1092, 1034, 968 cm-1. + HRMS (ESI) for C17H29IO5Na [M+Na] : calcd 463.0957, found 463.0932.

Rf = 0.40 (20% ethyl acetate/80% hexanes).

(Z)-3-Oxobutyl 4-acetoxy-2-iodooct-2-enoate (V-58). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 10:1 to 8:1) afforded the title product and the isomer in 64% yield as a colorless oil. Z:E ratio: 12:1.

1 H NMR (CDCl3, 400 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.29-1.39 (m, 4H), 1.60-1.74 (m, 2H), 2.06 (s, 3H), 2.20 (s, 3H), 2.82 (t, J = 6.4 Hz, 2H), 4.45 (t, J = 6.4 Hz, 2H), 5.36- 5.41 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H).

13 C NMR (CDCl3, 100 MHz): δ 13.81, 20.86, 22.39, 26.90, 30.29, 32.28, 41.99, 61.74, 77.61, 93.70, 150.63, 162.25, 170.14, 205.03. IR (film): 2957, 2856, 1716, 1370, 1223, 1167, 1022, 746 cm-1.

+ HRMS (ESI) for C14H21IO5Na [M+Na] : calcd 419.0331, found 419.0322.

Rf = 0.40 (20% ethyl acetate/80% hexanes). 208

1 (E)-3-Oxobutyl 4-acetoxy-2-iodooct-2-enoate. H NMR (CDCl3, 400 MHz): δ 0.90 (t, J = 7.2 Hz, 3H), 1.26-1.36 (m, 4H), 1.57-1.69 (m, 2H), 2.03 (s, 3H), 2.21 (s, 3H), 2.84 (t, J = 6.6 Hz, 2H), 4.43-4.49 (m, 2H), 5.77-5.80 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.85, 20.93, 22.40, 26.96, 30.27, 33.22, 41.82, 61.39, 73.08, 86.85, 152.92, 162.97, 170.07, 205.03. IR (film): 2960, 2861, 1716, 1369, 1223, 1166, 1018, 971 cm-1. + HRMS (ESI) for C14H21IO5Na [M+Na] : calcd 419.0331, found 419.0312.

Rf = 0.45 (20% ethyl acetate/80% hexanes).

(Z)-(13S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3yl 2-iodo-4-(pivaloyloxy)oct-2-enoate (V-59). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1-15:1-10:1) afforded the title product and the isomer in 50% yield as a light-yellow foam. Z:E ratio: 5:1. 1 H NMR (CDCl3, 400 MHz): δ 0.91 (s, 3H), 0.94 (t, J = 6.8 Hz, 3H), 1.23 (s, 9H), 1.35- 1.80 (m, 12H), 1.95-2.19 (m, 4H), 2.26-2.32 (m, 1H), 2.39-2.44 (m, 1H), 2.51 (dd, J = 18.4, 8.8 Hz, 1H), 2.91 (dd, J = 8.4, 4.4 Hz, 1H), 5.39-5.44 (m, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.78, 13.87, 21.54, 22.32, 25.72, 26.26, 26.96, 27.08, 29.33, 31.50, 32.04, 35.79, 37.94, 38.80, 44.10, 47.88, 50.39, 77.67, 93.11, 118.36, 121.20, 126.40, 137.75, 138.09, 148.88, 152.15, 161.20, 177.89, 220.65. IR (film): 2957, 2871, 1729, 1492, 1219, 1181, 1146, 1086, 910, 730 cm-1. + HRMS (ESI) for C31H41IO5Na [M+Na] : calcd 643.1896, found 643.1899.

Rf = 0.45 (20% ethyl acetate/80% hexanes). (E)-(13S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3yl 2-iodo-4-(pivaloyloxy)oct-2-enoate (V-59). 1H NMR

209

(CDCl3, 600 MHz): δ 0.87 (t, J = 7.2 Hz, 3H), 0.91 (s, 3H), 1.21 (s, 9H), 1.28-1.75 (m, 12H), 1.95-2.08 (m, 3H), 2.15 (tt, J = 18.0, 9.0 Hz, 1H), 2.29 (dt, J = 10.2, 3.6 Hz, 1H), 2.40-2.43 (m, 1H), 2.51 (dd, J = 18.6, 8.4 Hz, 1H), 2.92 (dd, J = 9.0, 4.2 Hz, 1H), 5.85- 5.89 (m, 1H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.94 (dt, J = 8.4, 2.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.86, 13.95, 21.62, 22.41, 25.79, 26.34, 27.14, 29.42, 31.58, 33.17, 35.89, 38.02, 38.81, 44.20, 47.98, 50.48, 73.35, 85.30, 85.34, 118.50, 121.29, 121.30, 126.53, 137.96, 138.22, 148.51, 155.61, 155.69, 161.93, 161.95, 177.73, 220.78. IR (film): 2957, 2871, 1732, 1492, 1222, 1179, 1150, 1083, 912, 731 cm-1. + HRMS (ESI) for C31H41IO5Na [M+Na] : calcd 643.1896, found 643.1882.

Rf = 0.50 (20% ethyl acetate/80% hexanes).

(Z)-3-Iodo-3-(triethylsilyl)allyl acetate (V-60). Following GP4, 10% Mn2(CO)10 was used. Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 95:5) afforded the title product in 46% yield as a light-yellow oil. Z:E ratio: >20:1. 1 H NMR (CDCl3, 400 MHz): δ 0.71 (q, J = 7.9 Hz, 6H), 0.96 (t, J = 7.9 Hz, 9H), 2.10 (s, 3H), 4.67 (d, J = 4.9 Hz, 1 H), 6.42 (t, J = 4.9 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 3.03, 7.18, 20.98, 71.12, 110.96, 143.48, 170.75. IR (film): 2953, 2874, 1742, 1373, 1220, 1034, 1003, 720, 692 cm-1. + HRMS (ESI) for C11H21IO2Na [M+Na] : calcd 363.0253, found 363.0225.

Rf = 0.35 (5% ethyl acetate/95% hexanes).

210

(Z)-1-Iodo-4-methyl-1-(triethylsilyl)pent-1-en-3-yl acetate (V-61). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 98:2) afforded the title product in 70% yield as a light yellow oil. Z:E ratio: >20:1.

1 H NMR (CDCl3, 400 MHz): δ 0.71 (q, J = 7.83 Hz, 6H), 0.95 (t, J = 7.83 Hz, 9H), 0.96 (d, J = 6.64 Hz, 1H), 1.98-2.10 (m, 1H), 2.06 (s, 3H), 5.38 (dd, J = 5.64, 7.52 Hz, 1H), 6.13 (d, J = 7.52 Hz, 1H).

13 C NMR (CDCl3, 150 MHz): δ 3.10, 7.20, 17.72, 18.46, 21.19, 31.98, 83.61, 111.88, 145.87, 170.15. IR (film): 2956, 2874, 1741, 1368, 1227, 1004, 977, 721, 692 cm-1.

+ HRMS (ESI) for C14H27IO2SiNa [M+Na] : calcd 405.0723, found 405.0698.

Rf = 0.35 (5% ethyl acetate/95% hexanes).

(Z)-4-Iodo-1-phenyl-4-(triethylsilyl)but-3-en-2-yl acetate (V-62). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 9:1) afforded the title product and the isomer in 68% yield as a colorless oil. Z:E ratio: 9:1.

1 H NMR (CDCl3, 600 MHz): δ Z-isomer (major): 0.95 (t, J = 8.0 Hz, 9H), 2.03 (s, 3H), 5.72 (qm, J = 6.4 Hz, 1H), 6.18 (dm, J = 6.9 Hz, 1H); E-isomer (minor): 0.78-0.82 (m, 3H), 0.91 (t, J = 7.9 Hz, 9H), 2.01 (s, 3H), 2.85 (dd, J = 13.7, 6.2 Hz, 1H), 5.45-5.49 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H); Overlap (major and minor): 0.68-0.72 (q), 2.94-3.04 (m), 7.23-7.26 (m), 7.28-7.33 (m).

13 C NMR (CDCl3, 150 MHz): δ Z-isomer (major): 3.29, 7.13, 21.08, 39.37, 80.48, 111.10, 126.82, 128.39, 129.95, 136.60, 146.70, 169.79; E-isomer (minor): 4.94, 7.35, 41.35, 75.22, 112.62, 127.01, 128.59, 129.86, 136.17, 154.24. 211

IR (film): 3028, 2953, 1741, 1369, 1227, 732, 698 cm-1.

+ HRMS (ESI) for C18H27INaO2Si [M+Na] : calcd 453.0723, found 453.0718.

Rf = 0.56 (major), 0.59 (minor) (10% ethyl acetate/90% hexanes).

(Z)-1-(4-Fluorophenyl)-4-iodo-4-(triethylsilyl)but-3-en-2-yl acetate (V-63). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 5.7:1) afforded the title product and the isomer in 73% yield as a yellow oil. Z:E ratio: 11:1. 1 H NMR (CDCl3, 600 MHz): δ Z-isomer (major): 2.01 (s, 3H), 5.65-5.68 (m, 1H), 6.14 (d, J = 7.0 Hz, 1H), 7.17-7.20 (m, 2H); E-isomer (minor): 0.77-0.82 (m, 3H), 1.99 (s, 3H), 2.80 (dd, J = 13.8, 6.3 Hz, 1H), 5.39-5.43 (m, 1H), 7.12-7.14 (m, 2H); Overlap (major and minor): 0.66-0.70 (m), 0.88-0.94 (m), 2.89-2.98 (m), 6.94-6.98 (m). 13 C NMR (CDCl3, 150 Hz): δ Z-isomer (major): 3.04, 7.12, 21.08, 38.39, 80.35, 111.28, 115.13 (d, J = 21.6 Hz,) 131.28 (d, J = 7.8 Hz), 132.14 (d, J = 3.23 Hz), 146.30, 161.97 (d, J = 244.5 Hz), 169.79; E-isomer (minor): 4.71, 7.31, 40.36, 74.98, 112.82, 115.37 (d, J = 21.6 Hz), 131.20 (overlap with major), 153.83, 169.73. 19 F NMR (CDCl3, 564 MHz): δ -116.05 (E-isomer), -116.36 (Z-isomer). IR (film): 2954, 2875, 1740, 1509, 1222, 1019, 732 cm-1. + HRMS (ESI) for C18H26FINaO2Si [M+Na] : calcd 471.0628, found 471.0617.

Rf = 0.50 (both isomers, 10% ethyl acetate/90% hexanes).

(Z)-4-Iodo-1-(4-methoxyphenyl)-4-(triethylsilyl)but-3-en-2-yl acetate (V-64). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 9:1) afforded the

212

title product in 67% yield as a yellow oil. Z:E ratio: >20:1.

1 H NMR (CDCl3, 600 MHz): δ 0.68 (q, J = 7.9 Hz, 6H), 0.92 (t, J = 7.9 Hz, 9H), 2.01 (s, 3H), 2.88-2.95 (m, 2H), 3.78 (s, 3H), 5.63-5.66 (m, 1H), 6.15 (d, J = 6.9 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H).

13 C NMR (CDCl3, 150 MHz): δ 3.27, 7.11, 21.05, 38.45, 55.37, 80.62, 110.92, 113.95, 128.64, 130.84, 146.80, 158.76, 169.73. IR (film): 2953, 2874, 1739, 1512, 1228, 1020, 721 cm-1.

+ HRMS (ESI) for C19H29INaO3Si [M+Na] : calcd 483.0828, found 483.0827.

Rf = 0.46 (10% ethyl acetate/90% hexanes).

(Z)-1-((tert-Butyldiphenylsilyl)oxy)-4-iodo-4-(triethylsilyl)but-3-en-2-yl acetate (V- 65). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 20:1) afforded the title product in 76% yield as a yellow oil. Z:E ratio: >20:1.

1 H NMR (CDCl3, 600 MHz): δ 0.70 (q, J = 8.0 Hz, 6H), 0.94 (t, J = 7.9 Hz, 9H), 1.04 (s, 9H), 2.05 (s, 3H), 3.79-3.85 (m, 2H), 5.64-5.66 (m, 1H), 6.33 (d, J = 7.0 Hz, 1H), 7.37-7.44 (m, 6H), 7.65-7.69 (m, 4H).

13 C NMR (CDCl3, 150 MHz): δ 3.26, 7.12, 19.41, 21.00, 26.90, 64.23, 80.45, 112.16, 127.81, 129.80, 129.83, 133.53, 133.63, 135.69, 135.79, 144.56, 169.78. IR (film): 3071, 2954, 2873, 1742, 1229, 1111 cm-1.

+ HRMS (ESI) for C28H41INaO3Si2 [M+Na] : calcd 631.1537, found 631.1524.

Rf = 0.33 (5% ethyl acetate/95% hexanes).

213

(Z)-5-((tert-Butyldiphenylsilyl)oxy)-1-iodo-1-(triethylsilyl)pent-1-en-3-yl acetate (V- 66). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 5.7:1) afforded the title product and the isomer in 81% yield as a colorless oil. Z:E ratio: 4:1. 1 H NMR (CDCl3, 600 MHz): δ Z-isomer (major): 0.69 (q, J = 7.8 Hz, 6H), 1.87-1.93 (m, 1H), 3.71-3.75 (m, 2H), 5.65-5.68 (m, 1H), 6.18 (d, J = 6.9 Hz, 1H); E-isomer (minor): 0.80-0.85 (m, 3H), 1.81-1.84 (m, 2H), 3.64-3.67 (m, 2H), 5.51-5.55 (m, 1H), 7.16 (d, J = 9.99 Hz, 1H); Overlap (major and minor): 0.88-0.98 (m), 1.06 (s, minor), 1.07 (s, major), 1.98 (s, minor), 1.99 (s, major), 1.97-2.02 (m), 7.36-7.43 (m), 7.64-7.70 (m).

13 C NMR (CDCl3, 150 MHz): δ Z-isomer (major): 3.05, 7.18, 19.33, 21.14, 27.00, 35.96, 59.74, 77.59, 109.90, 127.78, 129.71, 129.73, 133.83, 133.87, 135.75, 147.20, 169.92; E- isomer (minor): 4.65, 7.45, 19.23, 26.88, 37.59, 59.47, 71.88, 111.38, 127.82, 129.79, 129.81, 133.58, 133.61, 135.45, 135.69, 155.20. IR (film): 3070, 2953, 2874, 1742, 1427, 1228, 1110, 700 cm-1.

+ HRMS (ESI) for C29H43INaO3Si2 [M+Na] : calcd 645.1693, found 645.1687.

Rf = 0.36 (major), 0.44 (minor) (10% ethyl acetate/90% hexanes).

(Z)-1-(1,3-Dioxoisoindolin-2-yl)-4-iodo-4-(triethylsilyl)but-3-en-2-yl acetate (V-67). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 5.7:1) afforded the title product in 60% yield as a colorless oil. Z:E ratio: >20:1. 1 H NMR (CDCl3, 600 MHz): δ 0.67 (qm, J = 5.7 Hz, 6H), 0.90 (t, J = 7.8 Hz, 9H), 2.02 (s, 3H) 3.95 (d, J = 6.2 Hz, 2H), 5.82 (dt, J = 7.2, 6.2 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 214

7.69-7.74 (m, 2H), 7.81-7.86 (m, 2H). 13 C NMR (CDCl3, 100 MHz): δ 2.98, 7.12, 21.02, 39.31, 77.32, 114.21, 123.48, 132.09, 134.17, 143.59, 168.09, 169.86. IR (film): 2953, 2874, 1776, 1742, 1714, 1390, 1368, 1221, 1021, 720, 715 cm-1. + HRMS (ESI) for C20H26INNaO4Si [M+Na] : calcd 522.0573, found 522.0569.

Rf = 0.5 (25% ethyl acetate/75% hexanes).

(Z)-5-(1,3-Dioxoisoindolin-2-yl)-1-iodo-1-(triethylsilyl)pent-1-en-3-yl acetate (V- 68). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 5.7:1) afforded the title product and the isomer in 72% yield as a yellow oil. Z:E ratio: 6:1. 1 H NMR (CDCl3, 600 MHz): δ Z-isomer (major) 0.92 (t, J = 7.9 Hz, 9H), 2.00 (s, 3H), 2.12-2.17 (m, 1H), 3.74-3.79 (m, 1H), 5.43-5.47 (m, 1H), 6.23 (d, J = 6.7 Hz, 1H); E- isomer (minor): 0.74-0.78 (m, 3H), 0.85 (t, J = 7.7 Hz, 9H), 2.06 (s, 3H), 3.67-3.71 (m, 1H), 5.18-5.22 (m, 1H), 7.12 (d, J = 9.4 Hz, 1H); Overlap (major and minor) 0.65-0.69 (m), 2.03-2.09 (m), 3.82-3.88 (m), 7.69-7.72 (m), 7.83-7.85 (m). 13 C NMR (CDCl3, 150 MHz): δ Z-isomer (major): 2.95, 7.12, 21.00, 31.36, 34.11, 78.19, 110.67, 123.35, 132.24, 134.06, 146.39, 168.22, 169.93; E-isomer (minor): 4.48, 7.28, 21.07, 33.14, 33.92, 72.00, 111.76, 123.38, 132.12, 134.14, 154.17, 168.16, 170.15. IR (film): 2953, 2874, 1772, 1741, 1710, 1394, 1369, 1226, 1005, 718 cm-1. + HRMS (ESI) for C21H28INNaO4Si [M+Na] : calcd 536.0730, found 536.0724.

Rf = 0.42 (both isomers, 25% ethyl acetate/75% hexanes).

215

(Z)-4-Iodo-1-(1-tosylpiperidin-4-yl)-4-(triethylsilyl)but-3-en-2-yl (V-69). Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 5.7:1) afforded the title product and the isomer in 66% yield as a colorless oil. Z:E ratio: 7:1.

1 H NMR (CDCl3, 600 MHz): δ Z-isomer (major): 0.67 (q, J = 7.9 Hz, 6H), 0.91 (t, J = 7.9 Hz, 9H), 1.83 (dd, J = 111.4, 2.9 Hz, 2H), 2.01 (s, 3H), 2.43 (s, 3H), 5.50-5.53 (m, 1H), 6.13 (d, J = 6.8 Hz, 1H); E-isomer (minor): 0.72-0.79 (m, 3H), 0.82-0.86 (m, 3H), 0.94 (t, J = 7.8 Hz, 9H), 1.65-1.69 (m, 2H), 1.85 (d, J = 12.6 Hz, 1H), 1.98 (s, 3H), 2.17 (s, 3H), 5.31-5.35 (m, 1H), 7.11 (d, J = 9.6 Hz, 1H); Overlap (major and minor): 1.25- 1.30 (m), 1.35-1.42 (m), 1.45-1.49 (m), 1.59-1.63 (m), 2.18-2.25 (m), 3.74-3.77 (m), 7.32 (d, J = 8.1 Hz), 7.63 (d, J = 8.3 Hz).

13 C NMR (CDCl3, 100 MHz): δ Z-isomer (major): 2.96, 7.11, 21.18, 21.61, 31.06, 31.63, 32.24, 39.62, 46.34, 46.35, 77.94, 110.45, 127.82, 129.67, 133.34, 143.46, 147.09, 170.01; E-isomer (minor): 4.64, 7.40, 29.78, 30.99, 31.34, 41.40, 72.16, 111.61, 127.65, 129.89, 133.23, 143.54, 154.74. IR (film): 2952, 2874, 1737, 1229, 1163, 722, 548 cm-1.

+ HRMS (ESI) for C24H38INNaO4SSi [M+Na] : calcd 614.1233, found 614.1225.

Rf = 0.54 (both isomers, 25% ethyl acetate/75% hexanes).

(Z)-8-Chloro-1-iodo-1-(triethylsilyl)oct-1-en-3-yl acetate (V-70). Following GP4,

10% Mn2(CO)10 catalyst and 0.5 equiv. KOAc were used instead of DIPEA. Column chromatography on silica gel (eluent: hexanes/ethyl actetate = 99:1) afforded the title product in 67% yield as a brown oil. Z:E ratio: >20:1. 216

1 H NMR (CDCl3, 600 MHz): δ 0.70 (q, J = 7.9 Hz, 6H), 0.94 (t, J = 7.9 Hz, 9H), 1.37- 1.43 (m, 2H), 1.46-1.51 (m, 2H), 1.62-1.73 (m, 2H), 1.76-1.81 (m, 2H), 2.06 (s, 3H), 3.53 (t, J = 6.7 Hz, 2H), 5.47-5.51 (m, 1H), 6.17 (d, J = 6.9 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 3.05, 7.18, 21.25, 24.28, 26.84, 32.57, 33.13, 45.02, 79.87, 110.53, 147.14, 170.13. IR (film): 2952, 2874, 1740, 1457, 1370, 1231, 1018, 733 cm-1. + HRMS (ESI) for C16H30ClINaO2Si [M+Na] : calcd 467.0646 and 469.0616, found 467.0633 and 469.0616.

Rf = 0.57 (10% ethyl acetate/90% hexanes).

(Z)-1,8-Diiodo-1-(triethylsilyl)oct-1-en-3-yl acetate (V-71). Following GP4, 10%

Mn2(CO)10 catalyst and 0.5 equiv. KOAc were used instead of DIPEA. Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 98:2) provided the title product in 64% yield as a light-yellow oil. Z:E ratio: >20:1.

1 H NMR (CDCl3, 400 MHz): δ 0.70 (q, J = 7.84 Hz, 6H), 0.94 (t, J = 7.84 Hz, 9H), 1.41 (m, 4H), 1.66 (m, 2H), 1.83 (m, 2H), 2.06 (s, 3H), 3.18 (t, J = 7.09 Hz, 2H), 5.48 (m, 1H), 6.17 (d, J = 7.03 Hz, 1H).

13 C NMR (CDCl3, 100 MHz): δ 3.05, 6.89, 7.21, 21.28, 23.93, 30.43, 33.09, 33.45, 79.86, 110.55, 147.12, 170.13. IR (film): 2952, 2873, 1738, 1369, 1228, 1004, 721, 692 cm-1.

+ HRMS (ESI) for C16H30I2O2SiNa [M+Na] : calcd 559.0002, found 558.9973.

Rf = 0.33 (5% ethyl acetate/95% hexanes).

217

(Z)-1,1,1-Trifluoro-4-iodo-2-methyl-4-(triethylsilyl)but-3-en-2-yl acetate (V-72). To

an 8 mL vial was added the premade α-acyloxy iodide (0.5 mmol), CH2Cl2 (0.5 mL) and DIPEA (0.25 mmol) at 0 ºC, then the mixture was stirred for another 15 min. After that

triethylsilyl acetylene (2.5 mmol) and Mn2(CO)10 (0.025 mmol) were added to the mixture. The reaction mixture was degassed by chill-pump-thaw for 20 min, then irradiated with 90 W blue LED lamp at approximately 5 cm away from the light source. The reaction temperature was around 40 ºC. After 2 h, the solvent was removed under vacuum and the crude product was purified by Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 100:1) to afford the title product in 78% yield as a colorless oil. Z:E ratio: >20:1. 1 H NMR (CDCl3, 600 MHz): δ 0.71 (q, J = 7.8 Hz, 6H), 0.94 (t, J = 7.8 Hz, 9H), 1.83 (d, J = 0.6 Hz, 3H), 2.19 (s, 3H), 6.56 (d, J = 0.6 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 2.95, 6.82, 20.07, 21.34, 80.30 (q, J = 29.6 Hz), 109.94, 124.07 (q, J = 283.4 Hz), 139.55, 167.36. IR (film): 2952, 2873, 1758, 1367, 1226, 1159, 1104, 1004, 732 cm-1. + HRMS (ESI) for C13H22F3IO2SiNa [M+Na] : calcd 445.0284, found 445.0285.

Rf = 0.35 (5% ethyl acetate/95% hexanes).

(Z)-2,5,7,8-Tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl 4-acetoxy-2- iodooct-2-enoate (V-75). Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 200:1-150:1-100:1) afforded the title product and the isomer in 63% yield as a colorless oil. Z:E ratio: 1.6:1. 1 H NMR (CDCl3, 600 MHz): δ 0.84-0.87 (m, 12H), 0.94 (t, J = 7.2 Hz, 3H), 1.04-1.16 (m, 6H), 1.20-1.45 (m, 19H), 1.50-1.57 (m, 3H), 1.72-1.84 (m, 4H), 1.97 (s, 3H), 2.01 (s, 218

3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.59 (t, J = 6.0 Hz, 2H), 5.51-5.54 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H). 13 C NMR (CDCl3, 150 MHz): δ 11.78, 12.15, 12.99, 13.87, 19.59, 19.62, 19.64, 19.68, 19.74, 20.60, 20.93, 21.02, 22.44, 22.61, 22.69, 23.63 (br), 24.22 (br), 24.44, 24.79, 27.00, 27.97, 31.15 (br), 32.40, 32.69, 32.72, 32.78, 32.80, 37.30, 37.35, 37.40, 37.42, 37.46, 37.49, 37.54, 37.57, 39.38, 39.58 (br), 40.45 (br), 75.16, 77.60, 92.60, 117.54, 123.23, 124.78, 126.54, 141.03, 149.69, 151.41, 161.10, 170.17. IR (film): 2924, 2863, 1741, 1459, 1373, 1200, 1072, 1020, 738 cm-1. + HRMS (ESI) for C39H63IO5Na [M+Na] : calcd 761.3618, found 761.3636.

Rf = 0.35 (5% ethyl acetate/95% hexanes). (E)-2,5,7,8-Tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl 4-acetoxy-2- 1 iodooct-2-enoate (V-75). H NMR (CDCl3, 600 MHz): δ 0.84-0.88 (m, 15H), 1.06-1.16 (m, 6H), 1.21-1.44 (m, 19H), 1.49-1.60 (m, 3H), 1.66-1.84 (m, 4H), 2.04 (br, 3H), 2.07 (s, 3H), 2.08 (br, 3H), 2.10 (s, 3H), 2.60 (t, J = 6.6 Hz, 2H), 5.88-5.92 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 11.80, 12.19, 13.04, 13.88, 19.57, 19,61, 19.63, 19.67, 19.73, 20.58, 20.97, 21.01, 22.44, 22.61, 22.70, 23.67 (br), 24.11 (br), 24.43, 24.79, 27.15, 27.96, 31.08, 32.69, 32.75, 33.25, 37.27, 37.38, 37.43, 37.51, 37.53, 39.36, 39.62 (br), 40.40 (br), 73.76, 75.11, 84.90, 117.52, 123.24, 124.86, 126.60, 140.63, 149.72, 155.55, 161.64, 170.15. IR (film): 2924, 2861, 1743, 1459, 1374, 1228, 1188, 1107, 1017, 972 cm-1. + HRMS (ESI) for C39H63IO5Na [M+Na] : calcd 761.3618, found 761.3591.

Rf = 0.40 (5% ethyl acetate/95% hexanes).

1-Iodo-1-(trimethylsilyl)heptan-3-yl acetate (V-73). Following GP5, 5% Mn2(CO)10 was used. Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 100:1) 219

afforded the title product of two isomers in 76% yield as a colorless oil. Ratio of the two isomers: 2:1. 1 H NMR (CDCl3, 600 MHz): δ 0.14 (s, minor), 0.15 (s, major), 0.87-0.91 (m, overlap), 1.26-1.32 (m, overlap), 1.43-1.66 (m, overlap), 1.75-1.88 (m, overlap), 2.04 (s, minor), 2.05 (s, major), 2.93 (dd, J = 12.0, 3.6 Hz, minor), 3.07 (dd, J = 12.0, 3.0 Hz, major), 5.06-5.12 (m, overlap). 13 C NMR (CDCl3, 150 MHz): δ -2.29, -2.25, 13.89, 13.94, 14.93, 16.87, 21.13, 21.29, 22.55, 22.61, 26.82, 27.30, 31.86, 34.19, 37.50, 38.27, 74.81, 75.76, 170.42, 170.48. IR (film): 2954, 2858, 1736, 1372, 1232, 1020, 837 cm-1. + HRMS (ESI) for C12H15IO2SiNa [M+Na] : calcd 379.0566, found 379.0538.

Rf = 0.35 (5% ethyl acetate/95% hexanes).

1,1,1-Trifluoro-4-iodo-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)butan-2-yl acetate (V-74). To an 8 mL vial was added the premade α-acyloxy iodide

(0.5 mmol), CH2Cl2 (0.5 mL) and KOAc (0.25 mmol) at 0 ºC, then the mixture was stirred for another 15 min. After that alkenyl boronate ester (1.0 mmol) and Mn2(CO)10 (0.025 mmol) were added to the mixture. The reaction mixture was degassed by chill-pump- thaw for 20 min, then irradiated with 90 W blue LED lamp at approximately 5 cm away from the light source. The reaction temperature was around 40 ºC. After 2 h, the solvent was removed under vacuum and the crude product was purified by Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1 to 20:1) afforded the title product of two isomers in 36% yield as a colorless oil. Ratio of the two isomers: 1.3:1. 1 H NMR (CDCl3, 400 MHz): δ 1.25 (s, minor), 1.26 (s, major), 1.65-1.66 (m, overlap), 2.07 (s, minor), 2.10 (s, major), 2.66 (dd, J = 14.8, 4.0, minor), 2.77 (dd, J = 15.6, 10.4,

220 major), 2.85-2.92 (m, minor), 2.98-3.03 (m, major), 3.35 (dd, J = 10.4, 3.6, major), 3.42- 3.46 (m, minor). 13 C NMR (CDCl3, 100 MHz): δ 18.16, 18.83, 21.88, 22.07, 24.06, 24.23, 24.30, 24.34, 38.97, 39.55, 82.34 (q, J = 19 Hz), 82.53 (q, J = 19 Hz), 84.13, 84.16, 124.54 (q, J = 188.2 Hz), 124.68 (q, J = 188.1 Hz), 168.85. IR (film): 2980, 2933, 1752, 1382, 1372, 1158, 1142, 1097, 969, 865 cm-1. + HRMS (ESI) for C13H21BF3IO4Na [M+Na] : calcd 459.0427, found 459.0410.

Rf = 0.25 (9% ethyl acetate/91% hexanes).

(Z)-Allyl 4-acetoxy-2-iodooct-2-enoate (V-80). GP5. Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1 to 20:1) afforded the title product and the isomer in 42% yield as a colorless oil. Z:E ratio: 11:1. 1 H NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.6 Hz, 3H), 1.31-1.40 (m, 4H), 1.63-1.76 (m, 2H), 2.07 (s, 3H), 2.56-2.65 (m, 2H), 4.69-4.71 (m, 2H), 5.27-5.30 (m, 1H), 5.36-5.45 (m, 2H), 5.90-6.00 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.86, 20.92, 22.42, 26.91, 32.31, 67.41, 77.67, 94.10, 118.92, 131.41, 150.52, 162.08, 170.20. IR (film): 2957, 2930, 2861, 1718, 1370, 1220, 1020, 746 cm-1. + HRMS (ESI) for C13H19IO4Na [M+Na] : calcd 389.0226, found 389.0205.

Rf = 0.25 (9% ethyl acetate/91% hexanes).

221

(Z)-3-Methylbut-2-en-1-yl 4-acetoxy-2-iodooct-2-enoate (V-81). GP5. Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1 to 20:1) afforded the title product and the isomer in 44% yield as a colorless oil. Z:E ratio: 7:1. 1 H NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.31-1.40 (m, 4H), 1.63-1.76 (m, 2H), 1.73 (d, J = 0.8 Hz, 3H), 1.77 (d, J = 0.8 Hz, 3H), 2.07 (s, 3H), 4.70 (d, J = 7.2 Hz, 2H), 5.36-5.45 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.87, 18.12, 20.93, 22.43, 25.78, 26.92, 32.35, 63.83, 77.74, 94.98, 118.00, 139.85, 149.99, 162.45, 170.20. IR (film): 2960, 2933, 2861, 1713, 1370, 1219, 1017, 733 cm-1. + HRMS (ESI) for C15H23IO4Na [M+Na] : calcd 417.0539, found 417.0521.

Rf = 0.25 (9% ethyl acetate/91% hexanes).

(Z)-Prop-2-yn-1-yl 4-acetoxy-2-iodooct-2-enoate (V-82). GP5. Column chromatography on silica gel (eluent: hexanes/ethyl acetate = 30:1 to 20:1) afforded the title product and the isomer in 42% yield as a colorless oil. Z:E ratio: 8:1. 1 H NMR (CDCl3, 400 MHz): δ 0.92 (t, J = 7.6 Hz, 3H), 1.30-1.42 (m, 4H), 1.62-1.79 (m, 2H), 2.08 (s, 3H), 2.53 (t, J = 2.4 Hz, 1H), 4.81 (dd, J = 2.4, 0.8 Hz, 2H), 5.39-5.44 (m, 1H), 7.23 (d, J = 7.6 Hz, 1H). 13 C NMR (CDCl3, 100 MHz): δ 13.86, 20.91, 22.42, 26.93, 32.25, 54.19, 75.62, 76.96, 77.70, 93.08, 151.53, 161.70, 170.23. IR (film): 2955, 2933, 2858, 1725, 1369, 1219, 1032, 744 cm-1.

222

+ HRMS (ESI) for C13H17IO4Na [M+Na] : calcd 387.0069, found 387.0047.

Rf = 0.25 (9% ethyl acetate/91% hexanes).

To an 8 mL vial was added DCM (0.5 mL), AcI (0.6 mmol), Zn(OTf)2 (0.025 mmol) and aldehyde (0.5 mmol) consecutively at 0 ºC. The mixture was stirred at the same temperature for 15 min. To this mixture was added DIPEA (0.25 mmol) at 0 ºC, then the mixture was

stirred for another 15 min. Triethylsilyl acetylene (2.5 mmol) and Mn2(CO)10 (0.025 mmol) was added to the mixture. The reaction was degassed by chill-pump-thaw for 20 min at - 78 °C, then irradiated with one 90 W Blue LED lamp (at approximately 5 cm away from the light source). After 2 h, the crude product was purified by column chromatography on silica gel (eluent: hexanes/ethyl acetate = 95:5) to provide solely 45 in 63% yield as a light- yellow oil. E:Z ratio: 2:1. *Note: Same yield and selectivity were obtained without triethylsilyl acetylene. 1 (E)-methyl 2-(2-acetoxycyclopentylidene)-2-iodoacetate (V-84). H NMR (CDCl3, 400 MHz): δ 1.70-1.81 (m, 1H), 2.02 (s, 3H), 1.84-2.04 (m, 2 H), 2.08-2.18 (m, 1H), 2.37-2.48 (td, J = 7.82, 18.97 Hz, 1H), 2.61-2.72 (m, 1H), 3.76 (s, 3H), 5.99 (m, 1H). 13 C NMR (CDCl3, 150 MHz): δ 21.03, 21.85, 35.60, 42.00, 53.34, 74.43, 162.91, 164.01, 169.89. IR (film): 1705, 1226, 1021, 756 cm-1. + HRMS (ESI) for C10H13IO4Na [M+Na] : calcd 346.9756, found 346.9728.

Rf = 0.23 (10% ethyl acetate/90% hexanes). 1 (Z)-Methyl 2-(2-acetoxycyclopentylidene)-2-iodoacetate (V-84). H NMR (CDCl3, 600 MHz): δ 1.83-2.04 (m, J = 4H), 2.10 (s, 3H), 2.73 (m, 1 H), 2.93-3.00 (m, 1H), 3.81 (s, 3H), 5.56 (m, 1H).

223

13 C NMR (CDCl3, 150 MHz): δ 21.09, 24.91, 33.19, 35.52, 53.35, 82.28, 85.83, 164.40, 164.46, 170.29. IR (film): 2952, 1736, 1709, 1220, 1030 cm-1. + HRMS (ESI) for C10H13IO4Na [M+Na] : 346.9756, found 346.9744.

Rf = 0.31 (10% ethyl acetate/90% hexanes).

First fraction (22% yield, containing two isomers): Rf = 0.30 (9% ethyl acetate/91% hexanes). Ratio of the two Z isomers: 3:1, Z:E ratio of the major isomers > 20:1. 1 H NMR (CDCl3, 400 MHz): δ 0.64-0.71 (q, overlap), 0.89-0.93 (t, overlap), 1.22-1.26 (t, overlap), 1.60-1.92 (m, overlap), 1.98 (s), 2.05 (s), 2.32-2.40 (m), 2.46-2.53 (m), 3.57 (t, J = 8.8 Hz), 3.72 (dd, J = 10.8, 8.8 Hz), 4.11-4.17 (q, overlap), 4.89-4.93 (m), 4.99 (t, J = 5.2 Hz), 6.08 (d, J = 8.8 Hz), 6.21 (d, J = 9.2 Hz). 13 C NMR (CDCl3, 100 MHz): δ 3.00, 3.01, 6.97, 7.02, 14.17, 14.19, 21.25, 21.83, 22.04, 22.84, 27.63, 28.29, 32.27, 32.57, 46.03, 47.15, 55.70, 57.67, 60.78, 60.81, 76.16, 78.38, 112.60, 113.67, 144.55, 144.98, 170.29, 170.34, 171.52, 171.85.

224

IR (film): 2953, 2874, 1731, 1370, 1235, 1148, 1017, 732 cm-1. + HRMS (ESI) for C19H33IO4SiNa [M+Na] : calcd 503.1090, found 503.1067.

Second fraction (25% yield, containing three isomers): Rf = 0.25 (9% ethyl acetate/91% hexanes). Ratio of the two Z isomers: 4:1, Z:E ratio of the major isomers 4:1. 1 H NMR (CDCl3, 400 MHz): δ 0.66-0.87 (q, overlap), 0.90-1.00 (t, overlap), 1.18-1.26 (t, overlap), 1.53-1.97 (m, overlap), 1.98 (s), 2.00 (s), 2.06 (s), 2.21-2.30 (m), 2.32-2.40 (m), 2.43-2.50 (m), 3.30 (t, J = 10.8 Hz), 3.61 (t, J = 8.8 Hz), 3.79 (dd, J = 10.4, 9.2 Hz), 4.05- 4.16 (q, overlap), 4.90-4.94 (m), 5.10-5.13 (m), 5.15-5.18 (m), 6.04 (d, J = 9.2 Hz), 6.13 (d, J = 9.2 Hz), 7.13 (d, J = 11.2 Hz). 13 C NMR (CDCl3, 100 MHz): δ 3.00, 3.01, 4.78, 7.02, 7.27, 7.31, 14.04, 14.07, 14.10, 20.98, 21.15, 21.23, 21.90, 22.02, 22.56, 27.48, 27.55, 28.20, 32.03, 32.64, 32.74, 45.82, 47.05, 51.20, 55.29, 57.20, 60.79, 60.85, 60.92, 76.05, 76.12, 78.30, 109.82, 112.66, 113.48, 144.32, 145.13, 153.12, 170.04, 170.43, 171.27, 171.66, 172.02. IR (film): 2953, 2874, 1732, 1370, 1236, 1149, 1019, 723 cm-1. + HRMS (ESI) for C19H33IO4SiNa [M+Na] : calcd 503.1090, found 503.1080.

225

References

1. Godula, K.; Sames, D. Science 2006, 312, 67–72.

2. Berkowitz, J.; Ellison, G. B.; Gutman, D. J. Phys. Chem. 1994, 98, 2744–2765.

3. Bender, M. ChemBioEng Rev. 2014, 1, 136–147.

4. Hofmann, A. W. Berichte der Dtsch. Chem. Gesellschaft 1883, 16, 558–560.

5. Löffler, K.; Freytag, C. Berichte der Dtsch. Chem. Gesellschaft 1909, 42, 3427– 3431.

6. Fritz, J. S.; Gjerde, D. T. Radicals in Organic Synthesis; 1999.

7. Xue, X.-S.; Ji, P.; Zhou, B.; Cheng, J.-P. Chem. Rev. 2017, 117, 8622–8648.

8. Chen, M. S.; White, M. C. A Science 2007, 318, 783–787.

9. Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072–5074.

10. Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–1597.

11. Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc., 1997, 119, 9075–9076.

12. Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. Chem. Soc. Rev. 2016, 45, 546-576.

13. Gomberg, M. Preparation of Triphenylchlormethane. J. Am. Chem. Soc. 1900, 22, 815.

14. Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771.

15. Gomberg, M. J. Am. Chem. Soc. 1902, 24, 597–628.

16. Romero, K. J.; Galliher, M. S.; Pratt, D. A.; Stephenson, C. R. J. Chem. Soc. Rev. 2018, 47, 7851–7866.

17. Paneth, F.; Lautsch, W. Nature 1930, 125, 564–564. 226

18. Paneth, F.; Hofeditz, W. Berichte der Dtsch. Chem. Gesellschaft A B Ser. 1929, 62, 1335–1347.

19. Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1960, 82, 1657–1668.

20. Wawzonek, S.; Thelen, P. J. J. Am. Chem. Soc. 1950, 72, 2118–2120.

21. Hey, D. H.; Waters, W. A. Chem. Rev. 1937, 21, 169–208.

22. Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82, 2640–2641.

23. Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo, M. Tetrahedron 1971, 27, 3575–3579.

24. Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317–323.

25. Walling, C. Tetrahedron 1985, 41, 3887–3900.

26. Beckwith, A. L. J. Chem. Soc. Rev. 1993, 22, 143–151.

27. Laarhoven, L. J. J.; Mulder, P.; Wayner, D. D. M. Acc. Chem. Res. 1999, 32, 342 – 349.

28. Baguley, P. A.; Walton, J. C. Angew. Chemie Int. Ed. 1998, 37, 3072–3082.

29. Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188–194.

30. Rowlands, G. J. Tetrahedron. 2009, 65, 8603–8655.

31. Kharasch, M. S.; Mayo, F. R. J. Am. Chem. Soc. 1933, 55, 2468–2496.

32. Giese, B. Angew. Chemie Int. Ed. English 1983, 22, 753–764.

33. Newcomb, M. Radical Kinetics and Clocks. In Encyclopedia of Radicals in Chemistry, Biology and Materials; John Wiley & Sons, Ltd: Chichester, UK, 2012.

34. Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925–3941.

35. Sustmann, R.; Korth, H. G. Adv. Phys. Org. Chem. 1990, 26, 131–178.

36. Stella, L.; Janousek, Z.; Merényi, R.; Viehe, H. G. Angew. Chem. Int. Ed. 1978, 17, 691–692. 227

37. Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25–35.

38. Julia, M. Acc. Chem. Res. 1970, 4, 386–392.

39. Burnett, D. A.; Choi, J. K.; Hart, D. J.; Tsai, Y. M. J. Am. Chem. Soc. 1984, 106, 8201–8209.

40. Hart, D. J. Science 1984, 223, 883–887.

41. Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237–1286.

42. Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448–1449.

43. Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943–3958.

44. Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976–1991.

45. Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 4904–4916.

46. Cha, J. Y.; Yeoman, J. T. S.; Reisman, S. E. Chem. Soc. 2011, 133, 14964–14967.

47. Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451–3479.

48. Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369–375.

49. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347–361.

50. Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651–2710.

51. Chassaing, S.; Specklin, S.; Weibel, J.-M.; Pale, P. Curr. Org. Synth. 2012, 9, 806– 827.

52. Hansch, C.; Fujita, T. J. Am. Chem. Soc. 1964, 86, 1616–1626.

53. Topliss, J. G. J. Med. Chem. 1972, 15, 1006–1011.

54. Johnson, T. W.; Gallego, R. A.; Edwards, M. P. J. Med. Chem. 2018, 61, 6401– 6420.

55. Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.; Resnati, G.; Terraneo, G. Chem. Rev. 2016, 116, 2478–2601. 228

56. Willgerodt. Willgerodt’s Reagent. J. Prakt. Chem 1886, 33, 155.

57. Zhdankin, V. V.; Kuehl, C. J.; Krasutsky, A. P.; Formaneck, M. S.; Bolz, J. T. Tetrahedron Lett. 1994, 35, 9677–9680.

58. Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chemie Int. Ed. 2007, 46, 754–757.

59. Hartmann, C.; Meyer, V. Berichte der Dtsch. Chem. Gesellschaft 1894, 27, 502– 509.

60. Meyer-Hartmann Reaction. In Comprehensive Organic Name Reactions and Reagents; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2010; pp 1910–1912.

61. Merritt, E.; Olofsson, B. Angew. Chemie Int. Ed. 2009, 48, 9052–9070.

62. Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328–3435.

63. Hartmann, C.; Meyer, V. Berichte der Dtsch. Chem. Gesellschaft 1893, 26, 1727– 1732.

64. Fallis, A. G.; Tessier, P. E. 2-Iodoxybenzoic Acid (IBX). In Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd: Chichester, UK, 2003.

65. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.

66. Dohi, T.; Morimoto, K.; Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y. J. Org. Chem. 2007, 72, 109-116.

67. Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684–3691.

68. Koser, G. F.; Telu, S.; Laali, K. K. Tetrahedron Lett. 2006, 47, 7011–7015.

69. Bovonsombat, P.; Djuardi, E.; McNelis, E. Tetrahedron Lett. 1994, 35, 2841–2844.

70. Souto, J. A.; Zian, D.; Muñiz, K. J. Am. Chem. Soc. 2012, 134, 7242–7245.

71. Sharma, A.; Hartwig, J. F. Nature 2015, 517, 600–604.

72. Huang, H.; Zhang, G.; Gong, L.; Zhang, S.; Chen, Y. J. Am. Chem. Soc. 2014, 136, 2280–2283.

73. Sokolovs, I.; Lubriks, D.; Suna, E.. J. Am. Chem. Soc. 2014, 136, 6920–6928. 229

74. Labattut, A.; Tremblay, P. L.; Moutounet, O.; Legault, C. Y. J. Org. Chem. 2017, 82, 11891–11896.

75. Izquierdo, S.; Essafi, S.; del Rosal, I.; Vidossich, P.; Pleixats, R.; Vallribera, A.; Ujaque, G.; Lledós, A.; Shafir, A. J. Am. Chem. Soc. 2016, 138, 12747–12750.

76. Evans, P. A.; Brandt, T. A. J. Org. Chem. 1997, 62, 5321–5326.

77. Braddock, D. C.; Cansell, G.; Hermitage, S. A. Synlett 2004, 3, 461–464.

78. Pialat, A.; Liégault, B.; Taillefer, M. Org. Lett. 2013, 15, 1764–1767.

79. Itoh, N.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. J. Org. Chem. 2002, 67, 7424– 7428.

80. Song, S.; Sun, X.; Li, X.; Yuan, Y.; Jiao, N. Org. Lett. 2015, 17, 2886–2889.

81. Zefirov, N. S.; Zhdankin, V. V.; Dan`kov, Y. V.; Sorokin, V. D.; Semerikov, V. N.; Koz`min, A. S.; Caple, R.; Berglund, B. A. Tetrahedron Lett. 1986, 27, 3971– 3974.

82. Kitamura, T.; Nagata, K.; Nakamura, T.; Furuki, R.; Taniguchi, H. Tetrahedron 1995, 51, 6229–6236.

83. Iwai, T.; Sawamura, M. ACS Catal. 2015, 5, 5031–5040.

84. Tiwari, V. K.; Pawar, G. G.; Jena, H. S.; Kapur, M. Chem. Commun. 2014, 50, 7322–7325.

85. Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483–11498.

86. Louërat, F.; Fort, Y.; Mamane, V. Tetrahedron Lett. 2009, 50, 5716–5718.

87. Hasebe, M.; Tsuchiya, T. Tetrahedron Lett. 1988, 29, 6287–6290.

88. Mallinger, A.; Schiemann, K.; Rink, C.; Sejberg, J.; Honey, M. A.; Czodrowski, P.; Stubbs, M.; Poeschke, O.; Busch, M.; Schneider, R.; et al. ACS Med. Chem. Lett. 2016, 7, 573–578.

89. Sawanishi, H.; Kamiya, Y. Chem. Pharm. Bull. (Tokyo). 1975, 23, 2949–2957.

230

90. Rodriguez, R. A.; Pan, C.-M.; Yabe, Y.; Kawamata, Y.; Eastgate, M. D.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 6908–6911.

91. Wang, M.; Zhang, Y.; Wang, T.; Wang, C.; Xue, D.; Xiao, J. Org. Lett. 2016, 18, 1976–1979.

92. Ren, Y.; Lantvit, D. D.; Deng, Y.; Kanagasabai, R.; Gallucci, J. C.; Ninh, T. N.; Chai, H.-B.; Soejarto, D. D.; Fuchs, J. R.; Yalowich, J. C.; et al. J. Nat. Prod. 2014, 77, 1494–1504.

93. Woodard, J. L.; Huntsman, A. C.; Patel, P. A.; Chai, H.-B.; Kanagasabai, R.; Karmahapatra, S.; Young, A. N.; Ren, Y.; Cole, M. S.; Herrera, D.; et al. Bioorg. Med. Chem. 2018, 26, 2354–2364.

94. Cotter, J. L.; Andrews, L. J.; Keefer, R. M. J. Am. Chem. Soc. 1962, 84, 793–797.

95. Kang, K.; Lee, S.; Kim, H.. Asian J. Org. Chem. 2015, 4, 137–140.

96. Tao, J.; Tran, R.; Murphy, G. K. J. Am. Chem. Soc. 2013, 135, 16312–16315.

97. Mendez, F.; Gazquez, J. L. J. Am. Chem. Soc. 1994, 116, 9298–9301.

98. Bedford, R. B.; Engelhart, J. U.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Dalt. Trans. 2010, 39, 10464 –10472.

99. Gowda, S.; Gowda, B. T. Magn. Reson. Chem. 2006, 62, 84–90.

100. Yan, J.-X.; Li, H.; Liu, X.-W.; Shi, J.-L.; Wang, X.; Shi, Z.-J. Angew. Chemie Int. Ed. 2014, 53, 4945–4949.

101. Zhong, Z.; Snowden, T. S.; Best, M. D.; Anslyn, E. V. J. Am. Chem. Soc. 2004, 11, 3488–3495.

102. Zhang, Q.-B.; Jia, W.-L.; Ban, Y.-L.; Zheng, Y.; Liu, Q.; Wu, L.-Z. Chem. - A Eur. J. 2016, 22, 2595–2598.

103. Tang, B.-X.; Song, R.-J.; Wu, C.-Y.; Liu, Y.; Zhou, M.-B.; Wei, W.-T.; Deng, G.- B.; Yin, D.-L.; Li, J.-H. J. Am. Chem. Soc. 2010, 132, 8900–8902.

104. Gershon, H.; Clarke, D. D.; Gershon, M. Monatshefte für Chemie - Chem. Mon. 1993, 124, 367–379.

105. Cai, H.; Liu, Q.; Gao, D.; Wang, T.; Chen, T.; Yan, G.; Chen, K.; Xu, Y.; Wang, H.; Li, Y.; et al. Eur. J. Med. Chem. 2015, 90, 241–250. 231

106. Kamplain, J. W.; Lynch, V. M.; Bielawski, C. W. Org. Lett. 2007, 9, 5401–5404.

107. van Veldhuizen, A.; van Dijk, M.; Sanders, G. M. Org. Magn. Reson. 1980, 13, 105–109.

108. Stefani, H. A.; Pereira, C. M. P.; Almeida, R. B.; Braga, R. C.; Guzen, K. P.; Cella, R. A Tetrahedron Lett. 2005, 46, 6833–6837.

109. Gupton, J. T.; Wysong, E.; Norman, B.; Hertel, G.; Idoux, J. P. Synth. Commun. 1985, 15, 43–52.

110. Belmadoui, N.; Climent, M. J.; Miranda, M. A. Tetrahedron 2006, 62, 1372– 1377.

111. Koul, S.; Koul, J. L.; Singh, B.; Kapoor, M.; Parshad, R.; Manhas, K. S.; Taneja, S. C.; Qazi, G. N. Tetrahedron: Asymmetry 2005, 16, 2575–2591.

112. Asakura, J.; Robins, M. J. J. Org. Chem. 1990, 55, 4928–4933.

113. Celewicz, L.; Koroniak, H. Synth. Commun. 1985, 15, 1001–1005.

114. Maddox, S. M.; Nalbandian, C. J.; Smith, D. E.; Gustafson, J. L. Org. Lett. 2015, 17, 1042–1045.

115. Martı́nez, E.; Martınez,́ L.; Treus, M.; Estévez, J. C.; Estévez, R. J.; Castedo, L. Tetrahedron 2000, 56, 6023–6030.

116. Charlton, J. L.; Oleschuk, C. J.; Chee, G.-L. J. Org. Chem. 1996, 61, 3453–3457.

117. Conway, B.; Crosbie, E.; Kennedy, A. R.; Mulvey, R. E.; Robertson, S. D. Chem. Commun. 2012, 48, 4674–4676.

118. Coleman, G. H.; Goheen, G. E. J. Am. Chem. Soc. 1938, 60, 730–730.

119. Stateman, L.; Nakafuku, K.; Nagib, D. Synthesis, 2018, 50, 1569–1586.

120. Kimura, M.; Ban, Y. Synthesis. 1976, 201-202.

121. de Armas, P.; Carrau, R.; Concepción, J. I.; Francisco, C. G.; Hernández, R.; Suárez, E. Tetrahedron Lett. 1985, 26, 2493–2496.

122. Martínez, C.; Muñiz, K. Angew. Chemie Int. Ed. 2015, 54, 8287–8291.

232

123. Paz, N. R.; Rodríguez-Sosa, D.; Valdés, H.; Marticorena, R.; Melián, D.; Copano, M. B.; González, C. C.; Herrera, A. J. Org. Lett. 2015, 17, 2370–2373.

124. Wolff, M. E. Chem. Rev. 1963, 63, 55–64.

125. Martínez, C.; Muñiz, K. Angew. Chemie Int. Ed. 2015, 54, 8287–8291.

126. Giri, R.; Yu, J.-Q. Iodine Monoacetate. In Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd: Chichester, UK, 2008.

127. Courtneidge, J. L.; Lusztyk, J.; Pagé, D. Tetrahedron Lett. 1994, 35, 1003–1006.

128. Borodine, A. Ann. der Chemie und Pharm. 1861, 119, 121–123.

129. Hunsdiecker, H.; Hunsdiecker, C. Berichte der Dtsch. Chem. 1942, 75, 291–297.

130. Bunce, N. J.; Murray, N. G. Tetrahedron 1971, 27, 5323–5335.

131. Kochi, J. K. J. Am. Chem. Soc. 1965, 87, 2500–2502.

132. Wilson, C. V. The Reaction of Halogens with Silver Salts of Carboxylic Acids. In Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2011; pp 332– 387.

133. Prévost, C.; Delepine, M. Comptes Rendus 1933, 1129.

134. Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80, 209–211.

135. Chen, E. M.; Keefer, R. M.; Andrews, L. J. J. Am. Chem. Soc. 1967, 89, 428–430.

136. Burgess, A. E.; Davidson, J. C. A J. Chem. Educ. 2012, 89, 814–816.

137. Carter, J. S. J. Chem. Soc. 1928, 2227–2230.

138. Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P. Tetrahedron Lett. 1986, 27, 2099–2102.

139. Qin, Q.; Yu, S. Org. Lett. 2015, 17, 1894–1897.

140. Eleftheriadis, N.; Thee, S.; te Biesebeek, J.; van der Wouden, P.; Baas, B.-J.; Dekker, F. J. Eur. J. Med. Chem. 2015, 94, 265–275.

141. Pinner, A.; Klein, F. Berichte der Dtsch. Chem. Gesellschaft 1877, 10, 1889– 1897. 233

142. Nef, J. U. Justus Liebig’s Ann. der Chemie 1895, 287, 265–359.

143. Schaefer, F. C.; Peters, G. A. J. Org. Chem. 1961, 26, 412–418.

144. Roberts, R. M.; Higgins, T. D.; Noyes, P. R. J. Am. Chem. Soc. 1955, 77, 3801– 3805.

145. Caron, S.; Wei, L.; Douville, J.; Ghosh, A. J. Org. Chem. 2010, 75, 945–947.

146. Suydam, F. H.; Greth, W. E.; Langerman, N. R. J. Org. Chem. 1969, 34, 292–296.

147. Popov, K.; Somfai, P. J. Org. Chem. 2016, 81, 3470–3472.

148. Blake, J. A.; Pratt, D. A.; Lin, S.; Walton, J. C.; Mulder, P.; Ingold, K. U. J. Org. Chem. 2004, 69, 3112–3120.

149. Roger, R.; Neilson, D. G. Chem. Rev. 1961, 61, 179–211.

150. Mumm, O.; Möller, F. Berichte der Dtsch. Chem. 1937, 70, 2214–2227.

151. Overman, L. E. J.C.S. Chem. Comm. 1972, 1196–1198.

152. Overman, L. E. Tetrahedron 2009, 65, 6432–6446.

153. Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599.

154. Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910.

155. Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D. A. Angew. Chemie Int. Ed. 2016, 55, 9974–9978.

156. Wappes, E. A.; Nakafuku, K. M.; Nagib, D. A. J. Am. Chem. Soc. 2017, 139, 10204–10207.

157. Overman, L. E.; Carpenter, N. E. The Allylic Trihaloacetimidate Rearrangement. In Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2005; pp 1– 107.

158. Forrester, A. R.; Gill, M.; Meyer, C. J.; Sadd, J. S.; Thomson, R. H. J. Chem. Soc. Perkin Trans. 1 1979, 0, 606.

159. Boivin, J.; Fouquet, E.; Zard, S. Z. J. Am. Chem. Soc. 1991, 113, 1055–1057.

234

160. Faulkner, A.; Race, N. J.; Scott, J. S.; Bower, J. F. Chem. Sci. 2014, 5, 2416–2421.

161. Davies, J.; Svejstrup, T. D.; Fernandez Reina, D.; Sheikh, N. S.; Leonori, D. Visible- J. Am. Chem. Soc. 2016, 138, 8092–8095.

162. Miller, D. C.; Choi, G. J.; Orbe, H. S.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 13492–13495.

163. Çelik, M.; Alp, C.; Coşkun, B.; Gültekin, M. S.; Balci, M. Tetrahedron Lett. 2006, 47, 3659–3663.

164. Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. J. Org. Chem. 1986, 51, 4905–4910.

165. Glover, S. A.; Beckwith, A. L. J. Aust. J. Chem. 1987, 40, 701–709.

166. Svejstrup, T. D.; Ruffoni, A.; Juliá, F.; Aubert, V. M.; Leonori, D. Angew. Chemie Int. Ed. 2017, 56, 14948–14952.

167. Allen, L. J.; Cabrera, P. J.; Lee, M.; Sanford, M. S. J. Am. Chem. Soc. 2014, 136, 5607–5610.

168. Chan, D. M.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936.

169. Lam, P. Y.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. .; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944.

170. Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1967, 40, 935– 939.

171. Miller, D. C.; Choi, G. J.; Orbe, H. S.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 13492–13495.

172. Magnion, D. M.; Arnold, D. R. Acc. Chem. Res. 2002, 35, 297–304.

173. Borg, R. M.; Arnold, D. R.; Cameron, T. S. Can. J. Chem. 1984, 62, 1785–1802.

174. McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011, 334, 1114–1117.

175. Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C. Science 2013, 339, 1593–1596.

176. Hoshikawa, T.; Inoue, M. Chem. Sci. 2013, 4, 3118–3123. 235

177. Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3, 139–141.

178. Gu, Y.; Snider, B. B. Org. Lett. 2003, 5, 4385–4388.

179. Muchowski, J. M.; Naef, R.; Maddox, M. L. Tetrahedron Lett. 1985, 26, 5375– 5378.

180. Zhang, X.; Guo, S.; Tang, P. Org. Chem. Front. 2015, 2, 806–810.

181. Seebach, D.; Kolb, M. Chem. Ind. 1974, 687–692.

182. Streuff, J. Synthesis 2013, 45, 281–307.

183. Seebach, D. Angew. Chemie Int. Ed. English 1979, 18, 239–258.

184. Wöhler; Liebig. Ann. der Pharm. 1832, 3, 249–282.

185. Lapworth, A. J. Chem. Soc., Trans. 1904, 85, 1206–1214.

186. Stetter, H.; Schreckenberg, M. Angew. Chemie Int. Ed. English 1973, 12, 81–81.

187. Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.

188. Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307–9387.

189. Wanzlick, H.-W.; Schönherr, H.-J. Angew. Chemie Int. Ed. English 1968, 7, 141– 142.

190. Schöllkopf, U.; Gerhart, F. Angew. Chemie Int. Ed. English 1967, 6, 805–805.

191. Arduengo, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361–363.

192. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237.

193. Connelly, N. G.; Geiger, W. E. Chem. Rev. 1996, 96, 877–910.

194. McMurry, J. E. Chem. Rev. 1989, 89, 1513–1524.

195. McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708–4709.

196. Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 2, 1041–1044.

197. Tyrlik. Bull. Soc. Chim. Fr. 1973, 2147. 236

198. Sharpless, K. B.; Umbreit, M. A.; Nieh, M. T.; Flood, T. C. J. Am. Chem. Soc. 1972, 94, 6538–6540.

199. Procter, D. J.; Flowers, R. A.; Skrydstrup, T. Organic Synthesis Using Samarium Diiodide; Royal Society of Chemistry: Cambridge, 2009.

200. Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371–3404.

201. Stork, G.; Malhotra, S.; Thompson, H.; Uchibayashi, M. J. Am. Chem. Soc. 1965, 87, 1148–1149.

202. Pradhan, S. K.; Kadam, S. R.; Kolhe, J. N.; Radhakrishnan, T. V.; Sohani, S. V.; Thaker, V. B. J. Org. Chem. 1981, 46, 2622–2633.

203. Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821–2824.

204. Belotti, D.; Cossy, J.; Pete, J. P.; Portella, C. Tetrahedron Lett. 1985, 26, 4591– 4594.

205. Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 10022– 10025.

206. Roth, H.; Romero, N.; Nicewicz, D. Synlett 2015, 27, 714–723.

207. French, H. E.; Adams, R. J. Am. Chem. Soc. 1921, 43, 651–659.

208. Koh, M. J.; Nguyen, T. T.; Zhang, H.; Schrock, R. R.; Hoveyda, A. H. Nature 2016, 531, 459–465.

209. Udding, J. H.; Tuijp, K. C. J. M.; van Zanden, M. N. A.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1994, 59, 1993–2003.

210. Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307–338.

211. Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693–2698.

212. Corey, E.; Zheng, G. Z. Tetrahedron Lett. 1997, 38, 2045–2048.

213. Lee, K. N.; Lei, Z.; Ngai, M.-Y. J. Am. Chem. Soc. 2017, 139, 5003–5006.

214. Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc., 2000, 1122, 6950–6954.

215. Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc., 1999, 121, 6098–6099.

237

216. Montgomery, J. Angew. Chemie Int. Ed. 2004, 43, 3890–3908.

217. Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130–4131.

218. Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 11514–11515.

219. Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299–309.

220. Theriot, J. C.; Lim, C.-H.; Yang, H.; Ryan, M. D.; Musgrave, C. B.; Miyake, G. M. Science 2016, 352, 1082–1086.

221. Baird, M. C. Chem. Rev. 1988, 88, 1217–1227.

222. Koumura, K.; Satoh, K.; Kamigaito, M. Macromolecules 2008, 41, 7359–7367.

223. Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron Lett. 1986, 27, 4525–4528.

238