rhodium(iii)-catalyzed difunctionalization of alkenes
TRANSCRIPT
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
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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
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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.
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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
(2.5 mol%)[Cp*RhCl2]2
CsOAc (25 mol%)MeOH, 60 °C
N
OOPiv
H H R
R NH
O
RR
(2.5 mol%)[Cp*RhCl2]2
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
ReductiveElimination
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
CsOAc (2 equiv.)TFE (0.2M), rt
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
CsOAc (2 equiv.)TFE (0.2M), rt
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
CsOAc (2 equiv.)TFE (0.2M), rt
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
(5 mol%)[Cp*CF3RhCl2]2
CsOAc (2 equiv.)TFE (0.2M), rt
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
(5 mol%)[Cp*CF3RhCl2]2
CsOAc (2 equiv.)TFE-d1 (0.2M), rt
O
(5 mol%)[Cp*CF3RhCl2]2
CsOAc (2 equiv.)TFE-d1 (0.2M), rt
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
(5 mol%)[Cp*CF3RhCl2]2
CsOAc (2 equiv.)TFE (0.2M), rt
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
(5 mol%)[Cp*CF3RhCl2]2
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
(5 mol%)[Cp*CF3RhCl2]2
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.
(5 mol%)[Cp*CF3RhCl2]2
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
(5 mol%)[Cp*CF3RhCl2]2
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
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
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
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
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
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 ˚C
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
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C,
Me
Me
Me
OH
Me
Me
Me
OH
Ph O NPhth
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C,
n-PrPh
O
Ph O NPhth
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
n-Pr
3-5aa 12%>20:1 d.r.
n-Pr
Ph
O
Ph O NPhth
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
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
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
n-Pr
3-9ac77%
9.5:1 d.r.
NTsH NTsH
n-Pr
Ph
O
Ph O NPhth
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
n-Pr
3-9aatrace
OMe OMe
n-Pr
Ph
O
Ph O NPhth
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
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
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE-d1, 0 °C,
HH
Ph O NPhth
H/DD/H0% D
Incorporation
Ph O NPhth
(5 mol%)[Cp*CF3RhCl2]2
KOPiv (2 equiv.)TFE, 0 °C
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
(5 mol%)[Cp*CF3RhCl2]2
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
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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
(5 mol%)[Cp*CF3RhCl2]2
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
CsOAc (2 equiv.)TFE, rt
(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
KOPiv (2 equiv.)TFE, rt
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
ReductiveElimination
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
(5 mol%)[Cp*CF3RhCl2]2
AgSbF6 (50 mol%)
CsOAc (2 equiv.)TFE, rt
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
KOPiv (2 equiv.)TFE, rt
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
ReductiveElimination
- 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
ReductiveElimination
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
ReductiveElimination
- 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
(2.5 mol%)[Cp*RhCl2]2
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.
This procedure was performed according to literature precedent.
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.
This procedure was performed according to literature precedent.
Method B5 (1j)
Figure 4.
This procedure was performed according to literature precedent.
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
CsOAc (2 equiv.)TFE (0.2M), rt
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
CsOAc (2 equiv.)TFE (0.2M), rt
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
Yield = 56% Colorless oil. Rf = 0.39 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.98 (dt, J = 8.5, 1.5 Hz, 2H), 7.60 (td, J = 7.3,
1.5 Hz, 1H), 7.50 (td, J = 7.7, 1.6 Hz, 2H), 3.15 (dtdd, J = 9.6, 8.1, 6.6, 1.6 Hz, 1H),
2.76 (ddd, J = 7.6, 5.6, 1.4 Hz, 1H), 2.69 (qd, J = 6.8, 5.8, 1.5 Hz, 2H), 2.54 (ddd, J =
13.0, 9.5, 1.5 Hz, 1H), 1.61 (td, J = 5.3, 1.5 Hz, 1H), 1.33 (ddd, J = 8.4, 4.8, 1.5 Hz,
1H).
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
Yield = 87% Colorless oil. Rf = 0.78 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.90 (m, 2H), 7.59 – 7.51 (m, 1H), 7.51 –
7.42 (m, 2H), 2.69 (dd, J = 7.6, 5.5 Hz, 1H), 1.89 – 1.80 (m, 1H), 1.79 – 1.50 (m, 8H),
1.19 (dd, J = 7.7, 3.9 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C14H16O [M+H] 201.1, found 201.1.
Ph
O
Chemical Formula: C14H16OExact Mass: 200.12
- 100 -
3ad phenyl(spiro[2.5]octan-1-yl)methanone
Yield = 98% Colorless oil. Rf = 0.73 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 8.06 – 7.97 (m, 2H), 7.59 – 7.51 (m, 1H), 7.51 –
7.43 (m, 2H), 2.51 (dd, J = 7.3, 5.4 Hz, 1H), 1.70 – 1.39 (m, 10H), 1.19 (dt, J = 12.6,
6.1 Hz, 1H), 0.95 (dd, J = 7.4, 4.0 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C15H18O [M+H] 215.1, found 215.1.
Ph
O
Chemical Formula: C15H18OExact Mass: 214.14
- 101 -
3ae phenyl(spiro[2.6]nonan-1-yl)methanone
Yield = 70% Colorless oil. Rf = 0.74 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 8.07 – 7.97 (m, 2H), 7.60 – 7.52 (m, 1H), 7.47
(dd, J = 8.3, 6.9 Hz, 2H), 2.54 (dd, J = 7.5, 5.7 Hz, 1H), 1.80 – 1.66 (m, 4H), 1.58 (tdd,
J = 14.0, 5.9, 3.9 Hz, 6H), 1.49 (ddt, J = 10.9, 7.4, 5.5 Hz, 2H), 1.32 (dddd, J = 15.9,
9.5, 7.4, 3.6 Hz, 1H), 0.99 (dd, J = 7.5, 3.9 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C16H20O [M+H] 229.2, found 229.2.
Ph
O
Chemical Formula: C16H20OExact Mass: 228.15
- 102 -
3af phenyl(spiro[2.7]decan-1-yl)methanone
Yield = 53% Colorless oil. Rf = 0.69 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 8.04 – 7.92 (m, 2H), 7.58 – 7.52 (m, 1H), 7.47
(dd, J = 8.4, 6.9 Hz, 2H), 2.50 (dd, J = 7.5, 5.7 Hz, 1H), 1.92 (ddd, J = 14.4, 8.7, 2.8
Hz, 1H), 1.82 – 1.56 (m, 10H), 1.55 – 1.38 (m, 4H), 1.00 (dd, J = 7.5, 4.0 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C21H22O [M+H] 243.2, found 243.2.
Ph
O
Chemical Formula: C17H22OExact Mass: 242.17
- 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
Yield = 84% Colorless oil. Rf = 0.45 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.96 (m, 2H), 7.60 – 7.53 (m, 1H), 7.47
(dd, J = 8.3, 6.9 Hz, 2H), 3.61 – 3.49 (m, 2H), 3.37 (ddd, J = 13.1, 6.6, 4.2 Hz, 1H),
3.13 (ddd, J = 13.2, 7.0, 4.3 Hz, 1H), 2.62 (dd, J = 7.5, 5.4 Hz, 1H), 1.64 – 1.57 (m, 4H),
1.43 (s, 9H), 1.05 (dd, J = 7.5, 4.2 Hz, 1H).
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).
1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.94 (m, 2H), 7.61 – 7.54 (m, 1H), 7.53 –
7.46 (m, 2H), 7.34 – 7.28 (m, 2H), 7.27 – 7.23 (m, 2H), 7.23 – 7.17 (m, 1H), 2.58 (dq,
J = 8.5, 5.6, 4.6 Hz, 2H), 2.25 (tdd, J = 12.9, 3.8, 1.7 Hz, 1H), 1.94 (ddt, J = 21.9, 12.7,
2.7 Hz, 2H), 1.77 – 1.56 (m, 4H), 1.48 (tdd, J = 12.9, 3.7, 1.5 Hz, 1H), 1.31 (dq, J =
13.0, 3.0 Hz, 1H), 0.99 (ddd, J = 7.4, 4.0, 1.6 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C21H22O [M+H] 291.2, found 291.2.
Ph
OPh
Chemical Formula: C21H22OExact Mass: 290.17
- 106 -
3bd spiro[2.5]octan-1-yl(p-tolyl)methanone
Yield = 97% Colorless oil. Rf = 0.81 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H),
2.49 (dd, J = 7.3, 5.4 Hz, 1H), 2.42 (s, 3H), 1.73 – 1.54 (m, 4H), 1.47 (dddd, J = 28.0,
16.4, 9.6, 4.9 Hz, 6H), 1.17 (dt, J = 12.4, 6.1 Hz, 1H), 0.92 (dd, J = 7.3, 4.0 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C16H20O [M+H] 229.2, found 229.2.
O
MeChemical Formula: C16H20O
Exact Mass: 228.15
- 107 -
3cd (4-(tert-butyl)phenyl)(spiro[2.5]octan-1-yl)methanone
Yield = 89% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.99 – 7.93 (m, 2H), 7.51 – 7.44 (m, 2H), 2.49
(dd, J = 7.4, 5.4 Hz, 1H), 1.70 – 1.39 (m, 10H), 1.35 (s, 9H), 1.21 (dd, J = 11.2, 5.8 Hz,
1H), 0.92 (dd, J = 7.4, 4.0 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C19H26O [M+H] 271.2, found 271.2.
O
t-BuChemical Formula: C19H26O
Exact Mass: 270.20
- 108 -
3dd (4-fluorophenyl)(spiro[2.5]octan-1-yl)methanone
Yield = 96% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 8.08 – 7.99 (m, 2H), 7.19 – 7.10 (m, 2H), 2.45
(dd, J = 7.4, 5.4 Hz, 1H), 1.69 – 1.56 (m, 4H), 1.54 – 1.41 (m, 6H), 1.15 (d, J = 15.6
Hz, 1H), 0.95 (dd, J = 7.3, 4.0 Hz, 1H).
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
Yield = 75% Colorless oil. Rf = 0.84 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.84 – 7.79 (m, 2H), 7.36 (m, 1H), 7.35 (m, 1H),
2.50 (dd, J = 7.4, 5.5 Hz, 1H), 2.42 (s, 3H), 1.70 – 1.40 (m, 10H), 1.20 (dt, J = 12.1, 6.0
Hz, 1H), 0.93 (dd, J = 7.3, 4.0 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C16H20O [M+H] 229.2, found 229.2.
O
MeChemical Formula: C16H20O
Exact Mass: 228.15
- 110 -
3fd (3-methoxyphenyl)(spiro[2.5]octan-1-yl)methanone
Yield = 67% Colorless oil. Rf = 0.72 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.62 (dd, J = 7.7, 1.5 Hz, 1H), 7.52 (t, J = 2.0 Hz,
1H), 7.37 (t, J = 7.9 Hz, 1H), 7.09 (dd, J = 8.2, 2.6 Hz, 1H), 3.86 (s, 3H), 2.49 (dd, J =
7.3, 5.5 Hz, 1H), 1.70 – 1.40 (m, 8H), 1.19 (m, 1H), 0.94 (dd, J = 7.3, 4.0 Hz, 1H).
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
Yield = 90% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.80 (dt, J = 7.8, 1.3 Hz, 1H), 7.67 (ddd, J = 9.6,
2.7, 1.6 Hz, 1H), 7.44 (td, J = 8.0, 5.5 Hz, 1H), 7.28 – 7.20 (m, 1H), 2.45 (dd, J = 7.4,
5.4 Hz, 1H), 1.70 – 1.39 (m, 10H), 1.17 (d, J = 9.8 Hz, 1H), 0.98 (dd, J = 7.3, 4.0 Hz,
1H).
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
LRMS m/z (ESI APCI): calculated for C15H17FO [M+H] 233.1, found 233.1.
O
FChemical Formula: C15H17FO
Exact Mass: 232.13
- 112 -
3hd (2-fluorophenyl)(spiro[2.5]octan-1-yl)methanone
Yield = 59% Colorless oil. Rf = 0.75 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.76 (td, J = 7.6, 1.9 Hz, 1H), 7.48 (tdd, J = 7.2,
4.9, 1.9 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.13 (dd, J = 10.9, 8.4 Hz, 1H), 2.48 (ddd, J
= 7.2, 5.5, 3.4 Hz, 1H), 1.54 (ddtd, J = 33.0, 28.4, 11.4, 10.3, 5.2 Hz, 10H), 1.32 – 1.21
(m, 1H), 0.95 (dd, J = 7.3, 3.9 Hz, 1H).
13C NMR (126 MHz, Chloroform-d) δ 197.0 (d, J = 3.2 Hz), 161.6 (d, J = 253.5 Hz),
133.8 (d, J = 8.7 Hz), 130.5 (d, J = 2.7 Hz), 128.3 (d, J = 13.1 Hz), 124.4 (d, J = 3.5
Hz), 116.7 (d, J = 23.5 Hz), 37.9, 36.9, 36.3, 36.3, 28.4, 26.3, 26.2, 25.8, 25.8, 22.6.
IR(neat): 2930, 2854, 1672, 1479, 1453, 1346, 1204, 1102, 829, 757 cm-1
LRMS m/z (ESI APCI): calculated for C15H17FO [M+H] 233.1, found 233.1.
O
FChemical Formula: C15H17FO
Exact Mass: 232.13
- 113 -
3id naphthalen-2-yl(spiro[2.5]octan-1-yl)methanone
Yield = 67% Colorless oil. Rf = 0.77 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 8.56 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 8.6, 1.8 Hz,
1H), 8.04 – 7.96 (m, 1H), 7.90 (dd, J = 10.1, 8.1 Hz, 2H), 7.57 (dddd, J = 18.9, 8.1, 6.8,
1.4 Hz, 2H), 2.67 (dd, J = 7.4, 5.4 Hz, 1H), 1.57 (tddd, J = 50.6, 21.1, 10.8, 5.2 Hz,
10H), 1.20 (dq, J = 11.9, 6.1, 5.0 Hz, 1H), 1.00 (dd, J = 7.3, 4.0 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C19H20O [M+H] 265.2, found 265.2.
O
Chemical Formula: C19H20OExact Mass: 264.15
- 114 -
3jd 3-phenyl-1-(spiro[2.5]octan-1-yl)propan-1-one
Yield = 98% Colorless oil. Rf = 0.81 (4:1 hexanes: Ethyl Acetate).
1H NMR (500 MHz, Chloroform-d) δ 7.31 – 7.26 (m, 2H), 7.24 – 7.17 (m, 3H), 2.96 –
2.88 (m, 4H), 1.79 (dd, J = 7.4, 5.4 Hz, 1H), 1.58 – 1.38 (m, 9H), 1.28 (dd, J = 5.5, 3.9
Hz, 1H), 1.13 (p, J = 7.5 Hz, 1H), 0.80 (dd, J = 7.4, 4.0 Hz, 1H).
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
LRMS m/z (ESI APCI): calculated for C17H22O [M+H] 243.2, found 243.2.
OBn
Chemical Formula: C17H22OExact Mass: 242.17
- 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
(5 mol%)[Cp*CF3RhCl2]2
CsOAc (2 equiv.)TFE-d1 (0.2M), rt
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
(5 mol%)[Cp*CF3RhCl2]2
CsOAc (2 equiv.)TFE-d1 (0.2M), rt
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)
1H NMR (500 MHz, Chloroform-d) δ 7.85 – 7.77 (m, 1H), 7.77 – 7.70 (m, 1H), 7.66 –
7.55 (m, 4H), 7.49 – 7.36 (m, 3H), 4.63 (dq, J = 12.6, 8.4 Hz, 1H), 4.49 (dq, J = 12.6,
8.4 Hz, 1H), 2.02 (s, 3H).
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
(5 mol%)[Cp*CF3RhCl2]2
CsOAc (2 equiv.)TFE (0.2M), rt
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
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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
4500EJTP2322_B_pure.2.fid
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
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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
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8000
9000
10000
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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)
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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
32000EJTP2304_B_pure.1.fid
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
160000EJTP2304_B_pure.2.fid
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
32000EJTP2304_A_pure.1.fid
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
210000EJTP2304_A_pure.2.fid
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
EJTP2303_B_pure.1.fid
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
EJTP2303_B_pure.2.fid
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
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4000
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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
19000EJTP2328_pure.1.fid
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
consistent with the literature.9
This procedure was performed according to literature precedent and the compound was
consistent with the literature.10
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)
1H NMR (500 MHz, Chloroform-d) δ 8.03 – 7.95 (m, 2H), 7.61 – 7.54 (m, 1H), 7.46
(dd, J = 8.4, 7.0 Hz, 2H), 4.06 (dd, J = 7.9, 2.7 Hz, 2H), 2.73 (dd, J = 9.4, 7.9 Hz, 1H),
2.45 (s, 1H), 1.90 – 1.72 (m, 2H), 1.55 (ddt, J = 13.9, 8.4, 6.9 Hz, 1H), 1.49 – 1.40 (m,
1H), 1.35 – 1.25 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).
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
LRMS m/z (ESI APCI) calculated for C14H18O2 [M+H] 219.1, found 219.1.
n-Pr
Ph
O
OH
Chemical Formula: C14H18O2
- 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
LRMS m/z (ESI APCI) calculated for C15H20O2 [M+H] 233.2, found 233.2.
n-Pr
O
OH
Me
Chemical Formula: C15H20O2
- 158 -
3ca (4-(tert-butyl)phenyl)-2-(hydroxymethyl)-3-propylcyclopropyl)methanone
Y = 76%. Pale-yellow oil. Rf = 0.24 (4:1, Hexanes:EtOAc).
1H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz,
2H), 3.98 – 3.91 (m, 1H), 3.81 – 3.72 (m, 1H), 2.54 (dd, J = 8.4, 5.0 Hz, 1H), 2.18 (s,
1H), 1.87 – 1.80 (m, 1H), 1.73 (tdd, J = 8.3, 6.5, 4.6 Hz, 1H), 1.53 – 1.40 (m, 4H),
1.35 (s, 9H), 0.93 (t, J=6.9 Hz, 3H).
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
LRMS m/z (ESI APCI) calculated for C18H26O2 [M+H] 275.2, found 275.2.
n-Pr
O
OH
t-Bu
Chemical Formula: C18H26O2
- 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).
1H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz,
2H), 3.94 (dd, J = 12.0, 4.6 Hz, 1H), 3.87 (s, 3H), 3.75 (dd, J = 12.1, 8.2 Hz, 1H), 2.49
(dd, J = 8.4, 5.0 Hz, 1H), 2.26 (s, 1H), 1.80 (p, J = 6.3 Hz, 1H), 1.73 – 1.66 (m, 1H),
1.51 – 1.38 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H).
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
LRMS m/z (ESI APCI) calculated for C15H20O3 [M+H] 249.1, found 249.1.
n-Pr
O
OH
MeO
Chemical Formula: C15H20O3
- 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
LRMS m/z (ESI APCI) calculated for C15H20O2 [M+H] 233.2, found 233.2.
n-Pr
O
OH
Me
Chemical Formula: C15H20O2
- 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
LRMS m/z (ESI APCI) calculated for C15H20O3 [M+H] 249.1, found 249.1.
n-Pr
O
OH
OMe
Chemical Formula: C15H20O3
- 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
LRMS m/z (ESI APCI) calculated for C18H20O2 [M+H] 269.2, found 269.2.
n-Pr
O
OH
Chemical Formula: C18H20O2
- 166 -
3ka 1-(2-(hydroxymethyl)-3-propylcyclopropyl)-3-phenylpropan-1-one
1H NMR (500 MHz, Chloroform-d) δ 7.31 – 7.26 (m, 2H), 7.21 – 7.18 (m, 3H), 3.90 –
3.80 (m, 1H), 3.65 (t, J = 10.2 Hz, 1H), 3.02 – 2.88 (m, 4H), 2.01 (s, 1H), 1.83 (dd, J
= 8.3, 5.0 Hz, 1H), 1.62 (qd, J = 6.6, 4.9 Hz, 1H), 1.53 (tdd, J = 8.2, 6.6, 4.4 Hz, 1H),
1.42 – 1.28 (m, 3H), 0.89 (t, J = 7.2 Hz, 3H).
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
LRMS m/z (ESI APCI) calculated for C16H22O2 [M+H] 247.3, found 247.3.
O OH
n-Pr
Bn
Chemical Formula: C16H22O2
- 167 -
3ac (2-(hydroxymethyl)-3-methylcyclopropyl)(phenyl)methanone
Y = 89%. Light yellow solid. Rf = 0.50 (4:1 Hexanes:EtOAc).
1H NMR (500 MHz, Chloroform-d) δ 8.06 – 7.94 (m, 2H), 7.62 – 7.52 (m, 1H), 7.47
(dd, J = 8.3, 7.0 Hz, 2H), 3.96 (dd, J = 12.0, 4.7 Hz, 1H), 3.74 (dd, J = 12.0, 8.3 Hz,
1H), 2.50 (dd, J = 8.4, 5.0 Hz, 1H), 2.17 (s, 1H), 1.84 (h, J = 6.0 Hz, 1H), 1.73 (tdd, J
= 8.3, 6.4, 4.6 Hz, 1H), 1.26 (d, J = 6.0 Hz, 4H).
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
LRMS m/z (ESI APCI) calculated for C12H14O2 [M+H] 191.1, found 191.1.
Me
Ph
O
OH
Chemical Formula: C12H14O2
- 168 -
3ad (2-(hydroxymethyl)-2-methylcyclopropyl)(phenyl)methanone
Y = 62% Pale-yellow solid. Rf = 0.19 (4:1 Hexanes:EtOAc)
1H NMR (500 MHz, Chloroform-d) δ 8.02 – 7.97 (m, 2H), 7.59 – 7.54 (m, 1H), 7.47
(dd, J = 8.4, 7.0 Hz, 2H), 3.75 (dd, J = 11.8, 4.6 Hz, 1H), 3.61 (dd, J = 11.8, 5.0 Hz,
1H), 2.54 (dd, J = 7.8, 5.7 Hz, 1H), 1.89 (t, J = 6.0 Hz, 1H), 1.64 (dd, J = 5.7, 4.3 Hz,
1H), 1.42 (s, 3H), 1.10 (dd, J = 7.8, 4.3 Hz, 1H).
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
LRMS m/z (ESI APCI) calculated for C12H14O2 [M+H] 191.1, found 191.1.
Ph
O
OHMe
Chemical Formula: C12H14O2
- 169 -
3ae (3-(hydroxymethyl)-2,2-dimethylcyclopropyl)(phenyl)methanone
Y = 82% Pale-yellow oil. Rf = 0.18 (4:1 Hexanes:EtOAc)
1H NMR (500 MHz, Chloroform-d) δ 7.98 – 7.89 (m, 2H), 7.61 – 7.54 (m, 1H), 7.48
(dd, J = 8.4, 7.0 Hz, 2H), 4.10 – 4.03 (m, 1H), 4.02 – 3.95 (m, 1H), 2.62 (q, J = 3.8
Hz, 1H), 2.41 (d, J = 7.9 Hz, 1H), 1.66 (ddd, J = 9.6, 8.0, 6.9 Hz, 1H), 1.41 (s, 3H),
1.11 (s, 3H).
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
LRMS m/z (ESI APCI) calculated for C13H16O2 [M+H] 205.1, found 205.1.
Ph
O
OH
Me Me
Chemical Formula: C13H16O2
- 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
LRMS m/z (ESI APCI) calculated for C17H16O2 [M+H] 273.2, found 273.2.
Chemical Formula: C18H24O2
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
LRMS m/z (ESI APCI) calculated for C13H14O2 [M+H] 203.1, found 203.1.
Ph
O OH
H
Chemical Formula: C13H14O2
- 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
LRMS m/z (ESI APCI) calculated for C12H14O2 [M+H] 191.1, found 191.1.
Ph
O
Me
OH
H
Chemical Formula: C12H14O2
- 173 -
3ai (2-(hydroxy(phenyl)methyl)cyclopropyl)(phenyl)methanone
Y = 62%. Light yellow solid. Rf = 0.54 (4:1 Hexanes:EtOAc).
1H NMR (500 MHz, Chloroform-d) δ 8.17 – 8.06 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H),
7.56 – 7.47 (m, 4H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 4.64 (d, J = 9.4
Hz, 1H), 2.93 (td, J = 8.1, 5.7 Hz, 1H), 2.26 (s, 1H), 2.01 (qd, J = 8.7, 6.9 Hz, 1H),
1.64 (dt, J = 6.8, 5.0 Hz, 1H), 1.26 (dt, J = 8.2, 4.1 Hz, 1H).
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
LRMS m/z (ESI APCI) calculated for C17H16O2 [M+H] 253.1, found 253.1.
Ph
O
Ph
OH
H
Chemical Formula: C17H16O2
- 174 -
3aj (2-(1-hydroxyethyl)-3-methylcyclopropyl)(phenyl)methanone
Y = 88% Pale-yellow oil. Rf = 0.19 (4:1 Hexanes:EtOAc)
1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.98 (m, 2H), 7.60 – 7.53 (m, 1H), 7.51 –
7.43 (m, 2H), 3.87 (dq, J = 8.8, 6.3 Hz, 1H), 2.47 (dd, J = 8.4, 5.1 Hz, 1H), 2.23 (s,
1H), 1.74 (td, J = 6.3, 5.2 Hz, 1H), 1.50 (td, J = 8.6, 6.4 Hz, 1H), 1.32 (d, J = 6.3 Hz,
3H), 1.24 (d, J = 6.1 Hz, 3H).
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
Chemical Formula: C13H16O2
- 175 -
3ak (2-(hydroxy(phenyl)methyl)-3-propylcyclopropyl)(phenyl)methanone
Y = 75%. Off-white solid. Rf = 0.34 (4:1 Hexanes:EtOAc).
1H NMR (500 MHz, Chloroform-d) δ 8.09 – 8.02 (m, 2H), 7.61 – 7.54 (m, 1H), 7.52 –
7.42 (m, 4H), 7.36 (t, J = 7.6 Hz, 2H), 7.31 – 7.24 (m, 1H), 4.77 (dd, J = 9.2, 3.7 Hz,
1H), 2.66 (dd, J = 8.4, 5.1 Hz, 1H), 2.28 (d, J = 3.8 Hz, 1H), 1.99 (qd, J = 6.6, 5.0 Hz,
1H), 1.81 (td, J = 8.9, 6.5 Hz, 1H), 1.48 – 1.37 (m, 1H), 1.31 – 1.26 (m, 1H), 1.22
(ddtd, J = 12.6, 8.1, 6.7, 6.3, 4.4 Hz, 2H), 0.77 (t, J = 7.2 Hz, 3H).
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
LRMS m/z (ESI APCI) calculated for C20H22O2 [M+H] 295.2, found 295.2.
Ph
O
Ph
OH
Hn-Pr
Chemical Formula: C20H22O2
- 176 -
3al (2-(cyclohexyl(hydroxy)methyl)-3-propylcyclopropyl)(phenyl)methanone
Y = 95%. Off-white solid. Rf = 0.54 (4:1 Hexanes:EtOAc).
1H NMR (500 MHz, Chloroform-d) δ 8.06 – 7.97 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H),
7.45 (t, J = 7.6 Hz, 2H), 3.41 (dd, J = 9.2, 6.6 Hz, 1H), 2.49 (dd, J = 8.7, 5.0 Hz, 1H),
1.99 – 1.86 (m, 2H), 1.86 – 1.80 (m, 1H), 1.80 – 1.71 (m, 3H), 1.62 (dtq, J = 12.8,
10.2, 3.8, 2.9 Hz, 3H), 1.43 (dt, J = 14.8, 7.4 Hz, 3H), 1.32 – 1.15 (m, 4H), 1.15 – 1.00
(m, 2H), 0.92 (t, J = 7.3 Hz, 3H).
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
LRMS m/z (ESI APCI) calculated for C20H28O2 [M+H] 301.2, found 301.2.
Ph
O
Cy
OH
Hn-Pr
Chemical Formula: C20H28O2
- 177 -
3an (2-hydroxybicyclo[6.1.0]nonan-9-yl)(phenyl)methanone
Y = 85%. Colorless oil. Rf = 0.05 (4:1 Hexanes:EtOAc)
1H NMR (500 MHz, Chloroform-d) δ 8.10 – 7.98 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H),
7.47 (t, J = 7.6 Hz, 2H), 4.13 (td, J = 10.9, 4.6 Hz, 1H), 3.14 (s, 1H), 2.58 (dd, J = 9.6,
7.7 Hz, 1H), 1.91 (tt, J = 12.0, 4.3 Hz, 1H), 1.77 (tdd, J = 17.0, 8.4, 4.2 Hz, 3H), 1.73
– 1.65 (m, 2H), 1.59 (ddt, J = 15.3, 12.2, 4.3 Hz, 1H), 1.49 (tdd, J = 13.6, 10.4, 4.4
Hz, 1H), 1.45 – 1.30 (m, 2H), 1.21 (tdd, J = 14.3, 8.0, 3.6 Hz, 2H).
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
LRMS m/z (ESI APCI) calculated for C16H20O2 [M+H] 245.3, found 245.3.
Ph
OH
H
OH
Chemical Formula: C16H20O2
- 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
aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for
16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation
and the residue was taken up in EtOAc and filtered through a silica plug flushing with
EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where
the solution was partitioned with the addition of 10% NaOH solution. The aqueous
layer was extracted three times with EtOAc and the combined organic extracts were
filtered through a pad of celite® and Na2SO4 then concentrated. The residue was
purified by flash chromatography (Hexane:EtOAc, 19:1®9:1®4:1) to afford the
cyclopropane product.
[Cp*CF3RhCl2]2 (5 mol%)
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).
1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.97 (m, 2H), 7.62 – 7.55 (m, 1H), 7.49
(dd, J = 8.4, 7.0 Hz, 2H), 3.96 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 2.56 (d,
J = 5.0 Hz, 1H), 2.21 (s, 1H), 1.86 (q, J = 6.2 Hz, 1H), 1.48 (ttd, J = 11.8, 5.8, 5.1, 2.5
Hz, 4H), 0.99 – 0.92 (m, 3H).
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
LRMS m/z (ESI APCI) calculated for C17H16O2 [M+H] 220.1, found 220.1.
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
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. The vial was sealed with a
screw-cap and placed in an aluminium block cooled to 0 ˚C surrounded by ice in an
insulated box and stirred for 3 hours. TFE-d1 was removed by rotary evaporation and
the residue was taken up in EtOAc and filtered through a silica plug flushing with
EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where
the solution was partitioned with the addition of 10% NaOH solution. The aqueous
layer was extracted three times with EtOAc and the combined organic extracts were
filtered through a pad of celite® and Na2SO4 then concentrated. The residue was
purified by flash chromatography (Hexane:EtOAc, 19:1®9:1®4:1) to re-isolate the
starting material.
O NPhth
H H
O NPhth
D/H H/D
[Cp*CF3RhCl2]2 (5 mol%)
KOPiv ( 2 equiv.)TFE-d1, 0 ˚C
1a 0% D1a
- 183 -
With homoallylic alcohol 4a
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 homoallylic
alcohol 4a (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed
in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred
for 16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation
and the residue was taken up in EtOAc and filtered through a silica plug flushing with
EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where
the solution was partitioned with the addition of 10% NaOH solution. The aqueous
layer was extracted three times with EtOAc and the combined organic extracts were
filtered through a pad of celite® and Na2SO4 then concentrated. Yield and
diastereoselectivity were determined by crude 1H NMR.
[Cp*CF3RhCl2]2 (5 mol%)
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
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 bis-homoallylic
alcohol 6a (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed
in an aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred
for 16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation
and the residue was taken up in EtOAc and filtered through a silica plug flushing with
EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where
the solution was partitioned with the addition of 10% NaOH solution. The aqueous
layer was extracted three times with EtOAc and the combined organic extracts were
filtered through a pad of celite® and Na2SO4 then concentrated. Yield and
diastereoselectivity were determined by crude 1H NMR.
[Cp*CF3RhCl2]2 (5 mol%)
KOPiv (2 equiv.)TFE, 0 °C
MePh
O
1a
6a 7aa
Me
17%, >20:1 d.r.
OH
OH
- 185 -
With allylic ether 6a
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 ether 8a
(1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an
aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for
16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation
and the residue was taken up in EtOAc and filtered through a silica plug flushing with
EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where
the solution was partitioned with the addition of 10% NaOH solution. The aqueous
layer was extracted three times with EtOAc and the combined organic extracts were
filtered through a pad of celite® and Na2SO4 then concentrated. Yield and
diastereoselectivity were determined by crude 1H NMR.
[Cp*CF3RhCl2]2 (5 mol%)
KOPiv (2 equiv.)TFE, 0 ˚C
n-Pr
OMe
Ph
O
1a
8a 9aatrace
OMe
n-Pr
- 186 -
With allylic carboxylic acid
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 carboxylic
acid (1.2 equiv., 0.144 mmol). The vial was sealed with a screw-cap and placed in an
aluminium block cooled to 0 ˚C surrounded by ice in an insulated box and stirred for
16 hours. Upon completion judged by TLC, TFE was removed by rotary evaporation
and the residue was taken up in EtOAc and filtered through a silica plug flushing with
EtOAc. The filtrate was concentrated to ~1mL and transferred to a 1.5-dram vial where
the solution was partitioned with the addition of 10% NaOH solution. The aqueous
layer was extracted three times with EtOAc and the combined organic extracts were
filtered through a pad of celite® and Na2SO4 then concentrated. Yield and
diastereoselectivity were determined by crude 1H NMR.
[Cp*CF3RhCl2]2 (5 mol%)
KOPiv (2 equiv.)TFE, 0 ˚C
n-Pr
CO2H
Ph
O
1a
8b 9abtrace
CO2H
n-Pr
- 187 -
With allylic amine
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 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.
[Cp*CF3RhCl2]2 (5 mol%)
KOPiv (2 equiv.)TFE, 0 ˚C
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.
[Cp*CF3RhCl2]2 (5 mol%)
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).
1H NMR (500 MHz, Chloroform-d) δ 7.80 – 7.74 (m, 1H), 7.71 – 7.65 (m, 1H), 7.62 –
7.58 (m, 2H), 7.56 – 7.50 (m, 2H), 7.44 – 7.37 (m, 3H), 5.81 (dqt, J = 15.3, 6.4, 1.2
Hz, 1H), 5.59 (dtq, J = 14.8, 6.5, 1.6 Hz, 1H), 4.68 (ddt, J = 12.3, 6.5, 1.2 Hz, 1H),
4.61 (ddt, J = 12.2, 6.5, 1.1 Hz, 1H), 2.01 (s, 3H), 1.71 (dq, J = 6.5, 1.2 Hz, 3H).
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
[Cp*CF3RhCl2]2 (5 mol%)
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
(5 mol%)[Cp*CF3RhCl2]2
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
300000EJTP1414_A_pure.2.fid
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
15000EJTP2213_A_pure.1.fidProton
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
13000EJTP2213_B_pure.3.fidProton
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
19000EJTP1458_B_pure.1.fidProton
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
EJTP1458_B_pure.2.fidCarbon13
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
650000EJTP2318_pure.2.fid
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
500000EJTP2252_B_pure.7.fidCarbon13
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
EJTP2269_A_pure.8.fidProton
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
EJTP2269_A_pure.9.fidCarbon13
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
EJTP2269_B_pure.6.fidCarbon13
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
EJTP2207_A_pure.3.fidProton
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
120000EJTP2207_A_pure.4.fidCarbon13
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
EJTP2207_B_pure.2.fidCarbon13
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
13000EJTP1441_B_pure.1.fidProton
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
150000EJTP1441_B_pure.2.fidCarbon13
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
EJTP2253_B_pure.1.fid
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
3400EJTP2253_B_pure.2.fid
-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
12000EJTP1441_A_pure.1.fidProton
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
90000EJTP1441_A_pure.2.fidCarbon13
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
6000EJTP2314_pure.2.fid
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
EJTP2252_A_pure.1.fidProton
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
EJTP2252_A_pure.2.fidCarbon13
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
KOPiv (2 equiv.)TFE, rt
4-483%(X-ray)
(1 atm)(5 equiv.)4-1a 4-2a
- 257 -
Yield: 83%
1H NMR (400 MHz, Chloroform-d) δ 8.21 – 8.14 (m, 2H), 7.60 – 7.43 (m, 3H), 5.37 –
5.26 (m, 1H), 4.78 (d, J = 10.2 Hz, 1H), 4.35 (d, J = 7.3 Hz, 1H), 3.61 (d, J = 12.4 Hz,
1H), 2.00 (d, J = 1.3 Hz, 3H), 1.58 (s, 3H), 1.49 (d, J = 1.1 Hz, 3H), 1.28 (s, 3H).
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%
1H NMR (500 MHz, Chloroform-d) δ 7.88 – 7.83 (m, 1H), 7.60 – 7.55 (m, 1H), 7.45 –
7.36 (m, 2H), 7.30 (q, J = 5.6 Hz, 1H), 3.82 (s, 3H), 2.46 (d, J = 5.7 Hz, 3H), 1.69 (s,
17H).
13C NMR (126 MHz, Chloroform-d) δ 177.8, 169.7, 155.8, 133.4, 132.0, 130.4, 130.4,
129.7, 128.3, 85.2, 52.4, 18.2, 8.9
LRMS m/z (ESI APCI) calculated for C21H25N2O3Ir[M+H] 547.2, found 547.2.
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
140000EJTP3048_pure.1.fid
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
160000EJTP3048_pure.2.fid
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