Rhodium(III)-Catalyzed Difunctionalization of Alkenes Initiated by Carbon–Hydrogen Bond Activation

Erik Johann Thorngren Phipps

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee in the Graduate School of Arts and Sciences

COLUMBIA UNIVERSITY

2021

© 2021

Erik J. T. Phipps

All Rights Reserved – Abstract –

Rhodium(III)-Catalyzed Difunctionalization of Alkenes Initiated by Carbon–Hydrogen Bond Activation

Erik J. T. Phipps

The direct conversion of carbon–hydrogen bonds into valuable carbon-carbon and carbon-heteroatom bonds is a significant challenge to synthetic organic chemists. More than ever, chemists are employing Rh(III)-catalysts bearing cyclopentadienyl (Cp) ligands to transform otherwise inert C–H bonds. Furthermore, manipulating the sterics and electronics of the Cp ligand show significant impact on catalytic transformations. Our group has developed a library of CpXRh(III)-precatalysts in hopes of enhancing known reactivity as well as discovering new C–H bond functionalizations. We have previously reported that N-enoxyphthalimides are a unique one-carbon component for the cyclopropanation of activated alkenes. In an effort to expand the scope to accessible alkenes, we have found a number of symmetrical unactivated alkenes undergo [2+1] annulation to afford intriguing spirocyclic cyclopropanes. Additionally, we have developed a Rh(III)-catalyzed diastereoselective [2+1] annulation onto allylic alcohols to furnish substituted cyclopropyl ketones. Notably, the traceless oxyphthalimide handle serves three functions: directing C–H activation, oxidation of Rh(III), and, collectively with the allylic alcohol, in directing cyclopropanation to control diastereoselectivity. Allylic alcohols are shown to be highly reactive olefin coupling partners leading to a directed diastereoselective cyclopropanation reaction, providing products not accessible by other routes. Next, an artifact of previous cyclopropanation reactions leads to the formation of a Rh-π-allyl complex. Attempts at 1,1-carboamination of alkenes are made using alkenes and nitrenoid precursors toward the 3-component synthesis of allylic amines. Stoichiometric studies help elucidate the mechanism and challenges. Lastly, efforts toward 1,2-carboamination of alkenes initiated by sp3 C–H bond activation are made with two different reactivity manifolds. Isolation of reaction intermediates are discussed as well as providing viable paths toward valuable products. – Table of Contents –

List of Figures and Scheme ...... iv

Acknowledgements ...... vii

Dedication ...... ix

Chapter One: Introduction to CpXRh(III)-catalyzed C–H Activation ...... 1-12 1.1 Importance of C–H Bond Activation ...... 1 1.2 Modes of C–H Activation ...... 2 1.3 Installation of Directing Groups ...... 3 1.4 Mechanistic Considerations ...... 6 1.5 Tuning Cycopentadienyl Ligands to Impact Catalysis ...... 9 1.6 Summary ...... 10 1.7 References ...... 11

Chapter Two: Rh(III)-catalyzed Cyclopropanation of Unactivated Alkenes Initiated by C–H Activation ...... 13-34 2.1 Introduction to Cyclopropanation ...... 13 2.2 Reactivity Profile of N-enoxyimides ...... 17 2.3 Reaction Optimization ...... 20 2.4 Scope of the Cyclopropanation Reaction ...... 23 2.5 Participation of Other Alkenes ...... 26 2.6 Mechanistic Studies ...... 27 2.7 Proposed Mechanism ...... 30 2.8 Summary ...... 31 2.9 References ...... 32

i Chapter Three: Rh(III)-catalyzed C–H Activation-Initiated Directed Cyclopropanation of Allylic Alcohols ...... 35-59 3.1 Cyclopropanation of Allylic Alcohols ...... 35 3.2 Reaction Optimization ...... 40 3.3 Stereoselectivity of the Cyclopropanation Reaction ...... 42 3.4 Scope of the Cyclopropanation Reaction ...... 43 3.5 Mechanistic Studies ...... 49 3.6 Proposed Mechanism ...... 55 3.7 Summary ...... 57 3.8 References ...... 57

Chapter Four: Validating Isolated Reaction Intermediates for 1,1-Carboamination of N-enoxyphthalimides ...... 60-71 4.1 Artifacts of the Cyclopropanation Reaction ...... 60 4.2 Overview of C–N Bond Formation from π-Allyl Species using Nitrenoid Precursors ...... 62 4.3 Envisioned 3-component Reaction ...... 64 4.4 Attempts at 3-component 1,1-Carboamination ...... 66 4.5 Stoichiometric Studies ...... 67 4.6 Summary ...... 70 4.7 References ...... 71

Chapter Five: Rh(III)-catalyzed 1,2-Carboamination of Alkenes via sp3 C–H Activation ...... 72-86 5.1 Introduction to 1,2-Carboamination ...... 72 5.2 Substrates Beyond N-enoxyphthalimides ...... 75 5.3 Envisioned Mechanism from N-acetoxyphthalimides ...... 77 5.4 Carboamination of Alkenes from N-acetoxyphthalimides ...... 78 5.5 Future Considerations Concerning sp3 C–H Functionalization of N- acetoxyphthalimides ...... 81 5.6 Activation of N-iminophthalimides ...... 82 5.7 Future Directions for sp3 C–H Activation N-iminophthalimides ...... 83

ii 5.8 Summary ...... 85 5.9 References ...... 86

Appendix A: Supplementary information for Chapter Two ...... 84-141

Appendix B: Supplementary information for Chapter Three ...... 142-255

Appendix C: Supplementary information for Chapter Four and Five ...... 256-263

iii – List of Figures and Schemes –

Figures Figure 1.1 Characteristics in the diversity of C–H bonds in organic synthesis ...... 1 Figure 1.2 Modes of C–H bond activation to furnish new carbon-metal bonds ...... 2 Figure 1.3 Selectivity challenges of C–H activation ...... 3 Figure 1.4 Directing group assisted Rh(III)-catalyzed ortho-C–H functionalization ...... 4 Figure 1.5 Mechanism of Rh(III)-catalyzed benzannulation of alkynes ...... 5 Figure 1.6 Installation of internal oxidant for the oxidative cyclization of ...... 6 benzamides with alkenes and alkynes. Figure 1.7 Proposed mechanism of alkene/alkyne benzannulation with an internal oxidant ...... 7 Figure 1.8 Proposed oxidative nitrene formation ...... 8 Figure 1.9 Selected examples of modified cyclopentadienyl ligands ...... 10 Figure 2.1 Selected examples of cyclopropane units in natural product synthesis ...... 13 Figure 2.2 General protocol for the synthesis of cyclopropanes from alkenes ...... 14 Figure 2.3 Simmons-Smith reactivity with unactivated alkenes ...... 15 Figure 2.4 Metal catalyzed diazo decomposition of unactivated alkenes ...... 16 Figure 2.5 Trans-Cyclopropanation ...... 17 Figure 2.6 Initially proposed mechanism of Rh(III)-catalyzed cyclopropanation ...... 18 Figure 2.7 Cis-Cyclopropanation ...... 19 Figure 2.8 Enantioselective cyclopropanation ...... 19 Figure 2.9 Proposed Rh(III)-catalyzed cyclopropanation of unactivated alkenes from N-enoxyphthalimides ...... 20 Figure 2.10 Original hit with Cp*Rh(III) precatalyst ...... 20 Figure 2.11 Deuterium labeling studies ...... 28 Figure 2.12 Dioxazoline formation and intermediacy test ...... 29 Figure 2.13 Proposed Mechanism ...... 30 Figure 3.1 General strategies for the cyclopropanation of allylic alcohols ...... 36 Figure 3.2 State-of-the-Art strategies for cyclopropanation of allylic alcohol-type alkenes .. 37 Figure 3.3 Limitations of competitive cyclopropanation strategies ...... 38 Figure 3.4 Previously described transformations with N-enoxyphthalimides ...... 39 Figure 3.5 Proposed Rh(III)-catalyzed directed cyclopropanation of allylic alcohols ...... 40

iv Figure 3.6 Cp ligand optimization ...... 41 Figure 3.7 Primary allylic alcohols bearing a trans or cis disubstituted alkene ...... 43 Figure 3.8 Comparison of secondary, cyclic allylic alcohols ...... 48 Figure 3.9 Regioselective applications of the cyclopropanation protocol ...... 50 Figure 3.10 Investigations of the nucleophilicity of the allylic functional group ...... 52 Figure 3.11 Deuterium labeling studies ...... 53 Figure 3.12 Observation and intermediacy test of dioxazoline ...... 54 Figure 3.13 Proposed mechanism ...... 56 Figure 4.1 Cyclopropanation reaction with ethylene as the alkene ...... 60 Figure 4.2 Formation of Rh-π-allyl complex ...... 60 Figure 4.3 Likely pathway for the formation of 4-4 ...... 61 Figure 4.4 Subjection of 4-4 to cyclopropanation reaction conditions ...... 62 Figure 4.5 Ir(III)-catalyzed intermolecular branched-selective allylic amination of terminal alkenes ...... 63 Figure 4.6 Intermolecular amination of internal alkenes ...... 63 Figure 4.7 Catalyst-dependent regioselective allylic amination of alkenes ...... 63 Figure 4.8 Proposed Rh(III)-catalyzed 3-component 1,1-carboamination of N- enoxyphthalimides ...... 64 Figure 4.9 Envisioned mechanism of 1,1-carboamination of N-enoxyphthalimides ...... 65 Figure 4.10 Attempted π-allyl complex synthesis with Cp* as a ligand ...... 68 Figure 4.11 Attempts at C–N bond formation from π-allyl precursors ...... 69 Figure 4.12 Potential catalyst incompatibility of key steps involved in 1,1-carboamination ...... 70 Figure 5.1 Rh(III)-catalyzed syn-1,2-carboamination of fumarate-type alkenes ...... 72 Figure 5.2 Proposed mechanism of 1,2-carboamination of alkenes from N-enoxyphthalimides ...... 74 Figure 5.3 N-enoxyphthalimide synthesis and potential alternatives ...... 76 Figure 5.4 Predicted pathways for 1,2-carboamination of alkenes from N-acetoxyamines ...... 77 Figure 5.5 Diagnostic 1H-NMR signal and isolation of undesired byproduct ...... 80 Figure 5.6 Proposed divergent C–H functionalization ...... 81 Figure 5.7 Attempted carboamination of alkenes with N-iminophthalimides ...... 82 Figure 5.8 Isolation of metallacycles ...... 83 Figure 5.9 Rh(III)-catalyzed pyrrole synthesis from Boc-hydrazones and alkynes ...... 84

v Figure 5.10 Proposed cyclic and acyclic carboamination of N-iminophthalimides ...... 84

Schemes Scheme 2.1 Cp Ligand screen ...... 22 Scheme 2.2 Scope of 1,1-disubstituted alkenes ...... 24 Scheme 2.3 Scope of N-enoxyphthalimides ...... 25 Scheme 2.4 Scope of alkenes with varying substitution ...... 27 Scheme 3.1 Reaction optimization–Examination of the effects of inorganic bases, solvents, and temperature ...... 42 Scheme 3.2 Scope of primary allylic alcohols ...... 44 Scheme 3.3 Scope of N-enoxyphthalimides ...... 45 Scheme 3.4 Scope of secondary allylic alcohols ...... 46 Scheme 4.1 Initial reaction screening toward 1,1-carboaminaiton ...... 66 Scheme 4.2 Screen of nitrenoid precursors ...... 67 Scheme 5.1 Carboamination screens in methanol ...... 78 Scheme 5.2 Solvent screen leading to TFE conditions ...... 79

vi – Acknowledgements –

I would like to start by thanking Tom who has been an amazing mentor during my time in graduate school. I’m very thankful that I was offered a spot in his group at CSU and then following him across the country to Columbia. It’s been a joy getting to know his family along this journey as well. I’ve enjoyed having a relationship that grants so much dialogue and sharing of responsibilities that have set me up for success in my future career. Allowing me total freedom is a dangerous thing sometimes, but I think for the most part it paid off. One day, I hope to emulate his qualities that have made this group as fun and productive as it is. I’d also like to thank my committee members. Jon, Jack, and Neel–it’s been great to have conversations with folks in the department interested and committed to furthering science. Simon–It was great hanging out with you at OMCOS 19 over in Germany. I’m very thankful you could lend your expertise to me by rounding out my committee. To the Rovis group–Thank you to the past members before who built the group up to what it is today. Thanks to the folks that made coming to lab easier and dealing with the times when I could be difficult. And to the future members of the lab, I expect to see continued success as well as keeping the good times rolling. Seeing the work hard/ play hard attitude as a first year made me want to join the group. I like to think I helped perpetuate that attitude throughout my time in the group. Specifically, I’d like to thank some great friends: Ben–for the great friendship from the mountains to the skyscrapers, it’s been so valuable having someone I can continually look up to. Melissa–I’m glad you started rowing in our ship and for our friendship in completing the 3-headed monster of our year. Sumin–thanks for being a loyal friend and Rh teammate, wherever you end up you’ll do great things. Sean–thanks for being an awesome roommate and friend. Scott–thanks for being an fantastic lab mate to help keep the late-night weird flowing. Finding someone who knows more baseball than me was one of the last things I expected to find in grad school. Darrin and Kyle–for the endless quotes and taking me under their wing as senior graduate students. Tiff and Fedor–for your mentorship when I needed it most and making me tougher. Neil–for helping me see things through and celebrating our weird Midwest upbringings.

vii I’d like to thank my undergraduate advisor Jeff Johnson. Jeff took me in his lab for 2 years at Hope College and taught me a lot about chemistry and introduced me to kubb. When I told him I was interested in the Rovis group, he said “Tom was a great boss when I was there! And he’ll never move!” Just to let everyone know…I think it’s his fault I ended up here! While at Hope, I made friendships that have lasted well beyond undergrad. Bill, CJ, Jake, Jon, and Nick–it’s always great to get away from the pressures of grad school for a weekend catching up with the fellas. Joey and Lisa–even after college, we always find a way to have a *~blast~*… Back home in Iowa, I am thankful for an enormous cohort of friends who I remain close to every time I return for a short break. To Barb and Rick Davis-thanks for being my second family and your continuing support from the baseball diamond to the laboratory throughout the years. Lastly, I’d like to thank my family. To my sister Elin for the check-up calls and support and inspiration you’ve provided. To Sue and Dave for your encouragement and always providing a place to stay. To my grandparents: My late grandfather Carl, or Pa, told me to “get a good education, because it’s something nobody can ever take away from you.” The way he led his life is what I strive to achieve every day. From the times we shared, I know he would be proud, but never satisfied. I can always “grab a broom and sweep.” And my Mor Mor for the countless cookies as well as the endless love and support you’ve sent throughout the years. The time, money, and prayers have paid off! Finally, my mom, Cristy: I truly cannot convey in words what she has meant to me. Whether it was a ball game or an orchestra concert or a research presentation, she is always there. She has passed down so many life lessons by her selflessness and commitment to others. All the love and goodness she has shown me throughout the years could never be accurately portrayed. Whatever future successes I may find, they are surely due to sacrifices she has made.

viii

Dedicated to:

My Grandfather, Carl Eric Thorngren

ix – Chapter One –

Introduction to CpXRh(III)-catalyzed C–H Activation

1.1 Importance of C–H Functionalization

The direct conversion of carbon–hydrogen bonds into valuable carbon- carbon and carbon-heteroatom bonds is a significant challenge to synthetic organic chemists. 1 Carbon–Hydrogen bonds are the most common motifs in small molecules, and due to this ubiquity, this makes C–H bonds among the most desirable candidates to be manipulated and transformed into valuable targets. The high bond dissociation energy (BDE) presents the first challenge.

Compared to that of pre-functionalized analogues such as aryl halides (Figure

1.1) C–H bonds are significantly more inert.

H I R H R H R H H >> R R R

BDE 98.2 95.1 93.2 110.0 110.9 51 (kcal/mol)

pKa 50 55 71 44 43

Figure 1.1 Characteristics in the diversity of C–H bonds in organic synthesis.

When considering C–H bonds, their high pKa value compared to that of heteroatom–H bonds presents another challenge to consider. For these reasons,

- 1 - a method that has gained significant traction in the field of organic synthesis throughout the years is metal-catalyzed C–H bond activation.

1.2 Modes of C–H Activation

Predominately, there are two pathways to break a C–H bond and form a new metal-carbon bond as an intermediate.

Pathway 1: Oxidative Addition

H H n n+2 Ln M Ln M R R

Pathway 2: Concerted Metallation-Deprotonation (CMD)

Ln Ln Ln

R n R n n M M O M O R O H O H O HO Me Me Me

Figure 1.2 Modes of C–H bond activation to furnish new carbon-metal bonds.

The first is oxidative addition, where the metal center is formally oxidized by 2 electrons to both a metal-carbon bond and a metal-hydride bond. The second pathway involves a ligand-assisted deprotonation event named concerted metallation-deprotonation (CMD). This pathway often involves weak bases with

κ2 binding modes (such as carboxylates, carbonates, phosphates, etc.) and is thought to occur in a redox-neutral concerted process.2 The process relies on an

- 2 - agostic interaction to acidify the C–H bond, enabling a 6-membered transition state for deprotonation and subsequent metalation of the carbon unit. Each mode of reactivity provides advantages and disadvantages; but on the whole,

CMD tends to be a much milder method to functionalize C–H bonds.

1.3 Installation of Directing Groups

While C–H bonds can be activated in a number of ways, the challenge of selectively cleaving a specific bond remains.

In order to combat this challenge, chemists install directing groups with heteroatoms that put the metal in close proximity to the C–H bond to be activated. This strategy relies heavily on confirmation of resulting metallacyclic species for further functionalization to occur.

H H H H H H H H R Me H H H H

Figure 1.3 Selectivity challenges of C–H activation.

Among other metals, rhodium(III) piano stool complexes bearing a cyclopentadienyl (Cp) ligand have shown great selectivity and diversity in functionalization methods in recent years. In association with a carboxylate-type base (shown in Figure 1.4 with an acetate ligand), the rhodium catalyst uses the

- 3 - 3 coordination sites beneath the Cp ligand to selectively convert a C–H bond into more important motifs such as C–C, C–N, C–O bonds.3

DG H DG FG H cat. [RhIII] H

H Base H

FG Rh O Functional Group Installation O Me

Rh DG Rh O DG H O Me

Rhodacycle intermediate

Figure 1.4 Directing group assisted Rh(III)-catalyzed ortho-C–H functionalization.

In 2010, our group joined the community and took advantage of this reactivity by treating secondary benzamides with alkynes in the presence of copper(II) acetate and a rhodium(III) catalyst bearing a pentamethylcyclopentadiene (Cp*) ligand.4 First the dimer pre-catalyst is broken up to liberate the Rh-diacetato active catalyst. This species can deprotonate the

N–H bond of the benzamide revealing a directing group toward the ortho-C–H bond. This complex undergoes C–H activation by a CMD type mechanism that

- 4 - gives rise to a 5-membered metallacycle. After migratory insertion affords the 7- membered metallacycle, reductive elimination forms a C–N bond and gives the isoquinolone product. Finally, 2 equivalents of CuII oxidize the resulting RhI species to regenerate the catalyst.

Rovis 2010: Oxidative Cyclization of Benzamides and Alkynes via C–H/N–H Activation O O (2.5 mol%) R R R [Cp*RhCl2]2 N N H R Cu(OAc)2 • H2O (2.1 equiv.) R H t-AmylOH, 110 °C R

O O R N R N H R III R AcO Rh O O AcOH R 2 CuI N–H Cu(OAc) Deprotonation 2 Re-Oxidation II 2 Cu (OAc)2 [Cp*RhCl2]2

O RhI Cp* R O N R N RhIII Cp* H R O O R Me

R R Reductive CMD and Elimination Association

AcOH O O R R N N RhIII Cp* RhIII Cp* R Migratory R R R Insertion

Figure 1.5 Mechanism of Rh(III)-catalyzed benzannulation of alkynes.

- 5 - Around the same time, Fagnou and coworkers published a similar reaction with the installation of an internal oxidant as opposed to exogenous, stoichiometric amounts of copper(II) acetate.5 This reactivity manifold allows for the same benzannulation to occur under milder conditions. Fagnou and coworkers then optimized the oxidative directing group from –OMe to –OPiv.6

This alteration allows for the chemistry to happen at room temperature as well as expanding its scope to the insertion of alkenes, giving dihydroisoquinolones.

Fagnou 2010: Installation of Internal Oxidant O O (2.5 mol%) OMe R [Cp*RhCl2]2 NH N H R CsOAc (25 mol%) R H MeOH, 60 °C R Fagnou 2011: Optimization of Internal Oxidant O O (2.5 mol%) OPiv R [Cp*RhCl2]2 NH N H R CsOAc (25 mol%) R H MeOH, rt R

Figure 1.6 Installation of internal oxidant for the oxidative cyclization of benzamides with alkenes and alkynes.

1.4 Mechanistic Considerations

Mechanistically, this system is proposed to work by N–H deprotonation,

CMD, and migratory insertion. Reductive elimination of the C–N bond is

- 6 - followed by oxidative addition of the N–O bond. Finally, protodemetallation furnishes the product and regenerates the catalyst.

O O R = Me or t-Bu NH OPiv N H R III R AcO Rh O O AcOH R AcOH N–H Proto- Deprotonation demetalation O CsOAc Cp* OPiv O N [Cp*RhCl2]2 RhIII RhIII Cp* N H OPiv O O R R Me R R Reductive Oxidative CMD and Addition Association Pathway

AcOH O RhI Cp* O OPiv N OPiv N RhIII Cp* R R R R Migratory Reductive Insertion Elimination O OPiv N RhIII Cp*

R R

Figure 1.7 Proposed mechanism of alkene/alkyne benzannulation with an internal oxidant.

Fagnou’s addition of the internal oxidant was revolutionary to Rh(III)- catalyzed C–H activation and alkene difunctionalization. While this proposed mechanism is perfectly reasonable, computational studies and related reactions

- 7 - have given new insights. 7 The major difference comes from the C–N bond forming event being reductive or oxidative in nature.

O O R = Me or t-Bu NH OPiv N H R III R AcO Rh O O AcOH R AcOH N–H Proto- demetalation Deprotonation CsOAc O Cp* OPiv O [Cp*RhCl2]2 N RhIII N RhIII Cp* OPiv H R O O R Me R R Oxidative Reductive CMD and Elimination Association Pathway

AcOH O O OPiv N OPiv N RhV Cp* RhIII Cp* R R R R Oxidative Migratory Addition/Nitrene Insertion Formation O OPiv “oxidative induced N reductive elimination” RhIII Cp*

R R

Figure 1.8 Proposed oxidative nitrene formation.

In the oxidative pathway, a metal-nitrene is formed by formal oxidation of the Rh center. The idea of oxidative induced reductive elimination has gained popularity in recent years among transition metal-catalyzed reactions.8 In this process, the nitrogen of the benzamide takes on electrophilic character. These ideas

- 8 - have had an impact on my own research as well as the field, as seen in the chapters to come.

1.5 Tuning Cyclopentadienyl Ligands to Impact Catalysis

Fundamental studies in the field of Rh(III)-catalyzed C–H activation have deployed Cp* as the parent cyclopentadienyl ligand. In metal-catalyzed reactions, the choice of ligand on the metal affects each step in the catalytic cycle, influencing reactivity and/or selectivity. In the past decade, our group and others have concocted a library of Cp ligands with varying electronic and steric properties on Rh complexes (figure 1.9).9 Employing these modified Cp ligands as pre-catalysts has affected the reactivity and selectivity the catalysts show in the synthesis of small molecules.10

- 9 - Electronically Tuned Cp Ligands

CF3

EtO2C CO2Et CF3

CF3 CpE Cp*CF3 Cp*bisCF3

Sterically Tuned Cp Ligands

Ph Ph R = H Ph Ph R CpTM CyCp CptriPh or CptetraPh

R = t-Bu t-Bu t-Bu i-Pr R Cy

CpT Cpi-Pr Cp*t-Bu or Cp*Cy

Ph Ph

Cp*diPh Ind*

Figure 1.9 Selected examples of modified cyclopentadienyl ligands.

1.6 Summary

The direct conversion of carbon–hydrogen bonds into valuable carbon- carbon and carbon-heteroatom bonds is a significant challenge to synthetic organic chemists. More than ever, chemists are employing Rh(III)-catalysts bearing cyclopentadienyl (Cp) ligands to transform otherwise inert C–H bonds.

Furthermore, manipulating the sterics and electronics of the Cp ligand has

- 10 - significant impact on catalytic transformations. Our group and others have developed a library of CpXRh(III)-precatalysts in hopes of enhancing known reactivity as well as discovering new C–H bond functionalizations.

1.7 References

(1) a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.

b) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16, 11212. c) Patureau, F.

W.; Wencel-Delord, J.; Glorius, F. Aldrichim. Acta 2012, 45, 31. d) Song,

G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.

(2) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.

(3) Walsh, A. P.; Jones, W. D. Organometallics 2015, 34, 3400.

(4) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565.

(5) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,

6908.

(6) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133,

6449

(7) a) Yang, Y.-F.; Houk, K. N.; Wu, Y.-D. J. Am. Chem. Soc. 2016, 138, 6861.

b) Vásquez-Céspedes, S.; Wang, X., Glorius, F. ACS Catal. 2018, 8, 242.

(8) a) Bour, J. R.; Camasso, N. M.; Sanford, M. S. J. Am. Chem. Soc. 2015,

- 11 -

137, 8034. b) Kim, J.; Shin, K.; Jin, S.; Kim, D.; Chang, S. J. Am. Chem.

Soc. 2019, 141, 4137. c) Harris, R. J.; Park, J.; Nelson, T. F.; Iqbal, N.;

Salgueiro, D. C.; Basca, J.; MacBeth, C. E.; Baik, M.-H.; Blakey, S. J. Am.

Chem. Soc. 2020, 142, 5842.

(9) a) Piou, T.; Rovis, T. Acc. Chem. Res. 2018, 51, 170. b) Romanov

Michaelidis, F.; Phipps, E. J. T.; Rovis, T. Chapter 20 of Rhodium Catalysis in

Organic Synthesis: Methods and Reactions. 2019, 593.

(10 ) Piou, T.; Romanov-Michailidis, F.; Romanova-Michaelides, M.; Jackson,

K. E.; Semakul, N.; Taggart, T. D.; Newell, B. S.; Rithner, C. D.; Paton, R.

S.; Rovis, T. J. Am. Chem. Soc. 2017, 139, 1296.

- 12 - – Chapter Two –

Rh(III)-catalyzed Cyclopropanation of Unactivated Alkenes Initiated by C–H Activation

2.1 Introduction to Cyclopropanation

The synthesis of cyclopropane-containing molecules has intrigued synthetic organic chemists for years because of their prevalence in synthetic targets1 as well as their susceptibility as reactive intermediates.2

Selected Examples of Cyclopropane-containing Natural Products

O Me Me HO Me Et Me H Me OMe Me Me O OH Me H OH Me Me H H Me Me i-Pr O (+)-Crispatine (+)-Omphadiol (–)-Cubebol

Figure 2.1 Selected examples of cyclopropane units in natural product synthesis.

Preferably, cyclopropane ring construction would be an intermolecular reaction involving a 1-carbon unit adding to a 2-carbon unit which is formally a [2+1] annulation.

The simplest 2-carbon units for use in the synthesis are alkenes. Generally, when probing for new reactivity using an alkene, chemists tend to start with activated alkenes bearing an electron withdrawing or donating group to help polarize the alkene. Alkenes bearing only alkyl groups have and continue to remain a challenge due to the chemical inertness.

– 13 – Furthermore, starting alkene geometry can translate to stereodefined cyclopropane products.

H R cat. or stoich. [M] H C R C R H [2+1] Annulation R H Alkenes Carbenes Stereodefined 2-carbon unit 1-carbon unit Cyclopropanes

EWG EDG Me ∂+ ∂- Challenging: Chemically R ∂- R ∂+ Me Inert

Figure 2.2 General protocol for the synthesis of cyclopropanes from alkenes.

Regarding the 1-carbon units, carbene precursors are known to be effective due to

A plethora of robust methods have been developed to afford cyclopropane motifs from alkenes. Generally, Simmons-Smith and diazo decomposition are regarded as the two most powerful methods for the cyclopropanation of alkenes.3, 4 Simmons-Smith type reactions are well-established to afford cyclopropanes from the generation of a zinc- carbenoid species that interacts with unactivated olefins with high stereoselectivity; however, these methods are limited by the substitution pattern of the carbenoid reagent5 and the stoichiometric use of zinc.6 Regarding unactivated olefins, Uyeda and coworkers noted that under standard Simmons-Smith type conditions, cyclopropanation of non- conjugated dienes is moderate in yield and only moderately selective for the terminal alkene.7 However, the addition of a Co catalyst bearing a pyridyldiimine ligand is able to

– 14 – distinguish between the two alkenes and perform in good yield. Uyeda demonstrated the power of this method on a number of similar unactivated alkenes.

Simmons-Smith

X R’ R’ R’ R’ [Zn] R’ R’ R

X X [Zn] R Generation of Zinc-Carbenoid Species

ZnEt2 CH2I2

DCM, rt

53%; 1 : 6.5

CoBr2 (6 mol%) i-PrPDI (6 mol%)

CH2Br2 Zn0 81%; >50 : 1 THF, rt

Figure 2.3 Simmons-Smith reactivity with unactivated alkenes.

Metal-catalyzed diazo decomposition has also provided complimentary reactivity to access stereodefined cyclopropanes with a more diverse substitution pattern albeit with two notable shortcomings. While numerous methods have been established for Rh- catalyzed cyclopropanation of alkenes,8 many of these methods require the use of high- energy diazo compounds.9 Davies and coworkers have been arguably the biggest influence on this chemistry for decades. Cyclopropanation of unactivated alkenes using

Rh(II) catalysts has been well known and demonstrated to work with a variety of alkenes.

– 15 – Notably, Davies and coworkers employed a Rh(II) catalyst bearing protected proline ligand to impart enantioselectivity on the transformation.10 These Rh(II) catalysts with other chiral ligands have cemented themselves to the field of metal-carbene transfer chemistry. Interestingly, to date, Fürstner and coworkers published the only example

Rh(III)-catalyzed cyclopropanation of styrene type alkenes from diazo one-carbon components.

Diazo Decomposition

R’ R’ R’ R’ [M] cat. R’ R’ R

N2 [M] R Catalytic Generation of Metal-Carbene Species

Ph Me CO2Me Ph CO2Me [Rh2(S-DOSP)4] (1 mol%) Me N2 pentane, rt Me Me 52% 95% ee

O O [Cp*RhI ] (1 mol%) PMP 2 2 PMP OMe PMP OMe pentane, rt N2 PMP 76% >20:1 d.r.

Figure 2.4 Metal catalyzed diazo decomposition of unactivated alkenes.

– 16 – 2.2 Reactivity Profile of N-enoxyimides

N-Enoxyphthalimides constitute valuable alternatives to potentially explosive diazo compounds and pyrophoric organozinc reagents due to the mild conditions and the allure of C–H functionalization reactions (Figure 1).11 Our initial report in 2014 showed that aryl N-enoxyphthalimides undergo C–H activation and smoothly undergo

[2+1] annulation with activated olefins bearing electron withdrawing groups, affording trans-cyclopropanes in good yield and diastereoselectivity.12

-trans-diastereoselective cyclopropanation i-Pr

Rh Cl Cl O 2 [Cpi-PrRhCl ] (5 mol%) Ar O 2 2 Ar N EWG EWG CsOAc O O TFE, rt up to >20:1 d.r.

Figure 2.5 Trans-Cyclopropanation.

Importantly, the mechanism first described does not propose the formation of a metal-carbene species. Instead, two migratory insertion events are thought to give rise to the trans-cyclopropane. From deuterium labeling studies scrambling is observed alpha to the ketone, indicating a reversible event during the catalytic cycle. To account for this, beta-hydride elimination is proposed to be reversible by Rh–H deprotonation. Due to the high pKa measured of Cp*Rh–H species,13 this event is unlikely with acetate base as the most viable candidate.

– 17 – O O N i-Pr Ar O EWG Ar Rh O O OAc AcO O Me Cp HOAc CsOAc O Rh O Cp i-Pr O H [Cp RhCl2]2 N Me EWG O Rh O O N O Ar O EWG Ph

HOAc Cp EWG OAc Cp OAc Cp O I EWG O Rh O N Rh EWG H Rh O N O O O O Ar Ar Ph N

O

Cp OAc EWG OAc O O Rh H EWG O N Rh N O O Cp O Ar Ar

Cp OAc O EWG Rh N O H O ‘ Ar

Figure 2.6 Initially proposed mechanism of Rh(III)-catalyzed cyclopropanation.

– 18 – In a follow-up report, we demonstrated that tuning the electronic properties of the Cp ligand as well as the phthalimide ring affords access to the cis-cyclopropane scaffold.14

-cis-diastereoselective cyclopropanation

Cy

Rh Cl O Cl 2 Ar O N [Cp*CyRhCl ] (5 mol%) 2 2 Ar EWG Cl EWG O NaOAc O TFE, rt Cl up to >1:20 d.r.

Figure 2.7 Cis-Cyclopropanation.

Here, the change in selectivity is proposed to arise by phthalimide ring opening by the alcoholic solvent.

Cramer and coworker have rendered the trans-cyclopropanation reaction asymmetric by employing their chiral Cp ligand to provide trans-cyclopropanes in high e.r.15 Additionally, they were able to expand the scope of the one-carbon unit beyond aryl substituents.

-Enantioselective cyclopropanation Me O O Me Me Rh Me O (5 mol%) R O R N EWG EWG (BzO) 2 O O CsOAc, TFE

up to 97.5:2.5 e.r.

Figure 2.8 Enantioselective cyclopropanation.

– 19 – In an effort to expand the scope of this transformation, we set out to examine stereodefined cyclopropanation of unactivated olefins.

III R O R’ cat. [Rh ] * * R’ NPhth R R R Base O

Figure 2.9 Proposed Rh(III)-catalyzed cyclopropanation of unactivated alkenes from N- enoxyphthalimides

2.3 Reaction Optimization

From the trans-cyclopropanation study, our group found that 1,1-dialkylalkenes undergo cyclopropanation in modest yield. The shortcoming in this transformation is

the reaction is unselective with [Cp*RhCl2]2 precatalyst.

(5 mol%) n-Bu Ph O n-Bu [Cp*RhCl2]2 NPhth Ph Me Me CsOAc (2 equiv.) O TFE (0.2M), rt 2-1a 2-2j 2-3aj 62% 1:1 d.r.

Figure 2.10 Original hit with Cp*Rh(III) precatalyst.

Because of the large library of CpXRh(III) precatalysts our group has built we predicted that by tuning the sterics and/or electronics of the Cp ligand, we could impart selectivity in cyclopropanation of unactivated alkenes. After screening 15+ ligands, we observed no change in diastereoselectivity. Notably, we found that electron-deficient Cp

– 20 – ligands improve the yield of the reaction. In particular, Cp*CF3 gives the highest yield of

82%.

– 21 – (5 mol%) [CpXRhCl ] Ph O n-Bu 2 2 n-Bu NPhth Ph Me Me CsOAc (2 equiv.) O TFE (0.2M), rt 2-1a 2-2l 2-3al; 1:1 d.r.

t-Bu i-Pr

Cp* Cp*t-Bu Cp*i-Pr 62% 0% 0%

TMS CF3 C3F7

Cp*TMS Cp*CF3 Cp*CF3 0% 82% 38% F

C6F5 PMP

F Cp*C6F5 Cp*bis(o-F) Cp*PMP 75% 34% 0%

CF3 F

CF3 CF3 F

CF3 dip-F dibisCF3 Ind* Cp* Cp* 0% 24% 75%

CF3

Ph C6F5 CF3 CF3 Ph Me

diPh Me/C6F5 dibisCF3 CyCp CyCp CyCp CF3 18% 58% 80%

Scheme 2.1 Cp Ligand screen.

– 22 – Due to the lack of diastereoselectivity imparted by the Cp ligand we chose to advance the project with symmetrical 1,1-disubstituted alkenes in the presence of

Cp*CF3Rh(III) catalyst.

2.4 Scope of the Cyclopropanation Reaction

We began by examining 3-methylenepentane as a coupling partner and found modest reactivity as cyclopropane 2-3aa was afforded in 40% yield. A number of exocyclic alkenes proved to be excellent participants in this reaction giving a wide range of [2.n]spirocyclic ketones. We interrogated the effect of different size carbocycles ranging from 4 to 8-membered rings (2-3ab to 2-3af). Notably, methylenecyclohexane gives [2.5]spirocycle 2-3ad in near quantitative yield. Both tosyl- and Boc-protected methylene piperidines display good reactivity affording cyclopropane 2-3ag in 72% and

2-3ah in 89% yield, respectively. Cyclopropanation of a methylene cyclohexane bearing a substituent at the 4-position proceeds efficiently, delivering cyclopropane 2-3ai in 97% yield and good diastereoselectivity (8.6:1 d.r.).16

– 23 – (5 mol%) [Cp*CF3RhCl ] Ph O R 2 2 R NPhth Ph R R CsOAc (2 equiv.) O 2-1a 2-2 TFE (0.2M), rt 2-3

Et Ph Ph Ph CN Et O O CN O

2-3aa 2-3ab 2-3ac 40% 56% 87%

Ph Ph Ph

O O O

2-3ad 2-3ae 2-3af 98% 70% 53%

Ph Ph Ph Ph NTs NBoc O O O 2-3ag 2-3ah 2-3ai 72% 84% 97% 8.6:1 d.r.

Scheme 2.2 Scope of 1,1-disubstituted alkenes.

Varying para- (2-3bd to 2-3dd) and meta- (2-3ed to 2-3gd) arene substitution on the enoxyphthalimide is tolerated, with each substrate displaying excellent yields. ortho-

Fluorine containing enoxyphthalimide delivers cyclopropane 2-3hd in 59% yield.

Naphthyl enoxyphthalimide gives cyclopropane 2-3id in 67% yield. Finally, an alkyl substituted N-enoxyphthalimide is also a competent substrate, affording cyclopropane

2-3jd in 98% yield.

– 24 – (5 mol%) [Cp*CF3RhCl ] R O 2 2 NPhth R CsOAc (2 equiv.) O 2-1 2-2d TFE (0.2M), rt 2-3

Me t-Bu F

O O O

2-3bd 2-3cd 2-3dd 97% 89% 96%

Me F MeO O O O

2-3ed 2-3fd 2-3gd 75% 90% 67%

Ph

F O O O

2-3hd 2-3id 2-3jd 59% 67% 92%

Scheme 2.3 Scope of N-enoxyphthalimides.

While these examples display a nice range of functional group tolerance, unactivated alkenes with different substitution patterns behave differently.

– 25 – 2.5 Participation of Other Alkenes

We also surveyed the reactivity pattern of different alkenes:

Knowing the cyclopropane 2-3aj is formed in good yield but unselective, we tried to increase the steric load by changing n-Bu to i-Pr and saw a dramatic drop in yield, with poor diastereoselectivity. Styrene gives the desired cyclopropane in good yield but poor d.r. Gratifyingly, we see the related unactivated alkene, 1-decene gives cyclopropane 2-

3am in moderate yield as well. Vinyl acetate does not participate in the cyclopropanation reaction; however, the related electron-rich alkene 2,3-dihydrofuran gives cyclopropane

2-3ao in low yield. Similarly, the locked cis alkene cyclopentene and the related trans-4- octene proceed in low yield. Interestingly, norbornene provides tricycle 2-3ar in moderate yield and importantly as a single diastereomer. Combining what we know from the performance of 1,1-disubstituted alkenes and styrenes, we were disappointed that a- methyl styrene does not participate in the cyclopropanation reaction. However, introducing a methylene spacer restores moderate reactivity and 1:1 diastereoselectivity.

Finally, similar to substrate 2-3aa, we see that extending the chain using 5- methylenenonane drops reactivity to 12% yield.

– 26 – (5 mol%) R R [Cp*CF3RhCl ] Ph O 2 2 R R NPhth Ph CsOAc (2 equiv.) R R TFE (0.2M), rt O 2-1a 2-2 2-3

n-Bu i-Pr Ph Ph Ph Ph Ph n-Oct Me Me O O O O 2-3aj 2-3ak 2-3al 2-3am 82% 17% 83% 58% 1:1 d.r. 1:1 d.r. 1:1 d.r. 1:1 d.r.

n-Pr

Ph O OAc Ph Ph Ph n-Pr O O O O 2-3an 2-3ao 2-3ap 2-3aq 0% 16% 14% 10% 1:1 d.r. 1:1 d.r.

H Ph Bn n-Bu Ph Ph Ph Ph Me Me n-Bu H O O O O 2-3ar 2-3as 2-3at 2-3au 63% 0% 41% 12% 1:1 d.r. single diastereomer

Scheme 2.4 Scope of alkenes with varying substitution.

2.6 Mechanistic Studies

Finally, we sought to interrogate the mechanism of this reaction (Figure 4).

Subjecting 2-1a to the reaction conditions using TFE-d1 leads to no deuterium incorporation upon re-isolation of 2-1a. In another experiment, we subjected 2-1a and

2-2d to the reaction conditions again with TFE-d1 that gives cyclopropane 2-3ad’ in 85%

– 27 – yield. From the analysis of the product, we observe a reversible deuterium exchange event at the alpha-position (54% D incorporation).

Deuterium Labeling Studies -Reversibility of C–H activation O (5 mol%) O CF3 Ph O [Cp* RhCl2]2 N Ph O N CsOAc (2 equiv.) O TFE-d1 (0.2M), rt H H/D O 2-1a 2-1a 0% D incorporation -Deuterium incorporation (5 mol%) [Cp*CF3RhCl ] D Ph O 2 2 NPhth Ph CsOAc (2 equiv.) O TFE-d1 (0.2M), rt 2-1a 2-2d 2-3ad’, 85% 54% D incorporation

Figure 2.11 Deuterium labeling studies.

We next probed the role of the phthalimide ring by subjecting 2-1a to 2 equiv. of

CsOAc in TFE and observed the formation of dioxazoline 2-4 in 59% yield, indicating

TFE opens the phthalimide ring. We believe the resulting amide is a key intermediate to direct the catalyst for the C–H activation step; however, attempts to isolate the opened phthalimide were unsuccesful. Finally, we subjected 2-4 to 2-2d and the reaction conditions. However, only trace product was observed indicating 2-4 does not significantly contribute as a competent reaction intermediate.

– 28 – Isolation of Off-cycle Intermediates -Dioxazoline formation O O Ph O CsOAc (2 equiv.) N F3C O TFE (0.2M), rt Ph O O Me O N 2-1a Key Intermediate 2-4, 59%

F3C O O O Acylation Cyclization Ph O N ± H H ± H

-Compatibility of 2-4

O (5 mol%) CF3 [Cp* RhCl2]2 F3C O Ph Ph O CsOAc (2 equiv.) O TFE (0.2M), rt Me O N 2-4 2-2d 2-3ad 2%

Figure 2.12 Dioxazoline formation and intermediacy test.

– 29 – 2.7 Proposed Mechanism

On the basis of these experiments, we propose the following mechanism:

2-1 R O NPhth

CsOAc TFE CF3 [Cp* RhCl2]2

CF3 CsOAc 2-3 II O R R HNPhth OAc + R O O O R TFE Me CF3 N O Rh O O H O F C O 3 I Ph O OAc CF Me O N 3 CF3 O 2-4 O O F3C OAc R O O R O O O N O N O O HN H R O H Rh Rh H Rh CF3 CF3 H O Cp* O Cp* R Cp*CF3 Ac III Ac R V R O R F3C O 2-2 R O N HOAc HOAc H Rh O R Cp*CF3 R IV

Figure 2.30 Proposed Mechanism.

First, the precatalyst undergoes salt metathesis with CsOAc to form the active catalyst I. Concurrently, 2-1 is opened by the solvent to give II which then intercepts I,

– 30 – before dioxazoline 2-4 formation, and undergoes C–H activation via concerted metalation-deprotonation to afford intermediate III. At this stage, we believe intermediate III displays enolic character to reversibly wash in deuterium before ligand exchange of 2-2. After exchanging acetic acid for alkene that gives intermediate V, we propose the formation of a Rh-carbene, intermediate V, via cleavage of the N–O bond.

Intermediate V then gives way to the desired cyclopropane product.

2.8 Summary

In conclusion, we have developed a Rh(III)-catalyzed cyclopropanation protocol for N-enoxyphthalimides and unactivated olefins. The N-enoxyphthalimide has been shown to undergo C–H activation that leads to a proposed metal-carbene to induce a

[2+1] annulation with alkenes that give a diverse range of cyclopropyl ketones in mild conditions.

– 31 – 2.9 References

(1) (a) Chen, D.Y.-K.; Pouwer, R. H.; Richard, J.-A. Chem. Soc. Rev. 2012, 41, 4631. (b)

Talele, T. T. J. Med. Chem. 2016, 59, 8712.

(2) (a) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.; Hamel, E.; Verdier-

Pinard, P. Org. Biomol. Chem. 2003, 1, 296. (b) Newhouse, T. R.; Kaib, P. S. J.; Gross,

A. W.; Corey, E. J. Org. Lett. 2013, 15, 1591.

(3) For a recent selection of many diazo decomposition reactions see: (a) Doyle, M. P.;

Forbes, D. C. Chem. Rev. 1998, 98, 911. (b) Davies, H. M. L.; Antoulinakis, E. G.

Org. React. 2004, 57, 1.

(4) For a recent selection of Simmons-Smith-type reactions see: (a) Lebel, H.; Marcoux,

J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 4977. (b) Charette, A. B.;

Beauchemin, A. Org. React. 2004, 58, 1.

(5 ) (a) Friedrich, E. C.; Biresaw, G. J. Org. Chem. 1982, 47, 1615. (b) Stahl, K.-J.;

Hertzsch, W.; Musso, H.; Liebigs Ann. Chem. 1985, 1474. (c) Roberts, C.; Walton, J.

C. J. Chem. Soc., Perkin Trans. 2 1985, 841. (d) Motherwell, W. B.; Roberts, L. R.

Chem. Commun. 1992, 1582.

(6) (a) Dolbier Jr., W. R.; Burkholder, C. R. J. Org. Chem. 1990, 55, 589. (b) Ilchenko,

N. O.; Hedberg, M.; Szabó, K. J. Chem. Sci, 2017, 8, 1056. (c) Werth, J.; Uyeda, C.

Chem. Sci. 2018, 9, 1604.

– 32 –

(7) Werth, J.; Uyeda, C. Chem. Sci. 2018, 9, 1604.

(8) For selected recent examples of Rh-catalyzed cyclopropanations see: (a)

Muthusamy, S.; Gunanathan, C. Synlett 2003, 11, 1599. (b) Hilt, G.; Galbiati, F.

Synthesis, 2006, 21, 3589. (c) Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem.

Soc. 2009, 131, 16383. (d) Lindsay, V. N. G.; Nicolas, C.; Charette, A. B. J. Am.

Chem. Soc. 2011, 133, 8972. (e) Negretti, S.; Cohen, C. M.; Chang, J. J.; Guptill, G.

M.; Davies, H. M. L. Tetrahedron 2015, 71, 7415. (f) Lehner, V.; Davies, H. M. L.;

Reiser, O. Org. Lett. 2017, 19, 4722. (g) Sun, G.-J.; Gong, J.; Kang, Q. J. Org. Chem.

2017, 82, 1796. (h) Tindall, D. J.; Werle, C.; ́ Goddard, R.; Philipps, P.; Fares, C.;

Fürstner, A. J. Am. Chem. Soc. 2018, 140, 1884. (i) Lindsay, V. N G. Rhodium(II)-

Catalyzed Cyclopropanation. In Rhodium Catalysis in Organic Synthesis: Methods and

Reactions; Tanaka, K., Ed.; Wiley-VCH; 2018; pp. 433-448.

(9) (a) Doyle, M. P.; Hu, W.; Phillips, I. M.; Moody, C. J.; Pepper, A. G.; Slawin, A. M.

Adv. Synth. Catal. 2001, 343, 112. (b) Doyle, M. P.; Hu, W. Adv. Synth. Catal. 2001,

343, 299. (c) Gharpure, S. J.; Shukla, M. K.; Vijayasree, U. Org. Lett. 2009, 11, 5466.

(d) Vanier, S. F.; Larouche, G. Wurz, R. P.; Charette, A. B. Org. Lett. 2009, 12, 672.

(e) Nani, R. R.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 7304. (f) Gu, H.; Huang,

S.; Lin, X. Org. Biomol. Chem. 2019, 17, 1154.

(10) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem.

Soc. 1996, 118, 6897.

– 33 –

(11) (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 2704. (b)

Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45,

6814. (c) Piou, T.; Rovis, T. Acc. Chem. Res. 2018, 51, 1170.

(12) Piou, T.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 11292.

(13) Hu, Y.; Norton, J. R. J. Am. Chem. Soc. 2014, 136, 5938.

(14) Piou, T.; Romanov-Michailidis, F.; Ashley, M. A.; Romanova- Michaelides, M.;

Rovis, T. J. Am. Chem. Soc. 2018, 140, 9587.

(15) Duchemin, C.; Cramer, N. Chem. Sci. 2019, 10, 2773.

(16) Diastereoselectivity assigned by analogy of other 3-membered rings formed from 4-

substituted-exocyclic alkenes: (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc.

1965, 87, 1353. (b) Carlson, R. G.; Behn, N. S. J. Org. Chem. 1967, 32, 1363. (c)

Bellucci, G.; Chiappe, C.; Lo Moro G.; Ingrosso, G. J. Org. Chem. 1995, 60, 6214.

– 34 – – Chapter Three –

Rh(III)-catalyzed C–H Activation-Initiated Directed Cyclopropanation of Allylic Alcohols

3.1 Cyclopropanation of Allylic Alcohols

Biological and synthetic targets containing cyclopropane units have intrigued organic chemists for years as a result of their unique properties and the synthetic challenges.1 A number of powerful methods have been developed for the stereoselective synthesis of cyclopropane motifs.2 These methods largely share a common approach of an alkene that undergoes a [2+1] annulation with carbenes, metal carbenes, or metal- carbenoid species. In particular, allylic alcohols have been exploited as coupling partners in cyclopropanation reactions for their leverageable, pendent hydroxyl group. Ultimately, this handle provides regio- and diastereoselective cyclopropanations. Two methods have emerged as preferred techniques for the cyclopropanation of alkenes: Simmons-Smith type reactions and catalyzed diazo decompositions.

- 35 - Simmons-Smith Diazo Decomposition R’

R’ R’ R’ Allylic Alcohols R O [Zn] [M] cat. 1 OH + R X R OH R’ R’ R' X R’ R’ R' N2 OH R

Figure 3.1 General strategies for the cyclopropanation of allylic alcohols.

The Simmons-Smith approach features stoichiometric zinc reagents to aid both the formation and transfer of carbenoid species from simple methylene sources. Similarly, metal-catalyzed diazo decomposition is a broadly powerful reactivity manifold for the cyclopropanation of alkenes, with Rh,3 Ru,4 Pd,5 Cu,6 Co,7 and Fe8 catalysts utilized for their carbenoid formation and transfer capabilities. Notably, both modes of reactivity have also been rendered asymmetric when using prochiral alkenes.9 Charette has implemented strategies for enantioselective cyclopropanation of unprotected allylic alcohols by employing chiral diamine ligands or catalytic Ti bearing a taddolate ligand for chirality transfer. Additionally, in the realm of asymmetric cyclopropanation, metal catalysts (Cu and Rh shown below) bearing chiral ligands have been used to decompose diazo compounds and undergo [2+1] annulation with protected allylic alcohols in stereoselective fashion. Here it is necessary for the allylic alcohol to be protected to minimize unwanted byproducts.

- 36 - State-of-the-Art Selected Cyclopropanation of Alkenes Simmons-Smith: Asymmetric methylenation H NMs

R 1 NMs R1 R OH (10 mol%) H 2 R2 OH

R ZnEt2, ZnI2, CH2I2 3 R3 up to 89% ee Et Et

O O Ph Ph Ph Ph O O Ti R 1 i-PrO Oi-Pr R1 R OH (25 mol%) 2 R2 OH R Zn(CH I) 3 2 2 R3 DCM, 0 °C 19 examples up to 92% ee

Diazo-Decomposition: Asymmetric cyclopropanation of protected allylic alcohols (1 mol%) Me Me

O O N N Cu EtO2C t-Bu t-Bu OTf Me OBn Me OBn N CHCO Et Me 2 2 Me 74% 98% ee MeO2C (1 mol%) N Rh O

O Rh EtO2C 4 Ph OMe Ph OMe

N2CHCO2Et 95%

Figure 3.2 State-of-the-Art strategies for cyclopropanation of allylic alcohol-type alkenes.

With regards to allylic alcohols, notable shortcomings have arisen in the two established methods outlined above. While Simmons-Smith reactivity is regio-, and

- 37 - diastereoselective, it is largely limited to methylenation10 Charette has shown that pre- functionalizing substituted methylene-zinc precursors allows for some functional groups to be carried through the cyclopropanation reaction. However, the substitution pattern of the one-carbon unit is limited to iodo- and boryl-functionalized units. In the case of metal-catalyzed diazo decomposition, the cyclopropanation of allyl alcohol is low yielding and instead O–H insertion is observed as the major product. Because the metal- carbene species is electrophilic, the pendant hydroxyl group reacts much faster than the alkene.

Simmons-Smith Substituted Methylene Transfer: Limited -Charette: iodocyclopropane synthesis I R Zn I • Et2O I 1 R1 R OH I 2 R2 OH R 3 R3

-Charette: Borylcyclopropane synthesis O PinB CF3 R Zn O PinB 1 R1 R OH I 2 R2 OH R 3 R3

Diazo-Decomposition: Outcompeted by O–H insertion

(0.5 mol%) H CO Et CO2Et CO2Et Rh2(OAc)4 2 OH N2 neat O OH

77% 6%

Figure 3.3 Limitations of competitive cyclopropanation strategies.

- 38 - We have previously reported that N-enoxyphthalimides are a unique one-carbon component for the cyclopropanation of activated alkenes.11 Furthermore, tuning the cyclopentadienyl (Cp) ligand on the RhIII catalyst delivers either cis- or trans-disubstituted cyclopropanes stereoselectively.12, 13 In a complementary approach, we found that by exchanging trifluoroethanol (TFE) solvent for methanol (MeOH) and again tuning the

Cp ligand on the Rh catalyst, activated alkenes undergo syn-1,2-carboamination.14

-trans-diastereoselective cyclopropanation i-Pr

Rh Cl Cl O 2 [Cpi-PrRhCl ] (5 mol%) Ar O 2 2 Ar N EWG EWG CsOAc O O TFE, rt up to >20:1 d.r.

-cis-diastereoselective cyclopropanation

Cy

Rh Cl O Cl 2 Ar O N [Cp*CyRhCl ] (5 mol%) 2 2 Ar EWG Cl EWG O NaOAc O TFE, rt Cl up to >1:20 d.r.

-syn-1,2-carboamination O t-Bu III O R Ar O [Cp* Rh ] O NPhth R Ar N R R Ar Rh O OMe 1-AdCO2Cs NPhth MeOH t-Bu R Cp* R

Figure 3.4 Previously described transformations with N-enoxyphthalimides.

- 39 - This chemodivergence is hypothesized to originate from MeOH participating as a nucleophile to open the phthalimide ring that allows the N-enoxyphthalimide to act as a bidentate ligand throughout catalysis. On the basis of these findings, we sought to expand the scope of our reported diastereoselective cyclopropanation toward unactivated alkenes.

R R R O cat. [RhIII] NPhth R * * Base OH O OH

Figure 3.5 Proposed Rh(III)-catalyzed directed cyclopropanation of allylic alcohols.

3.2 Reaction Optimization

Initial investigations began with phenyl-N-enoxyphthalimide 3-1a and trans-2- hexen-1-ol 3-2a in the presence of various Rh(III) catalysts in TFE at room temperature delivering cyclopropane 3aa in moderate yield but high diastereoselectivities. Ultimately, electron-deficient ligands proved best for this transformation–with Cp*CF3

- 40 - n-Pr (5 mol%) n-Pr CF3 Ph O [Cp* RhCl2]2 NPhth Ph KOAc (2 equiv.) OH TFE (0.2M), rt O OH 3-1a 3-2a 3-3aa

t-Bu t-Bu

Cp* Cpt Ind* 24% 6% 0%

t-Bu i-Pr EtO2C CO2Et

Cp*t-Bu Cpi-Pr CpE 22% 42% 45%

Ph C6F5 CF3

Cp*Ph Cp*C6F5 Cp*CF3 38% 45% 50%

Figure 3.6 Cp ligand optimization.

Solvent (entries B and C) and base screens revealed that KOPiv in TFE is optimal, providing 64% yield and >20:1 d.r. for the desired product (entry D). Our next thought was to heat the reaction to push it to completion; however, we observed only 11% yield of product. Furthermore, we discovered that reducing the reaction temperature to 0 °C

- 41 - leads to the desired cyclopropane in 81% yield while preserving excellent diastereoselectivity (entry F).

n-Pr (5 mol%) n-Pr CF3 Ph O [Cp* RhCl2]2 NPhth Ph Base (2 equiv.) OH Solvent (0.2M), Temp O OH 3-1a 3-2a 3-3aa

Entry Base Solvent Temperature Yield

A KOAc TFE rt 50%

B KOAc MeOH rt 36%

C KOAc THF rt 29%

D KOPiv TFE rt 64%

E KOPiv TFE 60 °C 11%

F KOPiv TFE 0 °C 81%

Scheme 3.1 Reaction optimization–Examination of the effects of inorganic bases, solvents, and temperature.

3.3 Stereoselectivity of the Cyclopropanation Reaction

We next examined if the diastereoselectivity of the tri-substituted cyclopropane product was directly correlated with initial alkene geometry (Scheme 2). Both trans- and cis-1,2-disubstituted primary allylic alcohols provide the desired cyclopropanes 3-3aa

- 42 - and 3-3ab in good yield–81% and 62%, respectively–and >20:1 d.r., implicating a stereospecific transformation.

n-Pr n-Pr OH 3-3aa Ph 81% 3-2a >20:1 d.r. O OH

(5 mol%) CF3 Ph O [Cp* RhCl2]2 NPhth KOPiv (2 equiv.) TFE, 0 ˚C 3-1a n-Pr 3-2b 3-3ab Ph 62% >20:1 d.r. n-Pr OH O OH

Figure 3.7 Primary allylic alcohols bearing a trans or cis disubstituted alkene.

3.4 Scope of the Cyclopropanation Reaction

Similar to the parent allylic alcohol, we found crotyl alcohol gives cyclopropane

3-3ac in excellent diastereoselectivity and 81% yield. Methallyl alcohol gives cyclopropane 3-3ad in 62% yield with 7:1 d.r. while prenyl alcohol furnishes 3-3ae in

82% yield and >20:1 d.r.

- 43 - R R (5 mol%) R R CF3 Ph O [Cp* RhCl2]2 R NPhth Ph R KOPiv (2 equiv.) OH TFE, 0 °C O OH 3-1a 3-2 3-3

Me Me Me Ph Me Ph Ph O HO O OH O OH 3-3ac 3-3ad 3-3ae 81% 62% 82% >20:1 d.r. 7.0:1 d.r. >20:1 d.r.

Scheme 3.2 Scope of primary allylic alcohols.

With optimized conditions in hand, we examined the scope of this reaction

(Scheme 3). Varying para- (3-3ba-3-3ea) and meta- (3-3fa-3-3ha) arene substitution on the enoxyphthalimide is tolerated, with each substrate displaying >20:1 diastereoselectivity. Ortho-Fluorine containing enoxyphthalimide delivers cyclopropane

3-3ia in 44% yield. Alkyl substituted N-enoxyphthalimide15 is also a competent substrate, affording cyclopropane 3-3ka in 92% yield.

- 44 - n-Pr (5 mol%) n-Pr CF3 R O [Cp* RhCl2]2 NPhth R KOPiv (2 equiv.) OH TFE, 0 °C O OH 3-1 3-2a 3-3

n-Pr n-Pr n-Pr Me t-Bu F

O OH O OH O OH

3-3ba 3-3ca 3-3da 72% 76% 69% >20:1 d.r. >20:1 d.r. >20:1 d.r.

n-Pr n-Pr n-Pr MeO

MeO Me O OH O OH O OH

3-3ea 3-3fa 3-3ga 77% 93% 50% >20:1 d.r. >20:1 d.r. >20:1 d.r.

n-Pr n-Pr n-Pr n-Pr Ph

F O OH F O OH O OH O OH

3-3ha 3-3ia 3-3ja 3-3ka 54%* 44%* 50%* 92% >20:1 d.r. >20:1 d.r. >20:1 d.r. >20:1 d.r.

*Low conversion at 0 °C, isolated yield at 21 °C

Scheme 3.3 Scope of N-enoxyphthalimides.

Next, a range of suitable allylic alcohols for the cyclopropanation reaction was explored (Scheme 4). Notably, chiral allylic alcohol substrates provide additional complexity leading to the potential of four different stereoisomers. In the event, these reactions deliver the corresponding cyclopropanes 3-3ag-3-3ai with varying levels of

- 45 - diastereoselectivity depending on the substituent size, from vinyl (73%, 2.5:1 d.r., major to S minor), to methyl (69%, 7.1:1 d.r.) and phenyl (62%, >20:1 d.r.). Using trans-1,2- disubstituted secondary allylic alcohols, we observed single diastereomers of cyclopropanes 3-3aj-3-3al ranging in good to excellent yields.

(Major) (Minor)

R (5 mol%) R R [Cp*CF3RhCl ] Ph O 2 2 H H NPhth R Ph R or Ph R KOPiv (2 equiv.) OH TFE, 0 °C O OH O OH 3-1a 3-2 3-3

H H H Ph Ph Me Ph Ph

O OH O OH O OH

3-3af 3-3ag 3-3ah 73% 69% 62% 2.5:1 d.r. 7.1:1 d.r. >20:1 d.r.

Me n-Pr n-Pr H H H Ph Me Ph Ph Ph Cy

O OH O OH O OH

3-3ai 3-3aj 3-3ak 88% 75% 95% >20:1 d.r. >20:1 d.r. >20:1 d.r.

Scheme 3.4 Scope of secondary allylic alcohols.

Interestingly, when our cyclopropanation protocol was applied to secondary, cyclic allylic alcohols, the results revealed a divergence in the mechanism. Using hexenol with 3-1a under the standard reaction conditions, the corresponding

- 46 - cyclopropane product was not observed. However, when cyclooctenol was used the corresponding cyclopropane was observed in 85% yield as a single diastereomer. This set of experiments revealed a few points about the mechanism of this reaction. On the basis of the crystal structure of 3-3ah, we confirmed the anti-addition of the carbene transfer. Under Simmons-Smith reaction conditions, similar selectivities are observed for syn-addition to cyclohexenol and anti-addition to cyclooctenol. It is hypothesized using cyclooctenol, the eight-membered ring prefers to adapt a chair-boat confirmation with the complexed hydroxyl group in the equatorial position, allowing methylene transfer to easily be delivered to the closes face of the alkene in anti fashion as a single diastereomer. In our system, we propose the hydroxyl group is not directly complexed to the metal; however, since it is linked through phthalimide opening, the methyle transfer still prefers anti-addition.

- 47 - OH H

Ph no reaction H OH (5 mol%) O CF3 Ph [Cp* RhCl2]2 O NPhth KOPiv (2 equiv.) TFE, 0 ˚C H 85% Ph >20:1 d.r. H O OH OH

- Selectivites of cyclic allylic alcohols under Simmons-Smith conditions syn anti

CH I 2 2 OH OH OH Zn-Cu couple H H H H 71%; >99 : 0

CH2I2 OH OH OH Zn-Cu couple H H H H

74%; 0.5 : 99.5

- Chair-boat conformers

I O CF3 NH Cp* Zn H Rh H O O O O Ar H H H H

Simmons-Smith Model Our Model

Figure 3.8 Comparison of secondary, cyclic allylic alcohols.

- 48 - 3.5 Mechanistic Studies

To interrogate the mechanism of this cyclopropanation reaction (Scheme 5), we first tested the length of the nucleophilic tether. Homoallylic alcohol 3-4a gives cyclopropane 3-5aa in only 12% yield indicating the chain length from the oxygen atom to the olefin is of great importance. Similarily, bis-homoallylic alcohol 3-6a gives cyclopropane 3-7aa in only 17% yield.

To showcase the regio-preference of our cyclopropanation protocol, 3-1a was subjected to substrate 3-2m (geraniol) bearing a tethered tri-substituted alkene as a potential competitive site for cyclopropanation. Gratifyingly, cyclopropane 3-3am was generated in 55% yield with good diastereoselectivity and excellent regioselectivity.

Nerol, the cis isomer, also gave the desired cyclopropane 3-3an in lower yield but similar selectivities to geraniol. With these studies, we conclude that our cyclopropanation protocol is regioselective.

- 49 - Regioselectivity -Tether length

(5 mol%) n-Pr Ph O n-Pr [Cp*CF3RhCl ] NPhth 2 2 Ph OH KOPiv (2 equiv.) OH TFE, 0 °C O 3-1a 3-4a 3-5aa 12% >20:1 d.r.

(5 mol%) n-Pr n-Pr Ph O [Cp*CF3RhCl ] NPhth 2 2 Ph KOPiv (2 equiv.) OH TFE, 0 °C O OH 3-1a 3-5a 3-7aa17% >20:1 d.r.

-Chemoselectivity test

Me Me Me (5 mol%) CF3 Ph O [Cp* RhCl2]2 Me Me NPhth Me KOPiv (2 equiv.) Ph OH TFE, 0 °C, O OH

3-1a 3-2m 3-3am 55% 8.6:1 d.r. >20:1 r.r.

Me Me Me (5 mol%) CF3 Ph O [Cp* RhCl2]2 Me Me NPhth Me KOPiv (2 equiv.) Ph OH TFE, 0 °C, O OH

3-1a 3-2n 3-3an 26% 8.4:1 d.r. >20:1 r.r.

Figure 3.9 Regioselective applications of the cyclopropanation protocol.

Next, we sought to test if the tethered nucleophile was needed for reactivity.

Allylic ether 3-8a is a poor substrate with only trace 3-9aa observed indicating the

- 50 - presence of an unhindered hydroxyl-group is necessary for the reaction to take place.

Allylic carboxylic acid 3-8b gives cyclopropane 3-9ab in trace yield. Interestingly, protected allylic amine 3-8c gives cyclopropane 3-9ac in 77% yield and 9.5:1 d.r. From these experiements, we conclude that a nucleophilic attack is necessary for reactivity.

The lack of reactivity with allylic ethers clearly shows this. Trace formation of 3-9ab could be due to reduced nucleophilicity of carboxylates; however, addition of a carboxylic acid buffers the solution. From optimization reactions, 2 equivalents of base is needed for this transformation to proceed. When reactivity is restored using a pendant sulfonamide, we believe this functional group is nucleophilic enough to open the phthalimide ring and does not affect the concentration of base present in the reaction.

- 51 - Nucleophilic Attack

(5 mol%) n-Pr n-Pr Ph O [Cp*CF3RhCl ] NPhth 2 2 Ph KOPiv (2 equiv.) OMe TFE, 0 °C O OMe 3-9aa 3-1a 3-8a trace

(5 mol%) n-Pr Ph O n-Pr [Cp*CF3RhCl ] NPhth 2 2 Ph CO H CO2H KOPiv (2 equiv.) 2 TFE, 0 °C O 3-1a 3-8b 3-9ab trace

n-Pr (5 mol%) n-Pr Ph O [Cp*CF3RhCl ] NPhth 2 2 Ph KOPiv (2 equiv.) HNTs TFE, 0 °C O HNTs 3-9ac 3-1a 3-8c 77% 9.5:1 d.r.

Figure 3.10 Investigations of the nucleophilicity of the allylic functional group.

We next subjected 3-1a to the reaction conditions in the absence of alkene with

TFE-d1 solvent and observed no deuteration of the alkenyl protons suggesting that the

C–H activation is irreversible. Using a deuterium labeled allylic alcohol at the alkene, we again observe a stereospecific transformation as the desired cyclopropane is observed in

82% yield while the proton and deuteron maintain complete trans relationship from the starting alkene.

- 52 - Deuterium Labeling Studies (5 mol%) Ph O [Cp*CF3RhCl ] Ph O NPhth 2 2 NPhth

H H KOPiv (2 equiv.) D/H H/D TFE-d , 0 °C, 1 0% D Incorporation

n-Pr H (5 mol%) CF3 n-Pr H Ph O [Cp* RhCl2]2 NPhth D D Ph KOPiv (2 equiv.) OH TFE, 0 °C O OH 82%

Figure 3.11 Deuterium labeling studies.

In another experiment, we set out to detect potential reactivity between 3-1a and

3-2b in the absence of Rh catalyst and we were surprised to observe the formation of dioxazoline 3-10ac in 38% yield with 1 equivalent of KOPiv in THF at room temperature.

We speculate this occurs via opening of the phthalimide ring and acylation of the allylic alcohol (eq. 8). Subjecting dioxazoline 3-10ac to the cyclopropanation reaction conditions did not afford cyclopropane, suggesting that dioxazoline 3-10ac is an off-cycle product.

- 53 - Isolation of off-cycle products Me O Me O Ph O KOPiv (2 equiv.) N Ph O THF, rt Me O O OH O N 3-1a 3-2c 3-10ac 38%

Me (5 mol%) Me O [Cp*CF3RhCl ] O 2 2 Ph Ph Me O KOPiv (2 equiv.) TFE, 0 °C or rt O OH O N 3-10ac 3-3ac not detected

Figure 3.12 Observation and intermediacy test of dioxazoline.

Furthermore, dioxazoline 3-10ac is observed while monitoring the reaction by crude 1H-

NMR (Appendix Two), indicating, that the phthalimide ring is opened during the reaction and not upon workup.

From these studies, we conclude that the cyclopropanation reaction: 1) is regioselective, 2) is conformationally dependent, 3) requires a tethered nucleophile, and

4) is initiated by an irreversible C–H activation.

- 54 - 3.6 Proposed Mechanism

On the basis of these experiments, we propose the following mechanism (Scheme

6). First, 3-2 undergoes acylation with 3-1 that gives intermediate I. Maintaining the reaction temperature at 0 °C inhibits cyclization to afford the dioxazoline product, which is instead intercepted by the active Rh(III) catalyst II. Intermediate I undergoes N–H deprotonation that gives intermediate III to initiate an irreversible C–H activation via concerted metalation-deprotonation that results in rhodacycle IV. At this stage, we hypothesize the formation of intermediate V by cleavage of the N–O bond and formation of a Rh-carbene. Due to the prior acylation of the allylic alcohol, intermediate VI is formed via the [2+1] annulation where the Rh-carbene is delivered across the alkene and on the same face as the pendent oxygen atom in stereoselective fashion.

Protodemetallation and subsequent phthalimide ring closure releases the product and turns the catalyst over.

- 55 - 3-1

R O NPhth

R R KOPiv, 0 °C OH 3-2

R R R R 3-3 O I O O R O > 23 °C O R H O R O II + Me N R R HNPhth H O N H OPiv O OH 3-10 O CF3 Rh t-Bu O

KOPiv

R KOPiv R O O OH H [Cp*CF3RhCl ] R R OO 2 2 t-Bu R III O N O H R Rh NH O H CF3 Rh VI F C O 3 O O O t-Bu

PivOH V PivOH R IV R H O R O R O R N R H H O Rh O Rh O NH F3C O F3C O

Figure 3.13 Proposed mechanism.

- 56 - 3.7 Summary

In conclusion, we have developed a directed diastereoselective cyclopropanation protocol for the [2+1] annulation of N-enoxyphthalimides and allylic alcohols. The diastereoselectivity of the reaction is speculated to arise from an intermediate generated by a ring-opening acylation of the allylic alcohol. Generation of a Rh-carbenoid leads to intramolecular cyclopropanation in excellent yield and diastereoselectivity.

3.8 References

(1) (a) Chen, D.Y.-K.; Pouwer, R.H.; Richard, J.-A. Chem. Soc. Rev. 2012, 41, 4631. (b)

Talele, T. T. J. Med. Chem. 2016, 59, 8712.

(2) (a) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911. (b) Lebel, H.; Marcoux, J.-

F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.

(3) For selected recent references, see: (a) Lindsay, V. N. G.; Lin, W.; Charette, A. B. J.

Am. Chem. Soc., 2009, 131, 16383. (b) Lindsay, V. N. G.; Nicolas, C.; Charette, A. B.

J. Am. Chem. Soc. 2011, 133, 8972. (c) Negretti, S.; Cohen, C. M.; Chang, J. J.;

Guptill, G. M.; Davies, H. M. L. Tetrahedron 2015, 71, 7415. (d) Lehner, V.; Davies,

H. M. L.; Reiser, O. Org. Lett. 2017, 19, 4722. (e) Tindall, D. J.; Werlé, C.; Goddard,

R.; Philipps, P.; Farès, C.; Fürstner, A. J. Am. Chem. Soc. 2018, 140, 1884.

- 57 -

(4) For selected recent references, see: (a) Chanthamath, S.; Iwasa, S. Acc. Chem. Res.

2016, 49, 2080. (b) Maas, G. Chem. Soc. Rev. 2004, 33, 183.

(5) For selected recent references, see: (a) Taber, D. F.; Amedio, J. C.; Sherrill, R. G. J.

Org. Chem. 1986, 51, 3382. (b) Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.;

Edwards, J. P. J. Org. Chem. 1997, 62, 3375. (c) Chen, S.; Ma, J.; Wang, J. Tetrahedron

Lett. 2008, 49, 6781.

(6) (a) Nozaki, H.; Takaya, H.; Moriuit, S.; Noyori, R. Tetrahedron 1968, 24, 3655. (b)

Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 3300.

(7) (a) Huang, L.; Chen, Y.; Gao, G.-Y.; Zhang, X. P. J. Org. Chem. 2003, 68, 8179. (b)

Chen, Y.; Fields, K. B.; Zhang, X. P. J. Am. Chem. Soc. 2004, 126, 14718. (c) Chen,

Y.; Zhang, X. P. J. Org. Chem. 2007, 72, 5931. (d) Chen, Y.; Ruppel, J. V.; Zhang, X.

P. J. Am. Chem. Soc. 2007, 129, 12074. (e) Zhu, S.; Ruppel, J. V.; Lu, H.; Wojtas, L.;

Zhang, X. P. J. Am. Chem. Soc. 2008, 130, 5042.

(8) (a) Hamaker, C. G.; Mirafzal, G. A.; Woo, L. K. Organometallics 2001, 20, 5171. (b)

Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001, 3, 2785. (c) Coelho,

P. S.; Brustad, E. M.; Kannan, A.; Arnold, F. H. Science 2013, 339, 307. (d) Allouche,

E. M. D.; Al-Saleh, A.; Charette, A. B. Chem. Commun. 2018, 54, 13256.

(9) Ebner, C.; Carreira, E. M. Chem. Rev. 2017, 117, 11161.

(10) (a) Dehmlow, E. V.; Stütten, J. Tetrahedron Lett. 1991, 32, 6105. (b) Charette, A. B.;

Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001, 123, 12168. (c) Bull, J. A.; Charette,

- 58 -

A. B. J. Am. Chem. Soc. 2010, 132, 1895. (d) Allouche, E. M. D.; Taillemaud, S.;

Charette, A. B. Chem. Commun. 2017, 53, 9606. (e) Benoit, G.; Charette, A. B. J. Am.

Chem. Soc. 2017, 139, 1364. (f) Werth, J.; Uyeda, C. Angew. Chem. Int. Ed. 2018, 57,

13092.

(11) Piou, T.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 11292.

(12) Piou, T.; Romanov-Michailidis, F.; Ashley, M. A.; Romanova-Michaelides, M.;

Rovis, T. J. Am. Chem. Soc. 2018, 140, 9587.

(13) This reaction has recently been rendered asymmetric by Cramer and coworkers;

see: Duchemin, C.; Cramer, N. Chem. Sci. 2019, 10, 2773.

(14) Piou, T.; Rovis, T. Nature 2015, 527, 86.

(15) Duchemin, C.; Cramer, N. Org. Chem. Front. 2019, 6, 209.

- 59 - – Chapter Four –

Validating Isolated Reaction Intermediates for 1,1-Carboamination of N-enoxyphthalimides

4.1 Artifacts of the Cyclopropanation Reaction

While probing the scope of cyclopropanation of unactivated alkenes, we subjected

4-1a to the standard reaction conditions under an atmosphere of ethylene. We found complete consumption of starting material but only trace desired cyclopropane 4-3aa.

(5 mol%) CF3 Ph O [Cp* RhCl2]2 NPhth Ph CsOAc (2 equiv.) (1 atm) O TFE, rt 4-1a 4-2a 4-3aa trace

Figure 4.1 Cyclopropanation reaction with ethylene as the alkene.

After purification, we observed the formation of a Rh-π-allyl complex in 83% yield. This was further confirmed by X-ray crystallography.

(1 equiv.) CF3 CF3 Ph O [Cp* RhCl2]2 O NPhth KOPiv (2 equiv.) Ph Rh Cl (5 equiv.) (1 atm) TFE, rt 4-1a 4-2a 4-4 83% (X-ray)

Figure 4.2 Formation of Rh-π-allyl complex.

- 60 - Similar to the mechanism described in chapters 2 and 3, we believe 4-4 is provided by CMD-type C–H activation of N-enoxyphthalimides. After migratory insertion, a 7- membered rhodacycle is likely formed. From here, the π-allyl species observed can be furnished by a number of transformations. The pathway we favor involves a beta-hydride elimination that gives a Rh-hydride that can undergo sigma bond metathesis to cleave the N–O bond. After Rh-enolate isomerization and ligand substitutions, 4-4 is formed.

Overall, this is a redox-neutral process, so the Rh-center may remain Rh(III) at all times.

However, the Rh could undergo earlier oxidation (via cleavage of the N–O bond) or reduction (likely by deprotonation of a metal-hydride).

Ph Ph Ph O O O N N N Rh Migratory Rh Beta-Hydride Rh H CF3 H Cp* Insertion CF3 Elimination Cp* Cp*CF3

Sigma Bond Metathesis

Ph CF3 Cp*CF3 O Cp* O O H

Ph Rh Ph Rh Rh N Cl Chlorine NH Isomerization Substitution CF3 Cp*

Figure 4.3 Likely pathway for the formation of 4-4.

We first wanted to evaluate if 4-4 played a role in the cyclopropanation of unactivated alkenes. To test this, we subjected 4-1a and 4-2b to 5 mol% of 4-4 in the

- 61 - presence of CsOAc and TFE at room temperature. We found that cyclopropane 4-3ab is afforded in 9% yield, which is dramatically lower than the µ-dichloride precatalyst.

O Cp*CF3 π-allyl species can act as a catalyst Ph Rh Ph O (5 mol%) Cl Ph NPhth CsOAc (2 equiv.) O 4-1a 4-2b TFE, rt 4-3ab 9%

Figure 4.4 Subjection of 4-4 to cyclopropanation reaction conditions.

While we observed turnover with 4-4 as the catalyst in the cyclopropanation of

4-2a, we wanted to leverage the formation of a π-allyl species to furnish a new bond.

4.2 Overview of C–N Bond Formation from π-Allyl Species from Nitrenoid Precursors

Building on previous success in CpXIr(III)-catalyzed transformations,1 our group first reported the branched-selective allylic amination of terminal alkenes from dioxazolones. In the presence of LiOAc, Ag-salt, and Cp*Ir(III) catalyst, terminal alkenes undergo allylic C–H activation to afford h-3 Ir-π-allyl complexes. Importantly, the isolable π-allyl complexes can be converted to the desired allylic amide when subjected to dioxazolone.2 It is suggested that the Ir-π-allyl complex is oxidized by cleavage of the

N–O bond that affords a Ir-nitrene. The resulting Ir(V)-nitrene then undergoes fast reductive elimination and protodemetallation.

- 62 - O [Cp*IrCl2]2 (2.5 mol%) O H AgNTf2 (15 mol%) O HN R' O R LiOAc (2 equiv.) N R' DCE, 35 °C R

Cp* Cp* R nitrene R formation Ir O Ir N O N - CO2 O O R' R'

Figure 4.5 Ir(III)-catalyzed intermolecular branched-selective allylic amination of terminal alkenes.

Soon after, Glorius and coworkers expanded the scope to include internal alkenes with minimal changes to the reaction conditions.3

O [Cp*IrCl2]2 (2 mol%) O H AgSbF6 (10 mol%) O HN R' O R R AgOAc (10 mol%) N R' DCM, 40 °C R R

Figure 4.6 Intermolecular amination of internal alkenes.

Blakey and coworkers also reported on the Ir-catalyzed branched-selective allylic amination in a report the same year.4 Interestingly, they found that in the presence of catalytic CsOAc and Ag-salt in DCE at 40 °C, simply switching from an Ir to a Rh precatalyst diverted the outcome to afford linear-selective allylic amination of alkenes.

O (5 mol%) O (2.5 mol%) O [Cp*Rh(MeCN)3](SbF6)2 O [Cp*IrCl2]2 O AgSbF6 (15 mol%) N R' AgSbF6 (15 mol%) HN R' HN R' CsOAc (5 mol%) H CsOAc (5 mol%) R DCE, 40 °C DCE, 40 °C R R Linear Branched

Figure 4.7 Catalyst-dependent regioselective allylic amination of alkenes.

- 63 - We looked to these previous successes of our group’s and others to provide new reactivity for the Rh-π-allyl complex 4-4.

4.3 Envisioned 3-component Reaction

Naturally, the idea we gravitated towards was subjecting a dioxazolone to the conditions established for the synthesis of 4-4. We would expect to see a number of regioisomers, with 4-6, the branched-selective terminal alkene, dominating (drawn below).

R

N O (5 mol%) O CF3 O O [Cp*CF3RhCl ] Cp* H R O 2 2 O N R NPhth R R Ph Rh KOPiv (2 equiv.) X 4-5 O 4-1 4-2 TFE, rt R R 4-6

Figure 4.8 Proposed Rh(III)-catalyzed 3-component 1,1-carboamination of N-enoxyphthalimides.

From a mechanistic standpoint, what we envisioned was a merger between the cyclopropanation chemistry and the allylic amination chemistry. We believe the formation of intermediate III is the same as previously described. At this point, insertion of 4-2 would afford Rhodacycle IV and most likely undergo beta-hydride elimination that gives a Rh-hydride diene complex. Intermediate V then affords π-allyl complex VI with dioxazolone bound. After oxidation, Rh-nitrene, intermediate VII, undergoes facile reductive elimination to afford 4-6 after protodemetallation turns over the catalyst.

- 64 - I O

F3C O O NPhth KOPiv O O H NH II N R R TFE O R CF3 4-6 O 4-1 R R 4-2 Rh PivO O PivOH PivOH R O t-Bu O CMD Reductive Elimination Cp F3C O KOPiv O O Ph Rh III CF3 N N Cp [Cp* RhCl2]2 O R Rh R O R VII

R Nitrene Migratory Formation Insertion O O Cp F C O VI 3 Ph Rh O N O Cp R O IV N O O Rh Beta-Hydride π-Allyl R Elimination O Formation R F3C O HNPhth R O TFE Cp V N O O Rh N H O O R R 4-5 R

Figure 4.9 Envisioned mechanism of 1,1-carboamination of N-enoxyphthalimides.

- 65 - 4.4 Attempts at 3-component 1,1-Carboamination

Initially, we subjected 4-1a under ethylene atmosphere to 4-5a in the presence of

Ag salt and Rh(III) catalysts. While none of the entries discussed provide the desired carboamination product, the consumption of 4-1a was measured in each case in hopes of pushing the reactivity forward. With Cp* and Cp*CF3 and catalytic amounts of base, 4-

1a remains untouched. However, when stoichiometric amount of base are used as in

Figure 4.2, degradation of 4-1a is observed. Furthermore, removing the Ag additive causes almost complete consumption of 4-1a with either precatalyst.

(10 mol%) [RhIII] O O Additive (50 mol%) H Ph O NPhth O NAc O Ph CsOAc (X equiv.) N Me TFE, rt 4-1a 4-2a 4-5a 0%

Entry [Rh] precatalyst Base Equiv. Additive 4-1a Remaining

A [Cp*RhCl2]2 0.2 AgSbF6 100%

CF3 B [Cp* RhCl2]2 0.2 AgSbF6 100%

C [Cp*RhCl2]2 2 AgSbF6 26%

CF3 D [Cp* RhCl2]2 2 AgSbF6 56%

E [Cp*RhCl2]2 2 none 10%

CF3 F [Cp* RhCl2]2 2 none 12%

Scheme 4.1 Initial reaction screening toward 1,1-carboaminaiton.

- 66 - Next, we briefly screened other nitrenoid precursors. However, seeing no amination products we chose to push forward using dioxazolones as we thought these could be an easier oxidation than others we tried.

(5 mol%) [Cp*CF3RhCl ] 2 2 O AgSbF6 (50 mol%) Ph O N NPhth N Ph CsOAc (2 equiv.) Nitrenoid TFE, rt Source 0%

O N Me OPiv OPiv BocN Ts N Ts N3 Me H H Me O

Scheme 4.2 Screen of nitrenoid precursors.

Facing a collection of results that showed catalysis was certainly not happening, we turned to stoichiometric studies to provide some answers.

4.5 Stoichiometric Studies

Typically, when prospecting for new reactivity in the realm of Rh(III)-catalyzed

C–H functionalization, we begin using the parent Cp* ligand. While consumption of 4-

1a is observed under both Rh(III) precatalysts, π-allyl complex formation is not observed

with [Cp*RhCl2]2 as the precatalyst. This result indicates that Cp* is not the correct ligand to initiate catalysis for this transformation.

- 67 - (1 equiv.) Ph O [Cp*RhCl2]2 O NPhth KOPiv (2 equiv.) Ph Rh TFE, rt Cl 4-1a 4-2a (5 equiv.) (1 atm) 0%

Figure 4.10 Attempted π-allyl complex synthesis with Cp* as a ligand.

Additionally, 4-4 was subjected to 4-5a in the presence of KOPiv in TFE at room temperature where neither branched nor linear products are observed. This tells us that the reaction conditions optimal for the synthesis of 4-4 are not conducive to allylic C–N bond formation events. Furthermore, subjecting 4-4 to 4-5a in the presence of 2 equivalents of a Ag salt in DCE at 40 °C–reaction conditions similar to the allylic amination in Figure 4.7–similarly results in no desired product observation. This further demonstrates that catalyst selection is even more important. While Cp*CF3 enables formation of 4-4, this ligand is not suitable for the C–N bond forming event.

- 68 - 4-5a O O Me O CF3 O O O N (2 equiv.) H NAc Ph Ph H NAc Ph Rh KOPiv (2 equiv.) Cl TFE, rt 4-4 0% 4-5a O O Me O CF3 O O O N (2 equiv.) H NAc Ph Ph H Ph Rh NAc AgSbF6 (2 equiv.) Cl DCE, 40 °C 4-4 0%

Figure 4.11 Attempts at C–N bond formation from π-allyl precursors.

From these stoichiometric studies, clearly π-allyl complex 4-4 does not provide the desired amination reaction as other unactivated alkenes provide. As of now, we believe it due predominately to electronics of the catalyst. From a follow-up report on allylic amination of nearly identical C–H bonds, the amination occurs at the more electron-rich carbon. The electron-deficient substituent resulting from employing 4-1 as starting material imparts a large electronic effect on the substrate. Furthermore, the Cp ligand probably needs to be electron deficient to afford the Rh-π-allyl complex. However, we believe that for Rh(III) species to undergo 2e- oxidation, the metal center would prefer to be as electron-rich as possible. This step should favor electron-rich Cp ligands, as demonstrated in Ir chemistry. This means that these potential 2 key steps lay at odds with one-another

- 69 - 2 Key Steps A) Formation of π-allyl species: Likely favored by electron-deficient Cp

R

O R Ph O RhIII NPhth π-allyl Ph Rh formation X

B) Formation of metal nitrene: Likely favored by electron-rich Cp

O R O R nitrene Ph formation Ph Rh O Rh N O - CO2 N O O R' R'

Figure 4.12 Potential catalyst incompatibility of key steps involved in 1,1-carboamination.

4.6 Summary

We have demonstrated that N-enoxyphthalimides, in the presence of

CF3 [Cp* RhCl2]2 complex under ethylene atmosphere, undergo efficient synthesis of a Rh-

π-allyl complex. Based on previous success centered around the design of π-allyl intermediates, we envisioned the construction of C–N bond would occur when subjected to a nitrenoid precursor. Attempts to catalyze a 1,1-carboamination reaction were made with a variety of conditions in the presence of different Rh precatalysts. From stoichiometric studies, we can conclude that the choice of catalyst is of utmost priority to unlock new reactivity.

- 70 - 4.7 References

(1) a) Lei, H.; Conway, J. H.; Cook, C. C.; Rovis, T. J. Am. Chem. Soc. 2019, 141, 11864.

b) Conway, J. H.; Rovis, T. J. Am. Chem. Soc. 2018, 140, 135. c) Romanov-

Michailidis, F.; Ravetz, B. D.; Paley, D. W.; Rovis, T. J. Am. Chem. Soc. 2018, 140,

5370. d) Lei, H.; Rovis, T. Nat. Chem. 2020, 12, 725.

(2) Lei, H.; Rovis, T. J. Am. Chem. Soc. 2019, 141, 2268.

(3) Knecht, T.; Mondal, S.; Ye, J.-H; Das, M.; Glorius, F. Angew. Chem. Int. Ed.

2019, 58, 7117.

(4) Burman, J. S.; Harris, R. J.; Farr, C. M. B.; Bacsa, J.; Blakey, S. ACS

Catalysis 2019, 9, 5474

- 71 - – Chapter Five –

Rh(III)-catalyzed 1,2-Carboamination of Alkenes via sp3 C–H Activation

5.1 Introduction to 1,2-Carboamination

In 2015, our group reported that under Rh(III) catalysis, 1,2-disubtituted alkenes undergo syn-1,2-carboamination using N-enoxyphthalimides.1 Notably, the phthalimide handle is incorporated in the product acting as a traceless directing group for C–H activation as well as an internal oxidant, making this an incredibly efficient process. This is achieved by modifying the Cp ligand on Rh and using methanol as solvent, where N- enoxyphthalimides–previously known to facilitate cyclopropanation chemistry– experience a chemoselective transformation.

(SbF ) I) t-Bu 6 2

Rh NCMe MeCN (5 mol%) NCMe Ph O E 1-AdCO2Cs (1 eq.) O N O MeOH, rt O Ph N E II) Toluene, 60 °C E O E O

Figure 5.1 Rh(III)-catalyzed syn-1,2-carboamination of fumarate-type alkenes.

Mechanistically, methanol is proposed to open the phthalimide ring revealing a bidentate directing group. After C–H activation, fumarate type alkenes undergo migratory insertion that give a 7-membered rhodacycle. From here, C–N bond formation

- 72 - is proposed via a reductive pathway that yields a Rh(I) complex that is turned over by oxidative addition of the N–O bond. Alternatively, C–N bond formation could occur through an oxidative pathway via nitrene formation followed by reductive elimination.

Removal of methanol and heating in toluene results in phthalimide ring closure to furnish the desired carboamination product.

- 73 - O O N O N Ar Ar O E O O E

+ MeOH Toluene - MeOH ∆

t-Bu O [Cp* Rh(NCMe)3](SbF6)2 OMe H N CsO2CR O Ar O HN O O Ar E R = t-Bu OMe O E O R Rh O RCO2H O2CR R t-Bu E O O O E H Rh N O OMe Rh O N t-Bu Ar O O E O E Ar E OMe t-Bu OMe Rh O E N O RCO2H Ar O E t-Bu t-Bu E E Oxidative O E Rh O Nitrene N N Formation Rh O O Ar O Ar O t-Bu OMe MeO E E OMe Rh O Reductive N Elimination O O Ar

Figure 5.2 Proposed mechanism of 1,2-carboamination of alkenes from N-enoxyphthalimides.

- 74 - Notably, this reaction has recently been rendered enatioselective by Cramer and coworker using N-enoxysuccinimides.2 1,2-carboamination of electron-rich alkenes using N-enoxyphthalimides has also been reported under photoredox catalysis.3

5.2 Substrates Beyond N-enoxyphthalimides

While N-enoxyphthalimides constitute valuable starting materials for the construction of C–C and C–N bonds, they come with a large downside of heavy pre- functionalization. Anderson and coworkers first reported their synthesis over 4 steps from styrenes.4 Recently, Cramer and coworker disclosed a concise 1-step alternative to the synthesis of N-enoxyimides from terminal alkynes under Au catalysis.5 Importantly, this pathway included the ability to produce alkyl substituted N-enoxyimides.

- 75 - - Traditional synthesis of N-enoxyphthalimides 4 Steps HO Ar NPhth Ar O NPhth

- Cramer’s Au-catalyzed one-step synthesis O O HO cat. [Au] R O Ar N N DCE, 80 °C O O

Viable alternatives to N-enoxyphthlimides - N–O bond internal oxidant: N-acetoxyamines

O OH O O PG HO PG N N R R H

- N–N bond internal oxidant: N-iminoamines

O N PG H N PG N 2 N R R H

Figure 5.3 N-enoxyphthalimide synthesis and potential alternatives.

As we began to ponder alternatives to N-enoxyphthalimides, three factors need to be considered. Alternatives must have: 1) a nitrogen directing group, 2) a nitrogen- heteroatom bond as an internal oxidant, and 3) simple starting materials and easy synthetic routes. Two candidates emerged as viable starting points: N-acetoxyamines, that come from esterification of carboxylic acids, and N-iminoamines, that are the product of condensation between ketone/aldehydes and protected hydrazines.

- 76 - 5.3 Envisioned Mechanism from N-acetoxyamines

Beginning our studies around N-acetoxyamine 5-1, we believe under Rh(III)- catalysis the nitrogen could direct the Rh to activate the sp3 C–H bond alpha to the carbonyl, also taking advantage of the lowered pKa of the bond. If C–H bond activation occurs, rhodacycle II may insert an alkene 5-2 that gives 7-membered rhodacycle III. As proposed previously, the C–N bond may be furnished via an oxidative or reductive mechanism, where both pathways meet at intermediate V. Protodemetallation would then turn over the catalyst and give desired carboxylic acid 5-3.

O N PG HO O H O H NPG 5-1 5-3 R R E Rh 5-2 E O OAc O CMD I Proto- 2 AcOH AcOH R demetallation Cp* O NPG V Oxidative Rh O Rh O Addition O Cp* Cp* N PG II R E Rh IV’ R E O O NPG

R E Migratory Reductive Elimination Insertion Reductive Elimination Reductive Cp* Pathway IV O NPG O O Rh N PG O Rh Cp* Nitrene R E R E Formation III Oxidative Pathway

Figure 5.4 Predicted pathways for 1,2-carboamination of alkenes from N-acetoxyamines.

- 77 - 5.4 Carboamination of Alkenes from N-acetoxyphthalimides

We began our studies using N-acetoxyphthalimide 5-1a with alkene 5-2a in the presence of Cp*Rh(III)-precatalyst, KOAc in methanol at varying temperatures. We were pleased to find MeOH is capable of phthalimide ring opening in each case. At the time, we believed we were seeing the formation of 5-3aa in 14% yield (entries A-C). Buffering the system with 1 equiv. of acetic acid caused the yield to decrease to 7% (entry D).

Varying base between catalytic (0.2 equiv.) and super-stoichiometric (2.5 equiv.) also show slight depression in yield of 5-3aa (entries E and F).

O (5 mol%) OMe [Cp*RhCl2]2 O N CO2Me HO O O O KOAc (X equiv.) HN O Additive (1 equiv.) Me O MeOH, temp. CO2Me

5-1a 5-2a proposed 5-3aa

Entry Base equiv. Temp Additive 5-3aa yield

A 1 rt none trace

B 1 40 °C none 14%

C 1 65 °C none 7%

D 1 40 °C AcOH 8%

E 0.2 40 °C none 10%

F 2.5 40 °C none 7%

Scheme 5.1 Carboamination screens in methanol.

- 78 - After a brief solvent screen, we were surprised to see that TFE was also leading to small amounts of 5-3aa (entry G) while other solvents were incapable of activating 5-

1a for functionalization (entries H-J). Similar to the cyclopropanation reaction conditions, super-stoichiometric amounts of KOAc showed an increase in yield to 18%

(entry K). Furthermore, Ag salt additive to render cationic Rh-species saw 5-3aa rise to

24% yield.

O (5 mol%) R [Cp*RhCl2]2 O N CO2Me HO O O O KOAc (X equiv.) HN O Additive (20 mol%) Me O Solvent, 40 °C CO2Me

5-1a 5-2a proposed 5-3aa

Entry Base equiv. Solvent Additive 5-3aa yield

G 1 TFE none 7%

H 1 DCE none 0%

I 1 THF none 0%

J 1 HFIP none 0%

K 2.5 TFE none 18%

L 2.5 TFE AgSbF6 24%

Scheme 5.2 Solvent screen leading to TFE conditions.

At this moment in optimizations, we judged the formation of 5-3aa on a doublet of doublet of doublet signal in the 1H-NMR from d 4.43-4.46. Unfortunately, upon

- 79 - attempted isolation of the acid, we found the formation of 5-4aa in its place. While this is a carboamination, it is selective for the sp2 C–H functionalization over the desired sp3

C–H bond functionalization.

OR

HO O O HN O H CO Me H H 2 ddd

F3C CF3 (5 mol%) O NPhth O O O [Cp*RhCl2]2 O O CO2Me HO O O Me KOAc (2 equiv.) HN O NH AgSbF6 (1 equiv.) TFE, 40 °C CO2Me CO2Me 5-1a 5-2a 5-3aa 5-4aa 0% 23% isolated

Figure 5.5 Diagnostic 1H-NMR signal and isolation of undesired byproduct.

- 80 - 5.5 Future Considerations Concerning sp3 C–H Functionalization of N- acetoxyphthalimides

We believe the phthalimide ring is being opened by alcoholic solvent and coordinating the Rh-catalyst with acetate ligand bound. From here, the catalyst discriminates between activating sp2 or sp3 C–H bonds. We believe that activation of the sp2 C–h bond, while possessing a higher pKa, supplies a more stable rhodacycle.

Concerning future studies, selection of a Cp ligand may be crucial in order to provide the desired sp3 C–H functionalized products.

RO O (sp2) C–H O bond activation N O Higher pKa Rh O Stable intermediate O Me Me RO HO O O O O N Rh H H O RO O O Me O

N O O Lower pKa Unstable intermediate 3 Rh (sp ) C–H O bond activation OH Me

Figure 5.6 Proposed divergent C–H functionalization.

- 81 - 5.6 Activation of N-iminophthalimides

We next shifted our focus on the functionalization of N-iminoamines. Similar to

5-1a, 5-5a was subjected to alkene 5-2a in the presence of a Cp*Rh(III)-precatalyst with base and methanol at reflux. We predicted that using the N–N bond as an internal oxidant could result in competing nitrogen sources for C–N bond formation. If the imine nitrogen is functionalized, cyclic carboamination would predominate, as opposed to acyclic carboamination by functionalization of the phthalimide nitrogen. Unfortunately, we did not see any desired product formation, but complete consumption of 5-5a.

Cyclic Acyclic HN

(5 mol%) Me HN CO Me [Cp*RhCl2]2 2 N N CO2Me AgOAc (2 equiv.) O NPhth CO Me MeOH, 65 °C 2 O

OMe 5-5a 5-2a 5-6aa 5-7aa Not Observed

Figure 5.7 Attempted carboamination of alkenes with N-iminophthalimides.

Because 5-5a was fully consumed, we decided to investigate the initial C–H

activation using stoichiometric amounts of group 9 [Cp*MCl2]2 complexes. Begininng with cobalt, no desired metallacycle was observed for most likely 1 of 2 reasons–either it does not provide the desired C–H activation, or it does activate the C–H bond but is too unstable to isolate. Using rhodium, metallacycle 5-8ab is formed in 73% yield.

Gratifyingly, iridium also provides metallacycle 5-8ac in moderate yield.

- 82 -

Me O (0.5 equiv.) OMe [Cp*MCl ] O N 2 2 N M AgOAc (2 equiv.) N MeOH, 65 °C N O (2 equiv.) O 5-5a 5-8aa Co = 0% 5-8ab Rh = 73% + MeOH 5-8ac Ir = 61% Ring Opening

CMD Me OMe OMe O Coordination AcO O N NH H M N N O O

Figure 5.8 Isolation of metallacycles.

5.7 Future Directions for sp3 C–H Activation N-iminophthalimides

With C–H activation experiments giving positive results, we now look to the future toward making this reactivity catalytic. Yu and coworkers recently reported using

Boc-hydrazones in combination with internal alkynes under Rh(III)-catalysis the synthesis of 2,3,5-substituted pyrroles.6 Importantly, the addition of AcOH provides a tautomerization from imine to enamine that sets up an sp2 C–H activation. After migratory insertion of the alkyne and proposed metallacycle contraction, the C–N bond

- 83 - is formed by reductive elimination. Cleavage of the N–N bond after protonation turns over the catalyst.

(2.5 mol%) [Cp*RhCl2]2 Ar Me R Na CO (25 mol%) 2 3 R Ar H HN N NBoc R AcOH (3 equiv.) MeCN, 120 °C R

R R R Ar H Rh Ar Rh HN NBoc N HN N NBoc Boc R H Ar

Figure 5.9 Rh(III)-catalyzed pyrrole synthesis from Boc-hydrazones and alkynes.

While this clearly provides a concise synthesis of substituted pyrroles, forcing conditions are still required. Potentially, the desired carboamination products could be observed with the addition of acid to our systems. Furthermore, other metals could provide a forward pathway for alkenes to render saturated N-heterocycles.

R HN R cat. R [Cp*MCl2]2 HN E E AgOAc N N O NPhth AcOH E MeOH, 65 °C O OMe 5-5 5-2 Acyclic Cyclic

Figure 5.10 Proposed cyclic and acyclic carboamination of N-iminophthalimides.

- 84 - 5.8 Summary

Building on previous 1,2 carboamination success using N-enoxypthalimides, we investigated two viable alternatives that simplify pre-functionalization and take on the additional challenge of activating sp3 C–H bonds. Using N-acetoxyphthlimides, sp2 C–H bond activation predominates despite higher activation barriers. Alternative investigations with directing groups without competing sp2 C–H bonds are underway.

Finally, N-iminophthalimides show productive pathways toward sp3 C–H bond activation. Isolation of Rh and Ir metallacycles show potential in furnishing new C–X bonds. Currently, stoichiometric studies are underway in an effort to push these substrates toward catalysis.

- 85 - 5.9 References

(1) Piou, T; Rovis, T. Nature 2015, 527, 86.

(2) Duchemin, C.; Cramer, N. Angew. Chem. Int. Ed. 2020, 59, 14129.

(3) Zhang, Y.; Liu, H.; Tang, L.; Tang, H.-J.; Wang, L.; Zhu, C.; Feng, C. J. Am. Chem.

Soc. 2018, 140, 10695.

(4) Patil, A. S.; Mo, D.-L.; Wang, H.-Y.; Mueller, D. S.; Anderson, L. A. Angew. Chem.

Int. Ed. 2012, 51, 7799.

(5) Duchemin, C.; Cramer, N. Org. Chem. Front., 2019, 6, 209.

(6) Chan, C.-M.; Zhang, Z.; Yu, W.-Y. Adv. Synth. Catal. 2016, 358, 4067.

- 86 - – Appendix A –

Supporting Information for Chapter Two

- 87 - Rh(III)-Catalyzed Cyclopropanation of Unactivated Olefins Initiated by C–H Activation

Supporting Information

Erik J. T. Phipps, Tiffany Piou, and Tomislav Rovis*

Table of Contents

A1.1 General Methods

A1.2 Synthesis of Starting Materials

A1.3 General Procedure for the Cyclopropanation Reaction and Characterization of Products

A1.4 Mechanistic Experiments

A1.5 Spectra

A1.6 References

- 88 - A1.1 General Methods

All reactions were carried out in oven-dried glassware with magnetic stirring. ACS grade

TFE and reagents were purchased from TCI, Strem, Alfa Aesar, and Sigma-Aldrich and were used without further purification. Dichloromethane, tetrahydrofuran, diethyl ether were degassed with argon and passed through two columns of neutral alumina. Column chromatography was performed on SiliCycle® SilicaFlash® P60, 40-63 µm 60 Å and in general were run using flash techniques.11 Thin layer chromatography was performed on SiliCycle® 250 µm 60 Å plates. Visualization was accomplished with UV light (254 nm). 1H, 19F, and 13C NMR spectra were collected at ambient temperature in CDCl3 on

Bruker 300 MHz, 400 MHz, or 500 MHz spectrometers. Chemical shifts are expressed as parts per million (δ, ppm) and are referenced to the residual solvent peak of chloroform (1H = 7.26 ppm; 13C = 77.2 ppm). Scalar coupling constants (J) are quoted in Hz. Multiplicity is reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m= multiplet). Mass spectra were obtained on a Waters Acquity PDA UPLC/MS

(LRMS). Infrared (IR) spectra were obtained with neat samples on a Bruker Tensor 27

FT-IR spectrometer with OPUS software. Typically, the experiment consisted measuring the transmission in 8 scans in the region from 4000 to 400 cm-1.

- 89 - A1.2 Synthesis of Starting Materials

CF3 2, 3 Synthesis of [Cp* RhCl2]2 Catalyst

Synthesis of 1,2,3,4-tetramethyl-5-(trifluoromethyl)cyclopenta-1,3-diene (+ isomers)

CF3 F C OH 0 3 Me Br O Li wire Me Me MeSO3H Me Me Me F3C OEt Et O, 0 to -40 ˚C DCM, 0 ˚C 2 Me Me Me Me + isomers Figure 1.

This procedure was performed according to literature precedent.

CF3 Synthesis of [Cp* RhCl2]2

CF3

Me Me MeOH, ∆ Cl Cl CF RhCl3 • 3 H2O F C Rh Rh 3 3 Cl Cl Me Me + isomers

Figure 2.

This procedure was performed according to literature precedent.

- 90 - Synthesis of N-enoxyphthalimides

Method A4 (1a-1i)

Ar Br Ar Br2 K2CO3 Ar Br

DCM, 0°C Br MeOH:THF (1:1)

t-BuLi B(O-iPr)3 Et2O -78 °C to rt

HO–NPhth Cu(OAc)2 • H2O Ar O Na2SO4 Ar B(OH) NPhth 2 pyridine 1,2-DCE O2, rt

Figure 3.

This procedure was performed according to literature precedent.

Method B5 (1j)

(5 mol%) [PPh3AuTFA] O HO Bn NPhth Bn NPhth 1,2-DCE (0.2M) 90 °C

Figure 4.

This procedure was performed according to literature precedent.

- 91 - Synthesis of alkene coupling partners6 (2e-2i)

Ph3PCH3Br O n-BuLi R R R R Et2O, 0 °C to rt

Figure 5

This procedure was performed according to literature precedent.7

N N Ts Boc Ph

2e 2f 2g 2h 2i

- 92 - A1.3 General Procedure for the Cyclopropanation Reaction and Characterization of Products

(5 mol%) [Cp*CF3RhCl ] O R O R 2 2 R NPhth R R CsOAc (2 equiv.) R TFE (0.2M), rt

Figure 6.

CF3 N-enoxyphthalimide (0.1 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.005 mmol, 3.7 mg), and CsOAc (2 equiv., 0.2 mmol, 38.5 mg) were weighed in a 1-dram vial with a magnetic stirbar. TFE (0.2 M, 500 µL) was added followed by alkene (1.2 equiv., 0.12 mmol). The vial was sealed with a screw-cap and stirred at room temperature for 12 hours. Upon completion judged by TLC, the crude solution was diluted with EtOAc and partitioned with the addition of DI water. The aqueous layer was extracted three times with EtOAc

® and the combined organic extracts were filtered through a pad of celite and Na2SO4 then concentrated. The crude residue was purified by flash chromatography (Hexane:EtOAc,

19:1) to afford the cyclopropane product.

Reaction Optimization

- 93 - (5 mol%) O Me [Cp*CF3RhCl ] Me Ph O 2 2 NPhth Ph n-Bu n-Bu Base (2 equiv.) (1.2 equiv.) TFE (0.2M), rt 1:1 d.r. Entry Base Yield

1 KOPiv 59%

2 KOAc 76%

3 1-AdCO2K 66%

4 LiOAc 64%

5 NaOAc 73%

6 CsOAc 82%

We first examined carboxylate bases beginning with the standard conditions from reference 3 using 2-methylenhexane to afford the two diastereomers of cyclopropane product. When KOAc proved to be the best we moved on to testing different alkali metal cations. We decided to move forward using CsOAc as our base.

- 94 - (5 mol%) O R [Cp*CF3RhCl ] R Ph O 2 2 NPhth Ph R' R' CsOAc (2 equiv.) (1.2 equiv.) TFE (0.2M), rt 1:1 d.r.

Alkene Product NMR Yield d.r.

O Me Me 82% 1:1 Ph n-Bu n-Bu

O Me Me 17% 1:1 Ph i-Pr i-Pr

H O n-Oct 58% 1:1 Ph n-Oct

O 99% - - Ph

Additionally, we surveyed different alkenes as potential coupling partners. From our previous optimization screen, we observed asymmetric 1,1-disubstituted olefins are not selective for one diastereomer but the yield drastically drops when the steric load is increased from 2-methylenhexane to 2,3-dimethylbut-1-ene. Using 1-decene, we observed moderate yield for the cyclopropane; however, the reaction remained

- 95 - unselective. Finally, we considered symmetrical 1,1-disubstituted alkenes where we observed methylencyclohexane gives 99% yield. While these products do not provide access to a single diastereomer, we considered this method could improve the synthesis of interesting spirocyclic species that can be difficult to access.

- 96 - Characterization of Products

3aa (2,2-diethylcyclopropyl)(phenyl)methanone

O Et Ph Et

Chemical Formula: C14H18O Exact Mass: 202.14

Yield = 40% Colorless oil. Rf = 0.74 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.99 (dt, J = 7.2, 1.3 Hz, 2H), 7.59 – 7.51 (m, 1H),

7.46 (t, J = 7.7 Hz, 2H), 2.51 (dd, J = 7.4, 5.6 Hz, 1H), 1.72 (dq, J = 14.7, 7.4 Hz, 1H),

1.56 – 1.37 (m, 4H), 1.02 (t, J = 7.4 Hz, 3H), 0.96 (dd, J = 7.5, 4.0 Hz, 1H), 0.77 (t, J =

7.4 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 198.7, 139.2, 132.5, 128.6, 128.2, 38.3, 32.1, 29.6, 21.3,

21.1, 11.3, 10.8.

IR(neat): 2963, 2930, 1666, 1448, 1396, 1215, 1024, 982, 712, 689 cm-1

LRMS m/z (ESI APCI): calculated for C14H18O [M+H] 203.1, found 203.1.

- 97 - 3ab 1-benzoylspiro[2.3]hexane-5,5-dicarbonitrile

O CN CN Ph

Chemical Formula: C15H12N2O Exact Mass: 236.09

Yield = 56% Colorless oil. Rf = 0.39 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.98 (dt, J = 8.5, 1.5 Hz, 2H), 7.60 (td, J = 7.3,

1.5 Hz, 1H), 7.50 (td, J = 7.7, 1.6 Hz, 2H), 3.15 (dtdd, J = 9.6, 8.1, 6.6, 1.6 Hz, 1H),

2.76 (ddd, J = 7.6, 5.6, 1.4 Hz, 1H), 2.69 (qd, J = 6.8, 5.8, 1.5 Hz, 2H), 2.54 (ddd, J =

13.0, 9.5, 1.5 Hz, 1H), 1.61 (td, J = 5.3, 1.5 Hz, 1H), 1.33 (ddd, J = 8.4, 4.8, 1.5 Hz,

1H).

13 C NMR (126 MHz, CDCl3) δ 197.6, 138.2, 133.3, 128.9, 128.1, 122.6, 35.2, 32.2, 31.5,

29.1, 22.3, 18.1.

IR(neat): 2992, 2942, 2236, 1661, 1449, 1390, 1335, 1230, 1012, 715, 689 cm-1

LRMS m/z (ESI APCI): calculated for C15H12N2O [M+H] 237.1, found 237.1.

- 98 - 3ac phenyl(spiro[2.4]heptan-1-yl)methanone

O

Ph

Chemical Formula: C14H16O Exact Mass: 200.12

Yield = 87% Colorless oil. Rf = 0.78 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.90 (m, 2H), 7.59 – 7.51 (m, 1H), 7.51 –

7.42 (m, 2H), 2.69 (dd, J = 7.6, 5.5 Hz, 1H), 1.89 – 1.80 (m, 1H), 1.79 – 1.50 (m, 8H),

1.19 (dd, J = 7.7, 3.9 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 199.1, 139.1, 132.6, 128.6, 128.0, 38.8, 37.5, 32.6, 30.0,

26.3, 26.2, 22.1.

IR(neat): 2952, 2864, 1665, 1448, 1390, 1216, 1012, 715, 691 cm-1

LRMS m/z (ESI APCI): calculated for C14H16O [M+H] 201.1, found 201.1.

- 99 - 3ad phenyl(spiro[2.5]octan-1-yl)methanone

O

Ph

Chemical Formula: C15H18O Exact Mass: 214.14

Yield = 98% Colorless oil. Rf = 0.73 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.06 – 7.97 (m, 2H), 7.59 – 7.51 (m, 1H), 7.51 –

7.43 (m, 2H), 2.51 (dd, J = 7.3, 5.4 Hz, 1H), 1.70 – 1.39 (m, 10H), 1.19 (dt, J = 12.6,

6.1 Hz, 1H), 0.95 (dd, J = 7.4, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.4, 139.1, 132.5, 128.6, 128.2, 38.0, 35.6, 32.2, 28.48,

26.3, 26.2, 26.0, 21.5.

IR(neat): 2921, 2850, 1664, 1447, 1396, 1216, 980, 718, 689 cm-1

LRMS m/z (ESI APCI): calculated for C15H18O [M+H] 215.1, found 215.1.

- 100 - 3ae phenyl(spiro[2.6]nonan-1-yl)methanone

O

Ph

Chemical Formula: C16H20O Exact Mass: 228.15

Yield = 70% Colorless oil. Rf = 0.74 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.07 – 7.97 (m, 2H), 7.60 – 7.52 (m, 1H), 7.47

(dd, J = 8.3, 6.9 Hz, 2H), 2.54 (dd, J = 7.5, 5.7 Hz, 1H), 1.80 – 1.66 (m, 4H), 1.58 (tdd,

J = 14.0, 5.9, 3.9 Hz, 6H), 1.49 (ddt, J = 10.9, 7.4, 5.5 Hz, 2H), 1.32 (dddd, J = 15.9,

9.5, 7.4, 3.6 Hz, 1H), 0.99 (dd, J = 7.5, 3.9 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.7, 139.2, 132.6, 128.6, 128.2, 40.8, 37.1, 33.5, 30.53,

28.2, 28.1, 26.6, 26.5, 23.3.

IR(neat): 2920, 2852, 1665, 1448, 1395, 1217, 981, 710, 689 cm-1

LRMS m/z (ESI APCI): calculated for C16H20O [M+H] 229.2, found 229.2.

- 101 - 3af phenyl(spiro[2.7]decan-1-yl)methanone

O

Ph

Chemical Formula: C17H22O Exact Mass: 242.17

Yield = 53% Colorless oil. Rf = 0.69 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.04 – 7.92 (m, 2H), 7.58 – 7.52 (m, 1H), 7.47

(dd, J = 8.4, 6.9 Hz, 2H), 2.50 (dd, J = 7.5, 5.7 Hz, 1H), 1.92 (ddd, J = 14.4, 8.7, 2.8

Hz, 1H), 1.82 – 1.56 (m, 10H), 1.55 – 1.38 (m, 4H), 1.00 (dd, J = 7.5, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.7, 139.3, 132.6, 128.6, 128.2, 39.1, 36.6, 34.6, 27.9,

27.4, 26.9, 25.9, 25.6, 25.3, 23.3.

IR(neat): 2944, 2911, 1668, 1472, 1447, 1216, 1010, 945, 734, 702 cm-1

LRMS m/z (ESI APCI): calculated for C21H22O [M+H] 243.2, found 243.2.

- 102 - 3ag phenyl(6-tosyl-6-azaspiro[2.5]octan-1-yl)methanone

O NTs Ph

Chemical Formula: C21H23NO3S Exact Mass: 369.14

Yield = 72% White solid. Rf = 0.22 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.82 (dd, J = 8.3, 1.4 Hz, 2H), 7.61 – 7.56 (m,

2H), 7.54 – 7.49 (m, 1H), 7.40 – 7.33 (m, 2H), 7.27 – 7.24 (m, 2H), 3.14 (qdd, J = 11.4,

7.0, 4.6 Hz, 2H), 2.94 (ddd, J = 11.3, 7.2, 3.8 Hz, 1H), 2.76 (ddd, J = 11.7, 7.3, 3.7 Hz,

1H), 2.50 (dd, J = 7.6, 5.5 Hz, 1H), 2.42 (s, 3H), 1.73 (dtdd, J = 21.2, 17.2, 13.1, 8.8

Hz, 4H), 1.51 (dd, J = 5.4, 4.5 Hz, 1H), 0.95 (dd, J = 7.6, 4.4 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 197.5, 143.6, 138.5, 133.0, 132.8, 129.7, 128.7, 128.0,

127.8, 46.5, 46.1, 36.1, 31.7, 30.6, 27.5, 21.7, 20.3.

IR(neat): 2972, 2819, 1666, 1602, 1451, 1373, 1239, 1170, 890, 711, 688 cm-1

LRMS m/z (ESI APCI): calculated for C21H23 NO3S [M+H] 370.1, found 370.1.

- 103 - 3ah tert-butyl 1-benzoyl-6-azaspiro[2.5]octane-6-carboxylate

O NBoc Ph

Chemical Formula: C19H25NO3 Exact Mass: 315.18

Yield = 84% Colorless oil. Rf = 0.45 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.96 (m, 2H), 7.60 – 7.53 (m, 1H), 7.47

(dd, J = 8.3, 6.9 Hz, 2H), 3.61 – 3.49 (m, 2H), 3.37 (ddd, J = 13.1, 6.6, 4.2 Hz, 1H),

3.13 (ddd, J = 13.2, 7.0, 4.3 Hz, 1H), 2.62 (dd, J = 7.5, 5.4 Hz, 1H), 1.64 – 1.57 (m, 4H),

1.43 (s, 9H), 1.05 (dd, J = 7.5, 4.2 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 197.8, 155.0, 138.7, 134.5, 132.9, 128.8, 128.2, 123.8,

79.7, 77.4, 36.8, 33.0, 30.9, 28.6, 20.6.

IR(neat): 2975, 2818, 1666, 1419, 1365, 1238, 1166, 1120, 903, 720, 689 cm-1

LRMS m/z (ESI APCI): calculated for C19H25NO3 [M+H] 316.2, found 316.2.

- 104 - 3ai phenyl(6-phenylspiro[2.5]octan-1-yl)methanone

O Ph Ph

Chemical Formula: C21H22O Exact Mass: 290.17

Yield = 97% White solid. Rf = 0.58 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.94 (m, 2H), 7.61 – 7.54 (m, 1H), 7.53 –

7.46 (m, 2H), 7.34 – 7.28 (m, 2H), 7.27 – 7.23 (m, 2H), 7.23 – 7.17 (m, 1H), 2.58 (dq,

J = 8.5, 5.6, 4.6 Hz, 2H), 2.25 (tdd, J = 12.9, 3.8, 1.7 Hz, 1H), 1.94 (ddt, J = 21.9, 12.7,

2.7 Hz, 2H), 1.77 – 1.56 (m, 4H), 1.48 (tdd, J = 12.9, 3.7, 1.5 Hz, 1H), 1.31 (dq, J =

13.0, 3.0 Hz, 1H), 0.99 (ddd, J = 7.4, 4.0, 1.6 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.2, 147.1, 139.1, 132.7, 128.7, 128.6, 128.2, 127.0,

126.2, 44.4, 40.3, 37.7, 33.6, 33.5, 32.4, 29.0, 20.4.

IR(neat): 2921, 2872, 1671, 1492, 1277, 1216, 970, 755, 698 cm-1

LRMS m/z (ESI APCI): calculated for C21H22O [M+H] 291.2, found 291.2.

- 105 - 3bd spiro[2.5]octan-1-yl(p-tolyl)methanone

O

Me

Chemical Formula: C16H20O Exact Mass: 228.15

Yield = 97% Colorless oil. Rf = 0.81 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H),

2.49 (dd, J = 7.3, 5.4 Hz, 1H), 2.42 (s, 3H), 1.73 – 1.54 (m, 4H), 1.47 (dddd, J = 28.0,

16.4, 9.6, 4.9 Hz, 6H), 1.17 (dt, J = 12.4, 6.1 Hz, 1H), 0.92 (dd, J = 7.3, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 197.9, 143.2, 136.7, 129.3, 128.3, 38.0, 35.2, 32.1, 28.5,

26.4, 26.2, 26.0, 21.8, 21.2.

IR(neat): 2923, 2854, 1663, 1410, 1217, 1155, 854, 806, 598 cm-1

LRMS m/z (ESI APCI): calculated for C16H20O [M+H] 229.2, found 229.2.

- 106 - 3cd (4-(tert-butyl)phenyl)(spiro[2.5]octan-1-yl)methanone

O

t-Bu

Chemical Formula: C19H26O Exact Mass: 270.20

Yield = 89% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.99 – 7.93 (m, 2H), 7.51 – 7.44 (m, 2H), 2.49

(dd, J = 7.4, 5.4 Hz, 1H), 1.70 – 1.39 (m, 10H), 1.35 (s, 9H), 1.21 (dd, J = 11.2, 5.8 Hz,

1H), 0.92 (dd, J = 7.4, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.0, 156.1, 136.6, 128.2, 125.6, 38.0, 35.2, 32.1, 31.3,

28.5, 26.4, 26.2, 26.1, 21.2.

IR(neat): 2903, 2868, 1662, 1409, 1223, 854, 808, 598 cm-1

LRMS m/z (ESI APCI): calculated for C19H26O [M+H] 271.2, found 271.2.

- 107 - 3dd (4-fluorophenyl)(spiro[2.5]octan-1-yl)methanone

O

F

Chemical Formula: C15H17FO Exact Mass: 232.13

Yield = 96% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.08 – 7.99 (m, 2H), 7.19 – 7.10 (m, 2H), 2.45

(dd, J = 7.4, 5.4 Hz, 1H), 1.69 – 1.56 (m, 4H), 1.54 – 1.41 (m, 6H), 1.15 (d, J = 15.6

Hz, 1H), 0.95 (dd, J = 7.3, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 196.7, 165.5 (d, J = 253.8 Hz), 135.5 (d, J = 3.0 Hz),

130.7 (d, J = 9.1 Hz), 115.7 (d, J = 21.6 Hz), 38.0, 35.7, 32.1, 28.5, 26.3, 26.2, 26.0,

21.5.

IR(neat): 2929, 2854, 1665, 1506, 1216, 1155, 854, 710, 598 cm-1

LRMS m/z (ESI APCI): calculated for C15H17FO [M+H] 233.1, found 233.1.

- 108 - 3ed spiro[2.5]octan-1-yl(m-tolyl)methanone

O

Me

Chemical Formula: C16H20O Exact Mass: 228.15

Yield = 75% Colorless oil. Rf = 0.84 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.84 – 7.79 (m, 2H), 7.36 (m, 1H), 7.35 (m, 1H),

2.50 (dd, J = 7.4, 5.5 Hz, 1H), 2.42 (s, 3H), 1.70 – 1.40 (m, 10H), 1.20 (dt, J = 12.1, 6.0

Hz, 1H), 0.93 (dd, J = 7.3, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.5, 139.2, 138.4, 133.3, 128.7, 128.5, 125.5, 38.0,

35.5, 32.2, 28.5, 26.3, 26.2, 26.0, 21.6, 21.5.

IR(neat): 2922, 2857, 1664, 1240, 1180, 755, 688 cm-1

LRMS m/z (ESI APCI): calculated for C16H20O [M+H] 229.2, found 229.2.

- 109 - 3fd (3-methoxyphenyl)(spiro[2.5]octan-1-yl)methanone

O

OMe

Chemical Formula: C16H20O2 Exact Mass: 244.15

Yield = 67% Colorless oil. Rf = 0.72 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.62 (dd, J = 7.7, 1.5 Hz, 1H), 7.52 (t, J = 2.0 Hz,

1H), 7.37 (t, J = 7.9 Hz, 1H), 7.09 (dd, J = 8.2, 2.6 Hz, 1H), 3.86 (s, 3H), 2.49 (dd, J =

7.3, 5.5 Hz, 1H), 1.70 – 1.40 (m, 8H), 1.19 (m, 1H), 0.94 (dd, J = 7.3, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.1, 159.9, 140.5, 129.6, 120.9, 118.9, 112.5, 55.6,

38.0, 35.7, 32.3, 28.5, 26.3, 26.1, 26.0, 21.6.

IR(neat): 2921, 2850, 1664, 1595, 1448, 1284, 1259, 1034, 870, 845, 762, 684 cm-1

LRMS m/z (ESI APCI): calculated for C16H20O2 [M+H] 245.2, found 245.2.

- 110 - 3gd (3-fluorophenyl)(spiro[2.5]octan-1-yl)methanone

O

F

Chemical Formula: C15H17FO Exact Mass: 232.13

Yield = 90% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.80 (dt, J = 7.8, 1.3 Hz, 1H), 7.67 (ddd, J = 9.6,

2.7, 1.6 Hz, 1H), 7.44 (td, J = 8.0, 5.5 Hz, 1H), 7.28 – 7.20 (m, 1H), 2.45 (dd, J = 7.4,

5.4 Hz, 1H), 1.70 – 1.39 (m, 10H), 1.17 (d, J = 9.8 Hz, 1H), 0.98 (dd, J = 7.3, 4.0 Hz,

1H).

13 C NMR (126 MHz, CDCl3) δ 197.0 (d, J = 2.1 Hz), 163.0 (d, J = 247.5 Hz), 141.2 (d,

J = 6.2 Hz), 130.3 (d, J = 7.7 Hz), 123.9 (d, J = 3.2 Hz), 119.5 (d, J = 21.6 Hz), 115.0

(d, J = 22.2 Hz), 38.0, 36.2, 32.3, 28.4, 26.3, 26.2, 26.1, 21.9.

IR(neat): 2929, 2854, 1667, 1511, 1410, 1214, 1111, 830, 757 cm-1

LRMS m/z (ESI APCI): calculated for C15H17FO [M+H] 233.1, found 233.1.

- 111 - 3hd (2-fluorophenyl)(spiro[2.5]octan-1-yl)methanone

O

F

Chemical Formula: C15H17FO Exact Mass: 232.13

Yield = 59% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.76 (td, J = 7.6, 1.9 Hz, 1H), 7.48 (tdd, J = 7.2,

4.9, 1.9 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.13 (dd, J = 10.9, 8.4 Hz, 1H), 2.48 (ddd, J

= 7.2, 5.5, 3.4 Hz, 1H), 1.54 (ddtd, J = 33.0, 28.4, 11.4, 10.3, 5.2 Hz, 10H), 1.32 – 1.21

(m, 1H), 0.95 (dd, J = 7.3, 3.9 Hz, 1H).

13C NMR (126 MHz, Chloroform-d) δ 197.0 (d, J = 3.2 Hz), 161.6 (d, J = 253.5 Hz),

133.8 (d, J = 8.7 Hz), 130.5 (d, J = 2.7 Hz), 128.3 (d, J = 13.1 Hz), 124.4 (d, J = 3.5

Hz), 116.7 (d, J = 23.5 Hz), 37.9, 36.9, 36.3, 36.3, 28.4, 26.3, 26.2, 25.8, 25.8, 22.6.

IR(neat): 2930, 2854, 1672, 1479, 1453, 1346, 1204, 1102, 829, 757 cm-1

LRMS m/z (ESI APCI): calculated for C15H17FO [M+H] 233.1, found 233.1.

- 112 - 3id naphthalen-2-yl(spiro[2.5]octan-1-yl)methanone

O

Chemical Formula: C19H20O Exact Mass: 264.15

Yield = 67% Colorless oil. Rf = 0.77 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 8.56 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 8.6, 1.8 Hz,

1H), 8.04 – 7.96 (m, 1H), 7.90 (dd, J = 10.1, 8.1 Hz, 2H), 7.57 (dddd, J = 18.9, 8.1, 6.8,

1.4 Hz, 2H), 2.67 (dd, J = 7.4, 5.4 Hz, 1H), 1.57 (tddd, J = 50.6, 21.1, 10.8, 5.2 Hz,

10H), 1.20 (dq, J = 11.9, 6.1, 5.0 Hz, 1H), 1.00 (dd, J = 7.3, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 198.1, 136.5, 135.5, 132.8, 129.7, 129.6, 128.4, 128.3,

127.9, 126.8, 124.4, 38.1, 35.7, 32.3, 28.6, 26.3, 26.2, 26.1, 21.6.

IR(neat): 2916, 2846, 1654, 1398, 1183, 1125, 1116, 808, 780 cm-1

LRMS m/z (ESI APCI): calculated for C19H20O [M+H] 265.2, found 265.2.

- 113 - 3jd 3-phenyl-1-(spiro[2.5]octan-1-yl)propan-1-one

O Bn

Chemical Formula: C17H22O Exact Mass: 242.17

Yield = 98% Colorless oil. Rf = 0.81 (4:1 hexanes: Ethyl Acetate).

1H NMR (500 MHz, Chloroform-d) δ 7.31 – 7.26 (m, 2H), 7.24 – 7.17 (m, 3H), 2.96 –

2.88 (m, 4H), 1.79 (dd, J = 7.4, 5.4 Hz, 1H), 1.58 – 1.38 (m, 9H), 1.28 (dd, J = 5.5, 3.9

Hz, 1H), 1.13 (p, J = 7.5 Hz, 1H), 0.80 (dd, J = 7.4, 4.0 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 207.7, 141.5, 128.6, 128.5, 126.2, 46.4, 37.9, 35.2, 34.7,

30.3, 28.1, 26.3, 26.2, 26.1, 22.1.

IR(neat): 2921, 2850, 1692, 1445, 1398, 1117, 1082, 748, 699 cm-1

LRMS m/z (ESI APCI): calculated for C17H22O [M+H] 243.2, found 243.2.

- 114 - A1.4 Mechanistic Experiments

(5 mol%) Ph O [Cp*CF3RhCl ] Ph O NPhth 2 2 NPhth

H H CsOAc (2 equiv.) H H TFE-d1 (0.2M), rt 0% D incorporation

Figure 7.

CF3 N-enoxyphthalimide 1a (0.1 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.005 mmol), and

CsOAc (2 equiv., 0.2 mmol) were weighed in a 1-dram vial with a magnetic stirbar. TFE-

d1 (0.2 M, 500 µL) was added. The vial was sealed with a screw-cap and stirred for 3 hours. Upon completion judged by TLC, the crude solution was diluted with EtOAc and partitioned with the addition of DI water. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were filtered through a pad of celite® and

Na2SO4 then concentrated. The crude residue was purified by flash chromatography

(Hexane:EtOAc, 19:1) to afford the starting material.

- 115 - (5 mol%) Ph O [Cp*CF3RhCl ] O NPhth 2 2 Ph H H CsOAc (2 equiv.) D/H TFE-d1 (0.2M), rt 85% yield 54% D incorporation

Figure 8.

CF3 N-enoxyphthalimide 1a (0.1 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.005 mmol), and

CsOAc (2 equiv., 0.2 mmol) were weighed in a 1-dram vial with a magnetic stirbar. TFE

(0.2 M, 500 µL) was added followed by addition of alkene 2d (1.2 equiv. 0.12 mmol).

The vial was sealed with a screw-cap and stirred for 3 hours. Upon completion judged by TLC, the crude solution was diluted with EtOAc and partitioned with the addition of

DI water. The aqueous layer was extracted three times with EtOAc and the combined

® organic extracts were filtered through a pad of celite and Na2SO4 then concentrated.

The crude residue was purified by flash chromatography (Hexane:EtOAc, 19:1) to afford cyclopropane 3ad’.

- 116 - O Ph O CsOAc( 2 equiv.) N Ph O CF3 TFE (0.2M), rt Me N O O O O

59% yield

Figure 9.

N-enoxyphthalimide 1a (0.1 mmol) and CsOAc (2 equiv., 0.2 mmol, 38.5 mg) were weighed in a 1-dram vial with a magnetic stirbar. TFE (0.2 M, 500 µL) was added and the vial was sealed with a screw-cap and stirred at room temperature for 12 hours. Upon completion judged by TLC, the crude solution was diluted with EtOAc and partitioned with the addition of DI water. The aqueous layer was extracted three times with EtOAc

® and the combined organic extracts were filtered through a pad of celite and Na2SO4 then concentrated. The crude residue was purified by flash chromatography (Hexane:EtOAc,

19:1) to afford dioxazoline 4 in 59% yield.

- 117 - 4 2,2,2-trifluoroethyl 2-(5-methyl-5-phenyl-1,4,2-dioxazol-3-yl)benzoate

Ph O CF3 Me N O O O

Chemical Formula: C18H14F3NO4 Exact Mass: 365.09

Yield = 59% Colorless oil. Rf = 0.60 (4:1 Hexanes: Ethyl Acetate)

1H NMR (500 MHz, Chloroform-d) δ 7.85 – 7.77 (m, 1H), 7.77 – 7.70 (m, 1H), 7.66 –

7.55 (m, 4H), 7.49 – 7.36 (m, 3H), 4.63 (dq, J = 12.6, 8.4 Hz, 1H), 4.49 (dq, J = 12.6,

8.4 Hz, 1H), 2.02 (s, 3H).

13 C NMR (126 MHz, CDCl3) δ 165.36, 157.63, 139.94, 132.19, 131.42, 130.27, 130.15,

129.84, 129.42, 128.63, 125.19, 123.14, 116.33, 61.34 (q, J = 36.9 Hz), 25.52.

IR(neat): 2975, 1746, 1494, 1292, 1163, 1123, 1097, 1010, 963, 698, 581 cm-1

LRMS m/z (ESI APCI): calculated for C18H14F3NO4 [M+H] 366.1, found 366.1.

- 118 - (5 mol%) CF3 [Cp* RhCl2]2 O Ph O CF3 Ph CsOAc (2 equiv.) Me O N O O TFE (0.2M), rt

2% yield

Figure 10.

CF3 Dioxazoline 4 (0.1 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.005 mmol), and CsOAc

(2 equiv., 0.2 mmol) were weighed in a 1-dram vial with a magnetic stirbar. TFE (0.2 M,

500 µL) was added followed by addition of alkene 2d (1.2 equiv. 0.12 mmol). The vial was sealed with a screw-cap and stirred for 3 hours. Upon completion judged by TLC, the crude solution was diluted with EtOAc and partitioned with the addition of DI water.

The aqueous layer was extracted three times with EtOAc and the combined organic

® extracts were filtered through a pad of celite and Na2SO4 then concentrated. The yield of 3ad was judged by the crude 1H-NMR to be 2%.

- 119 - Mechanistic hypothesis

F3C O Ph O CsOAc O O N O O TFE Ph O Ph CF N O 3 O N O H Me O

[Rh] cat. CsOAc R

R

O R Ph R

Figure 11.

Based on the experiment in figure 10, we conclude that the dioxazoline 4 does not contribute significantly to the cyclopropanation reaction and is instead an off-cycle intermediate.

- 120 - A1.5 NMR Spectra

- 121 - EJTP2323_A_pure.1.fid 3

l 19000 C

D 18000 C

0 9 9 8 8 4 2 7 7 6 4 6 2 1 1 0 4 3 1 0 9 2 3 2 0 7 6 6 8 7 5 17000 0 9 9 9 9 5 5 4 4 4 4 2 5 5 5 5 5 5 5 5 4 4 0 0 0 9 9 9 7 7 7 ......

8 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 16000

15000 O Me 14000 13000

Me 12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 8 8 0 8 8 0 3 7 2 4 1 1 1 0 1 0 1 1 ...... 2 1 2 1 1 4 3 1 3

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2323_A_pure.2.fid 3 l

C 10000 D C 7 2 5 6 2 . . . . . 2 3 1 6 3 1 3 8

8 9 2 8 8 ...... 9000 9 3 3 2 2 7 8 2 9 1 1 1 0 1 1 1 1 1 7 3 3 2 2 2 1 1

O Me 8000

Me 7000

6000

5000

4000

3000

2000

1000

0

-1000 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 122 - EJTP2322_A_pure_1stspot.1.fid 3

l 11000 C D C 10000 9 8 8 7 7 6 0 9 8 2 1 0 0 9 8 6 7 6 1 0 0 8 8 7 7 4 1 1 0 0 3 9 9 9 9 9 9 6 5 5 5 5 5 5 4 4 2 7 7 7 7 7 6 6 6 6 5 6 6 6 6 3 ...... 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 2 2 2 2 2 2 1 1 1 1 1 9000 N O 8000

N 7000

6000

5000

4000

3000

2000

1000

0 9 2 6 0 1 0 5 2 1 9 9 6 9 9 1 0 0 0 ...... 1 0 1 0 1 2 1 1 1 -1000 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2322_A_pure_1stspot.2.fid 3

l 9000 C

D 8500 C 6 2 2 9 1 6 ...... 2 2 2 5 1 3 1

7 8 3 8 8 2 ...... 8000 9 3 3 2 2 2 7 5 2 1 9 2 8

1 N 1 1 1 1 1 7 3 3 3 2 2 1 7500 O 7000 6500 N 6000

5500

5000

4500

4000

3500

3000

2500

2000

1500

1000

500

0

-500

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 123 - EJTP2322_B_pure.1.fid

3 28000 l C

D 26000 C

7 7 6 5 5 4 3 8 8 7 6 5 6 0 9 8 7 6 6 5 4 8 7 7 6 5 5 1 0 9 8 9 9 9 9 9 5 5 4 4 4 4 4 2 7 6 6 6 7 7 7 7 6 6 6 6 6 5 2 2 1 1

...... 24000 7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 O 22000

20000

18000

16000

14000

12000

10000

8000

6000

4000

2000

0 9 6 0 6 5 8 9 9 4 9 9 0 0 0 . .

. . . . . -2000 1 0 1 1 1 8 1

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2322_B_pure.2.fid 3 l 4500 C D C 1 1 6 6 0 . . . . . 2 8 5 6 0 3 2 1

9 9 2 8 8 ...... 4000 9 3 3 2 2 7 8 7 2 0 6 6 2

1 O 1 1 1 1 7 3 3 3 3 2 2 2

3500

3000

2500

2000

1500

1000

500

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 124 - EJTP2330_B_pure.1.fid 3 l 22000 C

D 21000 C

2 2 2 0 0 4 3 8 7 7 5 6 2 1 1 9 5 4 4 3 3 2 1 0 9 8 7 6 5 4 3 20000 0 0 0 0 0 5 5 4 4 4 4 2 5 5 5 4 6 6 5 5 5 5 5 5 4 4 4 9 9 9 9 ...... 19000 8 8 8 8 8 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 18000

O 17000

16000

15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 4 3 9 6 0 5 5 9 9 9 9 8 8 0 ...... 1 0 1 0 9 0 1 -2000

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2330_B_pure.2.fid 3 l 3500 C D C 4 1 5 6 2 . . . . . 2 0 6 2 5 3 2 0 5 8 9 2 8 8 ...... 9 3 3 2 2 7 8 5 2 8 6 6 6 1

1 O 1 1 1 1 7 3 3 3 2 2 2 2 2 3000

2500

2000

1500

1000

500

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 125 - EJTP2322_C_pure.1.fid 3 l C

D 5000 C

1 1 0 9 9 5 9 7 7 6 6 4 4 3 0 9 9 9 8 8 1 0 0 9 9 8 7 6 5 5 4 0 0 0 9 9 5 4 4 4 4 2 5 5 5 7 6 6 6 6 6 6 6 6 5 5 5 5 5 5 5 5 ......

8 8 8 7 7 7 7 7 7 7 7 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4500 O 4000

3500

3000

2500

2000

1500

1000

500

0 8 0 7 8 0 7 5 3 4 4 9 0 3 1 9 0 3 0 ...... 2 1 1 1 4 6 2 1 1 -500 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

EJTP2322_C_pure.2.fid 3 l

C 130000 D C 7 2 6 6 2 . . . . . 2 8 0 5 5 2 1 6 5 3 120000 8 9 2 8 8 ...... 9 3 3 2 2 7 0 7 3 0 8 8 6 6 3 1 1 1 1 1 7 4 3 3 3 2 2 2 2 2 O 110000

100000

90000

80000

70000

60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 126 - EJTP2322_D_pure.1.fid 3

l 26000 C D C

24000 9 9 8 7 7 4 3 8 8 7 6 5 6 1 0 0 9 0 9 9 8 7 7 6 6 5 3 6 2 1 0 9 9 9 9 9 5 5 4 4 4 4 4 2 5 5 5 4 6 5 5 5 5 5 5 5 5 5 4 0 0 0 ......

7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 22000

20000 O 18000

16000

14000

12000

10000

8000

6000

4000

2000

0 2 3 0 0 0 2 8 2 0 . 2 0 0 1 0 2 0 . . . -2000 . . . 0 . 2 1 2 1 1 1 4 1

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2322_D_pure_carbon.2.fid 3 360000 l C

D 340000 C 7 3 6 6 2 . . . . .

2 1 6 6 9 4 9 9 6 3 3 320000 8 9 2 8 8 ...... 9 3 3 2 2 7 9 6 4 7 7 6 5 5 5 3 O1 1 1 1 1 7 3 3 3 2 2 2 2 2 2 2 300000 280000

260000

240000

220000

200000

180000

160000

140000

120000

100000

80000

60000

40000

20000

0

-20000

-40000 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 127 - EJTP2322_E_pure.1.fid 3 l C

D 25000 C

3 2 1 1 8 8 7 7 2 0 8 6 6 5 6 6 6 4 1 0 0 9 2 3 2 1 2 1 1 6 5 8 8 8 8 5 5 5 5 5 5 3 3 3 3 2 2 2 2 5 5 5 4 4 7 7 7 5 5 5 9 9 ...... 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 2 1 1 1 1 1 1 0 0

Me 20000 O O S N O 15000

10000

5000

0 2 9 5 9 1 5 9 0 0 4 4 5 6 9 9 9 0 0 9 9 9 0 9 9 0 0 ...... 1 1 1 1 2 1 0 0 1 2 4 1 0

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

EJTP2322_E_pure.2.fid 3 l

C 150000 D C 5 6 5 0 8 7 7 0 8 140000 ...... 2 5 1 1 7 6 5 7 3 7 3 8 3 2 9 8 8 7 ......

9 4 3 3 3 2 2 2 2 7 6 6 6 1 0 7 1 0 130000 1 1 1 1 1 1 Me1 1 1 7 4 4 3 3 3 2 2 2 O 120000 O S 110000 N O 100000

90000

80000

70000

60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 128 - EJTP2323_C_pure.1.fid 3 l 100000 C D C

9 9 9 8 7 6 5 9 8 7 6 6 5 4 3 2 1 0 4 3 2 1 1 0 9 8 7 3 6 5 5 90000 9 9 9 9 9 5 5 4 4 4 4 2 5 5 6 6 6 6 6 6 6 6 6 6 5 5 5 4 0 0 0 ...... 7 7 7 7 7 7 7 7 7 7 7 7 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1

80000 O Me Me O 70000 N O Me

60000

50000

40000

30000

20000

10000

0 7 9 6 7 2 9 0 1 3 4 9 9 9 9 3 8 9 9 9 0 ...... 1 0 1 1 0 0 0 4 8 1

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2323_C_pure.2.fid 3 38000 l C

D 36000 C 7 0 7 5 9 8 2 8 ......

7 4 2 8 0 9 6 6 34000 7 5 8 4 2 8 8 3 ...... 9 5 3 3 3 2 2 2 9 7 7 6 3 0 8 0

1 1 1 O 1 1 Me1 1 1 7 7 7 3 3 3 2 2 32000 Me O 30000 N O Me 28000

26000

24000

22000

20000

18000

16000

14000

12000

10000

8000

6000

4000

2000

0

-2000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 129 - EJTP2322_F_pure.1.fid 3

l 22000 C 21000 D C 20000 9 8 8 7 7 7 5 0 9 9 7 2 1 9 6 6 5 5 4 3 0 0 8 8 7 2 9 9 9 8 8 9 9 9 9 9 5 5 5 4 4 4 3 3 2 2 2 2 2 2 2 2 6 5 5 5 6 5 5 5 5 5

...... 19000 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 18000 O 17000 16000

15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 9 1 0 1 1 0 2 3 9 0 4 7 5 9 6 0 0 0 9 0 9 9 0 0 0 0 ...... 1 1 2 1 1 1 2 0 2 4 1 1 1 -2000 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

7500 EJTP2322_E_pure_carbon.2.fid 3 l

C 7000 D C 2 1 1 7 7 5 2 0 2 ...... 2 4 3 7 6 5 4 0 4 6500 8 7 9 2 8 8 8 7 6 ...... 9 4 3 3 2 2 2 2 2 7 4 0 7 3 3 2 9 0 1 1 1 1 1 1 1 1 1 7 4 4 3 3 3 3 2 2 O 6000

5500

5000

4500

4000

3500

3000

2500

2000

1500

1000

500

0

-500

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 130 - EJTP2304_F_pure.1.fid 3

l 65000 C D C

60000 3 1 7 6 6 0 9 9 8 2 7 6 5 4 3 0 2 1 1 0 9 8 8 7 6 5 5 3 2 1 0 9 9 2 2 2 5 4 4 4 4 6 6 6 6 6 6 5 5 5 5 4 4 4 4 4 4 4 9 9 9 9 ......

7 7 7 7 7 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 55000

O 50000

45000

Me 40000

35000

30000

25000

20000

15000

10000

5000

0 4 2 3 0 6 5 5 9 . 0 2

9 0 0 0 -5000 . . . . 0 . . 1 2 1 3 1 1 1

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2304_F_pure_carbon.2.fid 100000 3 l C D C 9 2 7 3 3 90000 . . . . . 2 0 2 1 5 4 2 0 8 2 7 3 6 9 8 ...... 9 4 3 2 2 7 8 5 2 8 6 6 6 1 1

1 O 1 1 1 1 7 3 3 3 2 2 2 2 2 2 80000

70000 Me 60000

50000

40000

30000

20000

10000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 131 - EJTP2304_G_pure.1.fid

3 70000 l C

D 65000 C

6 6 5 5 9 8 8 7 6 0 9 9 8 5 4 6 2 1 1 0 0 9 8 8 7 6 5 3 2 1 1 9 9 9 9 4 4 4 4 2 5 4 4 4 6 6 5 5 5 5 5 5 4 4 4 4 4 3 9 9 9 9

...... 60000 7 7 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0

55000 O

50000

45000 Me Me 40000 Me 35000

30000

25000

20000

15000

10000

5000

0 3 4 9 7 4 0 4 4 . 9 6

8 8 0 0 -5000 . . . . 0 . . 1 1 0 1 8 1 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

EJTP2304_G_pure.2.fid 3 320000 l C

D 300000 C 0 1 6 1 6 . . . . . 2 0 2 1 3 5 4 2 0 3

8 6 6 8 5 ...... 280000 9 5 3 2 2 7 8 5 2 1 8 6 6 6 1 1 1 1 1 1 7 3 3 3 3 2 2 2 2 2 O 260000

240000

Me 220000 Me 200000 Me 180000

160000

140000

120000

100000

80000

60000

40000

20000

0

-20000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 132 - EJTP2304_E_pure.1.fid 3

l 18000 C

D 17000 C

5 4 4 3 2 6 5 3 3 2 6 5 5 4 4 3 2 7 3 3 2 2 9 9 8 8 7 6 5 5 4 16000 0 0 0 0 0 2 1 1 1 1 4 4 4 4 6 6 6 5 5 5 5 5 4 4 4 4 4 9 9 9 9 ......

8 8 8 8 8 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 15000

O 14000

13000

12000 F 11000 10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0 6 9 2 -1000 8 0 2 6 9 5 7 8 8 0 0 ...... 1 1 0 3 6 1 1

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2304_E_pure.2.fid 3

l 40000 C D C 7 5 5 5 5 7 7 7 6 ...... 2 0 7 1 5 3 2 0 5 6 6 4 5 5 0 0 5 5 ...... 35000 9 6 6 3 3 3 3 1 1 7 8 5 2 8 6 6 6 1 1 1 1 1 1 1 1 1 1 7 3 3 3 2 2 2 2 2 O 30000

F 25000

20000

15000

10000

5000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 133 - EJTP2304_B_pure.1.fid

3 32000 l C

D 30000 C

2 2 2 1 6 6 5 5 6 1 0 0 9 2 6 5 4 1 3 2 2 1 1 9 9 8 7 4 3 3 2 28000 8 8 8 8 3 3 3 3 2 5 5 5 4 4 6 6 6 6 5 5 5 5 5 4 4 4 4 9 9 9 9 ...... 7 7 7 7 7 7 7 7 7 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 26000

O 24000

22000

20000

18000 Me 16000

14000

12000

10000

8000

6000

4000

2000

0 7 8 9 8 6 8 5 0 7 -2000 . 9 9 9 9 9 0 0 ...... 0 . 1 1 0 0 2 1 0 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

EJTP2304_B_pure.2.fid 160000 3 l C

D 150000 C 3 9 6 8 6 7 8 5 1 3 2 6 4 4 0 1 6 4 7 4 5 3 1 6

...... 140000 2 0 4 2 4 3 1 0 6 4 8 9 8 3 8 8 5 ...... 9 3 3 3 2 2 2 7 8 5 2 8 6 6 6 1 1 O 130000 1 1 1 1 1 1 1 7 3 3 3 2 2 2 2 2 2

120000

110000

100000 Me 90000

80000

70000

60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 134 - EJTP2304_A_pure.1.fid 32000

30000 3 2 1 1 2 2 1 9 7 6 0 9 6 9 8 6 5 4 3 2 2 1 0 9 8 7 7 6 5 4 4

6 6 6 6 5 5 5 3 3 3 1 0 8 4 4 6 6 6 5 5 5 5 5 4 4 4 4 4 9 9 9 28000 ...... 7 7 7 7 7 7 7 7 7 7 7 7 3 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 26000 O 24000

22000

20000

18000 O Me 16000

14000

12000

10000

8000

6000

4000

2000

0 7 8 9 7 3

0 0 6 1 2 -2000 . 9 9 9 0 0 0 0 0 ...... 0 . . 1 0 0 0 3 1 1 1 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

210000 EJTP2304_A_pure.2.fid 3 l 200000 C D 190000 C 1 9 5 6 9 9 5 ...... 2 6 0 7 3 5 3 1 0 6

8 9 0 9 0 8 2 ...... 180000 9 5 4 2 2 1 1 7 5 8 5 2 8 6 6 6 1

O1 1 1 1 1 1 1 7 5 3 3 3 2 2 2 2 2 170000

160000

150000

140000

130000 O Me 120000 110000

100000

90000

80000

70000

60000

50000

40000

30000

20000

10000

0

-10000

-20000 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 135 - EJTP2303_B_pure.1.fid 3 l 19000 C D 18000 C

1 0 9 9 9 5 4 6 6 4 4 4 4 7 6 5 4 5 4 4 3 0 0 9 9 8 7 9 8 7 6 17000 8 8 7 7 7 4 4 2 2 2 2 2 2 4 4 4 4 5 5 5 5 5 5 4 4 4 4 9 9 9 9 ......

7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 0 0 0 0 16000 O 15000 14000

13000

12000

11000 F 10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 2 8 6 8 4 0 4 2 2 . 9 9 9 9 0 0 0 . . . . . 0 . . 0 0 0 0 1 1 1 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

EJTP2303_B_pure.2.fid 3 l C

D 1000000 C 0 0 0 0 3 2 3 2 9 9 6 4 0 9 ...... 2 0 2 3 4 3 2 1 9 7 7 4 2 1 1 0 0 3 3 9 9 5 4 ......

9 9 6 6 4 4 3 3 2 2 1 1 1 1 7 8 6 2 8 6 6 6 1 900000 1 O 1 1 1 1 1 1 1 1 1 1 1 1 1 7 3 3 3 2 2 2 2 2

800000

700000 F 600000

500000

400000

300000

200000

100000

0

-100000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 136 - EJTP2304_D_pure.1.fid 8500 3 l

C 8000 D C

6 6 6 3 1 0 5 3 3 1 9 8 8 8 9 8 7 6 5 4 3 2 1 0 0 8 7 6 6 5 4 7500 7 7 2 2 2 2 1 1 1 1 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 4 4 9 9 9 9 ......

7 7 7 7 7 7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 7000

O 6500

6000

5500

F 5000

4500

4000

3500

3000

2500

2000

1500

1000

500

0 3

3 4 6 4 6 -500 5 0 2 . 9 9 9 9 9 1 0 . . . . . 0 . . 0 0 0 0 0 1 1 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

EJTP2304_D_pure.2.fid 3 l 400000 C

D 380000 C 0 0 6 6 8 7 6 5 3 2 5 4 8 6 ...... 2 9 9 3 3 4 3 1 8 8 6

7 7 2 0 3 3 0 0 8 8 4 4 6 6 ...... 360000 9 9 6 6 3 3 3 3 2 2 2 2 1 1 7 7 6 6 6 8 6 6 5 5 2

1 O 1 1 1 1 1 1 1 1 1 1 1 1 1 7 3 3 3 3 2 2 2 2 2 2 340000 320000

300000

280000

F 260000

240000

220000

200000

180000

160000

140000

120000

100000

80000

60000

40000

20000

0

-20000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 137 - EJTP2304_H_pure.1.fid 3 l

C 6000 D C

6 5 9 9 8 7 0 8 2 0 9 8 0 9 5 6 8 7 0 9 1 0 0 9 5 4 4 3 8 0 0 5500 5 5 0 0 0 0 0 9 9 9 8 8 6 5 5 2 6 6 7 6 6 6 6 5 5 5 5 5 4 0 0 ...... 8 8 8 8 8 8 8 7 7 7 7 7 7 7 7 7 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 5000

O 4500

4000

3500

3000

2500

2000

1500

1000

500

0 8 8 8 9 8 4 0 0 6 6 . 9 9 9 9 9 9 0 0 ...... 0 . . -500 0 0 0 1 1 0 1 1 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

EJTP2304_H_pure.2.fid 3 l

C 140000 D C 1 5 5 8 7 6 4 3 9 8 4

...... 130000 2 1 7 3 5 3 2 1 6 8 6 5 2 9 9 8 8 7 6 4 ...... 9 3 3 3 2 2 2 2 2 2 2 7 8 5 2 8 6 6 6 1

1 O 1 1 1 1 1 1 1 1 1 1 7 3 3 3 2 2 2 2 2 120000

110000

100000

90000

80000

70000

60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 138 - EJTP2327_pure.1.fid

3 60000 l C D

C 55000

8 8 8 7 6 2 2 1 0 0 9 2 1 1 1 1 0 9 9 8 9 8 8 7 6 5 4 9 8 8 7 2 2 2 2 2 2 2 2 2 2 1 9 9 9 9 9 8 7 7 7 4 4 4 4 4 4 4 2 2 2 2 ......

7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 50000

O 45000

40000

35000

30000

25000

20000

15000

10000

5000

0 9 7 7 6 7 0 3 4 9 9 6 9 8 9 7 0 ......

1 2 3 0 8 1 0 1 -5000

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2327_pure.2.fid 3 l

C 6000 D C 7 5 6 5 2 . . . . . 2 4 9 1 7 3 1 3 2 1 1

7 1 8 8 6 ...... 5500 0 4 2 2 2 7 6 7 5 4 0 8 6 6 6 2

2 O 1 1 1 1 7 4 3 3 3 3 2 2 2 2 2 5000

4500

4000

3500

3000

2500

2000

1500

1000

500

0

-500

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 139 - EJTP2328_pure.1.fid 3 19000 l C

D 18000 C

1 0 0 9 9 4 4 3 3 2 1 0 0 0 9 9 8 3 2 2 2 1 1 0 0 6 2 0 2 0 2 17000 8 8 8 7 7 7 7 7 7 7 6 6 6 6 5 5 5 4 4 4 4 4 4 4 4 2 6 6 5 5 0 ...... 16000 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 4 4 4 4 2

15000

14000

13000 O CF 12000 O 3 N O 11000 Me O 10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

6 -1000 1 0 4 0 7 0 9 9 0 8 1 1 0 ...... 1 1 3 3 1 0 2

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

EJTP2328_pure.3.fid 3 l

C 300000 D C 4 6 9 2 4 3 2 8 4 6 2 1 3 ...... 2 8 5 2 9 5 5 7 9 2 1 0 0 9 9 8 5 3 6 ...... 6 5 3 3 3 3 3 2 2 2 2 2 1 7 1 1 1 0 5 1 1 1 1 1 1 1 1 1 1 1 1 1 7 6 6 6 6 2 250000

O CF O 3 N O 200000 Me O

150000

100000

50000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 140 - A1.6 References

(1) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

(2) Gassman, P. G.; Sowa, J. R. 1,2,3,4-Tetraalkyl-5-perfluoroalkyl-cyclopentadiene,

di-(perfluoroalkyl)-trialkylcyclopentadiene and transition metal complexes thereof,

U.S. Patent 5,245,064, Sep. 14, 1993.

(3) Phipps, E. J. T.; Rovis, T. J. Am. Chem. Soc., 2019, 141, 6807.

(4) 1a-1i: Piou, T.; Rovis, T. J. Am. Chem. Soc., 2014, 136, 11292.

(5) 1j: Duchemin, C.; Cramer, N. Org. Chem. Front., 2019, 6, 209.

(6) 2e: Kantorowski, E. J.; Borhan, B.; Nazarian, S.; Kurth M. J. Tetrahedron Lett. 1998,

39, 2483.

2f: Barluenga, J.; Fernández-Simón, J. L.; Cancellón, J. M.; Yus, M. J. Chem. Soc.

Perkin Trans. 1988, 1, 3339.

2g and general procedure: Romanov-Michailidis, F.; Sedillo, K. F.; Neely, J. M.;

Rovis, T. J. Am. Chem. Soc., 2015, 137, 8892.

2h: Green, S. A.; Vásquez-Céspedes, S.; Shenvi, R. A. J. Am. Chem. Soc., 2018, 140,

11317.

2i: Soulard, V.; Villa, G.; Vollmar, D. P.; Renaud, P. J. Am. Chem. Soc., 2018, 140,

155.

- 141 - – Appendix B –

Supporting Information for Chapter Three

PERMISSION/LICENSE IS GRANTED FOR YOUR ORDER AT NO CHARGE This type of permission/license, instead of the standard Terms & Conditions, is sent to you because no fee is being charged for your order. Please note the following:

- Permission is granted for your request in both print and electronic formats, and translations. - If figures and/or tables were requested, they may be adapted or used in part. - Please print this page for your records and send a copy of it to your publisher/graduate school. - Appropriate credit for the requested material should be given as follows: "Reprinted (adapted) with permission from (COMPLETE REFERENCE CITATION). Copyright (YEAR) American Chemical Society." Insert appropriate information in place of the capitalized words. - One-time permission is granted only for the use specified in your request. No additional uses are granted (such as derivative works or other editions). For any other uses, please submit a new request.

If credit is given to another source for the material you requested, permission must be obtained from that source.

- 142 - Rh(III)-Catalyzed C–H Activation-Initiated Diastereoselective Directed Cyclopropanation of Allylic Alcohols

Supporting Information

Erik J.T. Phipps and Tomislav Rovis*

Table of Contents

A2.1 General Methods

A2.2 General Procedures for the Synthesis of Starting Materials

A2.3 General Procedure for the Cyclopropanation Reaction and Characterization of Products

A2.4 Mechanistic Experiments

A2.5 Model for Diastereoselectivity

A2.6 X-ray Crystallographic Data

A2.7 NMR Spectra

A2.8 References

- 143 - A2.1 General Methods

All reactions were carried out in oven-dried glassware with magnetic stirring. ACS grade TFE and reagents were purchased from TCI, Strem, Alfa Aesar, and Sigma-

Aldrich and were used without further purification. Dichloromethane, tetrahydrofuran, diethyl ether were degassed with argon and passed through two columns of neutral alumina. Column chromatography was performed on SiliCycle® SilicaFlash® P60, 40-

63 µm 60 Å and in general were run using flash techniques.1 Thin layer chromatography was performed on SiliCycle® 250 µm 60 Å plates. Visualization was accomplished with UV light (254 nm). 1H, 19F, and 13C NMR spectra were collected at

ambient temperature in CDCl3 on Bruker 300Hz, 400 MHz, or 500MHz spectrometers.

Chemical shifts are expressed as parts per million (δ, ppm) and are referenced to the residual solvent peak of chloroform(1H = 7.26 ppm; 13C = 77.2 ppm). Scalar coupling constants (J) are quoted in Hz. Multiplicity is reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m= multiplet). Mass spectra were obtained on a

Waters (LRMS). Infrared (IR) spectra were obtained with neat samples on a Bruker

Tensor 27 FT-IR spectrometer with OPUS software. Typically, the experiment consisted measuring the transmission in 16 scans in the region from 4000 to 400 cm-1.

- 144 - A2.2 General Procedure for Starting Materials

CF3 2 A. Synthesis of [Cp* RhCl2]2 Catalyst

Synthesis of 1,2,3,4-tetramethyl-5-(trifluoromethyl)cyclopenta-1,3-diene (+ isomers)

CF3 F C OH 0 3 Me Br O Li wire Me Me MeSO3H Me Me Me F3C OEt Et O, 0 to -40 ˚C DCM, 0 ˚C 2 Me Me Me Me + isomers

Following a reported procedure, Li wire (1.291 g, 186 mmol, 4 equiv.) was cut into ~5

mm size pieces and added to Et2O (2.85 M, 69 mL) in a 250-mL 3-neck flask with a

magnetic stir bar and cooled to 0 ˚C in an ice bath. 2-bromo-2-butene (cis + trans)

(9.7 mL, 95.3 mmol, 2.05 equiv.) diluted with 10 mL Et2O was added dropwise over 10

minutes. The heterogeneous mixture was stirred for 2 hours then cooled to -40 ˚C

(MeCN, Dry Ice bath). Ethyl trifluoroacetate (5.4 mL, 46.5 mmol, 1 equiv.) diluted

with 5 mL Et2O was added dropwise over 10 minutes. The solution was stirred for an

additional 90 minutes. The solution was quenched with 20 mL of 2 M HCl solution

and diluted with 100 mL DI H2O. The solution was transferred to a separatory funnel

and the layers separated. The aqueous layer was extracted three times with Et2O. The

organic layers were combined and washed with saturated sodium bicarbonate, water,

and brine then dried over Na2SO4 and concentrated. The resulting yellow liquid was

- 145 - vacuum distilled to give the intermediate alcohol, a clear liquid, in 43% yield (4.1734 g).

The intermediate alcohol (1.0 g, 4.8 mmol, 1 equiv.) was dissolved in DCM (0.16 M,

30 mL) in a 50-mL flask equipped with a magnetic stir bar and cooled to 0 ˚C in an ice bath. Methanesulfonic acid (3.1 mL, 48 mmol, 10 equiv.) was quickly added and the solution was stirred for 5 minutes. The resulting dark red solution was then poured

into 50 mL of cooled DI H2O. The solution was transferred to separatory funnel and the layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined and washed with saturated sodium bicarbonate, dried

CF3 over dried over Na2SO4 and concentrated. HCp* (+ isomers) was purified by flash chromatography (Hexanes) and afforded in 69% yield (1.3374 g)

CF3 Synthesis of [Cp* RhCl2]2

CF3

Me Me MeOH, ∆ Cl Cl CF RhCl3 • 3 H2O F C Rh Rh 3 3 Cl Cl Me Me + isomers

From a reported procedure, in a 250-mL flask equipped with a magnetic stir bar and a

reflux condenser under N2 atmosphere was added RhCl3 • 3 H2O (700 mg, 2.6 mmol, 1 equiv.), MeOH (140 mL, 0.019 M), and HCp*CF3 (1.3374 g, 7.28 mmol, 2.7 equiv.).

- 146 - The solution was refluxed under N2 atmosphere for 3 days where a dark red precipitate was visible on the sides of the flask. The reaction was cooled to 0 ˚C in an ice bath and the precipitate was filtered and washed with EtOH two additional times. The resulting red solid was collected and dried to afford 72% yield (1.33 g). The

B. Synthesis of N-enoxyphthalimide Substrates

Method A3

Synthesis of (1,2-dibromoethyl)arenes

Br Br 2 Br R DCM, 0 ˚C R

Styrene (1 equiv.) in DCM (0.5M) was cooled to 0 ˚C and Br2 (1.2 equiv.) was added via syringe and stirred at 0 ˚C for ~1 hour. The solution was quenched with sat.

Na2S2O3 until the solution became colorless. The resulting solutions was then filtered through a pad a celite® and washed with DCM. The layers were then separated and the aqueous layer was extracted with DCM. The combined organic layers were then

washed with brine, dried over Na2SO4, and concentrated. The resulting white solid was directly carried on without purification.

- 147 - Synthesis of a-bromostyrenes

Br Br K CO Br 2 3 R MeOH:THF (1:1) R

(1,2-dibromoethyl)arenes (1 equiv.) was stirred in a 0.25M solution of 1:1 methanol and THF at room temperature. Potassium carbonate (2 equiv.) was added and the solution stirred until the reaction was judged complete by TLC (~3 hrs.). The reaction was then quenched with D.I. water and the volatiles were removed. The resulting aqueous layer was extracted with ether and the combined organic layers were then

washed with brine, dried over Na2SO4, and concentrated.

The resulting oil was directly carried on without purification.

Synthesis of (1-arylvinyl)boronic acids

HO OH Br t-BuLi B B(Oi-Pr)3 R R Et2O, -78 ˚C to rt

a-bromostyrene in dry diethyl ether was put under inert atmosphere in a 2-neck flask and cooled to -78 ˚C. A 1.7M solution of t-BuLi in pentanes (2.1 equiv.) was added dropwise and the solution was stirred at -78 ˚C for 30 minutes. Tri-isopropylborate

(1.2 equiv.) was added dropwise to the solution over 30 minutes. After the addition was complete, the solution was stirred at -78 ˚C for 2 hours after which the solution

- 148 - was removed from the cold bath and stirred at room temperature overnight. To the resulting yellow-orange solution was added 1M HCl solution and was stirred for 2 hours. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were then washed with 1M NaOH solution and the layers were separated. The aqueous layer was acidified to pH≈1 and extracted with ethyl

acetate. The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. The crude product was directly carried on without purification.

Synthesis of N-enoxyphthalimides

HO OH Cu(OAc) B O 2 ONPhth Na2SO4 N R HO Pyridine R 1,2-DCE, rt O

Boronic acid (2 equiv.), copper(II) acetate (1 equiv.), N-hydroxyphthalimide (1 equiv.), and anhydrous sodium sulfate (4 equiv.) were combined in a flask and diluted with

1,2-dichloroethane to form a 0.1M solution of N-hydroxyphthalimide. Pyridine (3 equiv.) was added via syringe and the solution was stirred at room temperature open to air for 2 days. At the end of the stirring period, the volatiles were removed and the resulting solids were purified by column chromatography. The purified solids were then used in the cyclopropanation reactions.

- 149 -

Method B4

[PPh3AuTFA] (5 mol%) R O NPhth NPhth R HO DCE, 90 ºC

Following a reported procedure, alkyne (3 equiv.), N-hydroxphthalimide (1 equiv.), and

Au catalyst (5 mol%) were combined in a 1.5 dram vial in the glove box under Ar and dissolved in 1,2-DCE (0.2M). The vial was sealed and removed from the glovebox and placed in an aluminum heating block overnight at 90 ºC. The reaction was then cooled to room temperature, diluted with DCM and passed through a pad of Celite®. The solvent was removed and the crude residue was purified by column chromatography

(19:1, Hex:EtOAc).

- 150 - Compounds Synthesized by Method A

ONPhth ONPhth ONPhth F

Me t-Bu F

ONPhth ONPhth ONPhth

ONPhth ONPhth ONPhth Me F MeO

Compounds Synthesized by Method B

MeO ONPhth ONPhth Bn

The known compounds are consistent with the literature precedents.

- 151 - C. Synthesis of Allylic Alcohol Substrates and Analogues.

Allylic alcohols were purchased from commercial suppliers unless noted below:

O OH X Et2O H Mg R R 0 ºC to rt n-Pr n-Pr

X = Cl or Br R = Cy or Ph

This procedure was performed according to literature precedent.5, 6, 7

1) NBS, AIBN CCl4 HO reflux

2) NaHCO3 acetone:H2O (2:1) reflux

This procedure was performed similar to literature precedent. The crude mixture was purified by flash chromatography (9:1®4:1, Hex:EtOAc). The compound was consistent with the literature.8

LiAlD D OH 4 OH n-Pr THF, 0 °C to rt n-Pr H

- 152 - This procedure was performed according to literature precedent and the compound was consistent with the literature.9

OH OMe NaH, MeI

DMF, rt n-Pr n-Pr

This procedure was performed according to literature precedent and the compound was consistent with the literature.10

OH HNPhth NPhth NH2 HNTs DIAD, PPh3 H2NNH2 • H2O TsCl THF, rt MeOH, rt DCM, rt n-Pr n-Pr n-Pr n-Pr

This procedure was performed according to the literature precedent and the compounds were consistent with the literature.11

- 153 - A2.3 General Procedure for the Cyclopropanation Reaction and Characterization of Products

OH CF3 R R [Cp* RhCl2]2 (5 mol%) R O R R R NPhth KOPiv (2 equiv.) R R R R TFE, 0 ˚C, 16 hr. O HO

CF3 N-enoxyphthalimide (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol, 4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added followed by allylic alcohol

(1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for

16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with

EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were

® filtered through a pad of celite and Na2SO4 then concentrated. The crude residue was purified by flash chromatography (Hexane:EtOAc, 19:1®9:1®4:1) to afford the cyclopropane product.

- 154 -

3aa 2-(hydroxymethyl)-3-propylcyclopropyl)(phenyl)methanone

n-Pr

Ph OH

O

Chemical Formula: C14H18O2

Y = 81%. Yellow oil. Rf = 0.22 (4:1 Hexanes:EtOAc)

1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.94 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H),

7.47 (t, J = 7.6 Hz, 2H), 3.95 (dd, J = 12.0, 4.7 Hz, 1H), 3.76 (dd, J = 12.0, 8.3 Hz,

1H), 2.55 (dd, J = 8.4, 5.0 Hz, 1H), 2.14 (s, 1H), 1.89 – 1.81 (m, 1H), 1.78 – 1.71 (m,

1H), 1.45 (tdd, J = 13.4, 10.7, 4.8 Hz, 4H), 0.93 (t, J = 6.9 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 200.2, 138.6, 133.0, 128.7, 128.2, 60.0, 35.6, 35.4, 30.3,

28.5, 22.4, 14.0.

IR(neat) 3456, 2924, 1660, 1453, 1228, 1019, 700 cm-1

LRMS m/z (ESI APCI) calculated for C14H18O2 [M+H] 219.1, found 219.1.

- 155 - 3ab 2-(hydroxymethyl)-3-propylcyclopropyl)(phenyl)methanone

n-Pr

Ph OH

O

Chemical Formula: C14H18O2

Y = 62%. Pale-yellow oil. Rf = 0.22 (4:1 Hexanes:EtOAc)

1H NMR (500 MHz, Chloroform-d) δ 8.03 – 7.95 (m, 2H), 7.61 – 7.54 (m, 1H), 7.46

(dd, J = 8.4, 7.0 Hz, 2H), 4.06 (dd, J = 7.9, 2.7 Hz, 2H), 2.73 (dd, J = 9.4, 7.9 Hz, 1H),

2.45 (s, 1H), 1.90 – 1.72 (m, 2H), 1.55 (ddt, J = 13.9, 8.4, 6.9 Hz, 1H), 1.49 – 1.40 (m,

1H), 1.35 – 1.25 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 200.7, 138.9, 133.1, 128.7, 128.3, 58.7, 28.0, 28.0, 26.5,

25.5, 23.1, 14.0.

IR(neat) 3433, 2957, 1680, 1449, 1209, 1020, 699 cm-1

LRMS m/z (ESI APCI) calculated for C14H18O2 [M+H] 219.1, found 219.1.

- 156 - 3ba 2-(hydroxymethyl)-3-propylcyclopropyl)(p-tolyl)methanone

n-Pr Me

OH

O

Chemical Formula: C15H20O2

Y = 72%. Yellow oil. Rf = 0.22 (4:1 Hexanes:EtOAc)

1H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.5 Hz,

2H), 3.94 (dd, J = 12.3, 4.8 Hz, 1H), 3.80 – 3.71 (dd, J = 9.0, 5.8 Hz, 1H), 2.52 (dd, J

= 8.4, 5.1 Hz, 1H), 2.42 (s, 3H), 2.19 (s, 1H), 1.86 – 1.79 (m, 1H), 1.72 (tdd, J = 8.3,

6.5, 4.6 Hz, 1H), 1.52 – 1.37 (m, 4H), 0.98 – 0.89 (t, J = 7.0 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 199.8, 143.8, 136.1, 129.4, 128.4, 60.1, 35.5, 35.4, 30.1,

28.3, 22.4, 21.8, 14.0.

IR(neat) 3441, 2957, 2923, 1663, 1607, 1454, 1233, 1179, 103, 665 cm-1

LRMS m/z (ESI APCI) calculated for C15H20O2 [M+H] 233.2, found 233.2.

- 157 - 3ca (4-(tert-butyl)phenyl)-2-(hydroxymethyl)-3-propylcyclopropyl)methanone

n-Pr t-Bu

OH

O

Chemical Formula: C18H26O2

Y = 76%. Pale-yellow oil. Rf = 0.24 (4:1, Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz,

2H), 3.98 – 3.91 (m, 1H), 3.81 – 3.72 (m, 1H), 2.54 (dd, J = 8.4, 5.0 Hz, 1H), 2.18 (s,

1H), 1.87 – 1.80 (m, 1H), 1.73 (tdd, J = 8.3, 6.5, 4.6 Hz, 1H), 1.53 – 1.40 (m, 4H),

1.35 (s, 9H), 0.93 (t, J=6.9 Hz, 3H).

13 13 C NMR (126 MHz, CDCl3) C NMR (126 MHz, CDCl3) δ 199.9, 156.8, 134.5, 128.2,

125.7, 123.8, 60.12, 35.5, 35.4, 31.3, 30.2, 28.3, 22.4, 14.0.

IR(neat) 3210, 2956, 2923, 2852, 1736, 1606, 1234, 1109, 834, 852, 796 cm-1

LRMS m/z (ESI APCI) calculated for C18H26O2 [M+H] 275.2, found 275.2.

- 158 - 3da (4-fluorophenyl)(2-(hydroxymethyl)-3-propylcyclopropyl)methanone

n-Pr F

OH

O

Chemical Formula: C14H17FO2

Y = 69%. Yellow Oil. Rf = 0.16 (4:1 Hexanes:EtOAc).

1H NMR 1H NMR (500 MHz, Chloroform-d) δ 8.02 (dd, J = 8.5, 5.4 Hz, 2H), 7.13 (t, J

= 8.5 Hz, 2H), 3.94 (dd, J = 11.9, 4.7 Hz, 1H), 3.72 (dd, J = 12.0, 8.4 Hz, 1H), 2.48

(dd, J = 8.4, 5.0 Hz, 1H), 2.14 (s, 1H), 1.82 (p, J = 6.2 Hz, 1H), 1.74 (qd, J = 8.3, 5.6

Hz, 1H), 1.44 (tt, J = 13.9, 7.1 Hz, 4H), 0.92 (t, J = 6.8 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 198.5, 166.8, 164.8, 135.0, 135.0, 130.9, 130.8, 115.9,

115.7, 60.0, 35.6, 35.4, 30.1, 28.4, 22.4, 14.0.

19F NMR (282 MHz, Chloroform-d) δ -104.95 (ddd, J = 13.7, 8.5, 5.4 Hz).

IR(neat) 3458, 2958, 2926, 1667, 1599, 1507, 1229, 1155, 1031, 838 cm-1

LRMS m/z (ESI APCI) calculated for C14H17FO2 [M+H] 237.1, found 237.1.

- 159 - 3ea (2-(hydroxymethyl)-3-propylcyclopropyl)(4-methoxyphenyl)methanone

n-Pr MeO

OH

O

Chemical Formula: C15H20O3

Y = 77%. Pale-Yellow Oil. Rf = 0.06 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz,

2H), 3.94 (dd, J = 12.0, 4.6 Hz, 1H), 3.87 (s, 3H), 3.75 (dd, J = 12.1, 8.2 Hz, 1H), 2.49

(dd, J = 8.4, 5.0 Hz, 1H), 2.26 (s, 1H), 1.80 (p, J = 6.3 Hz, 1H), 1.73 – 1.66 (m, 1H),

1.51 – 1.38 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 198.7, 131.6, 130.5, 113.9, 60.2, 55.7, 35.5, 35.1, 29.9,

28.0, 22.4, 14.0.

IR(neat) 3436, 2957, 2926, 1655, 1600, 1235, 1170, 1026, 845 cm-1

LRMS m/z (ESI APCI) calculated for C15H20O3 [M+H] 249.1, found 249.1.

- 160 - 3fa (2-(hydroxymethyl)-3-propylcyclopropyl)(m-tolyl)methanone

Me n-Pr

OH

O

Chemical Formula: C15H20O2

Y = 52%. Pale-yellow oil. Rf = 0.30 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 7.80 (q, J = 2.4 Hz, 2H), 7.42 – 7.32 (m, 2H),

3.94 (dd, J = 12.0, 4.6 Hz, 1H), 3.76 (dd, J = 12.0, 8.3 Hz, 1H), 2.54 (dd, J = 8.4, 5.0

Hz, 1H), 2.42 (s, 3H), 2.15 (s, 1H), 1.88 – 1.79 (m, 1H), 1.74 (tdd, J = 8.4, 6.5, 4.6 Hz,

1H), 1.51 – 1.38 (m, 4H), 0.97 – 0.89 (m, 3H).

13 C NMR (126 MHz, CDCl3) δ 200.3, 138.5, 138.4, 133.6, 128.6, 128.4, 125.3, 59.9,

35.4, 35.3, 30.1, 28.3, 22.2, 21.4, 13.8.

IR(neat) 3445, 2955, 2870, 1664, 1604, 1163, 1054, 1030, 708 cm-1

LRMS m/z (ESI APCI) calculated for C15H20O2 [M+H] 233.2, found 233.2.

- 161 - 3ga 2-(hydroxymethyl)-3-propylcyclopropyl)(3-methoxyphenyl)methanone

OMe n-Pr

OH

O

Chemical Formula: C15H20O3

Y = 93%. Yellow oil. Rf = 0.18 (4:1, Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 2.1 Hz,

1H), 7.38 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 8.2, 2.7 Hz, 1H), 3.94 (dd, J = 11.9, 4.7 Hz,

1H), 3.85 (s, 3H), 3.75 (dd, J = 12.2, 8.1 Hz, 1H), 2.53 (dd, J = 8.4, 5.0 Hz, 1H), 2.19

(bs, 1H), 1.86 – 1.79 (m, 1H), 1.78 – 1.70 (m, 1H), 1.53 – 1.37 (m, 4H), 0.96 – 0.90

(m, 3H).

13 C NMR (126 MHz, CDCl3) δ 200.0, 159.9, 139.9, 129.7, 120.9, 119.4, 112.5, 60.0,

55.6, 35.6, 35.4, 30.3, 28.6, 22.3, 13.9.

IR(neat) 3437, 2957, 2926, 1664, 1586, 1462, 1261, 1034, 778 cm-1

LRMS m/z (ESI APCI) calculated for C15H20O3 [M+H] 249.1, found 249.1.

- 162 - 3ha (3-fluorophenyl)-2-(hydroxymethyl)-3-propylcyclopropyl)methanone

F n-Pr

OH

O

Chemical Formula: C14H17FO2

Y = 54%. Yellow oil. Rf = 0.15 (4:1, Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 7.79 (dt, J = 7.8, 1.2 Hz, 1H), 7.66 (ddd, J = 9.5,

2.6, 1.6 Hz, 1H), 7.45 (td, J = 8.0, 5.5 Hz, 1H), 7.29 – 7.23 (m, 2H), 3.95 (dd, J =

11.9, 4.7 Hz, 1H), 3.73 (dd, J = 11.9, 8.4 Hz, 1H), 2.50 (dd, J = 8.4, 5.0 Hz, 1H), 1.98

(s, 1H), 1.88 – 1.82 (m, 1H), 1.78 (tdd, J = 8.5, 6.6, 4.7 Hz, 1H), 1.52 – 1.38 (m, 4H),

0.98 – 0.89 (m, 3H).

13 C NMR (126 MHz, CDCl3) δ 198.8 (d, J = 2.0 Hz), 164.0, 162.0, 130.4 (d, J = 7.7

Hz), 124.0 (d, J = 3.1 Hz), 120.0 (d, J = 21.6 Hz), 115.0 (d, J = 22.3 Hz), 59.9, 35.9,

35.34, 30.4, 28.8, 22.4, 14.0.

19F NMR (282 MHz, Chloroform-d) δ -111.15 (td, J = 9.0, 5.7 Hz).

IR(neat) 3439, 2958, 2925, 1670, 1588, 1443, 1252, 1030, 785 cm-1

LRMS m/z (ESI APCI) calculated for C14H17FO2 [M+H] 237.1, found 237.1.

- 163 - 3ia (2-fluorophenyl)(2-(hydroxymethyl)-3-propylcyclopropyl)methanone

n-Pr

F O OH

Chemical Formula: C14H17FO2

Y = 44%. Pale-yellow Oil. Rf = 0.19 (4:1 Hexanes:EtOAc).

1H NMR (300 MHz, Chloroform-d) δ 7.74 (td, J = 7.6, 1.9 Hz, 1H), 7.49 (dddd, J =

8.5, 7.1, 5.0, 1.9 Hz, 1H), 7.28 – 7.07 (m, 2H), 3.96 (dd, J = 12.0, 4.7 Hz, 1H), 3.78 (t,

J = 10.1 Hz, 1H), 2.54 (ddd, J = 8.1, 5.1, 2.7 Hz, 1H), 1.95 (s, 1H), 1.89 (ddd, J = 6.5,

5.1, 1.3 Hz, 1H), 1.77 (tdd, J = 8.3, 6.6, 4.8 Hz, 1H), 1.51 – 1.34 (m, 4H), 0.98 – 0.88

(m, 3H).

13 C NMR (126 MHz, CDCl3) δ 198.8 (d, J = 3.1 Hz), 161.6 (d, J = 255.0 Hz), 134.2

(d, J = 9.0 Hz), 130.4 (d, J = 2.6 Hz), 128.0 (d, J = 12.6 Hz), 124.6 (d, J = 3.6 Hz),

116.8 (d, J = 25.1 Hz), 59.9, 36.3, 35.3, 34.4 (d, J = 7.7 Hz), 29.6, 22.3, 14.0.

19 F NMR (282 MHz, CDCl3) δ -110.33 (dt, J = 8.3, 4.0 Hz).

IR(neat) 3213, 2956, 2922, 1653, 1607, 1234, 1109, 1036, 834 cm-1

LRMS m/z (ESI APCI) calculated for C14H16F2O2 [M+H] 237.1, found 237.1.

- 164 - 3ja 2-(hydroxymethyl)-3-propylcyclopropyl)(naphthalen-2-yl)methanone

n-Pr

OH

O

Chemical Formula: C18H20O2

Y = 50%. Pale-yellow solid. Rf = 0.18 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 8.55 (d, J = 1.7 Hz, 1H), 8.05 (dd, J = 8.6, 1.8

Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.89 (dd, J = 10.8, 8.3 Hz, 2H), 7.58 (dddd, J =

21.9, 8.1, 6.8, 1.3 Hz, 2H), 3.99 (dd, J = 12.0, 4.7 Hz, 1H), 3.80 (dd, J = 12.0, 8.3 Hz,

1H), 2.71 (dd, J = 8.4, 5.0 Hz, 1H), 2.14 (s, 0H), 1.96 – 1.87 (m, 1H), 1.81 (tdd, J =

8.3, 6.6, 4.7 Hz, 1H), 1.50 (dtd, J = 14.3, 12.8, 11.8, 6.9 Hz, 4H), 0.95 (t, J = 7.0 Hz,

3H).

13 C NMR (126 MHz, CDCl3) 200.0, 135.9, 135.6, 132.7, 129.8, 129.7, 128.5, 128.5,

127.9, 126.9, 124.1, 60.1, 35.7, 35.5, 30.3, 28.5, 22.4, 14.0.

IR(neat) 3300, 2872, 2857, 1657, 1181, 1123, 1046, 1027, 822, 749 cm-1

LRMS m/z (ESI APCI) calculated for C18H20O2 [M+H] 269.2, found 269.2.

- 165 - 3ka 1-(2-(hydroxymethyl)-3-propylcyclopropyl)-3-phenylpropan-1-one

n-Pr

Bn O OH

Chemical Formula: C16H22O2

1H NMR (500 MHz, Chloroform-d) δ 7.31 – 7.26 (m, 2H), 7.21 – 7.18 (m, 3H), 3.90 –

3.80 (m, 1H), 3.65 (t, J = 10.2 Hz, 1H), 3.02 – 2.88 (m, 4H), 2.01 (s, 1H), 1.83 (dd, J

= 8.3, 5.0 Hz, 1H), 1.62 (qd, J = 6.6, 4.9 Hz, 1H), 1.53 (tdd, J = 8.2, 6.6, 4.4 Hz, 1H),

1.42 – 1.28 (m, 3H), 0.89 (t, J = 7.2 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 210.2, 141.2, 128.7, 128.5, 126.3, 59.5, 46.3, 35.3,

33.1, 30.2, 28.7, 22.3, 13.9.

IR(neat) 3386, 2958, 2925, 2872, 1689, 1454, 1378, 1034, 733, 700 cm-1

LRMS m/z (ESI APCI) calculated for C16H22O2 [M+H] 247.3, found 247.3.

- 166 - 3ac (2-(hydroxymethyl)-3-methylcyclopropyl)(phenyl)methanone

Me

Ph OH

O

Chemical Formula: C12H14O2

Y = 89%. Light yellow solid. Rf = 0.50 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 8.06 – 7.94 (m, 2H), 7.62 – 7.52 (m, 1H), 7.47

(dd, J = 8.3, 7.0 Hz, 2H), 3.96 (dd, J = 12.0, 4.7 Hz, 1H), 3.74 (dd, J = 12.0, 8.3 Hz,

1H), 2.50 (dd, J = 8.4, 5.0 Hz, 1H), 2.17 (s, 1H), 1.84 (h, J = 6.0 Hz, 1H), 1.73 (tdd, J

= 8.3, 6.4, 4.6 Hz, 1H), 1.26 (d, J = 6.0 Hz, 4H).

13 C NMR (126 MHz, CDCl3) δ 200.3, 138.6, 133.1, 128.7, 128.3, 60.0, 36.5, 31.5, 22.9,

18.3.

IR(neat) 3412, 2955, 2889, 1660, 1598, 1219, 1021, 743, 688 cm-1

LRMS m/z (ESI APCI) calculated for C12H14O2 [M+H] 191.1, found 191.1.

- 167 - 3ad (2-(hydroxymethyl)-2-methylcyclopropyl)(phenyl)methanone

Me Ph OH

O

Chemical Formula: C12H14O2

Y = 62% Pale-yellow solid. Rf = 0.19 (4:1 Hexanes:EtOAc)

1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.97 (m, 2H), 7.59 – 7.54 (m, 1H), 7.47

(dd, J = 8.4, 7.0 Hz, 2H), 3.75 (dd, J = 11.8, 4.6 Hz, 1H), 3.61 (dd, J = 11.8, 5.0 Hz,

1H), 2.54 (dd, J = 7.8, 5.7 Hz, 1H), 1.89 (t, J = 6.0 Hz, 1H), 1.64 (dd, J = 5.7, 4.3 Hz,

1H), 1.42 (s, 3H), 1.10 (dd, J = 7.8, 4.3 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 199.7, 138.6, 133.0, 128.7, 128.3, 64.7, 33.3, 31.5, 22.8,

21.1.

IR(neat) 3439, 2914, 1669, 1269, 1230, 1022, 714

LRMS m/z (ESI APCI) calculated for C12H14O2 [M+H] 191.1, found 191.1.

- 168 - 3ae (3-(hydroxymethyl)-2,2-dimethylcyclopropyl)(phenyl)methanone

Me Me

Ph OH

O

Chemical Formula: C13H16O2

Y = 82% Pale-yellow oil. Rf = 0.18 (4:1 Hexanes:EtOAc)

1H NMR (500 MHz, Chloroform-d) δ 7.98 – 7.89 (m, 2H), 7.61 – 7.54 (m, 1H), 7.48

(dd, J = 8.4, 7.0 Hz, 2H), 4.10 – 4.03 (m, 1H), 4.02 – 3.95 (m, 1H), 2.62 (q, J = 3.8

Hz, 1H), 2.41 (d, J = 7.9 Hz, 1H), 1.66 (ddd, J = 9.6, 8.0, 6.9 Hz, 1H), 1.41 (s, 3H),

1.11 (s, 3H).

13 C NMR (126 MHz, CDCl3) δ 200.4, 138.8, 133.2, 128.8, 128.3, 59.5, 35.7, 35.6, 28.8,

28.5, 15.4.

IR(neat) 3222, 2911, 1668, 1273, 1220, 692 cm-1

LRMS m/z (ESI APCI) calculated for C13H16O2 [M+H] 205.1, found 205.1.

- 169 - 3af (3-(hydroxymethyl)-2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl)(phenyl)methanone

Me

Me Me

Ph

O OH

Chemical Formula: C18H24O2

Y = 55%. Colorless oil. Rf = 0.24 (4:1 Hexanes:EtOAc).

1H NMR (Major) (500 MHz, Chloroform-d) δ 7.99 – 7.89 (m, 2H), 7.61 – 7.51 (m,

1H), 7.46 (dd, J = 8.5, 7.0 Hz, 2H), 5.13 (tt, J = 6.9, 1.5 Hz, 1H), 4.09 – 3.98 (m, 2H),

2.45 (d, J = 8.0 Hz, 1H), 2.15 (hept, J = 7.5 Hz, 2H), 1.86 (ddd, J = 13.4, 9.2, 5.9 Hz,

1H), 1.69 (s, 3H), 1.63 (s, 3H), 1.36 (ddd, J = 13.5, 9.7, 6.8 Hz, 1H), 1.12 (s, 3H).

13 C NMR (Major) (126 MHz, CDCl3) δ 200.3, 138.9, 134.5, 133.1, 132.4, 128.7, 128.3,

123.8, 123.7, 59.4, 42.9, 35.2, 35.1, 32.5, 25.9, 25.3, 17.9, 12.6.

IR(neat) 3444, 2923, 1725, 1351, 1282, 1261, 1125, 1053, 964, 910, 759, 698 cm-1

LRMS m/z (ESI APCI) calculated for C17H16O2 [M+H] 273.2, found 273.2.

- 170 - 3ag (2-(1-hydroxyallyl)cyclopropyl)(phenyl)methanone

H Ph

O OH

Chemical Formula: C13H14O2

Y = 73%. Yellow oil. Rf = 0.22 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 8.03 (d, J = 7.7 Hz, 2H), 7.56 (t, J = 7.4 Hz,

1H), 7.47 (t, J = 7.6 Hz, 2H), 6.00 (ddd, J = 16.6, 10.4, 5.6 Hz, 1H), 5.30 (d, J = 17.2

Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.06 (dd, J = 9.0, 5.6 Hz, 1H), 2.81 (td, J = 8.1, 5.7

Hz, 1H), 2.16 (s, 1H), 1.75 (p, J = 8.4 Hz, 1H), 1.49 (q, J = 5.8 Hz, 1H), 1.26 (td, J =

7.9, 4.5 Hz, 2H).

13 C NMR (126 MHz, CDCl3) δ 199.9, 139.9, 138.6, 133.1, 128.7, 128.4, 114.9, 71.0,

31.1, 23.1, 13.0.

IR(neat) 3407, 2889, 1666, 1391, 1224, 1003, 714, 690 cm-1

LRMS m/z (ESI APCI) calculated for C13H14O2 [M+H] 203.1, found 203.1.

- 171 - 3ah (2-(1-hydroxyethyl)cyclopropyl)(phenyl)methanone

H Ph Me

O OH

Chemical Formula: C12H14O2

Y = 69%. Off-white solid. Rf = 0.26 (4:1 Hexanes:EtOAc).

1H NMR (Major) (500 MHz, Chloroform-d) δ 8.08 – 8.02 (m, 2H), 7.60 – 7.53 (m,

1H), 7.47 (t, J = 7.6 Hz, 2H), 3.74 (dt, J = 12.6, 6.4 Hz, 1H), 2.76 (td, J = 8.2, 5.7 Hz,

1H), 1.95 (s, 1H), 1.69 (qd, J = 8.7, 6.9 Hz, 1H), 1.43 – 1.35 (m, 1H), 1.33 (d, J = 6.3

Hz, 3H), 1.25 (td, J = 8.2, 4.4 Hz, 1H).

13 C NMR (Major) (126 MHz, CDCl3) δ 199.9, 138.5, 133.1, 128.7, 128.4, 66.6, 33.0,

23.4, 23.2, 13.2.

IR(neat) 3497, 2965, 1666, 1599, 1390, 1210, 999, 699, 690 cm-1

LRMS m/z (ESI APCI) calculated for C12H14O2 [M+H] 191.1, found 191.1.

- 172 - 3ai (2-(hydroxy(phenyl)methyl)cyclopropyl)(phenyl)methanone

H Ph Ph

O OH

Chemical Formula: C17H16O2

Y = 62%. Light yellow solid. Rf = 0.54 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 8.17 – 8.06 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H),

7.56 – 7.47 (m, 4H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 4.64 (d, J = 9.4

Hz, 1H), 2.93 (td, J = 8.1, 5.7 Hz, 1H), 2.26 (s, 1H), 2.01 (qd, J = 8.7, 6.9 Hz, 1H),

1.64 (dt, J = 6.8, 5.0 Hz, 1H), 1.26 (dt, J = 8.2, 4.1 Hz, 1H).

13 C NMR (126 MHz, CDCl3) δ 199.6, 144.0, 138.6, 133.0, 128.7, 128.6, 128.4, 127.7,

126.0, 72.1, 33.0, 23.8, 13.4.

IR(neat) 3495, 2944, 1669, 1591, 1390, 1223, 1210, 1010, 699 cm-1

LRMS m/z (ESI APCI) calculated for C17H16O2 [M+H] 253.1, found 253.1.

- 173 - 3aj (2-(1-hydroxyethyl)-3-methylcyclopropyl)(phenyl)methanone

Me H Ph Me

O OH

Chemical Formula: C13H16O2

Y = 88% Pale-yellow oil. Rf = 0.19 (4:1 Hexanes:EtOAc)

1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.98 (m, 2H), 7.60 – 7.53 (m, 1H), 7.51 –

7.43 (m, 2H), 3.87 (dq, J = 8.8, 6.3 Hz, 1H), 2.47 (dd, J = 8.4, 5.1 Hz, 1H), 2.23 (s,

1H), 1.74 (td, J = 6.3, 5.2 Hz, 1H), 1.50 (td, J = 8.6, 6.4 Hz, 1H), 1.32 (d, J = 6.3 Hz,

3H), 1.24 (d, J = 6.1 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 200.2, 138.6, 133.0, 128.7, 128.7, 128.7, 128.2, 66.0,

42.2, 32.0, 23.2, 23.1, 18.2.

IR(neat) 3214, 2975, 1735, 1602, 1224, 1115, 1062, 905, 732, 715 cm-1

LRMS m/z (ESI APCI) calculated C13H16O2 [M+H] 205.1, found 205.1.

- 174 - 3ak (2-(hydroxy(phenyl)methyl)-3-propylcyclopropyl)(phenyl)methanone

n-Pr H Ph Ph

O OH

Chemical Formula: C20H22O2

Y = 75%. Off-white solid. Rf = 0.34 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 8.09 – 8.02 (m, 2H), 7.61 – 7.54 (m, 1H), 7.52 –

7.42 (m, 4H), 7.36 (t, J = 7.6 Hz, 2H), 7.31 – 7.24 (m, 1H), 4.77 (dd, J = 9.2, 3.7 Hz,

1H), 2.66 (dd, J = 8.4, 5.1 Hz, 1H), 2.28 (d, J = 3.8 Hz, 1H), 1.99 (qd, J = 6.6, 5.0 Hz,

1H), 1.81 (td, J = 8.9, 6.5 Hz, 1H), 1.48 – 1.37 (m, 1H), 1.31 – 1.26 (m, 1H), 1.22

(ddtd, J = 12.6, 8.1, 6.7, 6.3, 4.4 Hz, 2H), 0.77 (t, J = 7.2 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 199.8, 144.1, 138.7, 132.9, 128.7, 128.6, 127.6, 126.0,

71.6, 41.3, 35.2, 31.2, 28.6, 22.1, 13.8.

IR(neat) 3437, 2958, 2923, 1666, 1587, 1442, 1251, 1032, 908, 730 cm-1

LRMS m/z (ESI APCI) calculated for C20H22O2 [M+H] 295.2, found 295.2.

- 175 - 3al (2-(cyclohexyl(hydroxy)methyl)-3-propylcyclopropyl)(phenyl)methanone

n-Pr H Ph Cy

O OH

Chemical Formula: C20H28O2

Y = 95%. Off-white solid. Rf = 0.54 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 8.06 – 7.97 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H),

7.45 (t, J = 7.6 Hz, 2H), 3.41 (dd, J = 9.2, 6.6 Hz, 1H), 2.49 (dd, J = 8.7, 5.0 Hz, 1H),

1.99 – 1.86 (m, 2H), 1.86 – 1.80 (m, 1H), 1.80 – 1.71 (m, 3H), 1.62 (dtq, J = 12.8,

10.2, 3.8, 2.9 Hz, 3H), 1.43 (dt, J = 14.8, 7.4 Hz, 3H), 1.32 – 1.15 (m, 4H), 1.15 – 1.00

(m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 200.3, 138.8, 132.8, 128.6, 128.3, 73.7, 44.4, 38.8, 35.4,

29.3, 29.0, 26.7, 26.4, 26.3, 22.2, 14.1.

IR(neat) 3438, 2922, 2851, 1656, 1451, 1232, 1020, 711, 685, 660 cm-1

LRMS m/z (ESI APCI) calculated for C20H28O2 [M+H] 301.2, found 301.2.

- 176 - 3an (2-hydroxybicyclo[6.1.0]nonan-9-yl)(phenyl)methanone

H Ph H O OH

Chemical Formula: C16H20O2

Y = 85%. Colorless oil. Rf = 0.05 (4:1 Hexanes:EtOAc)

1H NMR (500 MHz, Chloroform-d) δ 8.10 – 7.98 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H),

7.47 (t, J = 7.6 Hz, 2H), 4.13 (td, J = 10.9, 4.6 Hz, 1H), 3.14 (s, 1H), 2.58 (dd, J = 9.6,

7.7 Hz, 1H), 1.91 (tt, J = 12.0, 4.3 Hz, 1H), 1.77 (tdd, J = 17.0, 8.4, 4.2 Hz, 3H), 1.73

– 1.65 (m, 2H), 1.59 (ddt, J = 15.3, 12.2, 4.3 Hz, 1H), 1.49 (tdd, J = 13.6, 10.4, 4.4

Hz, 1H), 1.45 – 1.30 (m, 2H), 1.21 (tdd, J = 14.3, 8.0, 3.6 Hz, 2H).

13 C NMR (126 MHz, CDCl3) δ 200.3, 138.4, 133.4, 128.7, 128.6, 67.7, 36.7, 30.4, 29.8,

27.0, 26.6, 26.2, 25.1, 24.5.

IR(neat) 3446, 2924, 2854, 1660, 1448, 1394, 1212, 1050, 1011, 956, 718 cm-1

LRMS m/z (ESI APCI) calculated for C16H20O2 [M+H] 245.3, found 245.3.

- 177 - A2.4 Mechanistic Experiments

Deuterated allylic alcohol–Retention of stereochemistry at the alkene

OH n-Pr H CF3 Ph O D [Cp* RhCl2]2 (5 mol%) NPhth H D KOPiv ( 2 equiv.) Ph OH n-Pr H TFE, 0 ˚C O 1a 2a-d1 3aa’ 82% >20:1 d.r.

CF3 N-enoxyphthalimide 1a (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol,

4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added followed by allylic alcohol

2a-d1 (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for

16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with

EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were

® filtered through a pad of celite and Na2SO4 then concentrated. The residue was purified by flash chromatography (Hexane:EtOAc, 19:1®9:1®4:1) to afford the cyclopropane product.

- 178 - 3aa’ 2-(hydroxymethyl)-3-propylcyclopropyl-2-d)(phenyl)methanone

n-Pr D

O OH

Chemical Formula: C14H17DO2

Y = 82%. Colorless Oil. Rf = 0.22 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.97 (m, 2H), 7.62 – 7.55 (m, 1H), 7.49

(dd, J = 8.4, 7.0 Hz, 2H), 3.96 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 2.56 (d,

J = 5.0 Hz, 1H), 2.21 (s, 1H), 1.86 (q, J = 6.2 Hz, 1H), 1.48 (ttd, J = 11.8, 5.8, 5.1, 2.5

Hz, 4H), 0.99 – 0.92 (m, 3H).

13 C NMR (126 MHz, CDCl3) δ 199.6, 144.0, 138.6, 133.0, 128.7, 128.6, 128.4, 127.7,

126.0, 72.1, 33.0, 23.8, 13.4.

IR(neat) 3458, 2921, 1657, 1450, 1228, 1020, 699 cm-1

LRMS m/z (ESI APCI) calculated for C17H16O2 [M+H] 220.1, found 220.1.

- 179 - Assignment of stereochemistry

The assignment of the major diastereomer for the substrates presented in this work

was determined by analogy of this result. When 2a-d1 is subjected to the reaction conditions, the resulting cyclopropane 3aa’ is characterized by coupling constants of the a-hydrogen to the phenyl ketone (highlighted in red) that gives a doublet in the

1H-NMR spectrum. Assuming retention of stereochemistry at the alkene, if the hydroxymethyl substituent is trans to the ketone, the blue proton from the alkene should be cis to the ketone and give a large J value. Alternatively, if the hydroxymethyl substituent is cis to the ketone, the blue proton from the alkene should be trans to the ketone and give a small J value. We observe the doublet of the a-hydrogen to have a J value of 5.0 Hz indicating formation of the diastereomer in the highlighted box.

- 180 - n-Pr H doublet cis; large J H D Ph O OH

n-Pr H doublet trans; small J H D Ph O OH

- 181 - Deuterated solvent–Irreversibility of C–H activation

[Cp*CF3RhCl ] (5 mol%) O 2 2 O NPhth NPhth KOPiv ( 2 equiv.) H H D/H H/D TFE-d1, 0 ˚C 1a 1a 0% D

CF3 N-enoxyphthalimide 1a (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol,

4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added. The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an

insulated box and stirred for 3 hours. TFE-d1 was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with

EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were

® filtered through a pad of celite and Na2SO4 then concentrated. The residue was purified by flash chromatography (Hexane:EtOAc, 19:1®9:1®4:1) to re-isolate the starting material.

- 182 - With homoallylic alcohol 4a

n-Pr [Cp*CF3RhCl ] (5 mol%) OH 2 2 1a Ph KOPiv (2 equiv.) n-Pr O TFE, 0 ˚C OH 4a 5aa 12%, >20:1 d.r.

CF3 N-enoxyphthalimide 1a (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol,

4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added followed by homoallylic alcohol 4a (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for 16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with

EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were

® filtered through a pad of celite and Na2SO4 then concentrated. Yield and diastereoselectivity were determined by crude 1H NMR.

- 183 - With bis-homoallylic alcohol

Me CF3 Me OH [Cp* RhCl2]2 (5 mol%) 1a Ph KOPiv (2 equiv.) TFE, 0 °C O OH

6a 7aa 17%, >20:1 d.r.

CF3 N-enoxyphthalimide 1a (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol,

4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added followed by bis-homoallylic alcohol 6a (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for 16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with

EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were

® filtered through a pad of celite and Na2SO4 then concentrated. Yield and diastereoselectivity were determined by crude 1H NMR.

- 184 - With allylic ether 6a

n-Pr n-Pr CF3 [Cp* RhCl2]2 (5 mol%) 1a Ph KOPiv (2 equiv.) OMe TFE, 0 ˚C O OMe 8a 9aa trace

CF3 N-enoxyphthalimide 1a (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol,

4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added followed by allylic ether 8a

(1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for

16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with

EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were

® filtered through a pad of celite and Na2SO4 then concentrated. Yield and diastereoselectivity were determined by crude 1H NMR.

- 185 - With allylic carboxylic acid

n-Pr n-Pr CF3 [Cp* RhCl2]2 (5 mol%) 1a Ph KOPiv (2 equiv.) CO H 2 TFE, 0 ˚C O CO2H 8b 9ab trace

CF3 N-enoxyphthalimide (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol, 4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added followed by allylic carboxylic acid (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for

16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with

EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were

® filtered through a pad of celite and Na2SO4 then concentrated. Yield and diastereoselectivity were determined by crude 1H NMR.

- 186 - With allylic amine

n-Pr n-Pr CF3 [Cp* RhCl2]2 (5 mol%) 1a Ph KOPiv (2 equiv.) HNTs TFE, 0 ˚C O HNTs 8c 9ac 77%, 9.5:1 d.r.

CF3 N-enoxyphthalimide (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol, 4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE (0.2 M, 600 µL) was added followed by allylic amine (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for 16 hours.

Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with EtOAc.

The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were filtered

® through a pad of celite and Na2SO4 then concentrated. The crude residue was purified by flash chromatography (Hexane:EtOAc, 19:1®9:1®4:1) to afford the cyclopropane product.

- 187 - 9ac N-((2-benzoyl-3-propylcyclopropyl)methyl)-4-methylbenzenesulfonamide

n-Pr

Ph

O HNTs

Chemical Formula: C21H25NO3S

Y = 77%. Off-White Solid. Rf = 0.21 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 7.91 (dd, J = 8.3, 1.3 Hz, 2H), 7.66 (d, J = 8.2

Hz, 2H), 7.60 – 7.53 (m, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.65

(t, J = 6.4 Hz, 1H), 3.37 (ddd, J = 14.0, 6.9, 5.6 Hz, 1H), 3.11 (ddd, J = 14.3, 8.8, 5.9

Hz, 1H), 2.49 (dd, J = 8.4, 5.0 Hz, 1H), 2.40 (s, 3H), 1.71 (tt, J = 8.6, 6.0 Hz, 1H),

1.67 – 1.60 (m, 1H), 1.42 – 1.30 (m, 4H), 0.94 – 0.85 (m, 3H).

13 C NMR (126 MHz, CDCl3) δ 199.3, 143.4, 134.5, 133.2, 129.8, 128.8, 128.2, 127.2,

123.8, 41.3, 35.1, 33.0, 29.8, 29.7, 22.3, 21.7, 13.9.

IR(neat) 3520, 3189, 3061, 1666, 1602, 1373, 1305, 1239, 1159, 1049, 711, 647.

LRMS m/z (ESI APCI) calculated for C21H25O3S [M+H] 372.1, found 372.1.

- 188 - With NaH

n-Pr n-Pr CF3 Ph O [Cp* RhCl2]2 (5 mol%) NPhth Ph NaH (2 equiv.) OH TFE, 0 ˚C O OH 5%

CF3 N-enoxyphthalimide 1a (0.12 mmol) and catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol, 4.4 mg), were weighed in a 1-dram vial with a magnetic stirbar. Cooled TFE

(0.2 M, 600 µL) was added followed by allylic alcohol 6a (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for 2 mins. The vial was removed and

NaH (2 equiv., 0.24 mmol) was added and vigorous bubbling occurred. The vial was placed back in the cooling block at 0 °C and stirred for 16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was partitioned with the addition of 10% NaOH solution. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were filtered through a pad

® of celite and Na2SO4 then concentrated. Yield and diastereoselectivity were determined by crude 1H NMR.

- 189 - Isolation of off-cycle intermediate

O OH Ph O KOPiv ( 1 equiv.) N O THF, 21 °C O O O N Me Ph O Me 1a 2c Me 10ac 38%

N-enoxyphthalimide 1a (0.75 mmol) and KOPiv (1 equiv., 0.75 mmol) were weighed in a 1-dram vial with a magnetic stirbar. THF (0.2 M, 3.770 mL) was added followed by allylic alcohol 2b (1.2 equiv., 0.91 mmol). The vial was sealed with a screw-cap and stirred for 16 hours at room temperature. THF was removed by rotary evaporation and the crude residue was purified by flash chromatography (Hexane:EtOAc, 19:1) to afford the dioxazoline product.

- 190 - 10ac (E)-but-2-en-1-yl 2-(5-methyl-5-phenyl-1,4,2-dioxazol-3-yl)benzoate

O O Ph N O Me O Me

Chemical Formula: C20H19NO4

Y=38% Colorless Oil. Rf = 0.64 (4:1 Hexanes:EtOAc).

1H NMR (500 MHz, Chloroform-d) δ 7.80 – 7.74 (m, 1H), 7.71 – 7.65 (m, 1H), 7.62 –

7.58 (m, 2H), 7.56 – 7.50 (m, 2H), 7.44 – 7.37 (m, 3H), 5.81 (dqt, J = 15.3, 6.4, 1.2

Hz, 1H), 5.59 (dtq, J = 14.8, 6.5, 1.6 Hz, 1H), 4.68 (ddt, J = 12.3, 6.5, 1.2 Hz, 1H),

4.61 (ddt, J = 12.2, 6.5, 1.1 Hz, 1H), 2.01 (s, 3H), 1.71 (dq, J = 6.5, 1.2 Hz, 3H).

13 C NMR (126 MHz, CDCl3) δ 166.96, 158.13, 140.15, 132.41, 132.01, 131.28, 131.24,

129.99, 129.63, 129.30, 128.57, 125.22, 124.85, 122.70, 116.05, 66.62, 25.70, 17.98.

IR(neat) 2973, 1726, 1282, 1261, 1121, 910, 759, 697 cm-1

LRMS m/z (ESI APCI) calculated for C20H19NO4 [M+H] 338.1, found 338.1

- 191 - Compatibility of 10ac with the cyclopropanation reaction conditions

Me O CF3 [Cp* RhCl2]2 (5 mol%) O N O Ph Ph O KOPiv ( 2 equiv.) O OH Me TFE, 0 or 21 ˚C Me 10ac 3ac not observed

CF3 Dioxazoline 10ac (0.12 mmol), catalyst [Cp* RhCl2]2 (5 mol%, 0.006 mmol, 4.4 mg), and KOPiv (2 equiv., 0.24 mmol, 33.6 mg) were weighed in a 1-dram vial with a magnetic stirbar. Cooled (or room temperature) TFE (0.2 M, 600 µL) was added. The vial was sealed with a screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box (or placed on a stir plate at room temperature) and stirred for 16 hours. TFE was removed by rotary evaporation and the residue was taken up in EtOAc and filtered through a silica plug flushing with EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where the solution was

partitioned with the addition of H2O. The aqueous layer was extracted three times with

EtOAc and the combined organic extracts were filtered through a pad of celite® and

1 Na2SO4 then concentrated. Yield and diastereoselectivity were determined by crude H-

NMR.

- 192 -

D O D D N D D O O D CF3 D D Me O (25 mol%) [Cp* RhCl2]2 D D D NH D D D O O O KOPiv (2 equiv.) D D D TFE-d3 (0.1M), 0 °C D D D O OD OH Me Me

N-enoxyphthalimide 1aa’ (0.06 mmol) and KOPiv (2 equiv., 0.12 mmol) were weighed

in a 1-dram vial with a magnetic stirbar. TFE-d3 (0.1 M, 600 mL) was added followed by allylic alcohol 2c (1.7 equiv., 0.10 mmol). The vial was sealed with a screw-cap and stirred briefly and the solution transferred to an NMR tube and injected in the spectrometer set to 273 K.

- 193 - EJTP2319.5.55.1r D 1 O D D H-NMR NH 6 O O O TFE-d D 3 D D D 500 MHz EJTP2319.5.45.1r Me

5

EJTP2319.5.35.1r

4

EJTP2319.5.25.1r

3

EJTP2319.5.15.1r

2

D EJTP2319.5.5.1r O D D N O 1 D O D D D

9.1 9.0 8.9 8.8 8.7 8.6 8.5 8.4 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 f1 (ppm)

- 194 - EJTP2319.5.55.1r 1H-NMR

TFE-d3 6 500 MHz

EJTP2319.5.45.1r

5

EJTP2319.5.35.1r

4

EJTP2319.5.25.1r

3

EJTP2319.5.15.1r

2

EJTP2319.5.5.1r

1

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

- 195 - A2.5 Model for Diastereoselectivity

O (5 mol%) OH CF3 O OH [Cp* RhCl2]2 Ar O * N Ar * R' R' * KOPiv * O R TFE R

Phthalimide [2+1] Opening Annulation

O O O Ar O Ar O Ar O N Carbenoid CMD N formation NH H O O O Rh O Rh O R' R' R O R R

R' CF3 CF3

- Conformational analysis of the proposed ArOC Rh-carbenoid— O the diastereo-determining O NH O step of the reaction H R' Rh R substituent in psuedo-equatorial Steric clash CF3 position avoided Stereochemistry retained at the alkene

-Major Diastereomer -Minor Diastereomer -Stereochemistry retained at alkene -Stereochemistry retained at alkene -Steric clash avoided with Cp -Steric clash avoided with Cp -Substituent is equatorial -Substituent is axial O O HO O OH HO O OH Ar Ar R' R' H Ar R' H Ar R' H H H H H H R R R R

-Minor Diastereomer -Minor Diastereomer -Stereochemistry retained at alkene -Stereochemistry retained at alkene -Steric clash with Cp -Steric clash with Cp -Substituent is equatorial -Substituent is axial HO HO H O OH H O OH H R' H R' Ar R' Ar R' H H H H R Ar R R Ar R O O

- 196 - A2.6 X-Ray Data

Single crystal X-ray diffraction. Data for all compounds was collected on an Agilent

SuperNova diffractometer using mirror-monochromated Cu Ka radiation. Data collection, integration, scaling (ABSPACK) and absorption correction (face-indexed

Gaussian integration12 or numeric analytical methods13) were performed in

CrysAlisPro.14 Structure solution was performed using ShelXT15. Subsequent refinement was performed by full-matrix least-squares on F2 in ShelXL.16 Olex217 was used for viewing and to prepare CIF files. PLATON18 was used extensively for

CheckCIF. ORTEP graphics were prepared in CrystalMaker.19 Thermal ellipsoids are rendered at the 50% probability level.

A solution of EJTP2213_B_pure in CHCl3/hexanes was slowly evaporated to afford long, colorless needles. Part of a crystal (.46 x .06 x .04 mm) was separated carefully, mounted on a glass fiber with Paratone oil, and cooled to 100 K on the diffractometer.

Complete data were collected to 0.8 Å. 12900 reflections were collected (2666 unique,

2373 observed) with R(int) 5.9% and R(sigma) 4.2% after Gaussian absorption and beam profile correction (maximum correction factor 1.46).

- 197 - The space group was assigned tentatively as I2/a based on the systematic absences.

Using ShelXT, the structure solved readily in I2/a with 1 molecule in the asymmetric unit. All non-H atoms were located in the initial solution and refined anisotropically with no restraints. The O-H hydrogen was located in a difference map and refined with unrestrained coordinates and isotropic ADP. C-H hydrogens were placed in calculated positions and refined with riding coordinates and ADPs.

The final refinement (2666 data, 0 restraints, 176 parameters) converged with R1 (Fo >

4σ(Fo)) = 4.6%, wR2 = 12.1%, S = 1.04. The largest Fourier features were 0.25 and -

0.20 e- A-3.

- 198 - Molecular structure of EJTP2213_B_pure. The crystal is centrosymmetric and thus contains both enantiomers.

- 199 -

Compound EJTP2213_B_pure

Formula C17H16O2 MW 252.30 Space group I2/a a (Å) 20.0490(6) b (Å) 5.46156(14) c (Å) 25.6163(8) α (°) 90 β (°) 107.386(3) γ (°) 90 V (Å3) 2676.80(14) Z 8 -3 ρcalc (g cm ) 1.252

T (K) 100 λ (Å) 1.54184

2θmin, 2θmax 7, 146 Nref 12900 R(int), R(σ) .0591, .0416 μ(mm-1) 0.642 Size (mm) .46 x .06 x .04

Tmax / Tmin 1.46

Data 2666 Restraints 0 Parameters 176

R1(obs) 0.0458

wR2(all) 0.1212 S 1.036 Peak, hole 0.25, -0.20 (e- Å-3)

- 200 - A2.7 NMR Spectra

EJTP2313_pure.1.fid 3 l C

D 9000 C

1 9 9 6 5 9 7 6 6 4 3 6 6 5 4 3 4 4 5 8 7 6 5 4 4 3 3 2 4 3 2 0 9 9 5 5 4 4 4 2 9 9 7 5 5 5 5 8 8 7 4 4 4 4 4 4 4 4 4 9 9 9 ......

8 7 7 7 7 7 7 7 7 3 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 8000

7000 Me 6000

5000

O OH 4000

3000

2000

1000

0 9 8 2 5 2 5 2 3 0 4 7 8 9 2 1 0 0 0 0 0 0 0 ...... 2 1 2 1 1 1 0 0 1 4 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 201 - EJTP2313_pure.2.fid 3 l 160000 C D

C 150000 2 6 0 7 2 . . . . . 2 0 6 4 3 5 4 0 0 8 3 8 8 ......

0 3 3 2 2 7 0 5 5 0 8 2 4 140000 2 1 1 1 1 7 6 3 3 3 2 2 1

130000

120000

Me 110000

100000

90000

80000

O OH 70000

60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 202 - EJTP1414_A_pure.1.fid 23000 3 Proton l 22000 C

D 21000 C

0 0 8 8 6 5 8 7 6 5 6 7 6 5 5 5 3 3 1 5 9 0 0 9 8 8 7 4 7 5 4 20000 0 0 9 9 5 5 4 4 4 4 2 0 0 0 0 7 7 7 7 8 7 3 3 2 2 2 2 2 8 8 8 ...... 19000 8 8 7 7 7 7 7 7 7 7 7 4 4 4 4 2 2 2 2 1 1 1 1 1 1 1 1 1 0 0 0

18000

17000 Me 16000 15000

14000

13000

12000

11000 O OH 10000 9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 0 6 7 0 1 0 4 0 4 2 6 6 1 0 0 2 6 1 8 0 1 3 ...... 2 1 2 1 1 0 2 1 1 2 3 -2000 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 203 - EJTP1414_A_pure.2.fid 3

l 300000 C D C 7 9 1 7 3 . . . . . 2 7 0 0 5 5 1 0 0 8 3 8 8 ...... 0 3 3 2 2 7 8 8 8 6 5 3 4

2 1 1 1 1 7 5 2 2 2 2 2 1 250000

Me 200000

150000

O OH

100000

50000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 204 - Me

O OH

- 205 - Me

O OH

- 206 - EJTP2270_B_pure.1.fid 3

Proton l 38000 C

D 36000 C

0 9 9 8 8 6 5 9 9 8 7 6 6 4 3 3 2 5 4 4 3 9 5 5 4 3 2 1 0 9 9 34000 0 9 9 9 9 5 5 4 4 4 4 4 2 7 7 6 6 5 5 5 5 8 6 6 6 6 4 1 1 0 0 ......

8 7 7 7 7 7 7 7 7 7 7 7 7 3 3 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 32000

30000

28000

26000

24000

22000

Me 20000 OH 18000 O 16000

14000

12000

10000

8000

6000

4000

2000

0 3

1 5 -2000 5 4 0 5 5 0 0 9 1 0 0 1 0 0 0 0 0 ...... 2 1 2 1 1 1 0 1 3 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 207 - EJTP2270_B_pure.2.fid 3 Carbon 13 l 240000 C

D 230000 C 7 6 0 7 3

. . . . . 220000 2 7 3 5 8 1 9 8 3 8 8 ...... 210000 9 3 3 2 2 7 4 3 1 2 1

1 1 1 1 1 7 6 3 3 2 2 200000

190000

180000

170000

160000

150000

140000 Me 130000 120000 OH 110000 O 100000 90000

80000

70000

60000

50000

40000

30000

20000

10000

0

-10000

-20000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 208 - EJTP2270_A_pure.5.fid 3 Proton l 65000 C D C 60000 3 3 2 1 1 8 7 7 6 5 5 9 9 8 7 6 6 5 0 8 2 0 8 7 7 6 5 5 5 1 1 9 9 9 9 9 5 5 5 5 5 5 4 4 4 4 4 2 0 0 9 4 4 6 6 6 6 6 6 6 4 1 ......

7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 4 4 3 2 2 1 1 1 1 1 1 1 1 1 55000

50000

45000

Me Me 40000

OH 35000

30000 O

25000

20000

15000

10000

5000

0 2 3 3 3 7 4 4 5 0 4 9 0 0 0 0 0 0 0 0 0 ...... -5000 2 1 2 1 1 0 1 1 3 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 209 - EJTP2270_A_pure.6.fid 3

Carbon 13 l 1300000 C D C

4 8 2 8 3 1200000 . . . . . 2 5 7 6 8 5 4 0 8 3 8 8 ......

0 3 3 2 2 7 9 5 5 8 8 5 1100000 2 1 1 1 1 7 5 3 3 2 2 1

1000000

900000

Me Me 800000

OH 700000

600000 O

500000

400000

300000

200000

100000

0

-100000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 210 - H

1H-NMR O OH CDCl3 500 MHz

- 211 - H

O OH

- 212 - EJTP2213_A_pure.1.fid 3 Proton l 15000 C D

C 14000

5 5 5 4 3 7 6 5 5 9 7 6 6 6 6 5 5 9 9 8 9 9 8 8 8 7 4 3 6 5 4 0 0 0 0 0 5 5 5 5 4 4 4 4 2 7 7 9 6 6 6 3 3 3 3 3 3 3 3 2 2 2

...... 13000 8 8 8 8 8 7 7 7 7 7 7 7 7 7 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

12000

11000

10000

9000

H 8000 Me 7000 O OH 6000

5000

4000

3000

2000

1000

0 9 0 0 3 7 6 8 9 0 0 9 1 4 -1000 8 2 0 0 1 3 3 ...... 1 1 2 0 1 1 1 1 3 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 213 - EJTP2213_A_pure.2.fid 3

Carbon 13 l C 90000 D C 9 5 1 7 4 . . . . . 2 5 0 3 2 2 9 8 3 8 8 ......

9 3 3 2 2 7 6 3 3 3 3 80000 1 1 1 1 1 7 6 3 2 2 1

70000

60000

H Me 50000

O OH 40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 214 - EJTP2213_B_pure.3.fid Proto2 n 0 0 1 9 3 2 0 0 8 1 9 8 3 2 5 3 4 3 2 6 1 0 9 5 4 4 3 7 7 6 13000 1 1 1 6 5 5 5 5 5 4 4 3 3 3 3 6 6 9 9 9 2 0 0 9 6 6 6 6 2 2 2 ...... 8 8 8 7 7 7 7 7 7 7 7 7 7 7 7 4 4 2 2 2 2 2 2 1 1 1 1 1 1 1 1 12000

11000

10000

9000

8000

7000 H 6000

O OH 5000

4000

3000

2000

1000

0 9 6 6 9 8 5 0 0 1 6 3 9 9 9 0 0 9 0 0 0 0 1 ...... -1000 1 0 4 2 1 1 1 0 1 1 0

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 215 - EJTP2213_B_pure.4.fid 3

Carbon 13 l C 300000 D C 6 0 6 0 7 6 4 7 0 ...... 2 1 0 8 4 9 4 8 3 8 8 8 7 6 . . . . . 9 4 3 3 2 2 2 2 2 7 2 3 3 3 1 1 1 1 1 1 1 1 1 7 7 3 2 1

250000

200000 H

O OH 150000

100000

50000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 216 - EJTP1458_pure.1.fid 3

Proton l C

D 25000 C

1 1 0 0 9 9 6 4 8 8 7 6 5 5 6 7 7 8 7 6 5 5 4 3 3 1 9 2 1 5 3 0 0 0 0 9 9 5 5 4 4 4 4 4 4 2 8 8 4 4 4 4 7 7 7 7 5 4 3 3 2 2 ...... 8 8 8 8 7 7 7 7 7 7 7 7 7 7 7 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1

20000

Me 15000 H Me

O OH 10000

5000

0 5 9 2 0 6 1 0 5 1 4 8 1 1 1 1 0 0 0 0 0 ...... 2 1 2 1 1 0 1 1 3 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 217 - EJTP1458_pure.2.fid 3

Carbon 13 l C D 450000 C 2 6 0 7 7 7 2 ...... 2 0 2 0 2 1 2 0 8 3 8 8 8 8 ...... 0 3 3 2 2 2 2 7 6 2 2 3 3 8

2 1 1 1 1 1 1 7 6 4 3 2 2 1 400000

350000

Me 300000 H Me 250000

O OH 200000

150000

100000

50000

0

-50000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 218 - EJTP1458_B_pure.1.fid 3 Proton l 19000 C

D 18000 C

6 6 6 4 4 7 6 0 9 9 7 6 6 5 5 4 4 7 6 5 4 8 6 6 6 5 8 1 9 7 6 17000 0 0 0 0 0 5 5 5 4 4 4 4 4 4 4 4 4 3 3 3 3 2 2 6 6 6 2 2 7 7 7 ......

8 8 8 8 8 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 1 0 0 0 16000

15000

Me 14000

13000

12000 H 11000

10000

O OH 9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 5 1 6 2 2 1 5 2 0 0 1 6 2 9 9 9 8 1 0 0 5 9 0 0 0 0 0 0 ...... 1 1 4 2 0 1 1 0 1 1 1 0 2 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 219 - EJTP1458_B_pure.2.fid 3

Carbon 13 l C 100000 D C 8 1 7 9 7 6 3 6 0 ...... 2 6 3 2 2 6 1 8 9 4 8 2 8 8 8 7 6 ......

9 4 3 3 2 2 2 2 2 7 1 1 5 1 8 2 3 90000 1 1 1 1 1 1 1 1 1 7 7 4 3 3 2 2 1

80000

Me 70000

60000 H 50000

O OH 40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 220 - Me

H

O OH

- 221 - Me

H

O OH

- 222 - EJTP2318_pure.1.fid 10000

4 2 2 7 5 8 7 5 3 2 9 8 8 6 8 8 7 7 6 5 4 1 0 9 8 7 2 0 1 0 8 9000 0 0 0 5 5 4 4 4 1 1 5 5 5 5 7 7 7 7 7 7 7 7 7 6 6 6 4 4 2 2 1 ...... 8 8 8 7 7 7 7 7 4 4 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

8000

7000

6000 H

5000 H O OH 4000

3000

2000

1000

0 8 1 6 6 4 5 1 0 6 7 9 2 1 9 9 0 0 3 1 2 9 0 0 0 1 0 ...... 2 0 1 1 0 1 1 3 2 1 1 2 2

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 223 - EJTP2318_pure.2.fid 650000 3 l C

D 600000 C 3 4 4 7 6 . . . . . 2 7 7 4 8 0 6 2 1 5 0 8 3 8 8 ......

0 3 3 2 2 7 7 6 0 9 7 6 6 5 4 550000 2 1 1 1 1 7 6 3 3 2 2 2 2 2 2

500000

450000

400000

350000 H 300000

H 250000 O OH

200000

150000

100000

50000

0

-50000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 224 - 18000 EJTP2252_B_proton.1.fid 3 l

C 17000 D C 16000 4 4 4 2 2 6 4 4 4 8 8 6 6 6 5 4 6 3 3 3 4 3 0 6 4 7 5 3 9 3 2 9 9 9 9 9 5 5 5 5 4 4 4 4 4 4 4 2 1 1 1 0 0 0 4 4 1 1 1 6 6 1

...... 15000 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 5 5 5 4 4 4 2 2 2 2 2 1 1 1

14000

13000 Me 12000

Me Me 11000 10000

OH 9000

O 8000 7000

6000

5000

4000

3000

2000

1000

0 4 3 8 2 7 0 8 0 6 4 3 -1000 9 6 3 0 2 3 1 1 0 5 9 0 3 ...... 2 1 2 1 2 1 1 1 3 3 1 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 225 - EJTP2252_B_pure.7.fid 500000 3

Carbon 13 l C D

C 450000 3 9 5 1 4 7 3 8 7 ...... 2 4 9 2 1 5 9 3 9 6 0 8 4 3 2 8 8 3 3 ...... 0 3 3 3 3 2 2 2 2 7 9 2 5 5 2 5 5 7 2 2 1 1 1 1 1 1 1 1 7 5 4 3 3 3 2 2 1 1 400000

350000 Me 300000 Me Me

250000 OH

O 200000

150000

100000

50000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 226 - EJTP2269_A_pure.8.fid 3

Proton l

C 30000 D C

1 0 7 6 6 4 3 2 1 2 2 2 1 2 7 6 6 6 5 5 5 4 4 3 3 3 2 2 4 3 1 9 9 2 2 2 5 5 5 5 4 8 8 8 7 4 4 4 4 4 4 4 4 4 4 4 4 4 4 9 9 9 ...... 7 7 7 7 7 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 25000

Me 20000

Me

15000

O OH

10000

5000

0 6 8 9 9 9 9 7 9 9 0 7 9 9 8 9 9 0 2 9 9 9 0 ...... 1 2 0 0 1 2 0 0 0 4 2

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 227 - EJTP2269_A_pure.9.fid 3

Carbon 13 l C 120000 D C 8 8 1 4 4 . . . . . 2 1 5 4 1 3 4 8 0

9 3 6 9 8 ...... 110000 9 4 3 2 2 7 0 5 5 0 8 2 1 4 1 1 1 1 1 7 6 3 3 3 2 2 2 1

100000

90000 Me 80000

Me 70000

60000

O OH 50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 228 - EJTP2269_B_pure.5.fid 3

Proton l

C 70000 D C 65000 6 4 0 8 6 5 4 4 3 4 3 3 2 4 3 2 7 6 6 5 5 5 4 4 3 2 2 5 4 3 1 9 9 5 4 2 5 5 5 5 8 8 8 8 7 7 7 4 4 4 4 4 4 4 4 4 4 4 3 9 9 9 ......

7 7 7 7 7 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 60000

55000

Me 50000 Me Me 45000 Me 40000

35000 O OH 30000

25000

20000

15000

10000

5000

0 4 2 5 4 2 0 6 7 0 2 7 9 5 7 2 2 2 0 0 0 0 0 ......

. . . . . -5000 2 2 1 1 1 0 1 1 4 9 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 229 - EJTP2269_B_pure.6.fid 3

Carbon 13 l C D C

9 8 5 2 7 8 400000 ...... 2 1 5 4 3 2 3 4 0 9 6 4 8 5 3 ...... 9 5 3 2 2 2 7 0 5 5 1 0 8 2 4 1 1 1 1 1 1 7 6 3 3 3 3 2 2 1

350000

Me 300000 Me Me Me 250000

200000 O OH

150000

100000

50000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 230 - EJTP2207_A_pure.3.fid 3

Proton l C 9000 D C

4 3 3 1 6 6 4 2 7 6 5 4 5 4 3 1 0 9 8 3 2 5 7 6 5 4 2 1 4 3 2 0 0 0 0 2 1 1 1 9 9 9 9 7 7 7 5 5 4 4 8 8 7 4 4 4 4 4 4 9 9 9 ...... 8000 8 8 8 8 7 7 7 7 3 3 3 3 3 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 0 0 0

Me 7000

F 6000

5000 O OH

4000

3000

2000

1000

0 9 9 0 5 1 2 1 0 8 7 9 7 9 1 0 0 0 0 0 0 ...... 2 2 1 1 0 0 0 1 4 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 231 - EJTP2207_A_pure.4.fid 3 120000 Carbon 13 l C D C

5 8 8 0 9 9 8 8 7 110000 ...... 2 0 5 4 1 4 4 9 8 6 4 5 4 0 0 5 5 ...... 9 6 6 3 3 3 3 1 1 7 0 5 5 0 8 2 3

1 1 1 1 1 1 1 1 1 7 6 3 3 3 2 2 1 100000

90000

Me 80000

F 70000

60000

O OH 50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 232 - EJTP2104_Fluorine.2.fid 0 2 3 5 6 8 9 9 9 9 9 9 9 9 ......

4 4 4 4 4 4 4 6500 0 0 0 0 0 0 0 1 1 1 1 1 1 1

------6000

5500 Me 5000

F 4500

4000

O OH 3500

3000

2500

2000

1500

1000

500

0

-500

10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 f1 (ppm)

- 233 - EJTP2254_pure.1.fid 3

Proton l

C 15000 D C 14000 0 8 6 5 4 4 3 2 7 7 5 5 0 9 9 8 0 9 9 9 7 6 5 4 3 2 2 1 4 3 1 0 9 2 9 9 9 9 9 8 7 7 7 5 4 4 4 8 7 6 6 4 4 4 4 4 4 4 4 9 9 9 ......

8 7 7 6 6 3 3 3 3 3 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 13000

12000

11000

Me 10000

9000 MeO 8000

7000

O OH 6000

5000

4000

3000

2000

1000

0 8 8 8 6 0 1 4 1 2 0 3 9 2 0 1 1 0 -1000 1 1 0 0 1 ...... 2 2 1 3 1 1 0 1 1 4 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 234 - EJTP2254_pure.2.fid

3 230000 Carbon 13 l C 220000 D C

7 6 6 5 9 210000 . . . . . 2 2 7 5 1 9 0 4 0 8 3 1 0 3 ...... 200000 9 6 3 3 1 7 0 5 5 5 9 8 2 4

1 1 1 1 1 7 6 5 3 3 2 2 2 1 190000

180000 Me 170000 160000

150000 MeO 140000

130000

120000 O OH 110000 100000

90000

80000

70000

60000

50000

40000

30000

20000

10000

0

-10000

-20000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 235 - EJTP2207_C_pure.3.fid Proto3 n 3 2 2 0 0 8 7 6 5 0 8 8 8 7 6 5 5 6 0 9 8 8 7 6 5 5 7 5 4 4 8 8 8 8 4 4 3 9 9 9 8 7 7 5 5 5 5 4 8 5 4 4 4 4 4 4 4 9 9 9 9 20000 ......

7 7 7 7 7 7 7 3 3 3 3 3 3 2 2 2 2 2 1 1 1 1 1 1 1 1 1 0 0 0 0 19000

18000

17000 Me 16000

15000

14000

13000

Me 12000

O OH 11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 9 5 5 4 0 1 0 2 9 7 1 6 2 0 1 0 1 0 0 0 0 0 ...... 2 2 1 1 1 3 0 1 1 4 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 236 - EJTP2207_C_pure.4.fid 3 5 4 6 6 4 3

Carbon 13 ...... 9 4 3 1 3 2 4 8 0 8 8 3 8 8 5 ......

0 3 3 3 2 2 2 9 5 5 0 8 2 1 3 90000 2 1 1 1 1 1 1 5 3 3 3 2 2 2 1

Me 80000

70000

Me 60000 O OH 50000

40000

30000

20000

10000

0

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 237 - EJTP2207_B_pure.1.fid 3

Proton l C

D 30000 C

1 1 0 9 0 9 9 9 8 6 1 1 3 2 5 5 4 3 2 1 5 5 4 4 3 2 2 4 2 2 1 6 6 6 5 5 4 4 3 3 2 1 1 9 9 8 7 7 5 5 5 4 4 4 4 4 4 4 9 9 9 9 ...... 7 7 7 7 7 7 7 7 7 7 7 7 3 3 3 3 3 2 2 2 1 1 1 1 1 1 1 0 0 0 0

25000

Me

20000

MeO 15000 O OH

10000

5000

0 7 7 4 2 6 8 7 0 6 0 9 8 3 6 2 1 1 0 0 0 0 0 1 0 0 2 ...... 1 1 1 1 1 3 1 1 0 1 1 4 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 238 - EJTP2207_B_pure.2.fid 3

Carbon 13 l C 240000 D C 0 9 9 7 9 4 5 ...... 2 0 6 6 4 3 6 3 9 0 9 9 9 0 9 2 ...... 220000 0 5 3 2 2 1 1 7 0 5 5 5 0 8 2 3 2 1 1 1 1 1 1 7 6 5 3 3 3 2 2 1

200000

Me 180000

160000

140000 MeO O OH 120000

100000

80000

60000

40000

20000

0

-20000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 239 - EJTP1441_B_pure.1.fid 3 13000 Proton l C D

C 12000

0 0 9 8 8 8 5 4 6 6 6 5 5 4 1 0 9 8 6 6 5 5 4 4 4 3 3 2 4 3 2 8 8 7 7 7 7 4 4 2 2 2 2 9 9 5 5 4 4 4 4 4 4 4 4 4 4 4 4 9 9 9 ...... 11000 7 7 7 7 7 7 7 7 7 7 7 7 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 0 0 0

10000 Me

9000

8000

F 7000

O OH 6000

5000

4000

3000

2000

1000

0 3 2 4 0 2 0 1 0 3 5 6 0 8 3 1 0 0 0 5 0 0 0 0 1 ...... -1000 1 1 1 1 1 1 1 0 1 1 4 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 240 - EJTP1441_B_pure.2.fid 3

Carbon 13 l 150000 C

D 140000 C 8 8 0 0 4 3 0 0 0 9 1 0 ...... 2 9 9 4 4 8 4 9 8 8 4 2 0 0 4 4 0 9 5 5 ......

9 9 6 6 3 3 2 2 2 1 1 1 7 9 5 5 0 8 2 3 130000 1 1 1 1 1 1 1 1 1 1 1 1 7 5 3 3 3 2 2 1

120000

Me 110000

100000

90000

F 80000 O OH 70000

60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 241 - EJTP1441_B_Fluorine.2.fid 0 2 4 6 7 9

1 1 1 1 1 1 3600 ......

1 1 1 1 1 1 3400 1 1 1 1 1 1

Me 1 1 1 1 1 1 ------3200

3000

2800

F 2600 O OH 2400 2200

2000

1800

1600

1400

1200

1000

800

600

400

200

0

-200

-400

10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 f1 (ppm)

- 242 - EJTP2253_B_pure.1.fid 3 l

C 6000 D C

7 7 5 4 2 2 1 8 6 4 4 2 2 9 9 7 7 4 4 3 3 1 0 5 4 3 3 2 5 9 8 5500 7 7 7 7 7 7 5 4 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 5 5 5 5 5 9 8 8 ...... 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 2 1 1 1

5000 Me 4500

4000

3500

F O OH 3000

2500

2000

1500

1000

500

0 2 4 8 7 6 4 0 8 5 1 4 9 2 2 1 1 0 0 0 0 0 1 ......

1 1 2 1 1 1 0 1 1 4 3 -500

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm)

- 243 - EJTP2269_D_pure.6.fid 3

Carbon 13 l 360000 C

D 340000 C 9 9 6 6 2 1 4 4 0 9 6 5 9 7 ...... 2 9 5 3 4 4 6 3 9

8 8 2 0 4 4 0 0 8 7 4 4 6 6 ...... 320000 9 9 6 6 3 3 3 3 2 2 2 2 1 1 7 9 6 5 4 4 9 2 3

1 1 1 1 1 1 1 1 1 1 1 1 1 1 7 5 3 3 3 3 2 2 1 300000

280000

Me 260000

240000

220000

200000

180000 F O OH 160000

140000

120000

100000

80000

60000

40000

20000

0

-20000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 244 - EJTP2253_B_pure.2.fid 9 1 2 3 5 6 3400 2 3 3 3 3 3 ......

0 0 0 0 0 0 3200 1 1 1 1 1 1 1 1 1 1 1 1

Me ------3000

2800

2600

2400

2200 F O OH 2000

1800

1600

1400

1200

1000

800

600

400

200

0

-200

10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 f1 (ppm)

- 245 - EJTP1441_A_pure.1.fid 12000 3

Proton l C D 11000 C

5 5 6 5 4 4 9 7 1 9 9 7 0 0 6 6 8 3 2 1 0 0 0 9 8 7 7 6 6 5 4 5 5 0 0 0 0 9 9 9 8 8 8 6 6 5 2 9 7 7 7 7 5 5 4 4 4 4 4 9 9 9 ......

8 8 8 8 8 8 7 7 7 7 7 7 7 7 7 7 3 2 2 2 2 1 1 1 1 1 1 1 0 0 0 10000

Me 9000

8000

7000

6000 O OH

5000

4000

3000

2000

1000

0 4 9 9 8 6 9 2 5 0 0 3 0 3 9 9 8 1 0 0 9 0 0 0 0 0 1 ......

0 1 1 2 2 0 1 1 0 1 1 4 2 -1000

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 246 - EJTP1441_A_pure.2.fid 90000 3

Carbon 13 l

C 85000 D C 0 9 6 7 8 7 5 5 9 9 1 80000 ...... 2 1 7 5 3 5 4 0 0 5 5 2 9 9 8 8 7 6 4 ......

0 3 3 3 2 2 2 2 2 2 2 7 0 5 5 0 8 2 4 75000 2 1 1 1 1 1 1 1 1 1 1 7 6 3 3 3 2 2 1

70000 Me 65000

60000

55000

50000

O OH 45000 40000

35000

30000

25000

20000

15000

10000

5000

0

-5000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 247 - EJTP2042_pure.3.fid 3 l C 60000 D C

6 7 1 1 1 0 9 9 4 4 4 3 2 2 2 1 1 1 0 9 9 6 1 2 2 1 1 0 0 0 9

7 6 6 6 6 6 5 5 5 5 5 5 5 5 5 4 4 4 4 3 3 2 0 7 7 7 7 7 7 7 6 55000 ...... 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 2 1 1 1 1 1 1 1 1

50000

Me 45000

40000

35000

30000 O OH 25000

20000

15000

10000

5000

0

-5000 9 7 1 0 6 5 9 2 6 2 0 9 1 3 1 1 2 1 1 0 0 0 ...... 1 1 2 2 3 1 0 1 1 3 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 248 - EJTP2314_pure.2.fid 3 l 6000 C D C 2 2 6 5 3 5500 . . . . . 2 6 3 3 1 2 7 3 9 0 1 8 8 6 ...... 1 4 2 2 2 7 9 6 5 3 0 8 2 3

2 1 1 1 1 7 5 4 3 3 3 2 2 1 5000

Me 4500

4000

3500

3000 O OH 2500

2000

1500

1000

500

0

-500

-1000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm)

- 249 - EJTP2314_pure.1.fid 3 l C 40000 D C

0 8 8 7 6 1 9 6 5 4 4 3 3 2 2 5 4 3 2 2 8 6 5 3 2 2 2 0 1 9 8 3 2 2 2 2 2 1 9 9 9 9 9 9 9 9 8 8 8 8 6 3 3 3 3 3 3 3 3 9 8 8 ......

7 7 7 7 7 7 7 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 35000 Me

30000

O O 25000 N O O Me 20000

15000

10000

5000

0 6 2 9 0 6 0 3 2 0 4 5 1 3 0 1 1 0 0 0 0 0 0 ...... 2 3 1 1 4 1 1 1 1 4 3

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

- 250 - EJTP2042_pure.2.fid 3

Carbon 13 l

C 120000 D C 6 3 5 1 1 8 4 9 3 0 7 2 5 0 5

9 1 1 4 0 2 2 9 6 3 5 2 8 7 0 0 2 0 8 110000 ...... 2 6 7 9 6 8 0 2 2 1 1 9 9 9 8 5 4 2 6 . . . . 6 5 4 3 3 3 3 2 2 2 2 2 2 2 1 7 6 5 7

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 7 6 2 1 100000

90000 Me

80000

70000 O O 60000 N O O Me 50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 251 - EJTP2252_A_pure.1.fid Proto3 n 3 2 2 1 1 8 7 1 0 9 9 8 8 5 8 6 7 6 0 9 8 8 7 6 6 5 5 6 5 4 0 0 0 0 0 0 5 5 5 5 4 4 4 9 9 7 7 5 5 5 4 4 4 4 4 4 4 4 9 9 9

...... 19000 8 8 8 8 8 8 7 7 7 7 7 7 7 3 3 3 3 2 2 1 1 1 1 1 1 1 1 1 0 0 0 18000

17000

16000

15000 Me 14000 H 13000 D 12000 OH 11000

10000 O 9000

8000

7000

6000

5000

4000

3000

2000

1000

0

-1000 8 1 1 4 9 0 0 2 9 0 9 9 9 2 1 0 1 1 0 0 ...... 2 1 2 1 0 1 0 0 4 3

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 252 - EJTP2252_A_pure.2.fid 3

Carbon 13 l

C 140000 D C 3 6 0 7 2 . . . . .

2 9 4 2 4 4 0 130000 0 8 3 8 8 ...... 0 3 3 2 2 7 9 5 0 8 2 4

2 1 1 1 1 7 5 3 3 2 2 1 120000

110000

Me 100000 H 90000 D OH 80000

O 70000

60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 253 - A2.8 References

(1) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.

(2) Gassman, P.G.; Sowa, J.R. 1,2,3,4-Tetraalkyl-5-perfluoroalkyl-cyclopentadiene,

di-(perfluoroalkyl)-trialkylcyclopentadiene and transition metal complexes

thereof, U.S. Patent 5,245,064, Sep. 14, 1993.

(3) 3a-3j: Piou, T.; Rovis, T. J. Am. Chem. Soc., 2014, 136, 11292.

(4) 3k: Duchemin, C.; Cramer, N. Org. Chem. Front., 2019, 6, 209.

(5) Kim, J.D.; Lee, M.H.; Han, G.; Park, H.; Zee, O.P.; Jung, Y.H. Tetrahedron, 2001,

57, 8257.

(6) 2j: Tasukawa, T.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc., 2012, 134,

16963.

(7) 2k: Wonk, K.C.; Ng, E.; Wong, W.-T.; Chiu, P. Chem. Eur. J., 2016, 22, 3709.

(8) Cyclooctenol: Li, J.; Jia, S.; Chen, P. R. Nature Chemical Biology, 2014, 10, 1003.

(9) 2a-d1: Fox, R.J; Lalic, G; Bergman, R.G. J. Am. Chem. Soc., 2007, 129, 14144.

(10) 8a: Park, S. R.; Kim, C.; Kim, D.; Thrimurtulu, N.; Yeom, H.-S.; Jun, J.; Shin,

S.;Rhee, Y.H. Org. Lett., 2013, 15, 1166.

(11) 9a: Motokuni, K; Takeuchi, D.; Osakada, K.; Polym. Chem., 2015, 6, 1248.

(12) Blanc, E.; Schwarzenbach, D.; Flack, H. D. J. Appl. Cryst. 24 (1991), 1035-1041.

(13) Clark. R. C.; Reid, J. S. Acta Cryst. A51 (1995), 887-897.

(14) Version 1.171.38.46 (2015). Rigaku Oxford Diffraction.

- 254 -

(15) Sheldrick, G. M. Acta Cryst. A71 (2015), 3-8.

(16) Sheldrick, G. M. Acta Cryst. C71 (2015), 3-8.

(17) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H.

J. Appl. Cryst. 42 (2009), 339-341.

(18) Spek, A. Acta Cryst. D65 (2009), 148-155.

(19) CrystalMaker Software Ltd, Oxford, England (www.crystalmaker.com).

- 255 - – Appendix C –

Supporting Information for Chapter Four and Five

(1 equiv.) CF3 CF3 Ph O [Cp* RhCl2]2 O NPhth KOPiv (2 equiv.) Ph Rh Cl (5 equiv.) (1 atm) TFE, rt 4-1a 4-2a 4-4 83% (X-ray) In a flame-dried 1-dram vial equipped with a magnetic stir bar, 4-1a (5 equiv.),

CF3 [Cp* RhCl2]2 (1 equiv.), KOPiv (2 equiv.) were added and weighed in air. 2,2,2- trifluoroethanol (TFE) (0.2M) was added via micropipette and the vial was sealed with a teflon cap. The atmosphere was then replaced with ethylene gas and stirred at room temperature overnight. TFE was removed and the crude residue was purified by flash chromatography with silica eluting with Hexanes: Ethyl Acetate (9:1 to 4:1) giving the desired metal complex an orange oil. A crystal was grown by taking up 4-4 in DCM and layering pentane on top and letting the vial rest in the freezer (~-20 °C) overnight. The structure was proposed by the crystallographer and final data is still being worked up.

- 256 - O CF3

Ph Rh Cl

Chemical Formula: C20H21ClF3ORh

Yield: 83%

1H NMR (400 MHz, Chloroform-d) δ 8.21 – 8.14 (m, 2H), 7.60 – 7.43 (m, 3H), 5.37 –

5.26 (m, 1H), 4.78 (d, J = 10.2 Hz, 1H), 4.35 (d, J = 7.3 Hz, 1H), 3.61 (d, J = 12.4 Hz,

1H), 2.00 (d, J = 1.3 Hz, 3H), 1.58 (s, 3H), 1.49 (d, J = 1.1 Hz, 3H), 1.28 (s, 3H).

19 F NMR (282 MHz, CDCl3) δ -53.36

LRMS m/z (ESI APCI) calculated for C20H21ClF3ORh [M+H] 473.0, found 473.0.

- 257 - Me O (0.5 equiv.) OMe [Cp*MCl ] O N 2 2 N M AgOAc (2 equiv.) N MeOH (0.2M), 65 °C N O (2 equiv.) O 5-5a

In a flame-dried 1-dram vial equipped with a magnetic stir bar, 5-5a (2 equiv.),

[Cp*MCl2]2 (0.5 equiv.), AgOAc (2 equiv.) were added and weighed in air. Methanol

(0.2M) was added via micropipette and the vial was sealed with a teflon cap. The vial was then put in an aluminum heating block and stirred at 65 °C overnight. After letting the reaction cool, methanol was removed and the crude residue was purified by flash chromatography with silica eluting with DCM:MeOH (1% to 3% to 5%) giving the desired metal complex usually as an oil. Attempts at recrystallization are underway.

- 258 - OMe O Ir N N

O Chemical Formula: C21H25IrN2O3

Yield: 61%

1H NMR (500 MHz, Chloroform-d) δ 7.88 – 7.83 (m, 1H), 7.60 – 7.55 (m, 1H), 7.45 –

7.36 (m, 2H), 7.30 (q, J = 5.6 Hz, 1H), 3.82 (s, 3H), 2.46 (d, J = 5.7 Hz, 3H), 1.69 (s,

17H).

13C NMR (126 MHz, Chloroform-d) δ 177.8, 169.7, 155.8, 133.4, 132.0, 130.4, 130.4,

129.7, 128.3, 85.2, 52.4, 18.2, 8.9

LRMS m/z (ESI APCI) calculated for C21H25N2O3Ir[M+H] 547.2, found 547.2.

- 259 - EJTP2321_pure_Rhspot.1.fid 3

l 6000 C D C 5500 8 8 6 6 9 7 7 6 5 5 5 8 8 6 6 4 4 6 0 9 7 6 4 2 9 1 0 8 9 9 8 1 1 1 1 5 5 5 5 5 5 5 4 4 4 4 4 4 2 3 7 7 3 3 6 5 0 0 5 4 4 2 ......

8 8 8 8 7 7 7 7 7 7 7 7 7 7 7 7 7 7 5 4 4 4 4 3 3 2 2 1 1 1 1 5000

4500

CF3 4000 O

3500 Ph Rh

Cl 3000

2500

2000

1500

1000

500

0 0 0 6 5 0 1 2 0 1 0 8 0 0 0 2 0 0 0 0 0 ......

2 3 1 1 1 1 3 3 3 3 -500

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 260 - 10000 EJTP2321_Rh_fluorine.1.fid 6 3 . 3

5 9000 -

CF3 O 8000 Ph Rh Cl 7000

6000

5000

4000

3000

2000

1000

0

10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 f1 (ppm)

- 261 - EJTP3048_pure.1.fid 3 140000 l C D 130000 C

6 6 5 5 4 8 8 8 7 6 2 2 1 0 0 0 9 8 1 0 6 2 7 5 9 8 8 8 8 8 5 5 5 5 5 4 4 4 4 4 4 3 3 3 3 2 8 4 4 6

...... 120000 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 3 2 2 1

110000

100000

90000 OMe O 80000 Ir 70000 N N 60000

O 50000

40000

30000

20000

10000

0 3 6 6 4 1 0 0 1 . 9 9 1 9 2 -10000 0 ...... 4 1 0 2 0 2 2 1

13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 f1 (ppm)

- 262 - EJTP3048_pure.2.fid 160000 3 l C 150000 D C 8 7 8 4 0 4 4 7 3 ......

2 2 4 2 140000 7 9 5 3 2 0 0 9 8 . . . . 9 7 6 5 3 3 3 3 2 2 5 7 2 8 .

1 1 1 1 1 1 1 1 1 8 7 5 1 8 130000

120000

110000

OMe 100000 O Ir 90000

N N 80000

70000 O 60000

50000

40000

30000

20000

10000

0

-10000

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

- 263 -