rhodium(iii)-catalyzed difunctionalization of alkenes

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.

i

– 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

ii

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

iii

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

iv

– 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

v

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

vi

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

vii

– 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.

viii

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.

ix

Dedicated to:

My Grandfather, Carl Eric Thorngren

- 1 -

– 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.

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,

H

BDE(kcal/mol)

H

110.9110.0

R

R

HRR

R H

93.295.1

R H

98.2

pKa 434450 55 71

I

51

>>

- 2 -

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.

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

Ln Mn+2Ln MnH

R

OO

Me

MnR

H OO

Me

R

H HOO

Me

R

Pathway 1: Oxidative Addition

Pathway 2: Concerted Metallation-Deprotonation (CMD)

Ln

Mn

Ln

Mn

Ln

R

H

- 3 -

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.

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

HH

H

H

H

H

H

H

H

R Me

H

H

H

- 4 -

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

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

O

O

Me

DGH

Rh

DG HH

H

OO

Me

Rh

DG Rh

DG H

H

FG

FG

cat. [RhIII]

Base

Rhodacycleintermediate

Functional GroupInstallation

- 5 -

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.

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

N

OR

H H R

R N

OR

RR

(2.5 mol%)[Cp*RhCl2]2

Cu(OAc)2 • H2O (2.1 equiv.)t-AmylOH, 110 °C

Cp*

N

OR

RR

RhI

OO

R

RhIIIAcO

O O

Me

N

OR

H Cp*

RhIII

N

OR

Cp*RhIII

NO

R R

Cp*

R

R R

NH

OR

AcOH

AcOH

R R

2 CuII(OAc)2

N

O

RR

N–HDeprotonation

CMD andAssociation

MigratoryInsertion

ReductiveElimination

Re-Oxidation

2 CuI

R

Cu(OAc)2

[Cp*RhCl2]2

RhIII

Rovis 2010: Oxidative Cyclization of Benzamides and Alkynes via C–H/N–H Activation

- 6 -

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.

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

N

OOMe

H H R

R NH

O

RR


CsOAc (25 mol%)MeOH, 60 °C

N

OOPiv

H H R

R NH

O

RR


CsOAc (25 mol%)MeOH, rt

Fagnou 2010: Installation of Internal Oxidant

Fagnou 2011: Optimization of Internal Oxidant

- 7 -

followed by oxidative addition of the N–O bond. Finally, protodemetallation

furnishes the product and regenerates the catalyst.

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

OO

R

RhIIIAcO

O O

Me

N

OOPiv

H Cp*

RhIII

N

OOPiv

Cp*

RhIIIN

O

R R

Cp*

OPiv

Cp*

N

OOPiv

RR

RhI

R R

Cp*

N

O

RR

R = Me or t-Bu

RhIII

OPiv

NH

OOPiv

AcOH

AcOH

R R

AcOH

NH

O

RR

N–HDeprotonation

CMD andAssociation

MigratoryInsertion


OxidativeAddition

Proto-demetalation

ReductivePathway

CsOAc

[Cp*RhCl2]2

RhIII

- 8 -

have given new insights. 7 The major difference comes from the C–N bond

forming event being reductive or oxidative in nature.

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

Cp*

N

O

RR

RhIII

OPiv

RhVN

O

R R

Cp*OPiv

OO

R

RhIIIAcO

O O

Me

RhIII

N

OOPiv

H Cp*

RhIII

N

OOPiv

Cp*

RhIIIN

O

R R

Cp*

OPiv

R R

R = Me or t-Bu

NH

OOPiv

AcOH

AcOH

R R

AcOH

NH

O

RR

N–HDeprotonation

CMD andAssociation

MigratoryInsertion

OxidativeAddition/Nitrene

Formation

ReductiveEliminationOxidative

Pathway

CsOAc

[Cp*RhCl2]2

Proto-demetalation

“oxidative inducedreductive elimination”

- 9 -

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

- 10 -

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

R

Electronically Tuned Cp Ligands

Sterically Tuned Cp Ligands

R

Ph PhPh

t-Bu t-Bu R = t-Bu Cyi-Pr

R = H Ph

CF3EtO2C CO2Et

CF3

CF3

PhPh

Ind*

CyCpCpTM CptriPh or CptetraPh

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

Cp*diPh

CpE Cp*CF3 Cp*bisCF3

- 11 -

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,

- 12 -

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.

– 13 –

– 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

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.

HHOMe

H

MeMe

OH

(+)-Omphadiol

Me

Me

Me

HMe

O

Me

OMe

OMe

Et

O

Me

(+)-Crispatine

H MeOH

Me

i-Pr

(–)-Cubebol

Selected Examples of Cyclopropane-containing Natural Products

– 14 –

Furthermore, starting alkene geometry can translate to stereodefined cyclopropane

products.

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

CR

R

R

RC

H

H

H

H

Alkenes2-carbon unit

Carbenes1-carbon unit

[2+1] Annulation

EWG EDG Me

MeRR

∂+

∂-∂-

∂+

Challenging:Chemically

Inert

StereodefinedCyclopropanes

cat. or stoich. [M]

– 15 –

distinguish between the two alkenes and perform in good yield. Uyeda demonstrated the

power of this method on a number of similar unactivated alkenes.

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.

[Zn] RR’ R’

X X

R’ R’

R

Simmons-Smith

[Zn]

R’ R’X

Generation ofZinc-Carbenoid

Species

ZnEt2CH2I2

DCM, rt

53%; 1 : 6.5

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

CH2Br2Zn0

THF, rt 81%; >50 : 1

– 16 –

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.

Figure 2.4 Metal catalyzed diazo decomposition of unactivated alkenes.

PMP

N2

OMe

OPMP

OMe

O

PMP

PMP[Cp*RhI2]2 (1 mol%)

pentane, rt

76%>20:1 d.r.

N2

R’ R’ [M] cat.

[M]

R’ R’ R R’ R’

R

Diazo Decomposition

Catalytic Generationof Metal-Carbene

Species

CO2MePh

N2 Me

Me

MeMe

CO2MePh

[Rh2(S-DOSP)4] (1 mol%)

pentane, rt

52%95% ee

– 17 –

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

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.

Ar

OEWG

up to >20:1 d.r.

-trans-diastereoselective cyclopropanation

Ar O N

O

OEWG

[Cpi-PrRhCl2]2 (5 mol%)

CsOAcTFE, rt

RhCl Cl

i-Pr

2

– 18 –

‘

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

ArO

NO

O

ON

ORh

Ar

OCp

ON

RhH

Ar

O

O

ON

Ar

O Rh

Cp

EWGO

ON

ArO

EWGO Rh

Cp

H

ON

ArO

O RhI

Cp

EWG

N

O

O Cp

RhO

Ph

EWG

EWG

Cp

OMeO

RhAcO

OMe

O

i-Pr

ONPh

O

EWG

ORhH

Cp

ON

ArO

EWGORh

H

Cp

EWGAr

OOAc

EWG

HOAc

CsOAc

[Cpi-PrRhCl2]2

HOAc

OAc

OAcOAc

OAc

OAc

– 19 –

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

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.

Figure 2.8 Enantioselective cyclopropanation.

Ar O N

O

O Cl

Cl

Ar

OEWG

EWG

up to >1:20 d.r.

[Cp*CyRhCl2]2 (5 mol%)

NaOAcTFE, rt

RhCl Cl

Cy

2

-cis-diastereoselective cyclopropanation

R O N

O

O

R

OEWGEWG

Me

OO

Me

MeMe

(5 mol%)

(BzO)2CsOAc, TFE

Rh

up to 97.5:2.5 e.r.

-Enantioselective cyclopropanation

– 20 –

In an effort to expand the scope of this transformation, we set out to examine

stereodefined cyclopropanation of unactivated olefins.

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.

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

R’OR NPhth R

O

cat. [RhIII]

BaseR RR’* *

Ph O NPhthMe

n-Bu(5 mol%)

[Cp*RhCl2]2

CsOAc (2 equiv.)TFE (0.2M), rt

Ph

O

n-Bu

Me

2-1a 2-2j 2-3aj62%

1:1 d.r.

– 21 –

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

82%.

– 22 –

Scheme 2.1 Cp Ligand screen.

CF3

CF3

Ph O NPhthMe

n-Bu(5 mol%)

[CpXRhCl2]2


Ph

O

n-Bu

Me

2-1a 2-2l 2-3al; 1:1 d.r.

Ind*0%

Cp*62%

TMS

Cp*TMS

0%

t-Bu

Cp*t-Bu

0%

i-Pr

Cp*i-Pr

0%

CF3

Cp*CF3

82%

C3F7

Cp*CF3

38%

Cp*dip-F

24%

F

Cp*dibisCF3

75%

CF3

CF3

F

CyCpdiPh

18%

Ph

Ph

CyCpMe/C6F5

58%

Me

C6F5

CyCpdibisCF3

80%CF3

CF3CF3

CF3

PMP

Cp*PMP

0%

C6F5

Cp*C6F5

75%Cp*bis(o-F)

34%

F

F

– 23 –

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

– 24 –

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.

Ph O NPhthR

R(5 mol%)

[Cp*CF3RhCl2]2


Ph

O

R

R

Ph

OCN

CN

Ph

O

Ph

O

Ph

O

Ph

O

Ph

O

Et

Et

2-3ab56%

2-3ac87%

2-3ad98%

2-3ae70%

2-3af53%

2-3aa40%

Ph

ONTs

2-3ai97%8.6:1 d.r.

2-3ag72%

Ph

ONBoc

2-3ah84%

2-1a 2-22-3

Ph

Ph

O

– 25 –

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.

O

Me

2-3bd97%

OMe

2-3ed75%

OF

2-3hd59%

O

2-3id67%

O

2-3jd92%

Ph

OF

2-3fd90%

OMeO

2-3gd67%

O

t-Bu

2-3cd89%

O

F

2-3dd96%

R O NPhth

(5 mol%)[Cp*CF3RhCl2]2


R

O2-1 2-2d 2-3

– 26 –

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.

– 27 –

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%

Ph

O

n-Bu

MePh

On-Oct

2-3aj82%

1:1 d.r.

2-3ak17%

1:1 d.r.

2-3am58%

1:1 d.r.

Ph

O

i-Pr

MePh

OPh

2-3al83%

1:1 d.r.

Ph O NPhth

R

R



Ph

O

R

R

2-1a 2-2 2-3

R R

Ph

On-Pr

2-3aq10%

n-Pr

Ph

O

2-3ap14%

1:1 d.r.

Ph

O2-3ar63%

single diastereomer

H

HPh

O

Bn

Me

2-3at41%

1:1 d.r.

Ph

O

Ph

Me

2-3as0%

Ph

O

2-3ao16%

1:1 d.r.

OPh

OOAc

2-3an0%

Ph

O

n-Bu

n-Bu

2-3au12%

– 28 –

yield. From the analysis of the product, we observe a reversible deuterium exchange

event at the alpha-position (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.

Ph

H/DH2-1a0% D

incorporation


CsOAc (2 equiv.)TFE-d1 (0.2M), rt

O



Ph

O2-3ad’, 85%

54% Dincorporation

D

Deuterium Labeling Studies-Reversibility of C–H activation

-Deuterium incorporation

N

Ph O NPhth

2-1a 2-2d

Ph O N

O

O

2-1a

O

O

– 29 –

Figure 2.12 Dioxazoline formation and intermediacy test.

2-4, 59%

Ph O N

O

O

CsOAc (2 equiv.)

TFE (0.2M), rt

2-1a

Ph

O



O

O NPh

Me

O

OF3C

2-3ad2%

Isolation of Off-cycle Intermediates-Dioxazoline formation

-Compatibility of 2-4

2-2d2-4

O

O NPh

Me

O

OF3C

OO N

HPh

OO

F3C

Acylation

± H

Cyclization

± H

Key Intermediate

– 30 –

2.7 Proposed Mechanism

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

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,

OR NH

O O

O

CF3

Rh

OAcO

O

CF3Me

[Cp*CF3RhCl2]2

CsOAc

I

OR N O O

O

RhCp*CF3O

IIIH

Ac

CF3

HNO

O

O

RhCp*CF3

F3C

R

R

RO

R

O

R

R

OAc

CsOAcTFE

V

IV

II

OR N O O

O

RhCp*CF3O

Ac

CF3

H HH

2-3

HOAc

2-2 OR N

RhCp*CF3

H R

R

HNPhth

TFE+

O

OF3C

O

HOAc

OAc

R O NPhth

2-1

R

R

2-4

O

O NPh

Me

O

OF3C

– 31 –

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.

– 32 –

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.

– 33 –

(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.

– 34 –

(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.

- 35 -

– 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.

- 36 -

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.

R OH

Allylic Alcohols

R OH

R OHN2

R’ R’R’R’

R1 O

Simmons-Smith Diazo Decomposition

[M] cat.

R’

R’

+

R’R’[Zn]

XR'X

R'

- 37 -

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

R2 OH

R3

R1

R2 OH

R3

R1

ZnEt2, ZnI2, CH2I2

NH

HNMs

Ms(10 mol%)

up to 89% ee

R2 OH

R3

R1

R2 OH

R3

R1

19 examplesup to 92% ee

State-of-the-Art Selected Cyclopropanation of Alkenes

OTiO

OO

i-PrO Oi-Pr

PhPhPh

Ph

EtEt

(25 mol%)

Zn(CH2I)2DCM, 0 °C

Simmons-Smith: Asymmetric methylenation

Diazo-Decomposition: Asymmetric cyclopropanation of protected allylic alcohols

N NCu

OO

t-Bu t-BuMe OBn

Me

Me OBn

Me

EtO2C

MeMe

ON

O

MeO2C

Rh

Rh4

(1 mol%)

N2CHCO2Et

N2CHCO2Et

74%98% ee

Ph OMe Ph OMe

EtO2C

95%

OTf

(1 mol%)

- 38 -

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.

Figure 3.3 Limitations of competitive cyclopropanation strategies.

R2 OHZn

I

II • Et2O

R3

R1

R2 OH

R3

R1I

Simmons-Smith Substituted Methylene Transfer: Limited-Charette: iodocyclopropane synthesis

R2 OHZn

PinB

IO

R3

R1

R2 OH

R3

R1PinB

-Charette: Borylcyclopropane synthesis

OCF3

Diazo-Decomposition: Outcompeted by O–H insertion

OHO

CO2EtOH

CO2EtH(0.5 mol%)Rh2(OAc)4

neatN2

CO2Et

77% 6%

- 39 -

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

Figure 3.4 Previously described transformations with N-enoxyphthalimides.

Ar

OEWG

up to >20:1 d.r.

-trans-diastereoselective cyclopropanation

Ar O N

O

OEWG

[Cpi-PrRhCl2]2 (5 mol%)

CsOAcTFE, rt

RhCl Cl

i-Pr

2

Ar O N

O

O Cl

Cl

Ar

OEWG

EWG

up to >1:20 d.r.

[Cp*CyRhCl2]2 (5 mol%)

NaOAcTFE, rt

RhCl Cl

Cy

2

-cis-diastereoselective cyclopropanation

Ar ORR

[Cp*t-BuRhIII]

1-AdCO2CsMeOH

O NRh

Ar

O OMe

O

R R

Ar

O RR

NPhthCp*t-Bu

NPhth

-syn-1,2-carboamination

- 40 -

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.

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

R

OH

OR NPhth R

O

R

OH

cat. [RhIII]

Base* *

- 41 -

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

EtO2C CO2Et

CpE

45%Cpi-Pr

42%

C6F5

t-Bu

Cp*t-Bu

22%

Cp*C6F5

45%

Ind*0%

t-But-Bu

Cpt

6%Cp*24%

CF3

Cp*CF3

50%

i-Pr

Ph

Cp*Ph

38%

n-Pr

OH

Ph

O OH

Ph O NPhth


KOAc (2 equiv.)TFE (0.2M), rt

n-Pr

3-1a 3-2a 3-3aa

- 42 -

leads to the desired cyclopropane in 81% yield while preserving excellent

diastereoselectivity (entry F).

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

n-Pr

OH

Ph

O OH

Ph O NPhth


Base (2 equiv.)Solvent (0.2M), Temp

n-Pr

Base Solvent Yield

KOAc TFE

MeOH

THF

KOAc

KOAc

KOPiv TFE

Temperature

KOPiv TFE

KOPiv TFE

rt

rt

rt

rt

60 °C

0 °C 81%

64%

29%

36%

50%

11%

Entry

A

B

C

D

E

F

3-1a 3-2a 3-3aa

- 43 -

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

stereospecific transformation.

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.


KOPiv (2 equiv.)TFE, 0 ˚C

n-Pr

OHn-Pr

Ph

O OH

3-3aa81%>20:1 d.r.

Ph O NPhth

n-Pr OH

n-Pr

Ph

O OH

3-3ab62%>20:1 d.r.

3-1a

3-2a

3-2b

- 44 -

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.

Ph

O

Me

HOPh

O OH

MeMe

3-3ad62%

7.0:1 d.r.3-3ae82%

>20:1 d.r.

R

OH

Ph

O

R RR

ROH

RPh O NPhth


KOPiv (2 equiv.)TFE, 0 °C

Me

Ph

O OH3-3ac81%

>20:1 d.r.

3-1a 3-2 3-3

- 45 -

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

R O NPhth



O OH

n-PrMe

3-3ba72%

>20:1 d.r.

O OH

n-Pr

Me

3-3ga50%

>20:1 d.r.

O OH

n-Pr

3-3fa93%

>20:1 d.r.

O OH

n-Pr

3-3ja50%*

>20:1 d.r.

O OH

n-Pr

3-3ka92%

>20:1 d.r.

Ph

n-Pr

OH

R

O OH

n-Pr

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

O OH

n-Pr

F

3-3ha54%*

>20:1 d.r.

O OH

n-Pr

3-3ia44%*

>20:1 d.r.

O OH

n-Prt-Bu

3-3ca76%

>20:1 d.r.

O OH

n-PrF

3-3da69%

>20:1 d.r.

O OH

n-PrMeO

3-3ea77%

>20:1 d.r.

3-1 3-2a 3-3

F

MeO

- 46 -

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.

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

R

OH

Ph

O OH

Ph O NPhth



Me

Ph

O OH

HMe

3-3ai88%

>20:1 d.r.

n-Pr

Ph

O OH

HPh

3-3aj75%

>20:1 d.r.

n-Pr

Ph

O OH

HCy

3-3ak95%

>20:1 d.r.

Ph

O OH

H

3-3af73%

2.5:1 d.r.

Ph

O OH

HMe

3-3ag69%

7.1:1 d.r.

Ph

O OH

HPh

3-3ah62%

>20:1 d.r.

R RH

R

Ph

O OH

RH

R

or

3-1a 3-2 3-3

(Major) (Minor)

- 47 -

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.

- 48 -

Figure 3.8 Comparison of secondary, cyclic allylic alcohols.

OH

HHOH

CH2I2

Zn-Cu coupleOH

HH

OH OH OHHHH H

CH2I2

Zn-Cu couple

74%; 0.5 : 99.5

syn anti

71%; >99 : 0

no reaction

85%>20:1 d.r.

OH

Ph

OH

H

OH

Ph

OOH

H

H

OH



Ph

O NPhth

HO

HH

Zn

I

HO

HH

O

ONH

Rh

Ar

O

Cp*CF3

- Chair-boat conformers

Simmons-Smith Model Our Model

- Selectivites of cyclic allylic alcohols under Simmons-Smith conditions

- 49 -

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.

- 50 -

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

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

Ph

O OH

Me

Me

Me

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

Ph

O OH

Me

Me

Me

Ph O NPhth


KOPiv (2 equiv.)TFE, 0 °C,

Me

Me

Me

OH

Me

Me

Me

OH

Ph O NPhth


KOPiv (2 equiv.)TFE, 0 °C,

n-PrPh

O

Ph O NPhth



n-Pr

3-5aa 12%>20:1 d.r.

n-Pr

Ph

O

Ph O NPhth



n-Pr

3-7aa17%>20:1 d.r.

OHOH

OH OH

Regioselectivity-Tether length

-Chemoselectivity test

3-4a

3-5a

3-1a

3-1a

3-2m3-1a

3-2n3-1a

- 51 -

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.

- 52 -

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.

n-Pr

Ph

O

Ph O NPhth



n-Pr

3-9ac77%

9.5:1 d.r.

NTsH NTsH

n-Pr

Ph

O

Ph O NPhth



n-Pr

3-9aatrace

OMe OMe

n-Pr

Ph

O

Ph O NPhth



n-Pr

3-9abtrace

CO2H CO2H

Nucleophilic Attack

3-8a3-1a

3-8b3-1a

3-8c3-1a

- 53 -

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.

Ph O NPhth


KOPiv (2 equiv.)TFE-d1, 0 °C,

HH

Ph O NPhth

H/DD/H0% D

Incorporation

Ph O NPhth



n-Pr

OH

Ph

O OH82%

D

H Hn-PrD

Deuterium Labeling Studies

- 54 -

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.

OO

Me

O

O N

PhMe


KOPiv (2 equiv.)TFE, 0 °C or rt

Me

Ph

O OH

3-3acnot detected

Isolation of off-cycle products

OO

Me

O

O N

PhMe

KOPiv (2 equiv.)

THF, rtOH

MeOPh N

O

O

3-10ac38%

3-2c3-1a

3-10ac

- 55 -

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.

- 56 -

Figure 3.13 Proposed mechanism.

Rh

OPivO

t-BuO

CF3

R

OH

KOPiv

KOPiv

+

O O

NH

OOR

R

RhNH

H

RH

H

OR

O

OO

R

R

O

OO

OOHt-Bu

PivOH

R

O

R

R

RH

KOPiv, 0 °C

HNPhth

RhN

ORO

OO

R

R

R

OH

R R

R O NPhth

F3CF3C

[Cp*CF3RhCl2]2

> 23 °C

NOR

H RhO

t-Bu

OCF3

H

O

O

O

R

R

Rh NHF3C

O

H

H

OO

R R

O

O N

RMe

PivOH

II

I

III

IVV

VI

3-1

3-2

3-3

3-10

- 57 -

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.

- 58 -

(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,

- 59 -

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.

- 60 -

– 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.

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.

Figure 4.2 Formation of Rh-π-allyl complex.

Ph O NPhth


CsOAc (2 equiv.)TFE, rt

Ph

O(1 atm)

trace4-1a 4-2a 4-3aa

Ph

O

RhCl

CF3Ph O NPhth

(1 equiv.)[Cp*CF3RhCl2]2

KOPiv (2 equiv.)TFE, rt

4-483%(X-ray)

(1 atm)(5 equiv.)4-1a 4-2a

- 61 -

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).

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

Ph

O

RhCl

Cp*CF3

RhCp*CF3

NOPh

Rh

Cp*CF3

NO

Ph

MigratoryInsertion

HRh

Cp*CF3

NO

Ph

H

Rh

Cp*CF3

OPh

NH

Beta-HydrideElimination

Ph

O

RhNH

Cp*CF3

IsomerizationChlorineSubstitution

Sigma BondMetathesis

- 62 -

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.

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.

Ph

O

RhCl

Cp*CF3


(5 mol%)Ph O NPhth Ph

O4-3ab9%

π-allyl species canact as a catalyst

4-2b4-1a

- 63 -

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

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.

Figure 4.7 Catalyst-dependent regioselective allylic amination of alkenes.

RON

O

R'

O

R

HN

O

R'H

[Cp*IrCl2]2 (2.5 mol%)AgNTf2 (15 mol%)

LiOAc (2 equiv.)DCE, 35 °C

RIr

Cp*

ONO

R'

O

RIr

Cp*

NO

R'

- CO2

nitreneformation

RON

O

R'

O

R

HN

O

R'H

[Cp*IrCl2]2 (2 mol%)AgSbF6 (10 mol%)

AgOAc (10 mol%)DCM, 40 °C

RR

R

ON

O

R'

O

R

HN

O

R'

R

HN

O

R'H

(2.5 mol%)[Cp*IrCl2]2

AgSbF6 (15 mol%)

CsOAc (5 mol%)DCE, 40 °C

(5 mol%)[Cp*Rh(MeCN)3](SbF6)2

AgSbF6 (15 mol%)

CsOAc (5 mol%)DCE, 40 °C

Linear Branched

- 64 -

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).

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.

RHN R

O

O

R

Ph

O

RhX

Cp*CF3(5 mol%)[Cp*CF3RhCl2]2


R O NPhth R

ON O

R

O

R4-1 4-24-5

4-6

- 65 -

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

Ph

O

Rh

Cp

R

O RhH

CpN

OO

O

F3C

R

ORh

CpN

OO

O

F3C

RO Rh

CpN

OO

O

F3CON

ORO

Ph

O

Rh

Cp

N

OR

RhPivO

Ot-Bu

O

CF3R

ONH

OO

O

F3C

R

ONPhth

RHN R

O

OKOPiv

TFE

4-1

ON

ORO

HNPhth

TFE

KOPiv

[Cp*CF3RhCl2]2

CMD

MigratoryInsertion

Beta-HydrideElimination

π-AllylFormation

NitreneFormation


PivOH PivOH

I

II

III

IV

V

VI

VII

4-2R

R

R

R

R

R

R

4-5

4-6

- 66 -

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.

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

Ph NAcO

Ph O NPhth

(10 mol%)[RhIII]

Additive (50 mol%)

CsOAc (X equiv.)TFE, rt

ON

O

Me

O H

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

0%

[Cp*RhCl2]2

[Cp*CF3RhCl2]2

0.2

0.2

2

2

100%

100%

AgSbF6

AgSbF6

[Cp*RhCl2]2

[Cp*CF3RhCl2]2

AgSbF6

AgSbF6

2

2

[Cp*RhCl2]2

[Cp*CF3RhCl2]2

none

none

26%

4-1a 4-2a4-5a

56%

12%

10%

A

B

C

D

E

F

- 67 -

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.

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.

Ph NO

NPh O NPhth


AgSbF6 (50 mol%)


ON

OMe MeMe N

HOPivTs N3TsN

HOPivBoc

NitrenoidSource

0%

- 68 -

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.

Ph

O

RhCl

Ph O NPhth

(1 equiv.)[Cp*RhCl2]2


0%

4-2a(1 atm)

4-1a(5 equiv.)

- 69 -

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

Ph

O

RhCl

CF3 O N

O MeO

Ph NAcO

Ph

O

NAcKOPiv (2 equiv.)TFE, rt

0%

(2 equiv.)

Ph

O

RhCl

CF3 O N

O MeO

Ph NAcO

Ph

O

NAcAgSbF6 (2 equiv.)DCE, 40 °C

0%

(2 equiv.)

HH

HH

4-4

4-5a

4-4

4-5a

- 70 -

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

[Cp*CF3RhCl2]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.

ONO

R'

O NO

R'

- CO2

nitreneformation

O

Ph

O

PhRh

R

Rh

R

Ph O NPhthRhIII

R

π-allylformation X

O

Ph Rh

R

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

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

- 71 -

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

- 72 -

– 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.

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

Ph

OE

N

E

1-AdCO2Cs (1 eq.)MeOH, rt

Toluene, 60 °C

Ph

O N

O

O E

E

RhMeCN NCMe

NCMe

t-Bu (SbF6)2

(5 mol%)

I)

II)

O O

- 73 -

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.

- 74 -

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

Ar

O

HN

E

O

OMe

O

E

Ar

O

N

EE

OO

HN

OAr

O

O

OMe

NOAr

O

O

OMe

RhH

NOAr

O

O

MeO

RhE

E t-Bu

NO

Ar O

O OMeRhE

E

t-Bu

O

E E

Ar

N

O

O

OMe

Rh

t-Bu

ORhN

EE

Ar

O

O

OMe

t-Bu

Rh

O2CROR

Ot-Bu

t-BuO

R

O

CsO2CR

[Cp*t-BuRh(NCMe)3](SbF6)2

R =

E

E

RCO2H

- MeOH

RCO2H

NO

Ar O

O OMeRhE

E

t-Bu

+ MeOH

Ar ON

O

O

Toluene∆

Oxidative Nitrene

Formation


- 75 -

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.

- 76 -

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.

OAr NPhthAr

Ar cat. [Au]

DCE, 80 °C

OR N

HO NPhth

O

O

HO N

O

O

N NH2N NO

R R

PG PG

HO N PG NO PGO

R

OHO

R

4 Steps

- Traditional synthesis of N-enoxyphthalimides

- Cramer’s Au-catalyzed one-step synthesis

- N–N bond internal oxidant: N-iminoamines

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

H

H

- 77 -

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.

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

E

NOH

PGO

R

NO PGO

R

Rh

O NRh

E

PGO

R

O Rh NO

R E

PG

E

NH

R

PG

RhO OAc

O

Cp*

Cp*

Cp*

RAcOH

E

NO

E

O

R

PG

Rh

Cp*

OxidativePathway

CMD

MigratoryInsertion

NitreneFormation


Proto-demetallation

OxidativeAddition

I

II

III

IV

IV’

5-1

5-2

5-3

HO O

ON

E

O

R

PGRh

Cp*V

2 AcOH

ReductivePathway


- 78 -

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).

Scheme 5.1 Carboamination screens in methanol.

NO

MeO

5-1a

CO2Me

CO2Me

HN

5-2a proposed 5-3aa

HO O

O

OO O

OMe(5 mol%)[Cp*RhCl2]2

KOAc (X equiv.)Additive (1 equiv.)MeOH, temp.

Entry Base equiv. Temp Additive 5-3aa yield

1

1

rt

40 °C

65 °C

40 °C

trace

14%

none

none

1 none

AcOH

40 °C

40 °C

0.2

2.5

none

none

7%

8%

7%

10%

A

B

C

D

E

F

1

- 79 -

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.

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

NO

MeO

5-1a

CO2Me

CO2Me

HN

5-2a proposed 5-3aa

HO O

O

OO O

R(5 mol%)[Cp*RhCl2]2

KOAc (X equiv.)Additive (20 mol%)Solvent, 40 °C

Entry Base equiv. Solvent Additive 5-3aa yield

1

1

TFE

DCE

7%

0%

none

none

1 none

none

TFE

TFE

2.5

2.5

none

AgSbF6

0%

0%

24%

18%

G

H

I

J

L

1

THF

HFIP

K

- 80 -

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.

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

HNHO O O O

OR

CO2MeH

H H ddd

NH

O

CO2Me

O ONPhthO

MeO CO2Me

CO2Me

HNHO O O O

O(5 mol%)[Cp*RhCl2]2

KOAc (2 equiv.)AgSbF6 (1 equiv.)

TFE, 40 °C

CF3F3C

5-3aa0%

5-4aa23%

isolated

5-1a 5-2a

- 81 -

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.

Figure 5.6 Proposed divergent C–H functionalization.

ROO

O

O Me

H RhN

H

OO O

N O

MeO

ORO O

ORh

NRh

OO

OORO

Higher pKaStable intermediate

O

Me OH

HOMe

(sp2) C–Hbond

activation

(sp3) C–Hbond

activation

Lower pKaUnstable intermediate

- 82 -

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.

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.

NPhth

Me

N CO2Me

(5 mol%)[Cp*RhCl2]2

AgOAc (2 equiv.)MeOH, 65 °C

NCO2Me

CO2Me

HN

HN

O

OMe

O

Cyclic Acyclic

5-5a 5-2a 5-6aa 5-7aa

Not Observed

- 83 -

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

NM

N

O OMe

O

Me

N N

O

O

(0.5 equiv.)[Cp*MCl2]2

AgOAc (2 equiv.)MeOH, 65 °C

5-8aa Co = 0%5-8ab Rh = 73%5-8ac Ir = 61%

NH

Me

NO

OMe

ONM

N

O OMe

O

HAcO

+ MeOH

Ring Opening

Coordination

CMD

(2 equiv.)5-5a

- 84 -

is formed by reductive elimination. Cleavage of the N–N bond after protonation turns

over the catalyst.

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.

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

N NAr

MeH

Boc

HN NAr H

BocNRh

HN Boc

Ar

R

R

R

R


Na2CO3 (25 mol%)

AcOH (3 equiv.)MeCN, 120 °C

HNR

ArR

NRh

NBocAr H

RR

NPhthN

E

cat.[Cp*MCl2]2

AgOAc AcOH

MeOH, 65 °C

NE

E

HN

HN

O

OMe

O

Cyclic Acyclic5-5 5-2

R R

R

- 85 -

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.

- 86 -

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.

- 87 -

– Appendix A –

Supporting Information for Chapter Two

- 88 -

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

- 89 -

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.

- 90 -

A1.2 Synthesis of Starting Materials

Synthesis of [Cp*CF3RhCl2]2 Catalyst2, 3

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

Figure 1.

This procedure was performed according to literature precedent.

Synthesis of [Cp*CF3RhCl2]2

Figure 2.


Me Me

Br Li0 wire

Et2O, 0 to -40 ˚CF3C OEt

O Me Me

Me Me

OHF3C Me

MeMe

CF3

MeMeSO3H

DCM, 0 ˚C

+ isomers

RhCl3 • 3 H2OMe

MeMe

CF3

Me

+ isomers

MeOH, ∆F3C

ClRh

ClCF3

ClRh

Cl

- 91 -

Synthesis of N-enoxyphthalimides

Method A4 (1a-1i)

Figure 3.


Method B5 (1j)

Figure 4.


Ar Ar Br

Br

Ar Br

OAr NPhth Ar B(OH)2

Br2

DCM, 0°C

K2CO3

MeOH:THF (1:1)

t-BuLiB(O-iPr)3Et2O-78 °C to rt

HO–NPhthCu(OAc)2 • H2O

Na2SO4

pyridine1,2-DCE

O2, rt

O NPhthBnBn HO NPhth

(5 mol%)[PPh3AuTFA]

1,2-DCE (0.2M)90 °C

- 92 -

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

Figure 5

This procedure was performed according to literature precedent.7

R R

O

R R

Ph3PCH3Brn-BuLi

Et2O, 0 °C to rt

NTs

NBoc Ph

2e 2f 2g 2h 2i

- 93 -

A1.3 General Procedure for the Cyclopropanation Reaction and Characterization

of Products

Figure 6.

N-enoxyphthalimide (0.1 mmol), catalyst [Cp*CF3RhCl2]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

R

R(5 mol%)[Cp*CF3RhCl2]2


R

O

R

RR O NPhth

- 94 -

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.

Ph O NPhthn-Bu

Me(5 mol%)

[Cp*CF3RhCl2]2

Base (2 equiv.)TFE (0.2M), rt

Ph

O

n-Bu

Me

1:1 d.r.

BaseEntry

(1.2 equiv.)

Yield

KOPiv

KOAc

1-AdCO2K 66%

76%

59%

CsOAc

NaOAc 73%

LiOAc 64%

82%

1

2

3

4

5

6

- 95 -

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

Ph O NPhthR'

R(5 mol%)

[Cp*CF3RhCl2]2


Ph

O

R'

R

1:1 d.r.(1.2 equiv.)

Ph

O

Ph

O

n-Bu

Me

Ph

On-Oct

Ph

O

i-Pr

Me

Alkene Product

n-Bu

i-Pr

n-Oct

Me

Me

H

NMR Yield d.r.

1:1

1:1

1:1

- -

82%

17%

58%

99%

- 96 -

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.

- 97 -

Characterization of Products

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

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).

13C 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.

Ph

O

EtEt

Chemical Formula: C14H18OExact Mass: 202.14

- 98 -

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


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).

13C 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.

Ph

O CNCN

Chemical Formula: C15H12N2OExact Mass: 236.09

- 99 -

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


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).

13C 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


Ph

O


- 100 -

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



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).

13C 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


Ph

O


- 101 -

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


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).

13C 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


Ph

O


- 102 -

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



(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).

13C 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


Ph

O


- 103 -

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

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).

13C 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.

NTsPh

O

Chemical Formula: C21H23NO3SExact Mass: 369.14

- 104 -

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



(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).

13C 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.

NBocPh

O

Chemical Formula: C19H25NO3Exact Mass: 315.18

- 105 -

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

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


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).

13C 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


Ph

OPh


- 106 -

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


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).

13C 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


O

MeChemical Formula: C16H20O

Exact Mass: 228.15

- 107 -

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



(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).

13C 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


O

t-BuChemical Formula: C19H26O

Exact Mass: 270.20

- 108 -

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



(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).

13C 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.

O

FChemical Formula: C15H17FO

Exact Mass: 232.13

- 109 -

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


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).

13C 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


O

MeChemical Formula: C16H20O

Exact Mass: 228.15

- 110 -

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


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).

13C 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.

O

OMeChemical Formula: C16H20O2

Exact Mass: 244.15

- 111 -

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


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).

13C 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


O


Exact Mass: 232.13

- 112 -

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


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


O


Exact Mass: 232.13

- 113 -

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


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).

13C 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


O


- 114 -

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



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).

13C 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


OBn


- 115 -

A1.4 Mechanistic Experiments

Figure 7.

N-enoxyphthalimide 1a (0.1 mmol), catalyst [Cp*CF3RhCl2]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.

OPh NPhth

HH

OPh NPhth

HH



0% Dincorporation

- 116 -

Figure 8.

N-enoxyphthalimide 1a (0.1 mmol), catalyst [Cp*CF3RhCl2]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’.

OPh NPhth

HH



85% yield54% D

incorporation

D/HPh

O

- 117 -

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.

O

O NPh

Me O O

CF3

59% yield

CsOAc( 2 equiv.)

TFE (0.2M), rt

Ph O N

O

O

- 118 -

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

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


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).

13C 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.

O

O NPh

Me O O

CF3

Chemical Formula: C18H14F3NO4Exact Mass: 365.09

- 119 -

Figure 10.

Dioxazoline 4 (0.1 mmol), catalyst [Cp*CF3RhCl2]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%.

O N

OPh

Me OO

CF3



2% yield

Ph

O

- 120 -

Mechanistic hypothesis

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.

O NO

PhMe O O CF3

Ph O N

O

O

CsOAc

TFE Ph O NH

O OO

F3C

[Rh] cat.CsOAc

R

R

Ph

O

R

R

- 121 -

A1.5 NMR Spectra

- 122 -

-4-3-2-1012345678910111213141516f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000EJTP2323_A_pure.1.fid

3.18

1.123.18

4.48

1.17

1.00

2.08

1.132.10

0.75

0.77

0.78

0.96

0.96

0.97

1.00

1.02

1.03

1.42

1.49

1.50

1.51

1.53

1.54

2.50

2.51

2.51

2.52

7.26CDCl3

7.44

7.46

7.47

7.47

7.52

7.54

7.98

7.98

7.99

7.99

8.00

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

EJTP2323_A_pure.2.fid10.8

11.3

21.1

21.3

29.6

32.1

38.3

77.2CDCl3

128.2

128.6

132.5

139.2

198.7

O

Me

Me

O

Me

Me

- 123 -

-4-3-2-1012345678910111213141516f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000EJTP2322_A_pure_1stspot.1.fid

1.00

1.01

1.00

2.66

1.11

0.92

1.92

0.99

1.95

1.33

1.60

1.60

1.61

1.61

2.54

2.67

2.67

2.68

2.68

2.70

2.70

2.71

2.76

2.77

7.26CDCl3

7.48

7.49

7.50

7.50

7.51

7.52

7.58

7.59

7.60

7.96

7.97

7.97

7.98

7.98

7.99

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

8000

8500

9000EJTP2322_A_pure_1stspot.2.fid

18.1

22.3

29.1

31.5

32.2

35.2

77.2CDCl3

122.6

128.1

128.9

133.2

138.2

197.6

O

N

N

O

N

N

- 124 -

-4-3-2-1012345678910111213141516f1(ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000EJTP2322_B_pure.1.fid

1.05

8.46

1.06

1.00

1.99

0.99

1.98

1.18

1.19

1.20

1.21

1.55

1.65

1.66

1.67

1.67

1.68

1.74

1.75

1.76

1.76

2.67

2.68

2.69

2.70

7.26CDCl3

7.45

7.46

7.47

7.48

7.48

7.53

7.54

7.95

7.95

7.96

7.97

7.97

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

0

500

1000

1500

2000

2500

3000

3500

4000


22.1

26.2

26.3

30.0

32.6

37.5

38.8

77.2CDCl3

128.0

128.6

132.6

139.1

199.1

O

O

- 125 -

-4-3-2-1012345678910111213141516f1(ppm)

-2000

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

21000

22000

EJTP2330_B_pure.1.fid

1.00

0.99

9.96

0.93

1.85

0.94

1.85

0.93

0.94

0.95

0.96

1.47

1.48

1.49

1.50

1.51

1.52

1.53

1.53

1.54

1.64

1.65

2.49

2.51

2.51

2.52

7.26CDCl3

7.45

7.47

7.47

7.48

7.53

7.54

8.00

8.00

8.02

8.02

8.02

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

0

500

1000

1500

2000

2500

3000

3500

EJTP2330_B_pure.2.fid21.5

26.0

26.2

26.3

28.5

32.2

35.6

38.0

77.2CDCl3

128.2

128.6

132.5

139.1

198.4

O

O

- 126 -

-1012345678910111213f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

EJTP2322_C_pure.1.fid

1.07

1.33

2.38

6.90

4.48

1.00

1.95

1.14

2.07

1.54

1.55

1.55

1.56

1.57

1.58

1.59

1.59

1.60

1.60

1.61

1.68

1.68

1.69

1.69

1.69

1.70

2.53

2.54

2.54

7.26CDCl3

7.46

7.47

7.47

7.49

7.55

7.99

7.99

8.00

8.01

8.01

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

EJTP2322_C_pure.2.fid

23.3

26.5

26.6

28.1

28.2

30.5

33.5

37.0

40.8

77.2CDCl3

128.2

128.6

132.6

139.2

198.7

O

O

- 127 -

-4-3-2-1012345678910111213141516f1(ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000EJTP2322_D_pure.1.fid

1.08

4.20

10.22

1.22

1.00

2.00

1.102.03

1.00

1.01

1.02

1.46

1.53

1.55

1.56

1.56

1.57

1.57

1.58

1.59

1.59

1.60

2.49

2.50

2.50

2.51

7.26CDCl3

7.45

7.46

7.47

7.48

7.48

7.53

7.54

7.97

7.97

7.98

7.99

7.99

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-40000

-20000

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

240000

260000

280000

300000

320000

340000

360000EJTP2322_D_pure_carbon.2.fid

23.3

25.3

25.6

25.9

26.9

27.4

27.9

34.6

36.6

39.1

77.2CDCl3

128.2

128.6

132.6

139.3

198.7

O

O

- 128 -

-1012345678910111213f1(ppm)

0

5000

10000

15000

20000

25000

EJTP2322_E_pure.1.fid

0.99

1.00

4.02

2.95

1.00

0.95

0.99

1.96

2.01

1.95

1.09

1.94

1.94

0.95

0.96

1.51

1.51

1.52

1.71

1.72

1.73

2.42

2.49

2.50

2.50

2.51

7.24

7.26

7.26CDCl3

7.26

7.35

7.36

7.36

7.38

7.50

7.52

7.57

7.57

7.58

7.58

7.81

7.81

7.82

7.83

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000

EJTP2322_E_pure.2.fid

20.3

21.7

27.5

30.6

31.7

36.1

46.1

46.5

77.2CDCl3

127.8

128.0

128.7

129.7

132.8

133.0

138.5

143.6

197.5

O N SO

O

Me

O N SO

O

Me

- 129 -

-4-3-2-1012345678910111213141516f1(ppm)

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000EJTP2323_C_pure.1.fid

1.00

8.82

4.39

0.97

0.96

0.99

1.94

1.93

0.97

1.91

1.05

1.05

1.06

1.43

1.57

1.58

1.59

1.60

1.61

1.61

1.62

1.63

1.64

2.60

2.61

2.62

2.63

3.54

3.55

7.26CDCl3

7.46

7.47

7.48

7.49

7.55

7.56

7.97

7.98

7.99

7.99

7.99

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000EJTP2323_C_pure.2.fid

20.6

28.6

30.9

33.0

36.8

77.2CDCl3

77.4

79.7

123.8

128.2

128.8

132.9

134.5

138.7

155.0

197.7

O N O

O

Me

MeMe

O N O

O

Me

MeMe

- 130 -

-4-3-2-1012345678910111213141516f1(ppm)

-2000

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

21000

22000EJTP2322_F_pure.1.fid

1.00

1.09

1.03

4.61

2.01

0.99

2.01

1.02

1.95

1.97

2.00

1.00

1.94

1.58

1.58

1.59

1.59

1.59

1.62

2.57

2.58

2.58

2.60

7.20

7.23

7.24

7.25

7.25

7.26CDCl3

7.26

7.29

7.31

7.32

7.47

7.49

7.49

7.50

7.55

7.57

7.97

7.97

7.98

7.98

7.99

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500EJTP2322_E_pure_carbon.2.fid20.4

29.0

32.4

33.5

33.6

37.7

40.3

44.4

77.2CDCl3

126.2

127.0

128.2

128.5

128.7

132.7

139.1

147.1

198.2

O

O

- 131 -

-4-3-2-1012345678910111213141516f1(ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000EJTP2304_F_pure.1.fid

1.05

1.05

10.64

3.02

1.00

2.23

1.99

0.90

0.91

0.92

0.93

1.45

1.45

1.46

1.47

1.48

1.48

1.49

1.50

1.51

1.51

1.52

1.60

1.63

1.64

1.65

1.66

1.67

2.42

2.48

2.49

2.49

2.50

7.26

7.26CDCl3

7.27

7.91

7.93

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000EJTP2304_F_pure_carbon.2.fid

21.2

21.8

26.0

26.2

26.4

28.5

32.1

35.2

38.0

77.2CDCl3

128.3

129.3

136.7

143.2

197.9

O

Me

O

Me

- 132 -

-1012345678910111213f1(ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

70000EJTP2304_G_pure.1.fid

1.00

1.04

8.69

10.73

0.94

1.84

1.84

0.91

0.91

0.92

0.93

1.35

1.46

1.47

1.48

1.48

1.49

1.50

1.50

1.51

1.51

1.52

1.56

1.64

1.65

2.48

2.49

2.49

2.50

7.26CDCl3

7.47

7.48

7.48

7.49

7.95

7.95

7.96

7.96

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-20000

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

240000

260000

280000

300000

320000EJTP2304_G_pure.2.fid

21.3

26.0

26.2

26.4

28.5

31.3

32.1

35.2

38.0

77.2CDCl3

125.6

128.1

136.6

156.1

198.0

O

Me

MeMe

O

Me

MeMe

- 133 -

-4-3-2-1012345678910111213141516f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000EJTP2304_E_pure.1.fid

1.00

1.08

6.59

3.72

0.96

1.86

1.82

0.94

0.95

0.95

0.96

1.47

1.48

1.48

1.49

1.49

1.52

1.52

1.53

1.53

1.57

1.62

1.63

1.64

2.44

2.45

2.45

2.46

7.12

7.13

7.13

7.15

7.26CDCl3

8.02

8.03

8.04

8.04

8.05

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

0

5000

10000

15000

20000

25000

30000

35000

40000EJTP2304_E_pure.2.fid

21.5

26.0

26.2

26.3

28.5

32.1

35.7

38.0

77.2CDCl3

115.6

115.7

130.7

130.7

135.5

135.5

164.5

166.5

196.7

O

F

O

F

- 134 -

-1012345678910111213f1(ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000


1.00

0.98

10.57

2.96

0.99

0.98

1.08

1.97

0.92

0.93

0.93

0.94

1.47

1.48

1.49

1.49

1.51

1.51

1.52

1.52

1.53

1.61

1.64

1.65

1.66

2.42

2.49

2.50

2.50

2.51

7.26CDCl3

7.35

7.35

7.36

7.36

7.81

7.82

7.82

7.82

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000


21.46

21.61

26.03

26.15

26.34

28.47

32.24

35.46

38.01

77.20CDCl3

125.48

128.47

128.66

133.28

138.36

139.19

198.53

O

Me

O

Me

- 135 -

-1012345678910111213f1(ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000


1.02

1.01

10.67

1.00

3.03

0.97

0.99

0.98

1.00

0.94

0.94

0.95

1.46

1.47

1.47

1.48

1.49

1.50

1.51

1.52

1.52

1.53

1.64

1.65

1.66

2.48

2.49

3.86

7.09

7.10

7.36

7.37

7.39

7.51

7.52

7.52

7.61

7.61

7.62

7.63

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-20000

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000

160000

170000

180000

190000

200000


21.6

26.0

26.1

26.3

28.5

32.3

35.7

38.0

55.6

77.2CDCl3

112.5

118.9

120.9

129.6

140.5

159.9

198.1

O

O Me

O

O Me

- 136 -

-1012345678910111213f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000


1.02

1.02

10.42

1.00

0.94

0.98

0.96

0.98

0.96

0.97

0.98

0.99

1.47

1.48

1.49

1.49

1.50

1.50

1.53

1.54

1.54

1.55

2.44

2.45

2.46

2.47

7.24

7.24

7.24

7.24

7.26

7.26CDCl3

7.44

7.45

7.79

7.79

7.79

7.80

7.81

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-100000

0

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000


21.9

26.1

26.2

26.3

28.4

32.3

36.2

38.0

77.2CDCl3

114.9

115.0

119.4

119.6

123.9

123.9

130.2

130.3

141.2

141.3

162.0

164.0

197.0

197.0

O

F

O

F

- 137 -

-1012345678910111213f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

8000

8500EJTP2304_D_pure.1.fid

1.00

1.1210.53

0.96

0.94

0.96

0.94

0.93

0.94

0.95

0.96

0.96

1.47

1.48

1.50

1.50

1.51

1.52

1.53

1.54

1.55

1.56

1.57

1.58

1.59

2.48

2.48

2.48

2.49

7.11

7.13

7.13

7.15

7.20

7.21

7.23

7.26CDCl3

7.76

7.76

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-20000

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

240000

260000

280000

300000

320000

340000

360000

380000

400000

EJTP2304_D_pure.2.fid

22.6

25.8

25.8

26.1

26.3

28.4

36.3

36.3

36.9

37.9

77.2CDCl3

116.6

116.8

124.4

124.5

128.2

128.3

130.5

130.6

133.7

133.8

160.6

162.6

197.0

197.0

O

F

O

F

- 138 -

-1012345678910111213f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

EJTP2304_H_pure.1.fid

1.00

1.00

10.48

0.98

1.96

1.96

0.99

0.98

0.98

1.00

1.00

1.48

1.53

1.54

1.54

1.55

1.59

1.60

1.60

1.61

1.69

1.70

2.67

2.68

7.26CDCl3

7.55

7.59

7.60

7.88

7.89

7.90

7.92

7.98

8.00

8.07

8.08

8.09

8.09

8.55

8.56

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

EJTP2304_H_pure.2.fid

21.6

26.1

26.2

26.3

28.5

32.3

35.7

38.1

77.2CDCl3

124.4

126.8

127.9

128.3

128.4

129.6

129.7

132.8

135.5

136.5

198.1

O

O

- 139 -

-4-3-2-1012345678910111213141516f1(ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000EJTP2327_pure.1.fid

1.00

0.97

1.748.67

0.99

3.96

2.87

1.93

1.27

1.28

1.28

1.29

1.44

1.45

1.46

1.47

1.48

1.48

1.49

1.78

1.79

1.79

1.80

2.91

2.91

2.91

2.91

2.92

7.19

7.20

7.20

7.21

7.22

7.22

7.26CDCl3

7.27

7.28

7.28

7.28

-40-30-20-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

EJTP2327_pure.2.fid

22.1

26.1

26.2

26.3

28.1

30.3

34.7

35.1

37.9

46.4

77.2CDCl3

126.2

128.5

128.6

141.5

207.7

O

O

- 140 -

-4-3-2-1012345678910111213141516f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000


2.84

0.96

1.00

3.01

3.90

1.101.17

2.02

4.50

4.52

4.60

4.62

7.26CDCl3

7.40

7.40

7.41

7.41

7.42

7.42

7.42

7.43

7.58

7.59

7.59

7.60

7.60

7.60

7.61

7.72

7.73

7.73

7.74

7.74

7.79

7.79

7.80

7.80

7.81

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

0

50000

100000

150000

200000

250000

300000

EJTP2328_pure.3.fid25.5

60.9

61.2

61.5

61.8

77.2CDCl3

116.3

123.1

125.2

128.6

129.4

129.8

130.2

130.3

131.4

132.2

139.9

157.6

165.4

O NO

Me O O CF3

O NO

Me O O CF3

- 141 -

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.

- 142 -

– 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.

- 143 -

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

- 144 -

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.

- 145 -

A2.2 General Procedure for Starting Materials

A. Synthesis of [Cp*CF3RhCl2]2 Catalyst2

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

Me Me

Br Li0 wire

Et2O, 0 to -40 ˚CF3C OEt

O Me Me

Me Me

OHF3C Me

MeMe

CF3

MeMeSO3H

DCM, 0 ˚C

+ isomers

- 146 -

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

over dried over Na2SO4 and concentrated. HCp*CF3 (+ isomers) was purified by flash

chromatography (Hexanes) and afforded in 69% yield (1.3374 g)

Synthesis of [Cp*CF3RhCl2]2

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.).

RhCl3 • 3 H2OMe

MeMe

CF3

Me

+ isomers

MeOH, ∆F3C

ClRh

ClCF3

ClRh

Cl

- 147 -

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

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.

RR

BrBrBr2

DCM, 0 ˚C

- 148 -

Synthesis of a-bromostyrenes

(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

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

R

BrBr

R

BrK2CO3

MeOH:THF (1:1)

R

BHO OHt-BuLiB(Oi-Pr)3

Et2O, -78 ˚C to rtR

Br

- 149 -

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

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.

R

BHO OH

R

ONPhthCu(OAc)2Na2SO4

Pyridine1,2-DCE, rt

HON

O

O

- 150 -

Method B4

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).

HONPhth

R

[PPh3AuTFA] (5 mol%)

DCE, 90 ºC

R O NPhth

- 151 -

The known compounds are consistent with the literature precedents.

ONPhth

ONPhth

Me

ONPhth

t-Bu

ONPhth

F

ONPhthFONPhthMe ONPhthMeO

ONPhth ONPhth

F

ONPhth

MeOONPhthBn

Compounds Synthesized by Method A

Compounds Synthesized by Method B

- 152 -

C. Synthesis of Allylic Alcohol Substrates and Analogues.

Allylic alcohols were purchased from commercial suppliers unless noted below:

This procedure was performed according to literature precedent.5, 6, 7

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

n-Pr

O

HR Mg

X Et2O

0 ºC to rtn-Pr

OH

R

R = Cy or PhX = Cl or Br

HO1) NBS, AIBN CCl4 reflux

2) NaHCO3 acetone:H2O (2:1) reflux

n-PrOH

n-Pr

D

H

OHLiAlD4

THF, 0 °C to rt

- 153 -

This procedure was performed according to literature precedent and the compound was


This procedure was performed according to literature precedent and the compound was


This procedure was performed according to the literature precedent and the

compounds were consistent with the literature.11

n-Pr

OH

n-Pr

OMeNaH, MeI

DMF, rt

n-Pr

OH

n-Pr

NPhth

n-Pr

NH2

n-Pr

NTsHH2NNH2 • H2O

MeOH, rt

HNPhthDIAD, PPh3

THF, rt

TsCl

DCM, rt

- 154 -

A2.3 General Procedure for the Cyclopropanation Reaction and Characterization

of Products

N-enoxyphthalimide (0.12 mmol), catalyst [Cp*CF3RhCl2]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.

[Cp*CF3RhCl2]2 (5 mol%)

KOPiv (2 equiv.)TFE, 0 ˚C, 16 hr.R

OH

R

R R R

HOR

RR

O NPhthRO

R

- 155 -

3aa 2-(hydroxymethyl)-3-propylcyclopropyl)(phenyl)methanone

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).

13C 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.

n-Pr

Ph

O

OH

Chemical Formula: C14H18O2

- 156 -

3ab 2-(hydroxymethyl)-3-propylcyclopropyl)(phenyl)methanone

Y = 62%. Pale-yellow oil. Rf = 0.22 (4:1 Hexanes:EtOAc)


(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).

13C 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


n-Pr

Ph

O

OH


- 157 -

3ba 2-(hydroxymethyl)-3-propylcyclopropyl)(p-tolyl)methanone

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).

13C 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


n-Pr

O

OH

Me


- 158 -

3ca (4-(tert-butyl)phenyl)-2-(hydroxymethyl)-3-propylcyclopropyl)methanone

Y = 76%. Pale-yellow oil. Rf = 0.24 (4:1, Hexanes:EtOAc).


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).

13C NMR (126 MHz, CDCl3) 13C 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


n-Pr

O

OH

t-Bu


- 159 -

3da (4-fluorophenyl)(2-(hydroxymethyl)-3-propylcyclopropyl)methanone

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).

13C 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.

n-Pr

O

OH

F

Chemical Formula: C14H17FO2

- 160 -

3ea (2-(hydroxymethyl)-3-propylcyclopropyl)(4-methoxyphenyl)methanone

Y = 77%. Pale-Yellow Oil. Rf = 0.06 (4:1 Hexanes:EtOAc).


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).

13C 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


n-Pr

O

OH

MeO


- 161 -

3fa (2-(hydroxymethyl)-3-propylcyclopropyl)(m-tolyl)methanone

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).

13C 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


n-Pr

O

OH

Me


- 162 -

3ga 2-(hydroxymethyl)-3-propylcyclopropyl)(3-methoxyphenyl)methanone

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).

13C 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


n-Pr

O

OH

OMe


- 163 -

3ha (3-fluorophenyl)-2-(hydroxymethyl)-3-propylcyclopropyl)methanone

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).

13C 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.

n-Pr

O

OH

F

Chemical Formula: C14H17FO2

- 164 -

3ia (2-fluorophenyl)(2-(hydroxymethyl)-3-propylcyclopropyl)methanone

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).

13C 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.

19F 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.

O OH

n-Pr

FChemical Formula: C14H17FO2

- 165 -

3ja 2-(hydroxymethyl)-3-propylcyclopropyl)(naphthalen-2-yl)methanone

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).

13C 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


n-Pr

O

OH


- 166 -

3ka 1-(2-(hydroxymethyl)-3-propylcyclopropyl)-3-phenylpropan-1-one


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).

13C 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


O OH

n-Pr

Bn


- 167 -

3ac (2-(hydroxymethyl)-3-methylcyclopropyl)(phenyl)methanone

Y = 89%. Light yellow solid. Rf = 0.50 (4:1 Hexanes:EtOAc).


(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).

13C 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


Me

Ph

O

OH


- 168 -

3ad (2-(hydroxymethyl)-2-methylcyclopropyl)(phenyl)methanone

Y = 62% Pale-yellow solid. Rf = 0.19 (4:1 Hexanes:EtOAc)


(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).

13C 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


Ph

O

OHMe


- 169 -

3ae (3-(hydroxymethyl)-2,2-dimethylcyclopropyl)(phenyl)methanone

Y = 82% Pale-yellow oil. Rf = 0.18 (4:1 Hexanes:EtOAc)


(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).

13C 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


Ph

O

OH

Me Me


- 170 -

3af (3-(hydroxymethyl)-2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl)(phenyl)methanone

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).

13C 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



Me

Me

Me

OH

Ph

O

- 171 -

3ag (2-(1-hydroxyallyl)cyclopropyl)(phenyl)methanone

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).

13C 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


Ph

O OH

H


- 172 -

3ah (2-(1-hydroxyethyl)cyclopropyl)(phenyl)methanone

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).

13C 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


Ph

O

Me

OH

H


- 173 -

3ai (2-(hydroxy(phenyl)methyl)cyclopropyl)(phenyl)methanone

Y = 62%. Light yellow solid. Rf = 0.54 (4:1 Hexanes:EtOAc).


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).

13C 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


Ph

O

Ph

OH

H


- 174 -

3aj (2-(1-hydroxyethyl)-3-methylcyclopropyl)(phenyl)methanone

Y = 88% Pale-yellow oil. Rf = 0.19 (4:1 Hexanes:EtOAc)


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).

13C 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.

Ph

O

Me

OH

HMe


- 175 -

3ak (2-(hydroxy(phenyl)methyl)-3-propylcyclopropyl)(phenyl)methanone



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).

13C 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


Ph

O

Ph

OH

Hn-Pr


- 176 -

3al (2-(cyclohexyl(hydroxy)methyl)-3-propylcyclopropyl)(phenyl)methanone



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).

13C 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


Ph

O

Cy

OH

Hn-Pr


- 177 -

3an (2-hydroxybicyclo[6.1.0]nonan-9-yl)(phenyl)methanone

Y = 85%. Colorless oil. Rf = 0.05 (4:1 Hexanes:EtOAc)


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).

13C 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


Ph

OH

H

OH


- 178 -

A2.4 Mechanistic Experiments

Deuterated allylic alcohol–Retention of stereochemistry at the alkene

N-enoxyphthalimide 1a (0.12 mmol), catalyst [Cp*CF3RhCl2]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







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.


KOPiv ( 2 equiv.)TFE, 0 ˚C

H

Hn-Pr

DPh

OOH

3aa’82%>20:1 d.r.

1a 2a-d1

n-Pr H

DOH

OPh NPhth

- 179 -

3aa’ 2-(hydroxymethyl)-3-propylcyclopropyl-2-d)(phenyl)methanone

Y = 82%. Colorless Oil. Rf = 0.22 (4:1 Hexanes:EtOAc).


(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).

13C 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


O OH

n-PrD

Chemical Formula: C14H17DO2

- 180 -

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.

- 181 -

H D

Hn-Pr

OHOPh

doublettrans; small J

H D

Hn-Pr

OHOPh

doubletcis; large J

- 182 -

Deuterated solvent–Irreversibility of C–H activation



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




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.

O NPhth

H H

O NPhth

D/H H/D


KOPiv ( 2 equiv.)TFE-d1, 0 ˚C

1a 0% D1a

- 183 -

With homoallylic alcohol 4a



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





filtered through a pad of celite® and Na2SO4 then concentrated. Yield and

diastereoselectivity were determined by crude 1H NMR.


KOPiv (2 equiv.)TFE, 0 ˚Cn-Pr

Ph

O

1a

4a 5aa

n-Pr

12%, >20:1 d.r.

OH

OH

- 184 -

With bis-homoallylic alcohol



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









MePh

O

1a

6a 7aa

Me

17%, >20:1 d.r.

OH

OH

- 185 -

With allylic ether 6a



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











n-Pr

OMe

Ph

O

1a

8a 9aatrace

OMe

n-Pr

- 186 -

With allylic carboxylic acid



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











n-Pr

CO2H

Ph

O

1a

8b 9abtrace

CO2H

n-Pr

- 187 -

With allylic amine



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.



n-Pr

NTs

Ph

O

1a

8c 9ac77%, 9.5:1 d.r.

n-Pr

H NTsH

- 188 -

9ac N-((2-benzoyl-3-propylcyclopropyl)methyl)-4-methylbenzenesulfonamide

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).

13C 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.

Ph

O NTs

n-Pr

HChemical Formula: C21H25NO3S

- 189 -

With NaH

N-enoxyphthalimide 1a (0.12 mmol) and catalyst [Cp*CF3RhCl2]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.


NaH (2 equiv.)TFE, 0 ˚C

n-Pr

OH

Ph

O5%

OH

n-PrPh O NPhth

- 190 -

Isolation of off-cycle intermediate

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.

ONO

PhMe

OO

KOPiv ( 1 equiv.)

THF, 21 °C

10ac38%

Me

OH

Me

Ph O N

O

O

1a 2c

- 191 -

10ac (E)-but-2-en-1-yl 2-(5-methyl-5-phenyl-1,4,2-dioxazol-3-yl)benzoate

Y=38% Colorless Oil. Rf = 0.64 (4:1 Hexanes:EtOAc).


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).

13C 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

O

ON O

O

MePhMe

Chemical Formula: C20H19NO4

- 192 -

Compatibility of 10ac with the cyclopropanation reaction conditions

Dioxazoline 10ac (0.12 mmol), catalyst [Cp*CF3RhCl2]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

Na2SO4 then concentrated. Yield and diastereoselectivity were determined by crude 1H-

NMR.

ONO

PhMe

OO

Me10ac

Me

O

Ph

OH


KOPiv ( 2 equiv.)TFE, 0 or 21 ˚C

3ac not observed

- 193 -

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.

ON

O

O

DDD

DD

D

D

Me

OH

(25 mol%) [Cp*CF3RhCl2]2

KOPiv (2 equiv.)TFE-d3 (0.1M), 0 °C

ONH

O

DDD

DD

D

DOO

Me

Me

OD

D D

D

D

D

OD

- 194 -

6.86.97.07.17.27.37.47.57.67.77.87.98.08.18.28.38.48.58.68.78.88.99.09.1f1(ppm)

1

2

3

4

5

6

EJTP2319.5.55.1r

EJTP2319.5.45.1r

EJTP2319.5.35.1r

EJTP2319.5.25.1r

EJTP2319.5.15.1r

EJTP2319.5.5.1r

ONH

O

DDD

DD

D

DOO

Me

ON

O

O

DDD

DD

D

D

1H-NMRTFE-d3500 MHz

- 195 -

-4-3-2-1012345678910111213141516

f1(ppm)

1

2

3

4

5

6

EJTP2319.5.55.1r

EJTP2319.5.45.1r

EJTP2319.5.35.1r

EJTP2319.5.25.1r

EJTP2319.5.15.1r

EJTP2319.5.5.1r

1H-NMRTFE-d3500 MHz

- 196 -

A2.5 Model for Diastereoselectivity

RH

R'

OH

Ar

O

RH

OH

R'Ar

O

RH

R'

OH

Ar

O

RH

R'

OH

Ar

O

Steric clashavoided

substituent inpsuedo-equatorial

positionStereochemistry

retained atthe alkene

-Major Diastereomer-Stereochemistry retained at alkene-Steric clash avoided with Cp-Substituent is equatorial

-Minor Diastereomer-Stereochemistry retained at alkene-Steric clash with Cp-Substituent is axial

-Minor Diastereomer-Stereochemistry retained at alkene-Steric clash with Cp-Substituent is equatorial

-Minor Diastereomer-Stereochemistry retained at alkene-Steric clash avoided with Cp-Substituent is axial

O

RRhH

ArOC

ONH

R'

O

CF3

R

OH

R'OAr N

O

O


KOPivTFE R

R'

OH

Ar

O

RhN

OArO

OO

R R'

CF3

RhNH

OArO

OO

R R'

CF3

Ar O NH

O

O

O

R'

R

Phthalimide Opening

CMDCarbenoidformation

[2+1]Annulation

- Conformational analysis of the proposed Rh-carbenoid— the diastereo-determining step of the reaction

HR

H

OAr HO

R'H

HR

H HOR'H

O ArH

R

H HOR'H

O Ar

HR

H

OAr HO

R'H

**

**

- 197 -

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).

- 198 -

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.

- 199 -

Molecular structure of EJTP2213_B_pure. The crystal is centrosymmetric and thus

contains both enantiomers.

- 200 -

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 ρcalc (g cm-3) 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 (e- Å-3) 0.25, -0.20

- 201 -

A2.7 NMR Spectra

-1012345678910111213

f1(ppm)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

EJTP2313_pure.1.fid

3.17

4.22

1.04

0.98

0.89

1.00

1.03

1.02

2.05

1.05

2.02

0.92

0.93

0.94

1.42

1.43

1.43

1.44

1.44

1.45

1.46

1.47

1.48

1.75

1.84

1.84

2.53

2.54

2.55

2.56

3.76

3.93

3.94

7.26CDCl3

7.46

7.47

7.49

7.55

7.56

7.99

7.99

8.01

O OH

Me

- 202 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000

160000

EJTP2313_pure.2.fid

14.0

22.4

28.5

30.3

35.4

35.6

60.0

77.2CDCl3

128.2

128.7

133.0

138.6

200.2

O OH

Me

- 203 -

-1012345678910111213

f1(ppm)

-2000

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

21000

22000

23000EJTP1414_A_pure.1.fidProton

3.14

2.60

1.30

1.16

2.21

0.60

1.00

1.84

2.07

1.12

2.06

0.84

0.85

0.87

1.24

1.27

1.28

1.28

1.29

1.30

1.30

1.79

1.85

2.71

2.73

2.73

2.75

4.05

4.05

4.06

4.07

7.26CDCl3

7.45

7.46

7.47

7.48

7.55

7.56

7.98

7.98

8.00

8.00

O OH

Me

- 204 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

0

50000

100000

150000

200000

250000


14.0

23.1

25.5

26.5

28.0

28.0

58.7

77.2CDCl3

128.3

128.7

133.1

138.9

200.7

O OH

Me

- 205 -

Me

O OH

- 206 -

Me

O OH

- 207 -

-1012345678910111213

f1(ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000EJTP2270_B_pure.1.fidProton

1.05

3.10

1.05

0.93

1.00

1.04

1.05

2.05

1.10

2.01

1.09

1.09

1.10

1.11

1.42

1.63

1.64

1.65

1.65

1.89

2.53

2.54

2.54

2.55

3.62

3.63

3.73

3.74

7.26CDCl3

7.46

7.47

7.48

7.49

7.49

7.55

7.56

7.98

7.98

7.99

7.99

8.00

OOH

Me

- 208 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-20000

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000

160000

170000

180000

190000

200000

210000

220000

230000

240000EJTP2270_B_pure.2.fidCarbon13

21.1

22.8

31.5

33.3

64.7

77.2CDCl3

128.3

128.7

133.0

138.6

199.7

OOH

Me

- 209 -

-1012345678910111213

f1(ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

EJTP2270_A_pure.5.fidProton

3.03

3.03

1.04

1.00

0.92

1.05

1.04

2.07

1.04

2.03

1.11

1.41

1.65

1.65

1.65

1.66

1.67

1.67

1.68

2.40

2.42

3.98

4.00

4.05

7.26CDCl3

7.46

7.47

7.48

7.49

7.49

7.55

7.55

7.56

7.57

7.57

7.58

7.91

7.91

7.92

7.93

7.93

O

OH

MeMe

- 210 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-100000

0

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

1100000

1200000

1300000EJTP2270_A_pure.6.fidCarbon13

15.4

28.5

28.8

35.6

35.7

59.5

77.2CDCl3

128.3

128.8

133.2

138.8

200.4

O

OH

MeMe

- 211 -

O OH

H

1H-NMRCDCl3500 MHz

- 212 -

O OH

H

- 213 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000


1.39

3.18

1.36

1.10

1.03

1.00

0.99

2.40

1.20

1.87

1.24

1.25

1.26

1.33

1.34

1.37

1.38

1.38

1.38

1.39

1.39

1.68

1.69

1.69

1.95

2.75

2.76

7.26CDCl3

7.46

7.46

7.47

7.49

7.55

7.55

7.56

7.57

8.03

8.04

8.05

8.05

8.05

O OH

MeH

- 214 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

EJTP2213_A_pure.2.fidCarbon13

13.2

23.2

23.3

33.0

66.5

77.2CDCl3

128.4

128.7

133.1

138.5

199.9

O OH

MeH

- 215 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000


0.99

1.13

1.01

0.96

1.00

1.00

1.05

2.08

4.09

0.96

1.96

1.26

1.27

1.27

1.63

1.64

1.64

1.65

1.99

2.00

2.01

2.26

2.92

2.93

2.94

4.63

4.65

7.32

7.33

7.38

7.39

7.41

7.48

7.50

7.50

7.52

7.53

7.59

7.61

8.10

8.10

8.12

O OH

H

- 216 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

0

50000

100000

150000

200000

250000

300000

EJTP2213_B_pure.4.fidCarbon13

13.4

23.8

33.0

72.1

77.2CDCl3

126.0

127.7

128.4

128.6

128.7

133.0

138.6

144.0

199.6

O OH

H

- 217 -

-1012345678910111213

f1(ppm)

0

5000

10000

15000

20000

25000

EJTP1458_pure.1.fidProton

3.15

3.10

1.01

1.06

0.85

1.00

1.02

2.141.09

2.11

1.23

1.25

1.31

1.32

1.49

1.51

1.73

1.73

1.74

1.75

2.45

2.46

2.47

2.48

3.87

3.87

7.26CDCl3

7.45

7.45

7.46

7.47

7.48

7.48

7.54

7.56

7.99

7.99

8.00

8.00

8.01

8.01

O OH

Me

MeH

- 218 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-50000

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

EJTP1458_pure.2.fidCarbon13

18.2

23.1

23.2

32.0

42.2

66.0

77.2CDCl3

128.2

128.7

128.7

128.7

133.0

138.6

200.2

O OH

Me

MeH

- 219 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000


3.02

2.51

0.85

1.06

1.01

1.00

0.96

1.00

1.02

0.91

2.02

4.12

1.05

1.99

0.76

0.77

0.79

1.21

2.28

2.65

2.66

2.66

7.26CDCl3

7.28

7.34

7.35

7.36

7.37

7.44

7.44

7.45

7.45

7.46

7.46

7.47

7.49

7.49

7.50

7.56

7.57

8.04

8.04

8.06

8.06

8.06

O OH

H

Me

- 220 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000


13.8

22.1

28.6

31.2

35.2

41.3

71.6

77.2CDCl3

126.0

127.6

128.3

128.6

128.7

132.9

138.7

144.1

199.8

O OH

H

Me

- 221 -

O OH

H

Me

- 222 -

O OH

H

Me

- 223 -

-1012345678910111213

f1(ppm)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

EJTP2318_pure.1.fid

2.252.121.07

1.112.34

3.06

1.06

1.00

0.91

1.01

1.99

0.98

2.06

1.18

1.20

1.21

1.40

1.42

1.67

1.68

1.69

1.70

1.71

1.74

1.75

1.76

1.77

1.77

1.78

1.78

2.56

2.58

2.58

2.59

4.12

4.13

7.45

7.47

7.48

7.55

7.57

8.02

8.02

8.04

OH

H

OH

- 224 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-50000

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

500000

550000

600000


24.5

25.1

26.2

26.6

27.0

29.8

30.4

36.7

67.7

77.2CDCl3

128.6

128.7

133.4

138.4

200.3

OH

H

OH

- 225 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000EJTP2252_B_proton.1.fid

3.04

1.36

3.38

3.63

1.08

1.90

1.54

2.13

1.00

2.32

1.19

2.27

1.12

1.63

1.69

2.13

2.15

2.17

2.44

2.46

4.00

4.03

4.04

5.13

5.13

5.13

7.26CDCl3

7.44

7.45

7.46

7.46

7.46

7.48

7.48

7.54

7.54

7.54

7.56

7.92

7.92

7.94

7.94

7.94

OH

O

Me

Me

Me

- 226 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

0

50000

100000

150000

200000

250000

300000

350000

400000

450000


12.6

17.9

25.3

25.9

32.5

35.1

35.2

42.9

59.4

77.2CDCl3

123.7

123.8

128.3

128.7

132.4

133.1

134.5

138.9

200.3

OH

O

Me

Me

Me

- 227 -

-1012345678910111213

f1(ppm)

0

5000

10000

15000

20000

25000

30000


2.99

4.06

0.99

0.99

0.88

2.97

1.00

0.99

0.99

2.29

1.97

0.91

0.93

0.94

1.42

1.42

1.43

1.43

1.43

1.44

1.44

1.45

1.45

1.45

1.46

1.46

1.46

1.47

1.72

1.81

1.82

1.82

2.42

2.51

2.52

2.53

2.54

7.26

7.26CDCl3

7.27

7.90

7.91

O OH

Me

Me

- 228 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000


14.0

21.8

22.4

28.3

30.1

35.4

35.5

60.1

77.2CDCl3

128.4

129.4

136.1

143.8

199.8

O OH

Me

Me

- 229 -

-1012345678910111213

f1(ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

70000

EJTP2269_B_pure.5.fidProton

3.25

9.74

4.52

1.07

1.02

0.94

1.00

1.07

1.06

2.20

2.22

0.91

0.93

0.94

1.35

1.42

1.42

1.43

1.44

1.44

1.45

1.45

1.45

1.46

1.46

1.47

1.72

1.73

1.74

1.82

1.83

1.83

1.84

2.53

2.54

2.54

2.55

7.26CDCl3

7.48

7.50

7.94

7.96

O OH

Me

MeMe Me

- 230 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

0

50000

100000

150000

200000

250000

300000

350000

400000


14.0

22.4

28.3

30.2

31.3

35.4

35.5

60.1

77.2CDCl3

123.8

125.7

128.2

134.5

156.8

199.9

O OH

Me

MeMe Me

- 231 -

-1012345678910111213f1(ppm)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000


3.00

4.17

1.08

0.99

0.72

0.99

1.00

1.01

2.01

2.05

0.92

0.93

0.94

1.41

1.42

1.44

1.45

1.46

1.47

1.75

1.82

1.83

2.48

2.49

2.50

2.51

3.73

3.74

3.75

3.94

3.95

3.96

3.97

7.12

7.14

7.16

7.26CDCl3

8.01

8.03

8.03

8.04

O

F

Me

OH

- 232 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000


13.9

22.4

28.4

30.1

35.4

35.5

60.0

77.2CDCl3

115.7

115.8

130.8

130.9

134.9

135.0

164.8

166.8

198.5

O

F

Me

OH

- 233 -

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

EJTP2104_Fluorine.2.fid

-104.99

-104.98

-104.96

-104.95

-104.93

-104.92

-104.90

O

F

Me

OH

- 234 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

EJTP2254_pure.1.fidProton

3.14

4.26

1.131.01

0.98

1.00

1.103.08

1.12

2.08

2.11

0.91

0.93

0.94

1.41

1.42

1.42

1.43

1.44

1.45

1.46

1.47

1.69

1.69

1.79

1.80

2.48

2.49

2.49

2.50

3.75

3.75

3.77

3.87

3.92

3.93

3.94

6.94

6.95

7.26CDCl3

7.98

8.00

O OH

MeO

Me

- 235 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-20000

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000

160000

170000

180000

190000

200000

210000

220000

230000EJTP2254_pure.2.fidCarbon13

14.0

22.4

28.0

29.9

35.1

35.5

55.7

60.2

77.2CDCl3

113.9

130.5

131.6

163.6

198.7

O OH

MeO

Me

- 236 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

EJTP2207_C_pure.3.fidProton

3.17

4.24

1.09

1.02

0.69

3.05

1.00

1.01

1.00

2.11

2.05

0.94

0.94

0.95

0.97

1.45

1.45

1.46

1.47

1.48

1.48

1.49

1.50

1.86

2.45

2.55

2.56

2.57

2.58

3.78

3.78

3.80

3.95

3.96

3.97

7.38

7.40

7.40

7.82

7.82

7.83

7.83

O OH

Me

Me

- 237 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

EJTP2207_C_pure.4.fidCarbon13

13.8

21.4

22.2

28.3

30.1

35.3

35.4

59.9

125.3

128.4

128.6

133.6

138.4

138.5

200.3

O OH

Me

Me

- 238 -

-1012345678910111213

f1(ppm)

0

5000

10000

15000

20000

25000

30000

EJTP2207_B_pure.1.fidProton

3.19

4.27

1.28

1.06

0.67

1.00

1.13

3.10

1.07

1.08

1.06

1.02

1.04

0.91

0.92

0.92

0.94

1.42

1.42

1.43

1.44

1.44

1.45

1.45

2.51

2.52

2.53

3.74

3.75

3.85

3.92

3.93

7.11

7.11

7.26CDCl3

7.38

7.39

7.49

7.49

7.50

7.59

7.60

7.61

7.61

O OH

Me

MeO

- 239 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-20000

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

240000


13.9

22.3

28.6

30.3

35.4

35.6

55.6

60.0

77.2CDCl3

112.5

119.4

120.9

129.7

139.9

159.9

200.0

O OH

Me

MeO

- 240 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000


3.15

4.32

1.10

1.03

0.83

1.00

1.01

1.00

1.56

1.02

1.00

1.04

0.92

0.93

0.94

1.42

1.43

1.43

1.44

1.44

1.44

1.45

1.45

1.46

1.46

2.48

2.49

2.50

2.51

3.94

3.95

7.25

7.26

7.26

7.26CDCl3

7.44

7.45

7.78

7.78

7.78

7.79

7.80

7.80

O OHF

Me

- 241 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000


13.9

22.4

28.8

30.4

35.4

35.9

59.9

77.2CDCl3

115.0

115.1

119.9

120.0

124.0

124.0

130.3

130.4

162.0

164.0

198.8

198.8

O OHF

Me

- 242 -

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1(ppm)

-400

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

3400

3600EJTP1441_B_Fluorine.2.fid

-111.19

-111.17

-111.16

-111.14

-111.12

-111.10

O OHF

Me

- 243 -

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000


3.28

4.24

1.141.08

0.92

1.00

1.04

1.06

2.15

1.07

1.11

1.88

1.89

1.95

2.52

2.53

2.53

2.54

2.55

7.10

7.11

7.13

7.13

7.14

7.14

7.17

7.17

7.19

7.19

7.22

7.22

7.24

7.24

7.26CDCl3

7.48

7.51

7.72

7.72

7.74

7.75

7.77

7.77

O OHF

Me

- 244 -

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-20000

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

240000

260000

280000

300000

320000

340000

360000EJTP2269_D_pure.6.fidCarbon13

13.9

22.3

29.6

34.4

34.4

35.3

36.5

59.9

77.2CDCl3

116.7

116.9

124.5

124.6

127.9

128.0

130.4

130.4

134.1

134.2

160.6

162.6

198.9

198.9

O OHF

Me

- 245 -

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1(ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200


-110.36

-110.35

-110.33

-110.32

-110.31

-110.29

O OHF

Me

- 246 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000


2.99

4.10

1.13

1.03

0.84

1.00

1.00

0.99

2.06

2.08

1.05

1.02

0.99

0.94

0.95

0.96

1.46

1.47

1.47

1.48

1.49

1.50

1.50

2.70

2.71

2.72

2.73

3.98

7.26CDCl3

7.56

7.60

7.60

7.87

7.89

7.89

7.91

7.97

7.99

8.04

8.04

8.05

8.06

8.55

8.55

O OH

Me

- 247 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

70000

75000

80000

85000


14.0

22.4

28.5

30.3

35.5

35.7

60.1

77.2CDCl3

124.1

126.9

127.9

128.5

128.5

129.7

129.8

132.7

135.6

135.9

200.0

O OH

Me

- 248 -

-1012345678910111213f1(ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

EJTP2042_pure.3.fid

3.12

3.37

1.05

1.06

0.99

1.00

3.19

2.212.161.101.12

1.69

1.70

1.70

1.70

1.71

1.71

1.72

1.72

2.01

7.26CDCl3

7.39

7.39

7.40

7.41

7.41

7.41

7.52

7.52

7.52

7.53

7.54

7.54

7.54

7.59

7.59

7.60

7.61

7.61

7.61

7.67

7.76

O OH

Me

- 249 -

-40-30-20-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-1000

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500


13.9

22.3

28.7

30.2

33.1

35.3

46.3

59.6

77.2CDCl3

126.3

128.5

128.6

141.2

210.2

O OH

Me

- 250 -

-4-3-2-1012345678910111213141516

f1(ppm)

0

5000

10000

15000

20000

25000

30000

35000

40000

EJTP2314_pure.1.fid

3.14

4.32

1.02

1.03

1.00

1.06

4.10

1.00

1.09

3.06

2.15

0.88

0.89

0.91

1.30

1.32

1.32

1.32

1.33

1.35

1.36

1.38

1.62

1.82

1.83

1.84

1.85

2.92

2.92

2.93

2.93

2.94

2.94

2.95

2.96

7.19

7.21

7.26CDCl3

7.27

7.28

7.28

7.30

O

ON O

O

Me

Me

- 251 -

-100102030405060708090100110120130140150160170180190200210220

f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

EJTP2042_pure.2.fidCarbon13

17.98

25.70

66.62

77.20CDCl3

116.05

122.70

124.85

125.22

128.57

129.30

129.63

129.99

131.24

131.28

132.01

132.41

140.15

158.13

166.96

O

ON O

O

Me

Me

- 252 -

-1012345678910111213

f1(ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000


3.12

4.29

0.91

0.91

1.00

0.98

1.00

2.19

1.10

2.04

0.94

0.95

0.96

1.45

1.45

1.46

1.46

1.47

1.48

1.48

1.49

1.50

2.56

2.57

3.76

3.78

3.95

3.98

7.48

7.49

7.49

7.50

7.51

7.57

7.58

8.01

8.01

8.02

8.02

8.03

8.03

O

OH

HMe

D

- 253 -

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000


14.0

22.4

28.4

30.2

35.4

59.9

77.2CDCl3

128.2

128.7

133.0

138.6

200.3

O

OH

HMe

D

- 254 -

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.

- 255 -

(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).

- 256 -

– Appendix C –

Supporting Information for Chapter Four and Five

In a flame-dried 1-dram vial equipped with a magnetic stir bar, 4-1a (5 equiv.),

[Cp*CF3RhCl2]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.

Ph

O

RhCl

CF3Ph O NPhth

(1 equiv.)[Cp*CF3RhCl2]2


4-483%(X-ray)

(1 atm)(5 equiv.)4-1a 4-2a

- 257 -

Yield: 83%


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).

19F NMR (282 MHz, CDCl3) δ -53.36

LRMS m/z (ESI APCI) calculated for C20H21ClF3ORh [M+H] 473.0, found 473.0.

Cl

O

Ph Rh

CF3

Chemical Formula: C20H21ClF3ORh

- 258 -

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.

NM

N

O OMe

O

Me

N N

O

O

(0.5 equiv.)[Cp*MCl2]2

AgOAc (2 equiv.)MeOH (0.2M), 65 °C

(2 equiv.)5-5a

- 259 -

Yield: 61%


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.

NIr

N

O OMe

OChemical Formula: C21H25IrN2O3

- 260 -

-1012345678910111213f1(ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000EJTP2321_pure_Rhspot.1.fid

3.2

13

.06

3.0

0

3.0

0

1.0

0

1.0

1

1.0

0

1.0

2

3.8

5

2.0

0

1.28

1.49

1.49

1.58

2.00

2.01

3.59

3.62

4.34

4.36

4.77

4.79

5.30

7.26CDCl3

7.44

7.44

7.46

7.46

7.48

7.48

7.55

7.55

7.55

7.56

7.57

7.57

7.59

8.16

8.16

8.18

8.18

Ph

O

RhCl

CF3

- 261 -

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1(ppm)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000EJTP2321_Rh_fluorine.1.fid

-53.36

Ph

O

RhCl

CF3

- 262 -

-1012345678910111213f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000


14.03

2.21

2.94

0.96

2.110.96

1.00

1.69

2.45

2.47

3.82

7.26CDCl3

7.30

7.31

7.38

7.39

7.40

7.40

7.40

7.41

7.42

7.42

7.56

7.57

7.58

7.58

7.58

7.84

7.85

7.85

7.86

7.86

NIr

N

O OMe

O

- 263 -

-100102030405060708090100110120130140150160170180190200210220f1(ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000


8.9

18.2

52.4

77.2CDCl3

85.2

128.3

129.7

130.4

130.4

132.0

133.4

155.8

169.7

177.8

NIr

N

O OMe

O

rhodium(iii)-catalyzed difunctionalization of alkenes

Documents