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Singlet halofluorocarbenes: Modes of generation and their reactions with alkenes and various heteroatom nucleophiles

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Singlet halofluorocarbenes: Modes of generation and their reactions with alkenes and various heteroatom nucleophiles

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Singlet halofluorocarbenes:

Modes of generation and their reactions with alkenes and various heteroatom nucleophiles

by

Colby Barrett

A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)

May 2023

Copyright 2023 Colby Barrett
ii

Dedicated
To My
Parents

iii
Acknowledgements
My journey through chemistry was made possible by the support of so many people, and I
am forever in their debt for that support.
To my parents, Tim and Missy Barrett: I think you deserve your names on this dissertation
as much as I do. You have been my candle on the water, guiding me, reassuring me through
difficult times. You’ve suffered through countless late night phone calls in which I ramble
aimlessly and at length about whatever I was excited or annoyed about that day. You would always
listen, even if I’d stopped making sense a few minutes back. I love you both so much, and I can
never thank you enough for everything you’ve done to help me pursue my dreams and reach this
milestone.
To Jon “the master” Matheny: without your influence, I am certain I would not be writing
this. You helped to spark my interest in chemistry when I was just a first year undergraduate
student. You got me into research before I was even thinking about it. You’ve taught me so much
not only about chemistry, but also empathy, introspection, critical thinking, and Linux. You’ve
been a mentor and a dear friend.
To Professor G. K. Surya Prakash: I wrote in my personal statement for my application to
USC that I was not 100% sure that graduate school was for me (I was going for honesty). Even
though that is surely not the thing a professor wants to read from a prospective student, you took
a chance on me, and I thank you for that chance. You have been endlessly supportive throughout
my time at USC, including encouraging me to pursue opportunities aligned with my interest in
chemical education, even when they took time away from my lab work. I appreciate how your
warm, kind persona builds a positive environment in the lab, and I am glad I could be a part of it.
iv
To Vinayak Krishnamurti: you took me under your wing shortly after I arrived at USC,
and I think we became a great team. Though I’ll never match up to that exceedingly brilliant mind
of yours, you gave me a high bar to aspire to. The many skills I have picked up with your guidance
will be invaluable to me in the future. I am also thankful for our friendship. Having a buddy
though this process has made it much more bearable. You and Xanath Ispizua Rodriguez have
been the best of friends to me, and in spite of my eccentricities, you’ve been endlessly patient and
supportive. I hope you know how much that means to me.
So many people have played a role in me getting to this point. I am grateful to Ziyue Zhu
for your friendship and lively discussions about everything from chemistry to politics to food. You
are one of the hardest workers I’ve ever known, and I wish you, Fangyi, and baby Ellie all the best
in the world. CJ Koch, I have still never figured out just how many projects you are involved in
(or exactly what the phosphate was for). In spite of how busy that keeps you, you’re always up
for a good chat or venting session. Good luck with the new job; I hope it brings you everything
you’re looking for. Matt Coe, you have energy to rival the sun and a big heart to match. In spite
of all my jokes, as Dorothy said to the scarecrow, “I think I’ll miss you most of all.” Anushan
Alagaratnam, thank you for your persistence and hard work on our project. You’ve made a big
contribution to the work in this dissertation. Daniel Lin and Alex Knieb, thank you for being good
lab mates. I’m looking forward to seeing what the future holds for you both. Alain Goeppert,
thank you for always being willing to help when something goes wrong. You are an invaluable
asset to the lab. To all of the other members of the Prakash group, thank you for making it a
positive place to work.

v
Table of contents
Dedication ....................................................................................................................................... ii
Acknowledgements ........................................................................................................................ iii
Abstract ......................................................................................................................................... vii

[1] Chapter 1. Introduction to silicon based reagents for the generation of
halofluorocarbenes .........................................................................................................................1
1.1 Fluorine: What is it good for? ...........................................................................................1
1.2 Fluoroalkylsilanes as masked carbenoids .........................................................................2
1.3 TMSCF2X (X = Cl, Br, I) ................................................................................................3
1.4 Conclusions .....................................................................................................................24
1.5 References .......................................................................................................................25

[2] Chapter 2. One-pot preparation of (RSe)2CF2 and (RS)2CF2 compounds via
insertion of TMSCF3-derived difluorocarbene into diselenides and disulfides .....................32
2.1 Introduction and attempted siladifluoromethylation of diselenide-derived selenolate ...32
2.2 Unprecedented formal :CF2 insertion .............................................................................39
2.3 Optimization and scope of diselenide substrates ............................................................40
2.4 Optimization and scope of disulfide substrates ..............................................................43
2.5 Proposed mechanism ......................................................................................................44
2.6 Conclusions .....................................................................................................................45
2.7 Experimental ...................................................................................................................46
2.7.1 General information ..............................................................................................46
2.7.2 Synthesis of diselenide starting materials .............................................................46
2.7.3 Synthesis of difluoromethylene diselenoethers and dithioethers (2) ....................53
2.8 References .......................................................................................................................61

[3] Chapter 3. gem-Halofluorocyclopropanes via [2+1] cycloadditions of in situ
generated CFX carbene with alkenes .........................................................................................68
3.1 Introduction .....................................................................................................................68
3.2 Optimization ...................................................................................................................69
vi
3.3 Proposed mechanism ......................................................................................................71
3.4 Scope of bromofluorocyclopropanation .........................................................................71
3.5 Extension to chlorofluorocyclopropanes ........................................................................74
3.6 Potential synthetic utility of synthesized products ..........................................................76
3.7 Conclusions .....................................................................................................................77
3.8 Experimental ...................................................................................................................78
3.8.1 General information ..............................................................................................78
3.8.2 Synthesis of alkene starting materials ...................................................................79
3.8.3 General procedures ...............................................................................................80
3.8.4 Experimental and spectral data for halofluorocyclopropanes 2 and 3 ..................81
3.8.5 Post functionalization procedures and related information ..................................93
3.8.6 Additional NMR data ............................................................................................95
3.9 References .....................................................................................................................100

[4] Chapter 4. Accessing azidodifluoromethide (N3CF2¯ ) from azide and
difluorocarbene: A marriage that just clicks ..........................................................................104
4.1 Introduction ...................................................................................................................104
4.2 Optimization .................................................................................................................107
4.3 Scope of aldehyde azidodifluoromethylation ...............................................................108
4.4 Proposed mechanism ....................................................................................................111
4.5 Cycloadditions – demonstrating utility .........................................................................111
4.6 Conclusions ...................................................................................................................112
4.7 Experimental .................................................................................................................113
4.7.1 General experimental information ......................................................................113
4.7.2 Synthesis of products 2 .......................................................................................114
4.7.3 Synthesis of triazoles 3 .......................................................................................122
4.8 References .....................................................................................................................124

vii
Abstract
This dissertation is focused on the development of methods to install fluorinated single
carbon moieties into organic molecules. In particular these involve the generation and capture of
reactive intermediate singlet carbenes.
Chapter 1 covers the advancements in the use of common silicon based reagents, like
TMSCF2Br, including those involving an intermediate singlet difluorocarbene.
In Chapter 2, siladifluoromethylation of benzeneselenol with TMSCF3 is discussed, along
with how this exploration led us to our discovery of an unprecedented difluoromethylene insertion
reaction with diphenyl diselenide. The generation of difluorocarbene with TMSCF3 under basic
conditions in the presence of diaryl diselenides yielded the product difluoromethylene
diselenoethers in good to excellent yields. The method was also extended to the synthesis of the
sulfur analogues, starting with diaryl disulfides.
In Chapter 3, the development of an efficient and operationally simple synthesis of gem-
bromofluorocyclopropanes under mild conditions is discussed. The method employs ethyl
dibromofluoroacetate as an accessible and inexpensive source of the bromofluorocarbene (:CFBr)
intermediate. The protocol provides the bromofluorocyclopropane products in excellent yields,
including examples synthesized in multigram scales. The chlorinated ester, ethyl
dichlorofluoroacetate, is also utilized to make the analogous gem-chlorofluorocyclopropanes.
In Chapter 4, the first nucleophilic azidodifluoromethylation of aldehydes is discussed.
This involves the in situ generation of intermediate azidodifluoromethide from sodium azide and
TMSCF2Br-derived difluorocarbene. The O-silyl ether products are valuable as synthetic building
blocks and have potential in biochemical protein labeling as fluorinated tags using click chemistry.

1
Chapter 1: Introduction to silicon based reagents for the generation of halofluorocarbenes
1.1 Fluorine: What is it good for?
Fluorine chemists are always on the lookout for new and creative ways to inject fluorine
atoms into organic molecules. Progress toward both new reagents to accomplish this and further
development of existing ones is being made every day. Among the most valuable in this space are
those reagents used for fluoroalkylation. While fluorination reagents are undeniably useful, given
that the proverbial bread and butter of organic chemistry is in the formation of carbon-carbon
bonds, fluoroalkylation reagents seem arguably better suited for the limelight of popularity. But
why do fluorine chemists do what they do? To what end are these advancements in
fluoroalkylation methodology being made?
The justification most often cited for the development of fluorine chemistry is rooted in the
effect of fluorine atoms on bio-active organic molecules. From agrochemicals like carfentrazone-
ethyl and isoflucypram, to pharmaceuticals like celecoxib and gemcitabine, a large and ever-
growing number of fluorinated organic molecules are used around the world on a daily basis for a
broad range of applications (Scheme 1.1.1).
1–4

Scheme 1.1.1 Examples of fluoroalkyl-containing bio-active organic molecules
Fluorinated molecules are so popular in these contexts because of how fluorine can effect powerful
changes to the molecular properties in a biological system, such as the molecule’s metabolic
2
stability, bioavailability, binding affinity, and lipophilicity.
5–9
As such, the degree of fluorination
and position(s) of the fluorine(s) within the structure can be dialed in to fine tune these properties.
1.2 Fluoroalkylsilanes as masked carbenoids
Fluoroalkylsilanes are among the most successful classes of fluoroalkylation reagents, due
in large part to their versatility, accessibility, and general ease of use.
10
The silyl groups of these
compounds, most often trimethylsilyl (TMS-), effectively serves as a protecting group for the
fluoroalkyl group (RF) to which it is attached. The fluoroalkyl group can be deprotected using a
nucleophilic activator (A). This activator adds to the silicon, generating a pentacoordinate silicate
intermediate. One of two nucleofuges then leaves, A¯ or RF¯. Once the latter is expelled, it can
then be used in a multitude of ways dependent upon the identity of RF and the conditions under
which it is generated (Scheme 1.2.1).

Scheme 1.2.1 Nucleophilic desilylative liberation of fluoroalkyl anion
The most popular reagent of this class is TMSCF3, known as the Ruppert-Prakash reagent.
11,12
It
is most often used as a pronucleophilic source of trifluoromethide ( ¯CF3) for additions to various
carbon and heteroatom electrophiles.
1,13–15
However, given the right conditions, this anion can
also behave differently. Trihalomethides, such as ¯CF3, are often called “carbenoids” due to their
propensity to generate carbenes (Scheme 1.2.2).

Scheme 1.2.2 Difluorocarbene generation via fluoride elimination from carbenoid CF3¯
3
Trifluoromethide can undergo fluoride elimination to generate fluoride and singlet
difluorocarbene. A condition-dependent equilibrium is established between these species,
meaning it can be controlled by manipulating those conditions. Difluorocarbene is a very reactive
intermediate, but it is relatively stable when compared to other non-stabilized carbenes (e.g. :CH2).
This stability comes from orbital overlap of a non-bonding lone pair on fluorine and the empty
carbon p-orbital. In CF2 carbene, both fluorine atoms can contribute electron density to this
stabilizing interaction, and given the excellent size match of the orbitals involved (and therefore
the high degree of overlap), the stabilization is quite strong. To quantify, the singlet state of
difluorocarbene has been calculated to be more stable than the triplet state by as much as 60
kcal/mol.
16

In recent years TMSCF3 has become popular as a means for direct -CF2- incorporation
into molecules rather than CF3.
17–27
These often involve the intermediacy of difluorocarbene. This
work has been comprehensively reviewed by Ispizua-Rodriguez et al.,
10
and Krishnamoorthy et
al.
14
so it will not be covered here. The rest of this chapter will focus on the synthesis and use of
TMSCF2X reagents.
1.3 TMSCF2X (X = Cl, Br, I)
Halodifluoromethylsilanes have had a significant impact on the world of fluorine chemistry
due in no small part to the large variety of transformations they can facilitate, such as nucleophilic
halodifluoromethylation, electrophilic difluoromethylation, and radical siladifluoromethylation.
TMSCF2Br has distinguished itself, especially over the past five to ten years, as not only the most
popular member of this class but also among the most valuable fluoroalkylation reagents.
The initial report of a compound with the form [Si]CF2X (where X = Cl, Br, I) was in 1981
by Fuchikami and Ojima, in which (bromodifluoromethyl)phenyldimethylsilane (PhMe2SiCF2Br)
4
was synthesized in good yield via radical C–H bromination of the analogous [Si]–CF2H compound
with NBS (Scheme 1.3.1-a).
28
Though this bromination step was quite efficient, the
difluoromethylsilane starting material may serve as a limitation of this method, as it was isolated
from the reaction of phenyldimethylsilyl lithium and HCF2Cl in only 35% yield. Nine years later,
Broicher and Geffken published an alternative synthetic approach from CF2ClBr or CF2Br2 using
Ruppert-type conditions with tris(diethylamino)phosphine. The anion of the intermediate is then
trapped with a halosilane to give TMSCF2Cl or TMSCF2Br in low yields (Scheme 1.3.1-b).
29

Kvíčala et al. showed that a Grignard approach with CF2Br2 only provided TMSCF2Br in 12%
yield due to the low stability of the organomagnesium intermediate.
30
In 1997, Olah, Prakash, and
coworkers disclosed an aluminum metal mediated debromination-silylation of the Halons used by
Broicher and Geffken to access the same products in considerably higher yields (Scheme 1.3.1-
c).
31
The authors provide evidence that the reaction does not proceed via the possible
difluorocarbene mechanism but rather through an anionic mechanism, suggesting that the
aluminum species serves as an effective stabilizer of the anion. They also demonstrated that Cl/Br
exchange could be performed between TMSCF2Br and TMSCl to give TMSCF2Cl and TMSBr
quantitatively (Scheme 1.3.1-d).
31
This paradigm of TMSCF2Br as a synthon for accessing other
(halodifluoromethyl)trimethylsilanes via some form of halogen exchange has also been exploited
to make TMSCF2Cl using either LiCl
32
or AgCl,
33
or TMSCF2I using iodine
34
(Scheme 1.3.1-e).
32–
34
Due in part to the toxicity and ozone-depleting capabilities of many Halons (e.g. CF2ClBr),
29

significant effort has been expended to develop Halon‑free methods to access TMSCF2Br and
related compounds. TMSCF3, which can be derived from non-ozone-depleting fluoroform, has
been the most popular feedstock in this context as it is relatively inexpensive and can be efficiently
reduced to TMSCF2H with NaBH4.
35

5

Scheme 1.3.1 Synthesis of halodifluoromethylsilanes
Analogously to the C-H bromination shown by Fuchikami and Ojima,
28
TMSCF2H can be
converted to TMSCF2Br via reaction either with NBS or with aqueous HBr/H2O2 in the presence
of light as shown by the groups of Hu
36
and Dilman,
37
respectively. Alternatively, Hu and
6
coworkers also demonstrated that TMSCF2Br could be quickly accessed directly from TMSCF3
using BBr3 in comparable overall yield to the two-step procedures
36
(Scheme 1.3.1-f).
36,37

Among their various modes of reactivity, R3SiCF2X compounds are most commonly
exploited as precursors for the in situ generation of difluorocarbene (see Section 1.2). As shown
in Scheme 1.3.2, this process starts with nucleophilic activation of the silicon atom, forming the
anionic silicate intermediate. The released halodifluoromethide can then extrude halide to form
difluorocarbene. In this context, the advantage these TMSCF2X reagents (X = Cl, Br, I) have over
TMSCF3 (X = F) is the considerably poorer leaving group ability of fluoride, or conversely, the
higher nucleophilicity of fluoride and its resultant increase of the rate of the reverse reaction
(recombination with :CF2). In other words, TMSCF2X reagents can generate the valuable :CF2
electrophile more readily and under a wider range of conditions.

Scheme 1.3.2 Path of difluorocarbene generation from TMSCF2X
Halodifluoromethylsilanes are not the only reagents used to generate difluorocarbene,
38
but
they are often preferred over alternatives due to the mildness of conditions required for their
activation as well as their accessibility, ease of handling, and compatibility with aqueous systems.
The earliest reported use of a halodifluoromethylsilane as a :CF2 source was in a 2009 patent by
Hu and coworkers. As is the seemingly universal inaugural substrate for testing the efficacy of a
new difluorocarbene source, the authors reacted TMSCF2Cl with alkenes. The singlet :CF2
7
undergoes a concerted [2+1] cycloaddition with the π system of the alkene to give a gem-
difluorocyclopropane. TMSCF2Cl, activated by TBAC, reacted smoothly with a series of mono-,
di-, tri-, and tetrasubstituted alkenes, providing the corresponding cyclopropanes in modest to good
yields under moderately harsh conditions (Scheme 1.3.3-a).
39

Scheme 1.3.3 Cyclopropa(e)nation reactions with TMSCF2X
The same procedure was used in a 2011 paper by the same group, in which they demonstrated
improved yields (up to 99%) for the cyclopropanation reaction and successfully expanded the
method to alkyne substrates. Alkynes undergo a similar [2+1] cycloaddition to provide gem-
difluorocyclopropenes, which they were able to obtain in good to excellent yields under minimally
altered conditions (Scheme 1.3.3-b).
40
Two years later, TMSCF2Br was shown, again by the Hu
group, to perform these cyclopropanations and cyclopropenations with similar or higher efficiency
8
than TMSCF2Cl even with lower loadings of the silane and larger functional group diversity in the
substrates. Although the conditions were largely unchanged from the previous report, the authors
did note that it was important to use the bromide salt of tetrabutylammonium (TBAB) in place of
the chloride salt (TBAC) used in the TMSCF2Cl method (Scheme 1.3.3-c).
36

The noteworthy success of this [2+1] cycloaddition with TMSCF2Br inspired a series of
articles in which the method was applied to different enolizable systems. In the first report of this
type, Dilman and coworkers reported a three step, one-pot difluorohomologation of ketones using
TMSCF2Br. As shown in Scheme 1.3.4-a,
41
the starting ketone is O-silylated with TMS triflate,
allowing for α-deprotonation by triethylamine to form the silyl enol ether. Difluorocarbene,
generated from Lewis base activation of TMSCF2Br, then undergoes a cyclopropanation with the
olefinic π-system. Treating the resultant difluorocyclopropyl alcohol with strong acid at elevated
temperature promoted ring opening, selectively breaking the bond between the non-fluorinated
carbons to provide the α,α-difluoroketones in moderate to excellent yields.
41
A slightly modified
procedure was also applied to enolizable esters. The analogous difluorocyclopropyl intermediates
were found to be much less stable than those derived from ketones, and they underwent
spontaneous ring opening without acid treatment. Interestingly, the bond broken in the ring
opening step was different from the ketone substrates; the reaction yielded α-siladifluoromethyl
esters rather than the difluorohomologation products (Scheme 1.3.4-b).
41
When they applied this
method to the silyl gem-difluoroketene acetal shown in Scheme 1.3.4-c,
42
Dilman and coworkers
were able to access ethyl α,α-difluoro-α-siladifluoromethyl acetate via a tetrafluorocyclopropane
intermediate.
9

Scheme 1.3.4 Difluorocyclopropanation in enolic systems
This compound and an amide derivative were demonstrated to be useful as nucleophilic addition
reagents.
42
The same group also reported a similar ketone difluorohomologation procedure in
which the resultant carbanion from the ring opening is quenched with an electrophilic halogenating
10
agent (NBS or NIS). This gave β-bromo- or β-iodoketones in moderate to excellent yields
(Scheme 1.3.4-d).
43
Song et al. found that rather than using strong acids or electrophilic
halogenation reagents to facilitate the cyclopropane ring opening, elevated temperatures under
anhydrous conditions, followed by fluoride elimination, promoted ring opening to produce
monofluoroolefins. This was also shown to work with aldehydes, albeit in lower yields (Scheme
1.3.4-e).
44

Scheme 1.3.5 Difluorocyclopropane ring opening cascades
Chang and Song et al. further explored this chemistry in the context of indanones. The
monofluoroolefination gives a 2,5-cyclohexadieneone-like intermediate, which quickly
aromatizes via proton transfer to the corresponding naphthols in good yields. They also found that
11
2-cyclopentenones undergo the same transformation, producing mixtures of the 2-fluoro and 4-
fluoro isomers (Scheme 1.3.5-a).
45
The same authors then applied these conditions to acyclic
enolizable vinyl ketones. These first underwent the usual difluorocyclopropanation. Upon ring
opening, those derived from ketene dithioacetals underwent a copper(I)-assisted ring closure,
followed by elimination of Cu–S(alkyl) to give gem-difluorocyclopentenones.
46
The
difluorocyclopropanes not derived from ketene dithioacetals underwent a thermal VCP (vinyl
cyclopropane) rearrangement to the gem-difluorocyclopentenol
47
(Scheme 1.3.5-b).
46,47

Difluorocarbene can do much more than just [2+1] cycloadditions. It is also an excellent
way to install difluoromethyl groups. This is most commonly accomplished via the
straightforward reaction of a nucleophilic substrate with electrophilic CF2 carbene, but with an
appropriate Lewis base facilitator, the CF2 can be installed nucleophilically. The latter approach is
exemplified by Dilman and coworkers in two reports on formal difluoromethylation of
electrophiles, in which their choice of Lewis base was triphenylphosphine. TMSCF2Br is activated
by DMPU, and the difluorocarbene released reacts with PPh3 to form the ylide (Scheme 1.3.6-a).
With this approach, the authors added in situ-generated Ph3P=CF2 to ketones,
48
nitro alkenes,
48

and carboxylic acid-derived acyl chlorides
49
(Scheme 1.3.6-b).
48,49
The phosphonium
intermediates were subsequently dephosphorylated under appropriate conditions to provide the
desired products in mostly good yields. With acyl chloride substrates, the bis addition generally
dominated; the difluoromethyl ketones (the products of mono addition) could be obtained but only
when the R groups were bulky.
49

12

Scheme 1.3.6 Nucleophilic C-difluoromethylation with Ph3P=CF2
The more common electrophilic approach for difluoromethylation with CF2 carbene has
been successfully applied to several different atoms. Carbon is among them, but substrate scope
limitations in the addition of carbon nucleophiles to difluorocarbene have remained a challenge.
Employing HSAB theory, this can be described as a poor match between difluorocarbene, a
relatively soft electrophile, and carbon nucleophiles, which tend to be quite hard. The most
successful strategy to mitigate this effect has been via substrate engineering by employing special,
highly resonance stabilized carbon nucleophiles to make them effectively softer. Shibata and
coworkers chose to use β-ketoesters as the pronucleophiles. Lithium hydroxide and
tetraalkylammonium bromide in toluene facilitated α-deprotonation of the ketoester and
subsequent nucleophilic addition to :CF2 (generated from TMSCF2Br and LiOH). Protonation of
the carbanion gave difluoromethylated compounds in low to excellent yields (Scheme 1.3.7-a).
50

13

Scheme 1.3.7 Difluoromethylation of carbon nucleophiles
14
A 2019 report by Hu and coworkers detailed the C–H difluoromethylation of an impressive variety
of carbon acids using TMSCF2Br. This included: esters, amides, β-ketoesters, malonates, α-
sulfono esters, fluorenes, nitriles, terminal alkynes, an α-phosphono ester, and phenylbutazone.
Remarkably, all of these substrates were transformed to the difluoromethyl analogues under
virtually identical conditions. The short reaction times are also noteworthy, especially considering
they are carried out at room temperature (Scheme 1.3.7-b,c).
51

Difluoromethylation of heteroatom nucleophiles with TMSCF2X has been more
extensively studied than carbon nucleophiles. The first report was in 2013 by Hu and coworkers,
in which alcohols, thiols, phenyl sulfinic acid, and azoles were transformed to the corresponding
difluoromethyl compounds with TMSCF2Br under aqueous KOH/DCM conditions (Scheme 1.3.8-
a).
36
The method was surprisingly general, providing the desired difluoromethylated products in
mostly good yields. The authors also disclosed a minimally altered procedure for
difluoromethylation of secondary phosphine oxides, in which aqueous potassium carbonate is used
in place of KOH (Scheme 1.3.8-b).
36
Difluoromethylation of alcohols with the aqueous
KOH/DCM conditions works well when the alcohols are aromatic, but aliphatic alcohols tended
to give reduced yields.
36
Hu and coworkers found that milder activation conditions, employing
KOAc or KHF2, gave improved generality over the harsher NaOH conditions, which struggled
with electron deficient and sterically hindered alcohols. A variety of aliphatic alcohols were
difluoromethylated with TMSCF2Br using each of the three activators, giving a range of yields
dependent upon the sterics and electronics of the substrates (Scheme 1.3.8-c).
52
In 2019, a report
by Prakash and coworkers disclosed the synthesis of O-difluoromethyl esters from carboxylic
acids using TMSCF2Br in a basic aqueous medium under air. The reaction was performed on an
assortment of carboxylic acids, including amino acids and FDA approved drugs, providing the
15
difluoromethyl esters in modest to excellent yields (Scheme 1.3.8-d). Huang et al. recently
divulged an N-difluoromethylation of hydrazones using TMSCF2Br. The large table of examples
demonstrated good functional group tolerance, providing the N-difluoromethylhydrazones in low
to excellent yields (Scheme 1.3.8-e).
53

Scheme 1.3.8 Difluoromethylation of heteroatom nucleophiles
Difluoromethylation reactions can be made even more exciting when they are part of a
multi-step cascade, allowing for rapid combination of multiple synthetic building blocks. Dilman
and coworkers mixed secondary amines and potassium carbonate with carbon disulfide, followed
by TMSCF2Br to assemble S-difluoromethyl dithiocarbamates in modest to good yields (Scheme
1.3.9-a).
54
The same group expanded on this approach, using the potassium dithiocarbamate salt
as the initial nucleophile. S-difluoromethylation with difluorocarbene generates the
16
difluoromethyl anion, which adds to an aldehyde to give the corresponding alcohol in moderate to
good yields (Scheme 1.3.9-b).
55
Hu and coworkers recently published a three-component
phenylsulfonyl- and arylthiodifluoromethylation of aldehydes using TMSCF2Br as a carbene
source. Either sodium benzenesulfinate or aryl thiolates can be reacted with TMSCF2Br-derived
difluorocarbene; the resultant carbanion adds to the aldehyde. Subsequent treatment with TBAF
provided the desired alcohol products in moderate to excellent yields (Scheme 1.3.9-c). The
convenience and simplicity of this type of multi-component reaction makes it a great approach for
accessing diverse fluoroalkyl-containing scaffolds.

Scheme 1.3.9 S-difluoromethylation and reaction cascades
Halodifluoromethylsilanes can also be used to perform difluoroolefinations at activated
carbon centers. In 2014, Hu and coworkers reported a Wittig-type difluoroolefination of aldehydes
and ketones using a difluoromethylene phosphonium ylide generated in situ from TMSCF2Cl and
PPh3. The ylide first performed a nucleophilic attack on the carbonyl carbon, and the resulting
17
zwitterion formed the 4-membered oxaphosphetane ring system. Extrusion of triphenylphosphine
oxide gave the difluoroolefins in modest to good yields. (Scheme 1.3.10-a).
33

Scheme 1.3.10 Wittig-type gem-difluoroolefination of carbonyls
The same ylide, generated from TMSCF2Br, would later be used by the Dilman group for
nucleophilic difluoromethylation of carbonyl systems (see Scheme 1.3.6-a,b)
48,49
This intriguing
difference of reactivity was documented by Hu and coworkers in their difluoroolefination paper
(Scheme 1.3.10-b).
33
They found that when the ylide was formed from TMSCF2Cl, the
zwitterionic betaine intermediate was smoothly converted to the oxaphosphetane and subsequently
to the difluoroolefin. However, when TMSCF2Br was used to generate the phosphonium ylide,
the betaine did not cyclize to the oxaphosphetane. Rather, it was trapped as the O-silylated
phosphonium compound. The difference between the two systems stems from the byproducts of
difluorocarbene generation from the two halodifluoromethylsilanes. In each case this will produce
18
a stoichiometric quantity of the corresponding silyl halide. TMSBr is known to be a considerably
stronger silylating agent than TMSCl due to the weakness of the Si–Br bond relative to that of Si–
Cl. TMSBr is able to O-silylate the betaine, preventing the ring closure, and by extension, the
difluoroolefination. TMSCl is not reactive enough to perform the same silylation, so the
difluoroolefination proceeds.
33
TMSCF2Br and TMSCF2Cl can often perform quite similarly as
sources of difluorocarbene, and this has led many chemists to consider the two reagents equivalent.
However, this serves as an excellent example of how seemingly benign changes (in this case the
identity of the halide nucleofuge) can have significant effects on overall chemoselectivity.
In 2015, Hu and coworkers showed that diazo compounds could also serve as activated
systems for difluoroolefination with difluorocarbene. Using TMSCF2Br and catalytic TBAB, they
were able to convert α-diazoacetates to the corresponding difluoroolefin products in low to
excellent yields (Scheme 1.3.11-a).
24
Expansion of the substrate scope to arylalkyldiazomethanes,
which are considerably less stable than the diazoacetates, required the use of diazirines as diazo
surrogates. Thermal isomerization of the diazirine in situ generates the reactive diazo compound.
Its reaction with difluorocarbene provides the desired difluoroolefins in moderate to excellent
yields. This was only the case if TMSCF2Br was used as the limiting reagent with a two-fold
excess of the starting diazirine. If the silane was used in excess, the difluoroolefin product would
undergo a [2+1] cycloaddition with a second equivalent of :CF2, making up to 84% of the
tetrafluorocyclopropane (Scheme 1.3.11-b).
24
Zhang et al. further expanded this method to
diaryldiazomethanes both directly and via in situ generation of the diaryldiazomethane from
hydrazones (Scheme 1.3.11-c).
56
The same group used TMSCF2Br as a difluorocarbene source to
make difluoroketenimines in situ by reacting it with isonitriles. The reaction of the ketenimine
19
with N-sulfonyl imines gave 4-membered ring intermediates, which upon acid treatment were
hydrolyzed to α,α-difluoro-β-amino amides in overall good yields (Scheme 1.3.11-d).
57

Scheme 1.3.11 CF2 carbene incorporation into diazo compounds and isonitriles
The last major group of reactions involves organozinc reagents, using
halodifluoromethylsilanes as sources of either difluorocarbene or the siladifluoromethyl group. In
this work, pioneered by Alexander Dilman, an alkylzinc halide is treated with a
20
halodifluoromethylsilane. In the presence of a Lewis base (e.g. sodium acetate) to activate the
silane, the resultant difluorocarbene inserts into the Zn–C bond to give Alk(CF2)ZnX.
Alternatively, in the presence of a cobalt(II) catalyst, the difluoromethylsilyl group is formally
substituted for the alkyl group on the zinc. These two forms of organozinc reagents have been
used to provide access to a variety of either alkyldifluoromethylated or siladifluoromethylated
products (Scheme 1.3.12).
58–67
Since the halodifluoromethylsilane is not directly involved and
only serves as a precursor to the organozinc reagents, the entirety of their chemistry will not be
covered explicitly as it is not within the scope of this chapter.

Scheme 1.3.12 Dilman’s alkyl- and siladifluoromethylzinc reagents
Siladifluoromethylation using halodifluoromethylsilanes is a very valuable, yet
underexplored, synthetic approach because it not only installs the important CF2 fragment but also
the silyl group as a removable handle for further functionalization. As previously discussed,
Dilman and coworkers have achieved this by employing siladifluoromethylzinc bromide,
generated from TMSCF2Br and isopropylzinc iodide. The zinc reagent was then used to perform
formal nucleophilic siladifluoromethylations on unsaturated systems (i.e. arylidene Meldrum’s
acid derivatives
68
and propargyl halides
65
) via cross-coupling with catalytic copper cyanide. A
zinc to copper transmetallation generates a fluoroalkylcuprate. Oxidative addition and subsequent
reductive elimination provided the siladifluoromethylated products in moderate to excellent yields
(Scheme 1.3.13-a).
65,68
The same group has also reported a metal-free, light-initiated radical
21
siladifluoromethylation of electron deficient alkenes, using an NHC•BH3 complex as a hydrogen
atom donor. The authors propose the siladifluoromethyl radical, photochemically generated from
TMSCF2Br or TMSCF2I, reacts with the alkene, and the resulting carbon radical is quenched via
hydrogen atom abstraction from the NHC•BH3 to yield the siladifluoromethylated products
(Scheme 1.3.13-b).
69

Scheme 1.3.13 Siladifluoromethylation reactions with TMSCF2X
22
In 2012, Dilman and coworkers developed a new fluoroalkylsilicon reagent: TMSCF2CN. It was
synthesized from TMSCF2Br via a formal siladifluoromethylation of TMSCN-derived cyanide.
This likely proceeds via difluorocarbene trapping with ¯CN and subsequent silylation of the
-CF2CN anion. The authors used this new reagent, activated with lithium acetate, to perform
nucleophilic cyanodifluoromethylation on aldehydes and N-tosylimines (Scheme 1.3.13-c).
37

As shown in Scheme 1.3.2, nucleophilic activation of halodifluoromethylsilanes releases
the CF2X anion, which can then undergo elimination to generate :CF2. However, it has been shown
that the reaction conditions can be tuned such that they effectively discourage this elimination and
thus allow for the persistent anion to perform nucleophilic halodifluoromethylation. This was first
demonstrated by Broicher and Geffken in 1990 when they used TMSCF2Cl with catalytic TBAF
to chlorodifluoromethylate di-tert-butyl oxalate, providing the O-silyl product in 63% yield
(Scheme 1.3.14-a).
70
Interestingly, the analogous reaction with TMSCF2Br provided none of the
bromodifluoromethylated product. The increased leaving group ability of bromide relative to
chloride and its consequent increase in the rate of decomposition of the intermediate
halodifluoromethide is a consequence of this result. In 1997, Olah, Prakash, and coworkers used
similar conditions with aldehydes and a ketone to afford chlorodifluoromethyl alcohols. The
authors found that reaction efficiency was significantly dependent upon the conditions, namely the
source of fluoride initiator and the solvent (Scheme 1.3.14-b).
31
In the same paper, it was also
shown that TMSCF2Cl can be electrochemically coupled either with TMSCl to give TMSCF2TMS,
or with itself to give TMSCF2CF2TMS (Scheme 1.3.14-c).
31
Nucleophilic bromo- and
iododifluoromethylation using TMSCF2Br and TMSCF2I, respectively, were first exhibited by
Dilman and coworkers on aldehyde electrophiles. Excellent yields of the alcohol product could
be achieved when an excess of both the halide, in the form of Bu4NX and LiX, and the silane was
23
used (Scheme 1.3.14-d).
34
Control experiments showing the intermediacy of difluorocarbene in
this reaction suggest that the role of the excess halide is in shifting the equilibrium of
difluorocarbene formation back toward halodifluoromethide, the active nucleophile. As a follow
up to this report, the same group showed that there was no need to use TMSCF2I as the source of
iododifluoromethide. The use of excess halide to tune the carbanion/difluorocarbene equilibrium
was again exploited, but in this case the halide in excess (iodide) did not match the halide of the
silane (bromide). This allowed for ¯CF2I to be the predominant nucleophilic species, and its
addition to aldehydes gave high yields of the corresponding alcohols (Scheme 1.3.14-e).
71

Intriguingly, the reaction only worked efficiently if a small amount lithium bromide was added.
The authors propose that this may be due to the stronger ionic interaction of Na
+
with bromide
than with iodide. This would effectively increase the iodide concentration and further shift the
equilibrium toward ¯CF2I. In 2014, Dilman and coworkers demonstrated that nucleophilic
halodifluoromethylation with TMSCF2X is also possible with iminium triflate salts. These
iminium species, generated in situ via a two-step process from secondary amines and aldehydes,
were then treated with TMSCF2X in the presence of tetrabutylammonium halide and HMPA. This
procedure provided α-halodifluoromethylated tertiary amines in generally good yields (Scheme
1.3.14-f).
32,72
This nucleophilic halodifluoromethylation approach can also be applied to
heteroatom electrophiles. Selenium, an arguably underappreciated element, has been shown to be
a good electrophilic partner for bromodifluoromethide. In a 2016 report by Billard and coworkers,
(benzylselenyl)carbonitrile (BnSeCN) was reacted with TMSCF2Br in the presence of TBAF,
providing the formal substitution product, BnSeCF2Br, in excellent yield (Scheme 1.3.14-g).
73

Iakovenko and Dilman recently showed that halodifluoromethides, generated from TMSCF2X, can
24
also perform nucleophilic substitution on diphenylchlorophosphine. The corresponding
(halodifluoromethyl)-diphenylphosphines were obtained in good yields (Scheme 1.3.14-h).
74

Scheme 1.3.14 Nucleophilic halodifluoromethylation with TMSCF2X
1.4 Conclusions
Silicon-based fluoroalkylation reagents like TMSCF3 and TMSCF2Br have been used for
a variety of transformations, including ones involving the generation of singlet difluorocarbene.
The following chapters will focus on our efforts to advance the state of the art in the synthetic
utilization of halofluorocarbenes, generated from these and other reagents.

25
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Ketoesters by Using TMSCF2Br/Lithium Hydroxide/N,N,N-Trimethylhexadecan-1-
Ammonium Bromide. Chem. Commun. 2018, 54 (64), 8881–8884.
https://doi.org/10.1039/C8CC05135F.
(51) Xie, Q.; Zhu, Z.; Li, L.; Ni, C.; Hu, J. A General Protocol for C−H Difluoromethylation of
Carbon Acids with TMSCF2Br. Angewandte Chemie International Edition 2019, 58 (19),
6405–6410. https://doi.org/10.1002/anie.201900763.
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Alcohols Using TMSCF 2 Br as a Unique and Practical Difluorocarbene Reagent under
Mild Conditions. Angew. Chem. Int. Ed. 2017, 56 (12), 3206–3210.
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452–453. https://doi.org/10.1016/j.mencom.2015.11.018.
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https://doi.org/10.1016/j.mencom.2018.07.018.

32
Chapter 2: One-pot preparation of (RSe)2CF2 and (RS)2CF2 compounds via insertion of
TMSCF3-derived difluorocarbene into diselenides and disulfides
2.1 Introduction and attempted siladifluoromethylation of diselenide-derived selenolate
The second largest member of the non-radioactive chalcogen family, selenium is often
overlooked in the organic chemistry space. While admittedly more common than big brother
tellurium, selenium is massively overshadowed by the ubiquity of the smaller chalcogens—to the
extent that sulfur and oxygen have been in the lexicon of normal people (i.e., non-chemists) for
centuries. This is not to say that chemistry involving selenium does not exist; on the contrary,
selenium compounds have been shown to have utility in a diversity of spaces. For example, selenyl
moieties have been used in pericyclic reactions and as chiral auxiliaries to achieve asymmetric
synthesis, often exploiting the soft nature and/or the unique redox properties of selenium to obtain
the compounds desired. Organoselenium compounds can often exhibit condition-dependent
ambiphilic behavior, making them quite versatile. They have also been used extensively as ligands
in transition metal catalysis. Many of these are bidentate ligands with the selenium atom bound to
the metal as either an X-type or L-type donor. In other ligands, selenium was not directly bound
to the metal center, but it was far from benign to the ligands’ structures. In both sets, selenium
participates in special hypervalent intramolecular donor-acceptor interactions, which effect unique
changes to the ligands. These changes to the 3-D structure of the ligands can be used to tune their
properties, which is a valuable tool in ligand design.
2

Selenium compounds are relevant to biology as well. Selenium is an essential
micronutrient for humans and other animals, necessary for proper cardiac, skeletal, thyroid, and
immune system function.
3–5
There are a number of known enzymes and other proteins containing
selenium, most commonly as selenocysteine or selenomethionine residues. In one such
33
selenocysteine-containing enzyme, glutathione peroxidase, the selenol (RSe-H) moiety facilitates
the reduction of hydrogen peroxide. This process uses thiol-containing glutathione as the terminal
reductant, in which two glutathione molecules are oxidized to the dimeric disulfide form in the
process.
6,7
Selenium compounds have shown promising results in the medicinal space as well,
including in clinical trials on anti-cancer therapeutics.
4,8–10
The research into medicinal uses of
organoselenium compounds is relatively unexplored, but interest is rising. Given this potential,
and the well-documented powers of fluorination in tuning properties of bio-active molecules,
11–14

we chose selenium as our next heteroatom target for fluorofunctionalization.
Historically, fluoroalkylselenium compounds were quite rare in the literature. Apart from
some noteworthy exceptions,
15–17
the most common were divalent selenides with trifluoromethyl
groups of the general form RSeCF3, in which R is aryl or alkyl. These were typically accessed
following the general synthetic approach of prefunctionalized aryl- or alkylselenocyanates
(RSeCN) reacting with trifluoromethide, CF3¯, via nucleophilic substitution at selenium to
displace CN.
18,19
In 2002, Magnier and Wakselman documented the first synthesis of benzyl
trifluoromethyl selenide (BnSeCF3). The value of this work was not so much in the synthesis
itself, but in what this product could do. Simple treatment with sufuryl chloride at room
temperature gave nearly quantitative conversion to trifluoromethaneselenyl chloride (ClSeCF3)
within ten minutes (Scheme 2.1.1).
20

Scheme 2.1.1 First synthesis of ClSeCF3
Over a decade later, Billard and coworkers resurrected this protocol in their development of a two-
step one-pot process for the C-H trifluoromethylselenylation of arenes (Scheme 2.1.2).
21

34

Scheme 2.1.2 Billard’s trifluoromethylselenylation of arenes
They envisioned that the ClSeCF3 could be generated in situ to serve as an electrophilic source of
-SeCF3. Electron rich arene or heteroarene nucleophiles would then be added to the pot, and via
an electrophilic aromatic substitution (EAS) pathway the ArSeCF3 products would form. The
experiment matched the theory, and excellent yields were obtained under simple, mild conditions.
The authors then decided to explore whether this approach could work for more than just CF3.
Analogous BnSeRF substrates were synthesized and subjected to the conditions, and similarly
excellent yields confirmed the applicability to a range of fluoroalkyl groups, including RF = CF2Br,
CF2H, CF2CF3, CF2CF2CF3, CF2COOMe, and CF2SO2Ph (Scheme 2.1.3).

Scheme 2.1.3 Extension of Billard’s method to various fluoroalkylselenium derivatives
This work served to ignite a significant flare up in interest in the field, leading to a flood of
publications over the following several years. These publications documented a variety of
approaches toward the syntheses of -SeCF3,
22–33
-SeCF2H,
21–23,25–27,34–45
-SeCF2Br,
21,23,25–27,40

and even -SeCFH2
46–49
compounds.
A notable similarity among most of these works is that the fluoroalkyl moiety of the -SeRF
is a synthetic dead end, meaning it has little to no demonstrated potential for further
functionalization at the RF carbon. One might intuit that RSeCF2H compounds could serve as
valuable pronucleophiles, which upon deprotonation could be added to electrophiles. Surprisingly,
only one report of this use exists, in which Hu and coworkers reacted PhSeCF2H with carbonyl
35
and iminyl electrophiles in the presence of base to give good yields of the corresponding
tetrahedral addition products.
50
This same phenylselenyldifluoromethide (PhSeCF2¯ )
intermediate has been used for similar nucleophilic additions to carbonyls upon generation from
the silyl-protected analogue, PhSeCF2TMS, under mild and convenient catalytic fluoride
activation conditions (Scheme 2.1.4),
51
not unlike those often used with the well documented
Rupert-Prakash reagent, TMSCF3.
52,53

Scheme 2.1.4 PhSeCF2TMS as a pronucleophile for additions to carbonyls
The authors additionally showed that the CF2-Se bond of the product a,a-difluoro-b-phenylseleno
alcohol could be efficiently reduced to the CF2H alcohol. Since this first report of the reagent,
only a small set of publications have been generated demonstrating its utility, including examples
of asymmetric RSeCF2- addition.
54–59
It seemed apparent that this reagent had potential for
application to a variety of valuable transformations, but something was suppressing its popularity.
We hypothesized that this could be due to limited accessibility.
PhSeCF2TMS has only one reported synthesis in the literature, in which PhSeCF2Br
underwent magnesium-mediated reduction of the C-Br bond, followed by quenching of the
Grignard intermediate with TMSCl.
51
This precursor, PhSeCF2Br, also suffers from limited
synthetic routes. The only published procedure involves the generation of sodium
benzeneselenolate (PhSeNa), either via deprotonation of benzeneselenol or sodium borohydride
reduction of diphenyl diselenide. To the selenolate was then slowly added CF2Br2 at low
temperature to form PhSeCF2Br via nucleophilic substitution (Scheme 2.1.5).
51

36

Scheme 2.1.5 Known routes to PhSeCF2TMS
A large excess of NaBH4 was used in both cases due to the high oxygen/oxidant sensitivity of
benzeneselenolate. Oxidation of the selenolate would generate diselenide, which the excess
NaBH4 could then reduce back to the selenolate. A drawback of this approach is the reliance on
CF2Br2. While effective, it is a very toxic greenhouse gas, and its deleterious effects on the ozone
layer have led to its sale and use being restricted by the Montreal Protocol. The synthesis of
PhSeCF2TMS seemed to us like an area ripe for improvement.
We envisioned an adaptation of our P-H siladifluoromethylation protocol
1
to selenium
compounds, starting with benzeneselenol (PhSeH). Our devised one-pot, two-step procedure
consisted of deprotonation of PhSeH with lithium hydride in DMF, followed by addition of
TMSCF3 at room temperature. Initial trials were very fruitful, and after a short series of
optimization trials, we had gathered optimized conditions and a few key conclusions (Scheme
2.1.6). First, the reaction benefitted from higher concentration. Based on our observations from
this and other difluorocarbene chemistry, this is not uncommon. Higher concentrations allow for
faster kinetics of the active nucleophile adding to CF2 carbene, preventing it from accumulating.
Difluorocarbene transformations tend to become less efficient if its concentration increases too
much; this very reactive intermediate is quite promiscuous and such conditions often promote
dimerization, oligomerization, or other decomposition pathways. Second, just like with our
phosphonates, the reaction is fast. Even at multi-gram scale, the reaction was complete after 30
minutes and furnished 85% yield of PhSeCF2TMS. The short reaction time, along with the high
37
reaction concentration were both beneficial in avoiding loss of lithium selenolate via oxidation to
diselenide by O2. Fortunately, in contrast to the previous report, this circumvented the need for a
borohydride reducing reagent in our system.
Despite our success with this synthesis, we felt there were three significant drawbacks to
this approach, all revolving around the starting material: benzeneselenol. First, the stench. Thiols
have garnered an infamous reputation in organic chemistry spaces (as well as any nearby spaces)
for their malodorous nature. While their selenium analogues are heavier, and thus less volatile,
selenols are often described as having worse and more potent smells. Anecdotally, it requires only
the smallest of traces escaping the fume hood to encourage endlessly forgiving lab mates to take
an early lunch. In practice, this makes selenols tedious and difficult to handle. As with most
chemicals, if appropriate procedures are implemented and diligently followed, selenols can be
handled properly and with low risk of exposure (e.g. special storage, treatment, and disposal
protocols for any potentially contaminated materials before anything leaves the fume hood).
However, as with most chemicals, the benefit must outweigh the risk. Second, selenols can easily
be oxidized to diselenides upon exposure to air, albeit more slowly than selenolates. They are
often light sensitive as well. This makes them additionally difficult to handle, store, and
synthesize. The last is particularly relevant because third, they have extremely limited commercial
availability. At the time of writing, a cursory search found benzeneselenol to be the only
commercially available selenol. Considering that publication of our selenol
siladifluoromethylation methodology would require a table of examples from several different
selenols, the aforementioned drawbacks encouraged us to design a better approach.
Diselenides seemed more practical as starting materials, given their air stability, synthetic
accessibility, and delightful lack of stench. Generating benzeneselenolate from diphenyl
38
diselenide has been achieved with sodium borohydride,
51
typically in ethereal or alcohol solvents.
Our siladifluoromethylation system does not tolerate acidic protons, and it seems to require DMF
to work effectively. We also wanted to prepare the lithium selenolate, rather than the sodium salt.
During our prior optimization trials with diethyl phosphonate siladifluoromethylation,
1
we found
the choice of the cation to be crucial to the chemoselectivity. This is best exemplified by trials 5
and 8 (Figure 2.1.1).

Figure 2.1.1: Cation effects on chemoselectivity in TMSCF3 siladifluoromethylation
In trial 8, lithium salts were used for the base and salt additive, and the desired -PCF2TMS
compound was the only product (i.e. complete chemoselectivity). In trial 5, sodium variants of
the same salts were used, and none of the desired compound was formed. Instead, the only
significant product was the adduct formed upon the addition of intermediate -PCF2¯ to solvent
DMF, followed by silylation of the formamide oxygen. The simple switch from Li
+
to Na
+
gave
a complete swap in chemoselectivity. A comprehensive explanation is beyond the scope of this
39
discussion, but the key points are that the cation identity can make a huge difference in the outcome
and that there is a delicate balance in this reaction system, which is quite sensitive to any changes
in the interactions among the solvent, the cation, the substrate, and TMSCF3.
To generate lithium benzeneselenolate from diphenyl diselenide, we proposed that a nucleophilic
activator, LiOtBu, could add to one Se atom, breaking the Se-Se bond to generate PhSe-OtBu
and PhSeLi in situ. TMSCF3 would then be added to the pre-generated selenolate, and it should
undergo siladifluoromethylation just as it did from deprotonated benzeneselenol (Scheme 2.1.7).

Scheme 2.1.7 Attempted siladifluoromethylation and unexpected :CF2 insertion
The reaction did not proceed as anticipated. There was no evidence the desired PhSeCF2TMS, but
there was nearly quantitative yield of an unexpected product (vide supra).
2.2 Unprecedented formal :CF2 insertion
This unexpected difluoromethylene diselenoether product, arising from a formal insertion
of difluorocarbene into the Se-Se bond, was unprecedented in the literature. There was a single
report of an analogous dithioether from Han et al.,
60
wherein disulfides were converted to
difluoromethylene dithioethers by reaction of TMSCF2H with KOtBu in DMF. While seemingly
similar, the mechanism is quite different from our system (Scheme 2.2.1).
40

Scheme 2.2.1 Prior art on difluoromethylene dithioethers
TMSCF2H releases ¯CF2H upon activation by KOtBu, which then adds to S of disulfide to give
PhSCF2H. Deprotonation of this by another equivalent of KOtBu generates the PhSCF2¯
nucleophile that adds to another equivalent of diphenyl disulfide to furnish the final product. It
worth noting that with the disulfide as the limiting reagent in their system, the “second equivalent”
of disulfide must arise from oxidation of the thiolate (generated as a leaving group in the ¯CF2H
addition step) back into disulfide. Considering our analogous transformation uses TMSCF3, which
is much less expensive than TMSCF2H, and it can be applied to diselenides, we felt that exploration
of this reaction would be valuable.
2.3 Optimization and scope of diselenide substrates
Despite the excellent initial result, we felt it would be worthwhile to investigate the
sensitivity of the reaction to certain parameters (Figure 2.3.1). Reaction optimization focused on
the use of TMSCF3 as the difluorocarbene source and diphenyl diselenide (1a) as the model
substrate. The liberation of difluorocarbene from TMSCF3 proceeds through decomposition of
trifluoromethide, CF3¯, which is released from the silicate formed upon addition of a nucleophile
to TMSCF3. The presence of Li cation has been shown to promote the formation of CF2 carbene,
and in many cases is necessary for the success of the reaction.
1,61
Our first trial with LiOtBu, LiCl,
and TMSCF3 yielded 95% of 2a.
41

Entry
a
Activator (equiv) Silane (equiv) Yield (%)
2a 3a
1 LiOtBu (1.0) TMSCF3 (2.0) 95 5
2
b
LiOtBu (1.0) TMSCF3 (2.0) 89 6
3
b
NaOtBu (1.0) TMSCF3 (2.0) 83 8
4
b
KOtBu (1.0) TMSCF3 (2.0) 4 50
5 LiOtBu (1.0) TMSCF2Br (2.0) 1 5
c

a
Reactions performed with 0.5 mmol of 1a, in 0.63 mL of DMF, with 1.2 equiv
LiCl. Yields provided were determined by
19
F NMR using PhF (0.5 mmol) as internal
standard.
b
No LiCl added.
c
Yield of PhSeCF2Br.
Figure 2.3.1 Reaction optimization with diselenide substrates
In the absence of LiCl, a slightly diminished yield was observed. Performing the reaction with
NaOtBu in place of LiOtBu while also omitting LiCl again decreased the conversion to 2a. KOtBu
provided no reasonable yield of 2a, but a 50% yield of 3a (100% consumption of 1a). This clearly
demonstrates the role the cation plays in directing the chemoselectivity of the transformation. The
cation dependence stems from the identity of the generated fluoride salt (Scheme 2.3.1).

Scheme 2.3.1 Effect of cation on reversibility of difluorocarbene formation
Cations Li
+
and Na
+
both form very strong bonds with fluoride. Effectively, this makes the forward
reactions irreversible. In HSAB theory terms, Li
+
and Na
+
are both hard Lewis acids which bind
strongly with F¯, a hard Lewis base. In contrast, fluoride’s weaker bond with the softer K
+
allows
42
for its recombination with :CF2. This effects a persistence of the trifluoromethide under K
+

conditions, explaining the chemoselectivity for trifluoromethylation product 3a when KOtBu was
used. Finally, substituting TMSCF2Br in place of TMSCF3 as the source of difluorocarbene gave
no appreciable quantity of the desired product. It is likely that when using TMSCF2Br under these
conditions, the difluorocarbene generation is too fast and exothermic, resulting in uncontrolled
carbene oligomerization or decomposition.
The optimized conditions were then applied to a series of diselenides (Scheme 2.3.2).

Scheme 2.3.2 Substrate scope of diselenides
Product 2a was isolated in excellent yield (86%). To test the effects of substituent position, 2-, 3-
, and 4-methoxyphenyl derivatives were chosen. Despite the steric considerations of the methoxy
43
group, and its inability to donate significantly by resonance when in the meta position, 2b, 2d, and
2f were isolated in nearly identical yields (80%, 80%, and 82%, respectively). This indicates that
the difluorocarbene insertion may not be significantly influenced by substituent position. Both 2a
and 2b were prepared at 1-gram scales in good yields, demonstrating the potential for scalability.
1-naphthyl derivative 2c was also isolated in high yield (96%). The yield was lower (63%) for 2e
with its 2-dimethylamino substituent, which may be due to strong coordination of the nitrogen lone
pair with Li
+
in the system. This would make the corresponding ammonium-type species a strong
electron withdrawing group, thus promoting the SN2-type addition of CF3¯ to the Se-Se bond to
form the corresponding Se-CF3 compound. Difluoromethylene diselenoether 2g, with a 4-Cl
substituent, was obtained in excellent isolated yield, a product with a handle for further
functionalization. However, 4-OCF3 product 2h could not be isolated and was only observed by
19
F NMR. The diminished conversion and instability may be attributed to the good leaving group
ability of -OCF3 permitting an SNAr reaction by an equivalent of ArSeCF2¯ or ArSe¯.
Unfortunately, dimethyl and dibenzyl diselenides did not yield the corresponding products.
Dimethyl diselenide selectively gave the methyl trifluoromethyl selenide in 66% yield based on
19
F NMR. This is likely due to a much less hindered steric environment around selenium, allowing
for more facile nucleophilic addition of the trifluoromethide anion. In the case of dibenzyl
diselenide, deprotonation of a benzylic C-H bond by trifluoromethide, followed by elimination of
a phenyl selenolate and concomitant generation of a phenyl selenoaldehyde moiety may be
responsible for the loss of starting material.
62

2.4 Optimization and scope of disulfide substrates
Having tested the reaction conditions on diselenides, attempts to extend the conditions to
disulfides were made. The conditions optimized for diselenides did not furnish the desired
44
difluoromethylene dithioethers in appreciable yields, and instead displayed high conversions to
the corresponding trifluoromethyl thioethers. This can be attributed to the fact that S, as a harder
electrophile compared to Se, would react more readily with the hard nucleophile, CF3¯. To
circumvent this problem, a higher loading of LiOtBu (3 equiv) was used to increase the Li
+

concentration. We proposed this would hasten the decomposition of CF3¯ to difluorocarbene,
driven by the formation of LiF. Applying this strategy, product 2i, derived from diphenyl disulfide,
was furnished in 71% yield. Compounds 2j and 2k, with 3-F and 4-Me substituents, respectively,
were also produced in good yields. Finally, product 2l was obtained, albeit in lower yield, showing
compatibility with pyridyl moieties (Scheme 2.4.1).

Scheme 2.4.1 Substrate scope of disulfides
2.5 Proposed mechanism
The first step of the reaction pathway is likely the activation of LiOtBu, forming lithium
(tert-butyloxy)(trifluoromethyl)trimethylsilicate (I), which would liberate lithium trifluoromethide
(LiCF3) and TMS-OtBu (Scheme 2.5.1).
45

Scheme 2.5.1 Proposed mechanism of :CF2 insertion into diselenides
Due to the inherent electrophilicity of the chalcogen center, trifluoromethylation to form
trifluoromethyl selenoether 3 can occur, a non-constructive pathway. Decomposition of LiCF3
gives LiF and CF2 carbene. The carbene is then trapped by the diselenide, generating a
difluoromethyl selenonium ylide (II). Rearrangement of the ylide then affords product 2. The
same reaction pathway can be envisioned with disulfides in place of diselenides.
2.6 Conclusions
In summary, we have developed a novel difluoromethylenation of disulfides and
diselenides, yielding difluoromethylene dithioethers and previously unknown difluoromethylene
diselenoethers. Our method tolerates a number of commonly encountered functional groups. The
transformation is scalable, with 2a and 2b having been prepared in good yields. While this was
not the reaction on which we initially set our sights, perseverance and open minds led us from
accidental discovery to publication of interesting and worthwhile chemistry.
63

46
2.7 Experimental
2.7.1 General information
Unless otherwise mentioned, all chemicals were purchased from commercial sources and
used without further purification. N,N-dimethylformamide (DMF) was distilled from CaH2 under
N2 and stored over activated 3 Å molecular sieves in a Strauss flask. Where applicable, flash
column chromatography with silica gel stationary phase was performed to isolate the compounds.
Solid starting materials were dried under high vacuum (<0.1 Torr) under a P2O5 trap for at least
12 h prior to use.
1
H,
13
C, and
19
F NMR spectra were recorded on 400 MHz or 500 MHz Varian
NMR spectrometers. All chemical shifts are given in units of ppm relative to an internal standard.
1
H NMR chemical shifts were determined relative to CHCl3 at d 7.26.
13
C NMR shifts were
determined relative to the middle of the deuterium triplet of CDCl3 at d 77.16.
19
F NMR chemical
shifts were determined relative to CFCl3 at d 0.0. All
13
C NMR spectra were obtained with proton
decoupling unless otherwise specified. Mass spectral data were recorded on a high-resolution
mass spectrometer, EI or ESI mode. IR data were recorded on a JASCO FT/IR spectrometer.
2.7.2 Synthesis of diselenide starting materials
Note on diselenide synthesis using Grignard reagents and selenium metal: If the Grignard
reagent is prepared in situ from aryl halides and magnesium metal, it is important to make sure
that the aryl halide is fully consumed before adding the selenium. The aryl selenolate formed can
perform nucleophilic substitution on any residual aryl halide to give the diaryl selenoether. This
not only lowers yields of the product diselenides, often they are also difficult to separate. GCMS
works well to confirm full consumption of aryl halide.

47
1,2-Bis(2-methoxyphenyl) diselenide (1b)
Adapted from a reported procedure. To a 500 mL, oven-dried, three-neck flask fitted with
a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (30 mmol,
720 mg) and THF (180 mL) were added under N2. Keeping the vessel under N2, 2-bromoanisole
(30 mmol, 3.75 mL) was added slowly via syringe. The mixture was stirred for 45 minutes and
subsequently cooled to 0˚C. Under N2, Se (20 mmol, 1.58 g) was added in one portion, the bath
was removed, and the suspension was allowed to stir at room temperature for 4 hours. The reaction
mixture was then quenched with aqueous NH4Cl (saturated solution, 80 mL) and extracted with
Et2O (40 mL, three times). The combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. 1b was obtained after column chromatography (gradient of 0% to 10%
EtOAc in hexanes) was a light-brown solid in 81% yield (2.26 g).
1
H NMR (400 MHz,
Chloroform-d) δ 7.55 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 8.0 Hz, 2H), 6.87 (t, J = 7.6 Hz, 2H), 6.82
(d, J = 8.2 Hz, 2H), 3.91 (s, 6H). The NMR data matches previous reports.
64

1,2-Di(naphthalen-1-yl) diselenide (1c)
Adapted from a reported procedure. To a 500 mL, oven-dried, three-neck flask fitted with
a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (2.5 equiv,
600 mg) and LiCl (2.5 equiv, 1.1 g) were added, and the vessel was evacuated and heated for 5
mins with a heat gun. Next, the vessel was allowed to cool down to room temperature, re-
pressurized with N2, and THF (50 mL) was added via syringe. TMSCl (5 mol %, 64 µL) and 1,2-
dibromoethane (5 mol %, 43 µL) were added under N2, and the mixture was stirred at room
temperature for 10 minutes. The vessel was cooled to 0˚C in an ice bath (still under N2), and 1-
bromonaphthalene (10 mmol, 1,4 mL) was added slowly via syringe. The bath was removed, and
the mixture was stirred at room temperature until all the bromoarene was consumed (monitored by
48
taking a GC-MS spectrum of a worked-up aliquot of the reaction mix) (45 minutes), and the vessel
was once again cooled to 0˚C. Se (1.0 equiv, 790 mg) was added in one portion, the bath was
removed, and the mixture was stirred at room temperature for 2 hours. The crude product was
extracted with CHCl3 (50 mL, three times) from aqueous HCl (0.15 M, 150 mL). The combined
organic layer was washed with brine (75 mL, one time) and dried over MgSO4. The crude product
(caution: STENCH!) was re-dissolved in EtOH (200 mL), 11 pellets of NaOH (excess) were added,
and the suspension was stirred for 2 hours at room temperature. The observed precipitate was
collected and confirmed to be pure 1c. The EtOH solution was concentrated, and a second portion
of 1c was obtained by column chromatography (hexanes). Overall, 1c was obtained in 74% yield
(1.53 g) was a pale-yellow solid.
1
H NMR (399 MHz, Chloroform-d) δ 8.21 (ddd, J = 8.4, 1.3, 0.7
Hz, 2H), 7.85 – 7.80 (m, 4H), 7.77 (dd, J = 7.2, 1.2 Hz, 2H), 7.49 (ddd, J = 8.1, 6.9, 1.3 Hz, 2H),
7.42 (ddd, J = 8.3, 6.9, 1.4 Hz, 2H), 7.32 – 7.23 (m, 2H). The data matches reported values.
65

1,2-Bis(4-methoxyphenyl) diselenide (1d)
Adapted from a reported procedure. To a 500 mL, oven-dried, three-neck flask fitted with
a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (2.5 equiv,
300 mg) and LiCl (2.5 equiv, 551 mg) were added, and the vessel was evacuated and heated for 5
mins with a heat gun. Next, the vessel was allowed to cool down to room temperature, re-
pressurized with N2, and THF (20 mL) was added via syringe. TMSCl (5 mol %, 30 µL) and 1,2-
dibromoethane (5 mol %, 20 µL) were added under N2, and the mixture was stirred at room
temperature for 10 minutes. The vessel was cooled to 0˚C in an ice bath (still under N2), and 4-
bromoanisole (5 mmol, 625 µL) was added slowly via syringe. The bath was removed, and the
mixture was stirred at room temperature until all the bromoarene was consumed (monitored by
taking a GC-MS spectrum of a worked-up aliquot of the reaction mix) (45 minutes), and the vessel
49
was once again cooled to 0˚C. Se (2.0 equiv, 790 mg) was added in one portion, the bath was
removed, and the mixture was stirred at room temperature for 2 hours. The crude product was
extracted with CHCl3 (50 mL, three times) from aqueous HCl (0.15 M, 150 mL). The combined
organic layer was washed with brine (75 mL, one time) and dried over MgSO4. The crude product
(caution: STENCH!) was re-dissolved in EtOH (200 mL), 11 pellets of NaOH (excess) were added,
and the suspension was stirred for 2 hours at room temperature. The solution was concentrated
under reduced pressure, and the crude product was purified by column chromatography (gradient
of 0% to 5% EtOAc in hexanes) to give 1d in 60% yield (558 mg) as a pale-yellow solid.
1
H NMR
(399 MHz, Chloroform-d) δ 7.61 – 7.37 (m, 4H), 6.95 – 6.61 (m, 4H), 3.81 (s, 6H). The NMR data
matches previous reports.
64

1,2-Bis(4-(N,N-dimethylamino)phenyl) diselenide (1e)
Adapted from a reported procedure. To a 500 mL, oven-dried, three-neck flask fitted with
a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (2.5 equiv,
600 mg) and LiCl (2.5 equiv, 1.1 g) were added, and the vessel was evacuated and heated for 5
mins with a heat gun. Next, the vessel was allowed to cool down to room temperature, re-
pressurized with N2, and THF (20 mL) was added via syringe. TMSCl (5 mol %, 30 µL) and 1,2-
dibromoethane (5 mol %, 20 µL) were added under N2, and the mixture was stirred at room
temperature for 10 minutes. The vessel was cooled to 0˚C in an ice bath (still under N2), and 2-
bromo-N,N-dimethylaniline (10 mmol, 2.0 g) was added slowly. The bath was removed, and the
mixture was stirred at room temperature until all the bromoarene was consumed (monitored by
taking a GC-MS spectrum of a worked-up aliquot of the reaction mix) (60 minutes), and the vessel
was once again cooled to 0˚C. Se (1.0 equiv, 395 mg) was added in one portion, the bath was
removed, and the mixture was stirred at room temperature for 2 hours. The crude product was
50
extracted with CHCl3 (50 mL, three times) from water (150 mL). The combined organic layer was
washed with brine (75 mL, one time) and dried over MgSO4. The crude product (caution:
STENCH!) was re-dissolved in EtOH (200 mL), 11 pellets of NaOH (excess) were added, and the
suspension was stirred for 2 hours at room temperature. The solution was concentrated under
reduced pressure. 1e was obtained after column chromatography (gradient of 0% to 90% EtOAc
in hexanes) was a yellow solid on storing in a freezer (-20 ˚C) for 2 days, in 73% yield (1.45 g).
1
H NMR (399 MHz, Chloroform-d) δ 7.52 (dd, J = 7.9, 1.5 Hz, 2H), 7.22 – 7.12 (m, 4H), 7.00
(ddd, J = 7.8, 7.0, 1.5 Hz, 2H), 2.80 (s, 12H). The data matches reported values.
66

1,2-Bis(3-methoxyphenyl) diselenide (1f)
Adapted from a reported procedure. To a 500 mL, oven-dried, three-neck flask fitted with
a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (2.5 equiv,
600 mg) and LiCl (2.5 equiv, 1.1 g) were added, and the vessel was evacuated and heated for 5
mins with a heat gun. Next, the vessel was allowed to cool down to room temperature, re-
pressurized with N2, and THF (20 mL) was added via syringe. TMSCl (5 mol %, 30 µL) and 1,2-
dibromoethane (5 mol %, 20 µL) were added under N2, and the mixture was stirred at room
temperature for 10 minutes. The vessel was cooled to 0˚C in an ice bath (still under N2), and 3-
bromoanisole (10 mmol, 1.87 g) was added slowly. The bath was removed, and the mixture was
stirred at room temperature until all the bromoarene was consumed (monitored by taking a GC-
MS spectrum of a worked-up aliquot of the reaction mix) (60 minutes), and the vessel was once
again cooled to 0˚C. Se (1.0 equiv, 395 mg) was added in one portion, the bath was removed, and
the mixture was stirred at room temperature for 2 hours. The crude product was extracted with
CHCl3 (50 mL, three times) from water (150 mL). The combined organic layer was washed with
brine (75 mL, one time) and dried over MgSO4. The crude product (caution: STENCH!) was re-
51
dissolved in EtOH (200 mL), 11 pellets of NaOH (excess) were added, and the suspension was
stirred for 2 hours at room temperature. The solution was concentrated under reduced pressure. 1f
was obtained after column chromatography (gradient of 0% to 20% EtOAc in hexanes) was a
yellow solid on storing in a freezer (-20 ˚C) for 2 days, in 66% yield (1.45 g). The NMR data
matches previous reports.
67

1,2-Bis(4-chlorophenyl) diselenide (1g)
Adapted from a reported procedure. To a 500 mL, oven-dried, three-neck flask fitted with
a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (2.5 equiv,
600 mg) and LiCl (2.5 equiv, 1.1 g) were added, and the vessel was evacuated and heated for 5
mins with a heat gun. Next, the vessel was allowed to cool down to room temperature, re-
pressurized with N2, and THF (20 mL) was added via syringe. TMSCl (5 mol %, 30 µL) and 1,2-
dibromoethane (5 mol %, 20 µL) were added under N2, and the mixture was stirred at room
temperature for 10 minutes. The vessel was cooled to 0˚C in an ice bath (still under N2), and 4-
chloro-1-bromobenzene (10 mmol, 1.91 g) was added slowly. The bath was removed, and the
mixture was stirred at room temperature until all the bromoarene was consumed (monitored by
taking a GC-MS spectrum of a worked-up aliquot of the reaction mix) (60 minutes), and the vessel
was once again cooled to 0˚C. Se (1.0 equiv, 395 mg) was added in one portion, the bath was
removed, and the mixture was stirred at room temperature for 2 hours. The crude product was
extracted with CHCl3 (50 mL, three times) from HCl (1 M, 150 mL). The combined organic layer
was washed with brine (75 mL, one time) and dried over MgSO4. The crude product (caution:
STENCH!) was re-dissolved in EtOH (200 mL), 11 pellets of NaOH (excess) were added, and the
suspension was stirred for 2 hours at room temperature. The solution was concentrated under
52
reduced pressure. 1g was obtained after column chromatography (gradient of 0% to 20% EtOAc
in hexanes) as a yellow solid in 72% yield (3.6 g). The NMR data matches previous reports.
68

1,2-Bis(4-(trifluoromethoxy)phenyl) diselenide (1h)
Adapted from a reported procedure. To a 500 mL, oven-dried, three-neck flask fitted with
a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (2.5 equiv,
600 mg) and LiCl (2.5 equiv, 1.1 g) were added, and the vessel was evacuated and heated for 5
mins with a heat gun. Next, the vessel was allowed to cool down to room temperature, re-
pressurized with N2, and THF (20 mL) was added via syringe. TMSCl (5 mol %, 30 µL) and 1,2-
dibromoethane (5 mol %, 20 µL) were added under N2, and the mixture was stirred at room
temperature for 10 minutes. The vessel was cooled to 0˚C in an ice bath (still under N2), and 4-
bromo-1-trifluoromethoxybenzene (10 mmol, 2.41 g) was added slowly. The bath was removed,
and the mixture was stirred at room temperature until all the bromoarene was consumed
(monitored by taking a GC-MS spectrum of a worked-up aliquot of the reaction mix) (60 minutes),
and the vessel was once again cooled to 0˚C. Se (1.0 equiv, 395 mg) was added in one portion, the
bath was removed, and the mixture was stirred at room temperature for 2 hours. The crude product
was extracted with CHCl3 (50 mL, three times) from water (150 mL). The combined organic layer
was washed with brine (75 mL, one time) and dried over MgSO4. The crude product (caution:
STENCH!) was re-dissolved in EtOH (200 mL), 11 pellets of NaOH (excess) were added, and the
suspension was stirred for 2 hours at room temperature. The solution was concentrated under
reduced pressure. 1h was obtained after column chromatography (gradient of 0% to 20% EtOAc
in hexanes) as a yellow oil in 59% yield (1.42 g). The NMR data matches previous reports.
68

53
2.7.3 Synthesis of difluoromethylene diselenoethers and dithioethers (2)
Difluorobis(phenylselanyl)methane (2a)
In an argon glovebox, LiOtBu (0.5 mmol, 1.0 equiv, 40.0 mg), LiCl (0.6 mmol, 1.2 equiv,
25.4 mg) and 1,2-diphenyl diselenide (0.5 mmol, 156.1 mg) were weighed into an oven-dried,
crimp-top vial equipped with a magnetic stir bar and sealed. Under N2, DMF (0.63 mL) was added
by syringe, and the solution was stirred for 5 mins, followed by dropwise addition of TMSCF3 (1.0
mmol, 2 equiv, 148 µL). The solution was stirred for 10 mins, diluted with EtOAc (5 mL) and
poured into aqueous HCl (12 mL, 1 M concentration). The organic layer was decanted, and the
crude product was extracted from the aqueous layer two more times (5 mL EtOAc each time). The
organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Flash
column chromatography (n-pentane) of the crude mixture afforded 2a in 86% isolated yield (156
mg) as a colorless liquid.
1
H NMR (500 MHz, Chloroform-d) δ 7.80 – 7.69 (m, 4H), 7.46 (td, J =
7.4, 1.4 Hz, 2H), 7.39 (td, J = 7.4, 1.2 Hz, 4H).
13
C NMR (101 MHz, Chloroform-d) δ 137.0,
129.9, 129.4, 126.4, 119.1 (t, J = 347.1 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -43.8. FT-IR
(cm
-1
) 3073, 3056, 1577, 1561, 1476, 1438, 1329, 1310, 1075, 1032, 1019, 999, 804, 737, 688,
472. HRMS (M) 362.9014.
Difluorobis((2-methoxyphenyl)selanyl)methane (2b)
In an argon glovebox, LiOtBu (0.5 mmol, 1.0 equiv, 40.0 mg), LiCl (0.6 mmol, 1.2 equiv,
25.4 mg) and 1,2-bis(2-methoxyphenyl) diselenide (0.5 mmol, 186.1 mg) were weighed into an
oven-dried, crimp-top vial equipped with a magnetic stir bar and sealed. Under N2, DMF (0.63
mL) was added by syringe, and the solution was stirred for 5 mins, followed by dropwise addition
of TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution was stirred for 10 mins, the vial was opened,
the solution was diluted with EtOAc (5 mL) and poured into aqueous HCl (12 mL, 1 M
54
concentration). The organic layer was decanted, and the crude product was extracted from the
aqueous layer two more times (5 mL EtOAc each time). The organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated. Flash column chromatography (gradient of
0% to 10% EtOAc in hexanes) of the crude mixture afforded 2b in 80% isolated yield (218 mg)
as a pale-yellow solid.
1
H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 7.6 Hz, 2H), 7.38 (d, J
= 7.8 Hz, 2H), 6.98 – 6.90 (m, 4H), 3.85 (s, 6H).
13
C NMR (101 MHz, Chloroform-d) δ 159.0,
137.4 (t, J = 1.5 Hz), 131.3, 121.4, 119.0 (t, J = 348.6 Hz), 116.5, 111.3, 56.0.
19
F NMR (376
MHz, Chloroform-d) δ -43.0. FT-IR (cm
-1
) 3062, 3005, 2956, 2935, 2835, 1579, 1474, 1463,
1431, 1289, 1271, 1245, 1179, 1163, 1125, 1056, 1020, 941, 803, 748, 657, 458. HRMS (M-H
+
)
420.9196.
Difluorobis(naphthalen-1-ylselanyl)methane (2c)
In an argon glovebox, LiOtBu (0.5 mmol, 1.0 equiv, 40.0 mg), LiCl (0.6 mmol, 1.2 equiv,
25.4 mg) and 1,2-di(naphthalen-1-yl) diselenide (0.5 mmol, 206.1 mg) were weighed into an oven-
dried, crimp-top vial equipped with a magnetic stir bar and sealed. Under N2, DMF (0.63 mL) was
added by syringe, and the solution was stirred for 5 mins, followed by dropwise addition of
TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution was stirred for 10 mins, the vial was opened,
the solution was diluted with EtOAc (5 mL) and poured into aqueous HCl (12 mL, 1 M
concentration). The organic layer was decanted, and the crude product was extracted from the
aqueous layer two more times (5 mL EtOAc each time). The organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated. Flash column chromatography (gradient of
0% to 5% EtOAc in hexanes) of the crude mixture afforded 2c in 94% isolated yield (169 mg) as
a pale-yellow solid.
1
H NMR (399 MHz, Chloroform-d) δ 8.38 – 8.31 (m, 2H), 8.03 – 7.93 (m,
4H), 7.89 – 7.82 (m, 2H), 7.56 – 7.47 (m, 4H), 7.48 – 7.40 (m, 2H).
13
C NMR (100 MHz,
55
Chloroform-d) δ 138.2, 135.6, 134.3, 131.5, 128.7, 128.6, 127.3, 126.6, 126.0, 125.8, 119.5 (t, J =
349.0 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -41.6. FT-IR (cm
-1
) 3055, 3040, 2932, 2851,
1588, 1559, 1499, 1455, 1375, 1364, 1335, 1251, 1201, 1142, 1133, 1033, 1019, 979, 952, 910,
861, 812, 793, 763, 733, 650, 622, 599, 531, 525, 511. HRMS (M-H
+
) 462.9313.
Difluorobis((4-methoxyphenyl)selanyl)methane (2d)
In an argon glovebox, LiOtBu (0.23 mmol, 1.0 equiv, 18.4 mg), LiCl (0.28 mmol, 1.2
equiv, 1.7 mg) and 1,2-bis(4-methoxyphenyl) diselenide (0.23 mmol, 86.1 mg) were weighed into
an oven-dried, crimp-top vial equipped with a magnetic stir bar and sealed. Under N2, DMF (0.30
mL) was added by syringe, and the solution was stirred for 5 mins, followed by dropwise addition
of TMSCF3 (1.0 mmol, 2 equiv, 68 µL). The solution was stirred for 10 mins, the vial was opened,
the solution was diluted with EtOAc (5 mL) and poured into aqueous HCl (12 mL, 1 M
concentration). The organic layer was decanted, and the crude product was extracted from the
aqueous layer two more times (5 mL EtOAc each time). The organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated. Flash column chromatography (gradient of
0% to 10% EtOAc in hexanes) of the crude mixture afforded 2d in 80% isolated yield (77 mg) as
a yellow solid.
1
H NMR (399 MHz, Chloroform-d) δ 7.8 – 7.4 (m, 4H), 7.0 – 6.5 (m, 4H), 3.8 (s,
6H).
13
C NMR (100 MHz, Chloroform-d) δ 161.1, 138.9, 119.4 (t, J = 347.1 Hz), 116.9 (t, J = 1.3
Hz), 115.0, 55.4.
19
F NMR (376 MHz, Chloroform-d) δ -45.5. FT-IR (cm
-1
) 3067, 2969, 2942,
2889, 2837, 2541, 2367, 2284, 1895, 1583, 1571, 1489, 1462, 1434, 1406, 1299, 1289, 1249, 1190,
1179, 1104, 1021, 823, 793, 762, 707, 604, 517, 484. HRMS (M-H
+
) 420.9215.
2,2'-((Difluoromethylene)bis(selanediyl))bis(N,N-dimethylaniline) (2e)
In an argon glovebox, LiOtBu (0.5 mmol, 1.0 equiv, 40.0 mg), LiCl (0.6 mmol, 1.2 equiv,
25.4 mg) and 1,2-bis(4-(N,N-dimethylamino)phenyl) diselenide (0.5 mmol, 199.1 mg) were
56
weighed into an oven-dried, crimp-top vial equipped with a magnetic stir bar and sealed. Under
N2, DMF (0.63 mL) was added by syringe, and the solution was stirred for 5 mins, followed by
dropwise addition of TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution was stirred for 10 mins,
the vial was opened, the solution was diluted with EtOAc (5 mL) and poured into saturated K2CO3
(12 mL). The organic layer was decanted, and the crude product was extracted from the aqueous
layer two more times (5 mL EtOAc each time). The organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated. Flash column chromatography (gradient of 0% to 10%
EtOAc in hexanes) of the crude mixture afforded 2e in 63% isolated yield (141 mg) as a pale-
yellow oil.
1
H NMR (399 MHz, Chloroform-d) δ 7.81 (d, J = 7.9 Hz, 2H), 7.30 – 7.25 (m, 2H),
7.16 (dd, J = 8.0, 1.5 Hz, 2H), 7.07 (ddd, J = 7.9, 7.2, 1.4 Hz, 2H), 2.69 (s, 12H).
13
C NMR (100
MHz, Chloroform-d) δ 153.4, 133.3 (t, J = 2.2 Hz), 128.7, 128.2, 125.2, 120.9, 120.6 (t, J = 346.5
Hz), 45.3.
19
F NMR (376 MHz, Chloroform-d) δ -46.6. FT-IR (cm
-1
) 2940, 2824, 2785, 1570,
1491, 1473, 1291, 1250, 1173, 1018, 1013, 940, 794, 760, 731, 651, 518, 491. HRMS (M-H
+
)
447.2703.
Difluorobis((3-methoxyphenyl)selanyl)methane (2f)
In an argon glovebox, LiOtBu (0.5 mmol, 1.0 equiv, 40.0 mg), LiCl (0.6 mmol, 1.2 equiv,
25.4 mg) and 1,2-bis(3-methoxyphenyl) diselenide (0.5 mmol, 186.1 mg) were weighed into an
oven-dried, crimp-top vial equipped with a magnetic stir bar and sealed. Under N2, DMF (0.63
mL) was added by syringe, and the solution was stirred for 5 mins, followed by dropwise addition
of TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution was stirred for 10 mins, the vial was opened,
the solution was diluted with EtOAc (5 mL) and poured into aqueous HCl (12 mL, 1 M
concentration). The organic layer was decanted, and the crude product was extracted from the
aqueous layer two more times (5 mL EtOAc each time). The organic layers were washed with
57
brine, dried over MgSO4, filtered, and concentrated. Flash column chromatography (gradient of
0% to 10% EtOAc in hexanes) of the crude mixture afforded 2f in 82% isolated yield (174 mg) as
a pale-yellow oil.
1
H NMR (399 MHz, Chloroform-d) δ 7.30 – 7.27 (m, 4H), 7.25 – 7.23 (m, 2H),
7.01 – 6.95 (m, 2H), 3.82 (s, 6H).
13
C NMR (100 MHz, Chloroform-d) δ 159.8, 130.1, 129.0,
126.9, 121.9, 119.1 (t, J = 347.4 Hz), 115.9, 55.5.
19
F NMR (376 MHz, Chloroform-d) δ -43.5.
FT-IR (cm
-1
) 3085, 3053, 3017, 2964, 2938, 2837, 2518, 2059, 1587, 1571, 1477, 1465, 1455,
1440, 1421, 1301, 1286, 1232, 1184, 1169, 1035, 1013, 899, 877, 830, 800, 770, 684, 664, 574,
557, 453. HRMS (M-H
+
) 420.9156.
Bis((4-chlorophenyl)selanyl)difluoromethane (2g)
In an argon glovebox, LiOtBu (0.5 mmol, 1.0 equiv, 40.0 mg), LiCl (0.6 mmol, 1.2 equiv,
25.4 mg) and 1,2-bis(4-chlorophenyl) diselenide (0.5 mmol, 191.0 mg) were weighed into an oven-
dried, crimp-top vial equipped with a magnetic stir bar and sealed. Under N2, DMF (0.63 mL) was
added by syringe, and the solution was stirred for 5 mins, followed by dropwise addition of
TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution was stirred for 10 mins, the vial was opened,
the solution was diluted with EtOAc (5 mL) and poured into aqueous HCl (12 mL, 1 M
concentration). The organic layer was decanted, and the crude product was extracted from the
aqueous layer two more times (5 mL EtOAc each time). The organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated. Flash column chromatography (hexanes) of
the crude mixture afforded 2g in 84% isolated yield (181 mg) as a colorless solid.
1
H NMR (399
MHz, Chloroform-d) δ 7.64 – 7.57 (m, 1H), 7.38 – 7.30 (m, 1H).
13
C NMR (100 MHz,
Chloroform-d) δ 138.3 (d, J = 1.1 Hz), 136.7, 129.7, 124.3 (t, J = 1.2 Hz), 118.8 (t, J = 348.2 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -44.1. FT-IR (cm
-1
) 3084, 2923, 2851, 2761, 2645, 2359,
58
1909, 1645, 1579, 1558, 1470, 1435, 1387, 1350, 1291, 1267, 1084, 1023, 1009, 951, 801, 732,
486.
Difluorobis(phenylthio)methane (2i)
In an argon glovebox, LiOtBu (1.5 mmol, 3.0 equiv, 120.0 mg), and 1,2-diphenyl disulfide
(0.5 mmol, 109.0 mg) were weighed into an oven-dried, crimp-top vial equipped with a magnetic
stir bar and sealed. Under N2, DMF (0.63 mL) was added by syringe, and the solution was stirred
for 5 mins, followed by dropwise addition of TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution
was stirred for 10 mins, the vial was opened, the solution was diluted with EtOAc (5 mL) and
poured into aqueous HCl (12 mL, 1 M concentration). The organic layer was decanted, and the
crude product was extracted from the aqueous layer two more times (5 mL EtOAc each time). The
organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Flash
column chromatography (hexanes) of the crude mixture afforded 2i in 71% isolated yield (95 mg)
as a pale-yellow oil.
1
H NMR (399 MHz, Chloroform-d) δ 7.66 – 7.56 (m, 4H), 7.49 – 7.43 (m,
2H), 7.43 – 7.36 (m, 4H).
13
C NMR (100 MHz, Chloroform-d) δ 136.3, 132.4 (t, J = 312.4 Hz),
130.3, 129.2, 127.4.
19
F NMR (376 MHz, Chloroform-d) δ -49.5. The NMR data matches previous
reports.
60

Difluorobis((3-fluorophenyl)thio)methane (2j)
In an argon glovebox, LiOtBu (1.5 mmol, 3.0 equiv, 120.0 mg), and bis(3-fluorophenyl)
disulfide (0.5 mmol, 127.2 mg) were weighed into an oven-dried, crimp-top vial equipped with a
magnetic stir bar and sealed. Under N2, DMF (0.63 mL) was added by syringe, and the solution
was stirred for 5 mins, followed by dropwise addition of TMSCF3 (1.0 mmol, 2 equiv, 148 µL).
The solution was stirred for 10 mins, the vial was opened, the solution was diluted with EtOAc (5
mL) and poured into aqueous HCl (12 mL, 1 M concentration). The organic layer was decanted,
59
and the crude product was extracted from the aqueous layer two more times (5 mL EtOAc each
time). The organic layers were washed with brine, dried over MgSO4, filtered, and concentrated.
Flash column chromatography (gradient of 0% to 10% EtOAc in hexanes) of the crude mixture
afforded 2j in 62% isolated yield (94 mg) as a pale-yellow oil.
1
H NMR (399 MHz, Chloroform-
d) δ 7.4 – 7.3 (m, 6H), 7.2 (m, 2H).
13
C NMR (100 MHz, Chloroform-d) δ 162.5 (d, J = 250.2
Hz), 132.1 (t, J = 315.5 Hz), 131.8 (d, J = 3.2 Hz), 130.5 (d, J = 8.3 Hz), 129.0 (dt, J = 7.9, 1.4
Hz), 122.9 (d, J = 22.1 Hz), 117.7 (d, J = 21.0 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -49.2,
-110.5 – -113.3 (m). HRMS (M-H
+
) 303.0011.
Difluorobis(p-tolylthio)methane (2k)
In an argon glovebox, LiOtBu (1.5 mmol, 3.0 equiv, 120.0 mg), and di-p-tolyl disulfide
(0.5 mmol, 123.2 mg) were weighed into an oven-dried, crimp-top vial equipped with a magnetic
stir bar and sealed. Under N2, DMF (0.63 mL) was added by syringe, and the solution was stirred
for 5 mins, followed by dropwise addition of TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution
was stirred for 10 mins, the vial was opened, the solution was diluted with EtOAc (5 mL) and
poured into aqueous HCl (12 mL, 1 M concentration). The organic layer was decanted, and the
crude product was extracted from the aqueous layer two more times (5 mL EtOAc each time). The
organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Flash
column chromatography (gradient of 0% to 15% EtOAc in hexanes) of the crude mixture afforded
2k in 49% isolated yield (73 mg) as a pale-yellow solid.
1
H NMR (399 MHz, Chloroform-d) δ
7.51 (d, J = 8.2 Hz, 4H), 7.27 – 7.18 (m, 4H), 2.40 (s, 6H).
13
C NMR (100 MHz, Chloroform-d)
δ 140.7, 136.4 (d, J = 1.1 Hz), 132.4 (t, J = 314.1 Hz), 130.0, 124.0 (t, J = 1.4 Hz), 21.5.
19
F NMR
(376 MHz, Chloroform-d) δ -50.2. HRMS (M-H
+
) 295.0436.

60
Difluorobis(pyridin-2-ylthio)methane (2l)
In an argon glovebox, LiOtBu (1.5 mmol, 3.0 equiv, 120.0 mg), and di(pyridin-2-yl)
disulfide (0.5 mmol, 110.2 mg) were weighed into an oven-dried, crimp-top vial equipped with a
magnetic stir bar and sealed. Under N2, DMF (0.63 mL) was added by syringe, and the solution
was stirred for 5 mins, followed by dropwise addition of TMSCF3 (1.0 mmol, 2 equiv, 148 µL).
The solution was stirred for 10 mins, the vial was opened, the solution was diluted with EtOAc (5
mL) and poured into water (12 mL). The organic layer was decanted, and the crude product was
extracted from the aqueous layer two more times (5 mL EtOAc each time). The organic layers
were washed with brine, dried over MgSO4, filtered, and concentrated. Flash column
chromatography (hexanes) of the crude mixture afforded 2l in 25% isolated yield (34 mg) as a
light-brown oil.
1
H NMR (399 MHz, Chloroform-d) δ 8.60 (ddd, J = 4.8, 1.9, 1.0 Hz, 2H), 7.78 –
7.59 (m, 4H), 7.28 (ddd, J = 7.1, 4.8, 1.5 Hz, 2H).
19
F NMR (376 MHz, Chloroform-d) δ -47.5.
The NMR data matches previous reports.
60

61
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https://doi.org/10.1039/C5RA16879A.

68
Chapter 3: gem-Halofluorocyclopropanes via [2+1] cycloadditions of in situ generated
CFX carbene with alkenes
3.1 Introduction
Cyclopropanation via [2+1] cycloaddition of alkenes with singlet dihalocarbene has been
used to synthesize gem-dihalocyclopropanes since the 1960s.
1–4
Initially, these were limited to
symmetrical carbenes :CF2, :CCl2, and :CBr2. In particular, :CF2 and the corresponding gem-
difluorocyclopropanes have gained popularity due in no small part to the beneficial effects of
fluorination on the activity and metabolism of biologically relevant small molecules.
5–7

Cyclopropanation with non-symmetrical dihalocarbenes, especially ones containing fluorine, is
considerably less explored.
4,5
Bromofluorocarbene (:CFBr) is of special interest in [2+1]
cycloadditions because it incorporates the valuable C-F bond as well as a C-Br bond that may
serve as a handle for further functionalization. Such gem-bromofluorocyclopropanes have been
synthesized previously (Scheme 3.1.1),
8–11
but the methods typically rely on the use of
(per)halofluoromethanes as the source of bromofluorocarbene.

Scheme 3.1.1 Prior cyclopropanations with bromofluorocarbene
Due to their harmful ozone-depleting and greenhouse effects, many (per)halofluoromethanes
(Halons) have since had their industrial preparation banned by the Montreal Protocol, making them
difficult or impossible to access. In 2021, an excellent report from Hu and coworkers documented
69
the use of TMSCFBr2 as a source of :CFBr for [2+1] cycloaddition reactions.
12
While it is an
effective reagent for this transformation, TMSCFBr2 unfortunately is not commercially available,
and its synthesis is quite tedious, employing the banned Halon CFBr3. A Halon-free approach
utilized sodium dibromofluoroacetate in the presence of an (NHC)-silver(I) catalyst via thermal
decarboxylation at elevated temperatures; however, the lack of commercial availability of the
sodium salt and the requisite precious metal catalyst serve to limit the method’s accessibility.
13

We set out to develop a reagent system for this reaction using an easily accessible, bench stable
source of :CFBr. Ethyl dibromofluoroacetate (EDBFA) is commercially available, inexpensive,
and stable to ambient conditions. It has also been used to generate

bromofluorocarbene for the
synthesis of a fluorinated allylsilane through a bromofluorocyclopropane intermediate. This
unstable intermediate readily decomposed to the aforementioned allylsilane.
14

3.2 Optimization
Inspired by this study,
14
we set out to further explore this chemistry. Styrene 1a was chosen
as the model substrate, and the results from a series of optimization trials are summarized in Figure
1. Alkali metal hydroxides such as LiOH and KOH were unable to generate 2a, despite significant
consumption of EDBFA (Trials 1-2). Sodium ethoxide in hexanes was found to be a good system,
providing 91% yield of 2a at room temperature (Trial 3). Further optimization showed this
reaction to be quite sensitive to solvent identity. Strongly polar solvent DMAc led to uncontrolled,
exothermic decomposition of EDBFA and almost no formation of 2a (Trial 4). Mildly polar
solvents PhH and DCM both provided lower yields than hexanes (Trials 5-6). Concentration was
also important. Decreasing the concentration in DCM from 0.5 M to 0.38 M led to a significant
drop in yield (Trial 7), and increasing it to 0.7 M boosted the yield to quantitative (Trial 8).
70
Interestingly, this effect was only observed with DCM; higher concentration in hexanes provided
no improvement in yield (Trial 9).

Trial Solvent
Conc.
(M)
Activator
Yield (%)
a

2a (syn + anti)
1
b
hexanes 0.5 LiOH 0
2
b
hexanes 0.5 KOH 0
3 hexanes 0.5 NaOEt 91
4 DMAc 0.5 NaOEt 5
5 PhH 0.5 NaOEt 50
6 DCM 0.5 NaOEt 71
7 DCM 0.38 NaOEt 54
8 DCM 0.7 NaOEt quant.
9 hexanes 0.7 NaOEt 91
10
c
hexanes 0.7 NaOEt 78
11
c
DCM 0.7 NaOEt 80
a
determined by
19
F NMR of reaction mixes.
b
reaction was
performed at 60°C for 1 h.
c
reaction was set up and
performed under air. Shaded cells indicate the change made
in that trial.

Figure 3.2.1 Selected optimization trials of bromofluorocyclopropanation
As a test of the air and water sensitivity of this reaction, two additional trials were performed under
an atmosphere of air (Trials 10-11). The yields were surprisingly similar to the reactions under
inert gas, but it is likely that the hygroscopic nature of NaOEt may lead to yield variability
depending on length of its exposure to air. Regardless, it was valuable to discover that this
procedure is quite robust, exhibiting only mild moisture sensitivity. It is also worth noting that the
ratio of isomers 2a-syn:2a-anti (1 : 1.16) was not significantly affected by changes in conditions,
with the reaction showing minimal preference for the anti isomer.
71
3.3 Proposed mechanism
Based on prior art and the insights gained from the optimization experiments, we proposed
the following mechanism (Scheme 3.3.1).

Scheme 3.3.1 Proposed mechanism of carbene generation
Nucleophilic attack of the ethoxide anion on EDBFA gives tetrahedral intermediate I, which can
extrude either ethoxide, reforming EDBFA, or carbenoid II, forming diethyl carbonate (see SI).
Once formed, this unstable carbenoid II loses sodium bromide to generate singlet
bromofluorocarbene III, which then undergoes a [2+1] cycloaddition with the alkene to form the
product cyclopropane 2a. In contrast to most of our work with CF2 carbene,
15–18
in which fast
carbene generation was key for reaction efficiency, the present reaction benefits from a slower rate
of carbene generation. The rate of generation was effectively tuned with solvent polarity. We
hypothesize that the nonpolar solvents severely limited the amount of active ethoxide due to its
low solubility, limiting the rate of activation of EDBFA. It follows that the resultant low
concentration of intermediate I would limit the formation of II and could thus control the rate of
bromofluorocarbene III generation.
3.4 Scope of bromofluorocyclopropanation
Various para-substituted styrenes were subjected to the conditions (Scheme 3.4.1).
72

Scheme 3.4.1 Bromofluorocyclopropanation substrate scope
73
Both electron donating and electron withdrawing substituents OMe, Cl, and Br provided the
corresponding products 2b − 2d in good yields. A substrate with a p-phenyl group and one with
a p-chloromethyl group gave 2e and 2f, respectively, in nearly identical yields, suggesting this
reaction is minimally sensitive to substrate electronics. Notably, the chloromethyl group of 2f was
stable to the excess ethoxide, despite the propensity of benzylic chloride toward nucleophilic
substitution.
19–21
Sterics, however, can play a role, as evidenced by the lower yields of ortho-
substituted examples 2g and 2h relative to their para-substituted counterparts. 2-methoxy 2g was
formed in only 7% lower yield than 4-methoxy 2b by
19
F NMR. With 2-methyl 2h a larger drop
in yield of 15% was seen relative to the 4-chloromethyl 2f. The steric hindrance imposed by the
three methyl groups of the mesityl 2i, particularly those on the 2 and 6 positions, is likely to have
resulted in the moderate drop in yield. We also wanted to investigate how different alkene
substitution patterns affect the reactivity. 1,1-disubstituted alkenes were found to be well suited
to this method. 1,1-dialkyl, 1,1-diaryl, and 1-alkyl-1-aryl alkenes all provided the corresponding
cyclopropanes (2h — 2m) in excellent yields. 1,2-disubstituted alkenes proved more challenging
substrates, as the product cyclopropanes were prone to decomposition. Products from β-alkyl
styrenes (2n, 2o) were formed in quantitative and 82% yields, respectively, as determined by
19
F
NMR. It was found that these compounds were prone to decomposition on the time scale of
purification, particularly 2o. The cyclopropanes 2p and 2q, generated from trans-stilbene and cis-
stilbene, respectively, were much more susceptible to this phenomenon, with a considerable degree
of decomposition evident even on the time scale of the reaction. 67% yield of 2p was observed
by
19
F NMR of the reaction mixture, and 24% yield of 2q was observed. Both mixtures contained
multiple products of ring opening decomposition. The mechanistic pathway of this ring opening
is believed to be as shown in Scheme 3.4.2.
9,12,22

74

Scheme 3.4.2 Ring opening of 1-bromo-2,3-diarylcyclopropanes
An initial homolytic cleavage of the sigma bond between the 2 and 3 carbons generates diradical
intermediate IV. Loss of a bromine atom leads to allylic radical V, which is then quenched with
X
•
. This X
•
can either be a bromine radical or another equivalent of the allylic radical V, leading
to different degrees of oligomerization. In the cases of 2p and 2q, both radicals of IV are benzylic.
The increased stability of these intermediates due to resonance delocalization of both radicals
explains why these 2,3-diarylcyclopropanes are more prone to ring opening. To further expand our
substrate scope, we explored some interesting functionalities. Allyl(trimethyl)silane provided 2r
in 94% isolated yield, showing excellent tolerance of the method to TMS moieties.
Vinyl (thio)ethers were also successful substrates. Phenyl vinyl sulfide produced 2s in 81%
isolated yield, and isobutyl vinyl ether produced 2t in 71% yield by
19
F NMR. The latter was not
isolated due to product volatility. Interestingly, N-vinylpyrrolidinone also produced cyclopropane
2u in 62% yield by
19
F NMR, but the compound decomposed during isolation. Unfortunately,
alkynes were unable to furnish the corresponding cyclopropenes under these conditions.
3.5 Extension to chlorofluorocyclopropanes
During the course of our investigation, we discovered that the chlorinated analogue of our
ester reagent, ethyl dichlorofluoroacetate (EDCFA), is also commercially available; thus, we
decided to extend this methodology to the synthesis of gem-chlorofluorocyclopropanes.
75
Gratifyingly, the CFCl carbene insertion into alkenes was similarly successful. A representative
example of each type of substrate was chosen, and the results are given in Scheme 3.5.1.

Scheme 3.5.1 Chlorofluorocyclopropanation substrate scope
Examples include 3e from the styrene-type group, 3s from the heteroatom-containing group,
dialkyl 3k and diaryl 3m from 1,1-disubstituted alkenes, and 3n from the 1,2-disubstituted set. In
notable contrast to bromofluorocyclopropane 2n, we saw no evidence of decomposition of
chlorofluorocyclopropane 3n, even after prolonged exposure to light. This observation supports
the proposed decomposition pathway (Scheme 3.4.2), as the relative instability of the chlorine
radical compared to the bromine radical would make the former less likely to leave, thus depressing
the propensity toward decomposition. Product 3m has been shown to have strong activity as an
76
insecticidal agent.
23
To the best of our knowledge, this is the first report in the open chemical
literature of the synthesis of 3m. This compound can now be accessed easily and efficiently with
the present method, even on a larger scale (Scheme 3.5.2), with only a minimal drop in isolated
yield at 5 mmol.

Scheme 3.5.2 Results of trials performed at 5 mmol or greater scales
Products 2l and 2s were synthesized at 15 mmol and 20 mmol scales, respectively, and both were
isolated in excellent yields. The 20 mmol scale preparation of 2s is particularly noteworthy, as it
provided the same 81% yield as the 0.5 mmol trial. This is a strong testament to the method’s
excellent scalability. Though there is some prior precedent for using similar dichlorofluoroacetate
esters in [2+1] cycloadditions,
24–27
we believe this method represents a significant improvement
on the current state of the art, with benefits in convenience of conditions, scope of substrates, and
yields.
3.6 Potential synthetic utility of synthesized products
The underexplored nature of these gem-halofluorocyclopropanes is likely due, in part, to
their relative inaccessibility. In an effort to demonstrate the potential utility of our gem-
halofluorocyclopropanes, we subjected 2s to conditions suitable for different types of structure
modification. The results of these reactions are summarized in Scheme 3.6.1.

77

Scheme 3.6.1 Synthetic utility of gem-bromofluorocyclopropanes
Using n-butyllithium, 2s underwent a lithium-halogen exchange, and the cyclopropyllithium
intermediate was then quenched with trifluoroacetic acid as a proton source to give 4s in good
yield by
19
F NMR. Hu and coworkers recently demonstrated an analogous reduction using
tributyltin hydride.
12
Synthetic pathways to these types of monofluorocyclopropanes are generally
quite rare in the literature,
4,5
and our synthesis of 4s serves as good proof of concept for accessing
these compounds via halofluorocyclopropanes. While testing substrates for the [2+1] reactions, it
was found that vinyl sulfones were incompatible with our method. Undeterred, we attempted to
access the corresponding 2-sulfonylcyclopropane product indirectly. Cyclopropyl phenyl
thioether 2s, as prepared by our method, was efficiently converted to the sulfone 5s in excellent
isolated yield at gram scale using an adapted protocol.
28

3.7 Conclusions
In summary, we have developed an efficient and convenient method to synthesize gem-
bromofluorocyclopropanes and gem-chlorofluorocyclopropanes using commercially available,
inexpensive reagents.
29
Three examples were prepared at large scale (up to 20 mmol), including
3m, which has shown strong insecticidal activity.

78
3.8 Experimental
3.8.1 General information
Unless otherwise specified, all materials were purchased from commercial sources and
used without further purification. Br2FCCO2Et (DBFA) and Cl2FCCO2Et (DCFA) were purchased
from Synquest Laboratories and used as received. Anhydrous DriSolv® DCM (Millipore Sigma)
was used in all trials. Where applicable, flash column chromatography on silica gel was performed
with either a manual column or a Biotage autocolumn with UV detector (254 nm and 280 nm
detection) for product isolation with a hexanes/EtOAc eluent system.
1
H,
13
C, and
19
F spectra were
recorded on 400 MHz, 500 MHz, or 600 MHz Varian NMR spectrometers.
1
H NMR chemical
shifts were determined relative to CHCl3 as the internal standard at 7.26 ppm.
13
C NMR shifts
were determined relative to CDCl3 at 77.16 ppm.
19
F NMR chemical shifts were determined
relative to CFCl3 at 0.00 ppm. Multiplicity abbreviations (e.g. s, d, t) preceded by “b” denotes
those signals as being broad, and as such their finer coupling may be masked. NMR yields and
diastereomeric ratios were determined via
19
F spectral analysis of neat reaction mixture aliquots
after adding a known quantity of a fluorinated internal standard: PhF, PhCF3, or PhOCF3. Mass
spectral data were recorded on a high-resolution mass spectrometer (QTOF) in either EI or ESI
mode. Elemental analyses were performed on a Flash 2000 CHNS elemental analyzer. IR data
were recorded on a JASCO FT/IR spectrometer. Melting points are uncorrected.
Notes:
1. Solid starting materials were weighed into the reaction vial in an argon glovebox along
with NaOEt.
79
2. In our observations, the addition rate of the ester reagents did not affect the reaction,
but for the sake of consistency, they were added quickly dropwise for the trials
presented.
3. The crude samples can be loaded onto silica either by wet loading or dry loading.
4. There is typically a small amount (~0.5 equiv. or less) of the ester reagent remaining
after the reaction is complete. EDCFA is easily removed by rotary evaporation. The
heavier EDBFA requires longer times at lower vacuum (<20 Torr at 40°C) to be fully
removed, and for more volatile products this can lead to some loss of yield.
5. Preparations of more volatile products benefited from the use of pentane in place of
hexanes as the eluent for column chromatography.
3.8.2 Synthesis of alkene starting materials
1,1-bis(4’-chlorophenyl)ethene (1m)
Procedure was adapted from previous reports.
30,31
A 100 mL oven dried round bottom
flask equipped with a magnetic stir bar was charged with PPh3(Me)Br (12 mmol, 1.2 equiv, 4.3
g). Under a flow of N2, THF (0.3 M, 33 mL) was added, followed by slow, portion-wise addition
of solid KOtBu (12 mmol, 1.2 equiv, 1.3 g). The resultant suspension was stirred at room
temperature for 15 minutes, following which the flask was cooled in an ice bath for the portion-
wise addition of 4,4’-dichlorobenzophenone (10 mmol, 1 equiv, 2.5 g). Upon full addition, the
bath was removed, and the reaction mixture was stirred for 15 hours at room temperature. The
resultant suspension was filtered through celite, the filtrate was concentrated in vacuo, and the
residue was purified by column chromatography (hexanes) to yield the title compound as a
colorless solid (82% yield, 2.1 g).
1
H NMR (400 MHz, Chloroform-d) δ 7.36 – 7.31 (m, 4H), 7.29
– 7.24 (m, 4 H), 5.47 (s, 2H). The NMR data matches previous reports.
31

80
3.8.3 General Procedures
General Procedure Br
In an argon glovebox, NaOEt (78.3 mg, 2.3 equiv, 1.15 mmol) was weighed into an oven
dried, 5 mL, crimp top vial and sealed with a septum cap. DCM (0.7 mL, 0.7 M), the alkene
substrate 1 (0.50 mmol, 1 equiv), and Br2FCCO2Et (140 µL, 2.0 equiv, 1.00 mmol) were
sequentially added under N2. The resulting suspension was stirred at room temperature for 2.5
hours. The vial was uncapped, and the mixture was then diluted with DCM (4 mL), H2O (8 mL)
was added, and the resultant biphasic system was shaken. The organic layer was collected, and the
aqueous layer was extracted again with DCM (2 x 4 mL). The combined organic layers were dried
over either MgSO4 or Na2SO4, filtered, and concentrated in vacuo. The crude sample was purified
by normal phase liquid chromatography on silica to afford the target compound(s).
General Procedure Cl
In an argon glovebox, NaOEt (78.3 mg, 2.3 equiv, 1.15 mmol) was weighed into an oven
dried, 5 mL, crimp top vial and sealed with a septum cap. DCM (0.7 mL, 0.7 M), the alkene
substrate 1 (0.50 mmol, 1 equiv), and Cl2FCCO2Et (140 µL, 2.0 equiv, 1.00 mmol) were
sequentially added under N2. The resulting suspension was stirred at room temperature for 2.5
hours. The vial was uncapped, and the mixture was then diluted with DCM (4 mL), H2O (8 mL)
was added, and the resultant biphasic system was shaken. The organic layer was collected, and the
aqueous layer was extracted again with DCM (2 x 4 mL). The combined organic layers were dried
over either MgSO4 or Na2SO4, filtered, and concentrated in vacuo. The crude sample was purified
by normal phase liquid chromatography on silica to afford the target compound(s).

81
3.8.4 Experimental and spectral data for halofluorocyclopropanes 2 and 3
(2-bromo-2-fluorocyclopropyl)benzene (2a)
Prepared from styrene following General Procedure Br. Isolated by column
chromatography (hexanes) as a colorless oil in 94% yield (101 mg).
1
H NMR (400 MHz,
Chloroform-d) δ [7.41 – 7.27 (m), 7.25 – 7.18 (m), S 5H], [2.93 – 2.69 (m), 2.05 (ddd, J = 17.0,
11.7, 7.9 Hz), 1.97 – 1.79 (m), 1.71 (q, J = 7.9 Hz), S 3H].
19
F NMR (376 MHz, Chloroform-d) δ
[-125.5 (td, J = 17.7, 7.4 Hz), -146.8 (ddd, J = 17.1, 8.9, 2.7 Hz), S 1F].
13
C NMR (101 MHz,
Chloroform-d) δ 135.5, 133.6 (d, J = 1.7 Hz), 128.6 (d, J = 2.1 Hz), 128.6, 128.5, 128.4 (d, J = 1.4
Hz), 127.5, 127.5, 86.2 (d, J = 301.4 Hz), 80.5 (d, J = 302.0 Hz), 33.3 (d, J = 10.8 Hz), 30.7 (d, J
= 10.7 Hz), 22.7 (d, J = 10.3 Hz), 22.0 (d, J = 10.6 Hz). FT-IR l (cm
-1
) 3031, 2927, 2857, 1604,
1496, 1430, 1369, 1261, 1238, 1137, 1079, 1033, 975, 945, 821, 763, 690, 640, 543, 498. NMR
data matched a previous report.
1-(2-bromo-2-fluorocyclopropyl)-4-methoxybenzene (2b)
Prepared from 4-methoxystyrene following General Procedure Br. Isolated by column
chromatography (5% EtOAc in hexanes) as a colorless oil in 74% yield (90 mg).
1
H NMR (500
MHz, Chloroform-d) δ 7.23 – 7.17 (m, 1H), 7.17 – 7.11 (m, 1H), 6.89 (ddd, J = 8.7, 5.0, 2.2 Hz,
2H), [3.82 (s), 3.81 (s), S 3H], [2.81 – 2.67 (m), 2.08 – 1.93 (m), 1.89 – 1.74 (m), 1.63 (qd, J =
8.1, 2.5 Hz), S 3H].
19
F NMR (470 MHz, Chloroform-d) δ [-125.3 (td, J = 17.4, 7.1 Hz), -146.4
(dd, J = 17.0, 9.3 Hz), S 1F].
13
C NMR (126 MHz, Chloroform-d) δ 159.0, 129.7 (d, J = 1.9 Hz),
129.5 (d, J = 0.9 Hz), 127.6, 125.6 (d, J = 1.9 Hz), 114.0, 113.8, 86.8 (d, J = 301.5 Hz), 80.7 (d, J
= 301.6 Hz), 55.4, 55.3, 32.7 (d, J = 10.7 Hz), 30.0 (d, J = 11.0 Hz), 22.6 (d, J = 10.3 Hz), 22.0 (d,
J = 10.6 Hz). FT-IR l (cm
-1
) 3000, 2927, 2838, 1612, 1511, 1446, 1295, 1180, 1137, 1033, 983,
82
944, 829. HRMS (ESI) m/z: [M - Br]‾ Calcd for C10H10FO‾ 165.0721; Found 165.0713 (4.84
ppm).
1-(2-bromo-2-fluorocyclopropyl)-4-chlorobenzene (2c)
Prepared from 1-chloro-4-vinylbenzene following General Procedure Br.

Isolated by
column chromatography (hexanes) as a colorless oil in 63% yield (78 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 7.35 – 7.28 (m, 2H), 7.21 – 7.12 (m, 2H), [2.83 – 2.67 (m), 2.06 (ddd, J = 16.9,
11.6, 8.0 Hz), 1.91 – 1.80 (m), 1.64 (q, J = 8.0 Hz), S3H].
19
F NMR (376 MHz, Chloroform-d) δ
-125.5 (dt, J = 17.1, 8.7 Hz), -144.4 – -149.0 (m).
13
C NMR (101 MHz, Chloroform-d) δ 134.1,
133.5, 133.4, 132.2 (dd, J = 1.9, 0.9 Hz), 130.0 (dd, J = 2.1, 1.0 Hz), 129.8 (t, J = 1.1 Hz), 128.8
(d, J = 0.9 Hz), 128.7 (d, J = 0.9 Hz), 85.7 (d, J = 301.8 Hz), 80.0 (d, J = 301.1 Hz), 32.7 (d, J =
10.7 Hz), 30.1 (d, J = 11.3 Hz), 22.9 (d, J = 10.4 Hz), 22.2 (d, J = 10.6 Hz). NMR data matched a
previous report.
12

1-bromo-3-(2-bromo-2-fluorocyclopropyl)benzene (2d)
Prepared from 1-bromo-3-vinylbenzene following General Procedure Br. Isolated by
column chromatography (hexanes) as a colorless oil in 48% yield (71 mg).
1
H NMR (500 MHz,
Chloroform-d) δ [7.48 – 7.38 (m), 7.36 (s), 7.19 (tt, J = 14.1, 7.9 Hz), S4H], [2.83 – 2.68 (m), 2.06
(ddd, J = 16.9, 11.6, 8.1 Hz), 1.94 – 1.80 (m), 1.67 (q, J = 8.0 Hz), S3H].
19
F NMR (470 MHz,
Chloroform-d) δ -125.8 (td, J = 17.1, 7.1 Hz), -146.7 (dd, J = 17.0, 9.5 Hz).
13
C NMR (101 MHz,
Chloroform-d) δ 137.9, 135.9 (d, J = 1.8 Hz), 131.7, 131.7, 131.6, 131.5, 130.7, 130.6, 130.1,
130.0, 85.4 (d, J = 301.7 Hz), 79.9 (d, J = 302.1 Hz), 32.8 (d, J = 10.7 Hz), 30.2 (d, J = 11.2 Hz),
22.9 (d, J = 10.4 Hz), 22.2 (d, J = 10.6 Hz). FT-IR l (cm
-1
) 2952, 2918, 2849, 2361, 1596, 1564,
1475, 1434, 1417, 1356, 1266, 1237, 1210, 1136, 1067, 1036, 990, 948, 925, 878, 837, 770. Anal.
Calcd. for C9H7Br2F: C, 36.77; H, 2.40. Found: C, 36.61; H, 2.11.
83
4-(2-bromo-2-fluorocyclopropyl)-1,1'-biphenyl (2e)
Prepared from 4-vinyl-1,1'-biphenyl following General Procedure Br. Isolated by column
chromatography (hexanes) as a colorless waxy solid in 70% yield (102 mg). m.p. 62 – 64°C.
1
H
NMR (500 MHz, Chloroform-d) δ 7.60 (q, J = 8.6 Hz, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 – 7.32
(m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 2.89 – 2.77 (m, 1H), 2.08 (ddd, J = 16.8, 11.7, 8.0 Hz, 1H), 2.01
– 1.81 (m, 1H), 1.73 (q, J = 8.0 Hz, 1H), 0.89 (dt, J = 14.5, 6.9 Hz, 1H).
19
F NMR (470 MHz,
Chloroform-d) δ -125.4 (td, J = 17.6, 7.3 Hz), -146.8 (dd, J = 17.3, 9.1 Hz).
13
C NMR (126 MHz,
Chloroform-d) δ 140.8, 140.7, 140.5, 140.4, 134.6, 132.7, 129.0, 129.0, 128.9, 128.9, 128.8, 128.8,
127.5, 127.5, 127.3, 127.2, 127.2, 86.2 (d, J = 301.8 Hz), 80.6 (d, J = 302.1 Hz), 33.1 (d, J = 10.5
Hz), 30.5 (d, J = 11.1 Hz), 22.9 (d, J = 10.4 Hz), 22.2 (d, J = 10.6 Hz). FT-IR l (cm
-1
) 3033, 2954,
2925, 2852, 1523, 1486, 1450, 1431, 1406, 1363, 1318, 1267, 1240, 1137, 938, 963, 940, 904,
841, 809, 763, 731. HRMS (ESI) m/z: [M - Br]
+
Calcd for C15H12F
+
211.0918; Found 211.0913
(2.37 ppm).
1-(2-bromo-2-fluorocyclopropyl)-4-(chloromethyl)benzene (2f)
Prepared from 1-(chloromethyl)-4-vinylbenzene following General Procedure Br. Isolated
by column chromatography (hexanes) as a colorless oil in 73% yield (96 mg).
1
H NMR (500 MHz,
Chloroform-d) δ [7.42 – 7.35 (m), 7.26 (d, J = 8.1 Hz), 7.23 (d, J = 8.2 Hz), 4.61 (s), 4.59 (s), 2.86
– 2.75 (m), 2.07 (ddd, J = 16.9, 11.6, 8.0 Hz), 1.95 – 1.81 (m), 1.70 (q, J = 8.0 Hz), S3H].
19
F
NMR (470 MHz, Chloroform-d) δ -125.5 (td, J = 17.4, 7.2 Hz), -146.8 (dd, J = 17.4, 9.2 Hz).
13
C
NMR (126 MHz, Chloroform-d) δ 136.7 (d, J = 6.6 Hz), 135.8, 134.0 (d, J = 1.8 Hz), 129.0 (d, J
= 2.0 Hz), 128.8, 128.8 (d, J = 1.3 Hz), 128.7, 85.9 (d, J = 301.8 Hz), 80.3 (d, J = 301.9 Hz), 46.0,
33.0 (d, J = 10.7 Hz), 30.4 (d, J = 11.2 Hz), 22.9 (d, J = 10.4 Hz), 22.2 (d, J = 10.6 Hz). FT-IR l
(cm
-1
) 3027, 2954, 2923, 2857, 1909, 1612, 1515, 1435, 1365, 1261, 1138, 1068, 1029, 944, 837,
84
798. 761, 543, 501. HRMS (EI) m/z: [M - Cl]
+
Calcd for C10H9BrF
+
226.9866; Found 226.9865
(0.44 ppm).
1-(2-bromo-2-fluorocyclopropyl)-2-methoxybenzene (2g)
Prepared from 1-methoxy-2-vinylbenzene following General Procedure Br. Isolated by
column chromatography (pentane) as a yellow oil in 93% yield (114 mg).
1
H NMR (500 MHz,
Chloroform-d) δ [7.32 – 7.26 (m), 7.08 (d, J = 7.5 Hz), 6.97 – 6.88 (m), S 4H], [3.91 (s), 3.90 (s),
Σ 3H], [2.93 – 2.83 (m), 2.05 – 1.94 (m), 1.88 – 1.74 (m), 1.69 – 1.60 (m), S 3H].
19
F NMR (470
MHz, Chloroform-d) δ -127.4 (td, J = 17.5, 6.8 Hz), -146.3 (dd, J = 17.5, 9.0 Hz).
13
C NMR (126
MHz, Chloroform-d) δ 159.3, 159.1, 128.8, 128.7, 128.3 (d, J = 1.8 Hz), 128.2 (d, J = 3.9 Hz),
124.6, 122.4 (d, J = 2.4 Hz), 120.4, 120.3, 110.6, 110.4, 86.6 (d, J = 302.6 Hz), 81.2 (d, J = 300.7
Hz), 55.9, 55.7, 29.9, 28.8 (d, J = 10.6 Hz), 26.8 (d, J = 11.3 Hz), 21.7 (d, J = 10.3 Hz), 21.3 (d, J
= 10.5 Hz). FT-IR l (cm
-1
) 1496, 1462, 1437, 1288, 1245, 1146, 1113, 1070, 1027, 985, 944, 830,
796, 749, 719, 502, 485. HRMS (EI) m/z: [M]
+
Calcd for C10H10OBrF
+
243.9899; Found
243.9890 (3.50 ppm).
1-(2-bromo-2-fluorocyclopropyl)-2-methylbenzene (2h)
Prepared from 1-methyl-2-vinylbenzene following General Procedure Br. Isolated by
column chromatography (hexanes) as a colorless oil in 46% yield (53 mg).
1
H NMR (500 MHz,
Chloroform-d) δ [7.25 – 7.12 (m), 6.98 (d, J = 7.6 Hz), Σ 4H], [2.79 – 2.69 (m), 1.94 – 1.79 (m),
Σ 2H], [2.46 (s), 2.44 (s), Σ3H], [2.09 – 2.00 (m), 1.73 (ddd, J = 8.6, 7.6, 6.4 Hz), Σ 1H].
19
F NMR
(470 MHz, Chloroform-d) δ -127.6 (td, J = 17.3, 6.6 Hz), -145.7 (dd, J = 17.2, 8.5 Hz).
13
C NMR
(126 MHz, Chloroform-d) δ 139.1, 138.7, 134.4, 132.4 (d, J = 2.4 Hz), 130.0, 130.0, 128.1, 127.8
(d, J = 2.3 Hz), 127.4 (d, J = 4.3 Hz), 126.1, 86.3 (d, J = 302.4 Hz), 80.9 (d, J = 300.1 Hz), 32.4
85
(d, J = 11.4 Hz), 29.8 (d, J = 10.6 Hz), 21.5 (d, J = 6.0 Hz), 21.4 (d, J = 6.3 Hz), 20.3, 19.9. NMR
data matched a previous report.
12

2-(2-bromo-2-fluorocyclopropyl)-1,3,5-trimethylbenzene (2i)
Prepared from 1,3,5-trimethyl-2-vinylbenzene following General Procedure Br. Isolated
by column chromatography (hexanes) as a colorless oil in 37% yield (48 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 6.87 (s, 2H), [2.69 – 2.49 (m), 2.38 (s), 2.36 (s), 2.28 (s), 2.27 (s), 2.28 – 2.16
(m), 1.95 (ddd, J = 11.2, 8.8, 7.6 Hz), 1.70 – 1.57 (m), S 12H].
19
F NMR (376 MHz, Chloroform-
d) δ [-129.8 (dd, J = 17.0, 6.1 Hz), -142.0 (dd, J = 17.9, 8.3 Hz), S 1F].
13
C NMR (126 MHz,
Chloroform-d) δ 86.9 (d, J = 302.4 Hz), 82.3 (d, J = 299.6 Hz), 30.6 (d, J = 10.9 Hz), 28.2 (d, J =
10.6 Hz), 25.5 (d, J = 10.0 Hz), 24.1 (d, J = 10.1 Hz), 20.9 (d, J = 6.9 Hz), 20.7 (d, J = 1.5 Hz),
20.5. FT-IR l (cm
-1
) 3059, 3032, 2966, 2927, 1952, 1882, 1751, 1674, 1601, 1496, 1446, 1400,
1300, 1230, 1188, 1146, 1088, 1041, 960, 868, 764, 694, 509. HRMS (ESI) m/z: [M - Br]
+
Calcd
for C12H14F
+
177.1074; Found 177.1076 (1.13 ppm).
(2-bromo-2-fluoro-1-methylcyclopropyl)benzene (2j)
Prepared from prop-1-en-2-ylbenzene following General Procedure Br. Isolated by
column chromatography (hexanes) as a colorless oil in 89% yield (102 mg).
1
H NMR (500 MHz,
Chloroform-d) δ 7.42 – 7.28 (m, 5H), [1.98 (dd, J = 18.7, 7.9 Hz), 1.79 (t, J = 7.4 Hz), 1.67 (dd, J
= 17.5, 8.0 Hz), 2H], [1.63 (s), 1.61 (s), 1.43 (t, J = 8.2 Hz), S5H].
19
F NMR (470 MHz,
Chloroform-d) δ -128.8 (dd, J = 18.5, 8.5 Hz), -137.1 (dd, J = 17.1, 7.8 Hz).
13
C NMR (126 MHz,
Chloroform-d) δ 142.0 (d, J = 1.4 Hz), 138.9 (d, J = 4.5 Hz), 128.6, 128.4, 128.4, 128.3, 127.3,
127.2, 88.8 (d, J = 300.4 Hz), 88.3 (d, J = 306.0 Hz), 34.5 (d, J = 10.1 Hz), 33.8 (d, J = 9.4 Hz),
28.4 (d, J = 10.0 Hz), 28.0 (d, J = 9.9 Hz), 27.3 (d, J = 2.6 Hz), 21.5 (d, J = 8.4 Hz). FT-IR l (cm
-
86
1
) 3058, 2969, 2923, 2873, 1662, 1600, 1496, 1438, 1322, 1268, 1153, 1079, 1033, 925, 871, 817,
759, 705. Anal. Calcd. for C10H10BrF: C, 52.43; H, 4.40. Found: C, 52.78; H, 4.49.
((2-bromo-2-fluoro-1-methylcyclopropyl)methyl)benzene (2k)
Prepared from (2-methylallyl)benzene following General Procedure Br.

Isolated by
column chromatography (hexanes) as a colorless oil in 72% yield (87 mg).
1
H NMR (500 MHz,
Chloroform-d) δ [7.35 – 7.30 (m), 7.29 – 7.20 (m), S 5H], 2.97 – 2.69 (m, 2H), [1.57 – 1.46 (m),
1.39 – 1.27 (m), S 2H], [1.16 (s), 1.15 (s), 3H].
19
F NMR (470 MHz, Chloroform-d) δ [-134.5 (dd,
J = 18.8, 8.1 Hz), -136.4 (dd, J = 17.4, 8.3 Hz), S 1F].
13
C NMR (126 MHz, Chloroform-d) δ
138.6, 138.3, 129.3, 129.3, 129.3, 91.1 (d, J = 301.9 Hz), 90.8 (d, J = 303.5 Hz), 43.8 (d, J = 2.0
Hz), 38.8 (d, J = 8.3 Hz), 28.8 (d, J = 10.1 Hz), 28.6 (d, J = 9.5 Hz), 22.5 (d, J = 2.0 Hz), 16.6 (d,
J = 9.5 Hz). FT-IR l (cm
-1
) 3028, 2963, 2924, 2853, 1604, 1495, 1453, 1428, 1382, 1351, 1258,
1197, 1127, 1088, 1027, 975, 914, 826, 755, 722. HRMS (ESI) m/z: [M - Br]
+
Calcd for C11H12F
+

163.0918; Found 163.0910 (4.90 ppm).
(2-bromo-2-fluorocyclopropane-1,1-diyl)dibenzene (2l)
Prepared from ethene-1,1-diyldibenzene following General Procedure Br, but at 15 mmol
scale: an oven dried 50 mL round bottom flask equipped with magnetic stir bar was charged with
sodium ethoxide (2.35 g, 2.30 equiv, 34.5 mmol) in an argon glovebox. The flask was sealed with
a septum and removed from the glovebox. DCM (21.3 mL, 0.7 M) and ethene-1,1-diyldibenzene
(2.704 g, 2.65 mL, 1 equiv, 15.0 mmol) were added sequentially, and the mixture was stirred at
r.t. for the addition of ethyl dibromofluoroacetate (7.92 g, 4.18 mL, 2.0 equiv, 30.0 mmol). The
reaction mixture was allowed to stir at r.t. for 25 h. This extended reaction time was both for
convenience and to demonstrate long-term product stability to the reaction conditions. The
mixture was then extracted from water (80 mL) with DCM (3 x 40 mL). The combined organics
87
were washed with water (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
The product was isolated by column chromatography (hexanes) as a colorless solid in 80% yield
(3.49 g).
1
H NMR (399 MHz, Chloroform-d) δ 7.49 – 7.41 (m, 4H), 7.36 – 7.28 (m, 4H), 7.26 –
7.18 (m, 2H), 2.28 (dd, J = 17.6, 7.7 Hz, 1H), 2.17 (t, J = 7.9 Hz, 1H).
19
F NMR (376 MHz,
Chloroform-d) δ -128.2 (dd, J = 17.7, 8.1 Hz). NMR data matched a previous report.
12

4,4'-(2-bromo-2-fluorocyclopropane-1,1-diyl)bis(chlorobenzene) (2m)
Prepared from 4,4'-(ethene-1,1-diyl)bis(chlorobenzene) 1m following General Procedure
Br.

Isolated by column chromatography (hexanes) as a colorless solid in 100% yield (180 mg).
m.p. (
o
C) 83 – 86.
1
H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.29 (m, 8H), 2.26 (dd, J = 17.6,
7.9 Hz, 1H), 2.15 (t, J = 8.0 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -128.8 (dd, J = 17.6,
8.1 Hz).
13
C NMR (101 MHz, Chloroform-d) δ 139.4 (d, J = 2.7 Hz), 137.2 (d, J = 2.7 Hz), 133.7
(d, J = 2.9 Hz), 130.7, 130.2 (d, J = 1.9 Hz), 129.1, 129.0, 85.8 (d, J = 305.2 Hz), 41.9 (d, J = 10.3
Hz), 29.4 (d, J = 9.9 Hz). FT-IR l (cm
-1
) 3085, 1901, 1778, 1484, 1400, 1319, 1268, 1187, 1083,
1010, 944, 836, 740, 686, 543, 505. HRMS (ESI) m/z: [M]‾ Calcd for C15H9BrCl2F ‾ 356.9254;
Found 356.9254 (0.00 ppm).
1-(2-bromo-2-fluoro-3-methylcyclopropyl)-4-methoxybenzene (2n)
Prepared from (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene following General Procedure
Br. Isolated by column chromatography (hexanes) as a colorless oil in 92% yield (120 mg, 90%
purity).
1
H NMR (500 MHz, Chloroform-d) δ [7.16 (d, J = 8.7 Hz), 7.13 (d, J = 8.5 Hz), S 2H],
6.89 (td, J = 6.6, 5.5, 2.4 Hz, 2H), [3.83 (s), 3.81 (s), S 3H], [2.30 (d, J = 8.4 Hz), 2.27 (dd, J =
8.2, 3.0 Hz), 1.94 (d, J = 6.9 Hz), 1.90 – 1.84 (m), 1.77 (ddt, J = 20.8, 8.0, 6.2 Hz), 1.42 (d, J = 6.3
Hz), 1.38 (d, J = 6.3 Hz), S 5H].
19
F NMR (470 MHz, Chloroform-d) δ [-139.1 (d, J = 21.2 Hz),
-139.8 (d, J = 19.0 Hz), S 1F].
13
C NMR (126 MHz, Chloroform-d) δ 158.8, 158.8, 130.4 (d, J =
88
7.7 Hz), 129.4 (d, J = 2.0 Hz), 129.2 (d, J = 1.3 Hz), 126.1 (d, J = 2.2 Hz), 113.9, 113.7, 89.9 (d,
J = 306.3 Hz), 89.6 (d, J = 303.0 Hz), 55.3, 55.3, 39.5 (d, J = 10.9 Hz), 36.4 (d, J = 9.9 Hz), 28.8
(d, J = 10.7 Hz), 26.5 (d, J = 8.9 Hz), 16.5, 11.7 (d, J = 6.7 Hz). FT-IR data not obtained due to
compound decomposition. HRMS (ESI) m/z: [M - Br]
+
Calcd for C11H12FO
+
179.0867; Found
179.0867 (0.00 ppm).
(2-bromo-2-fluoro-3-methylcyclopropyl)benzene (2o)
Prepared from (Z)-prop-1-en-1-ylbenzene following General Procedure Br. Isolated by
column chromatography (hexanes) as a colorless oil in 44% yield (50 mg, 94% purity). Within 24
hours the material had undergone significant decomposition as evidenced by its appearance
(orange oil) and NMR spectra.
1
H NMR (400 MHz, Chloroform-d) δ 7.38 – 7.15 (m, 5H), [2.79
(d, J = 12.4 Hz), 2.74 (d, J = 12.2 Hz), S 1H], 2.09 – 1.86 (m, 1H), [1.09 (d, J = 6.6 Hz), 1.04 (d,
J = 6.6 Hz), S 3H].
19
F NMR (376 MHz, Chloroform-d) δ [-119.1 (t, J = 20.1 Hz), -155.4 (m), S
1F].
13
C NMR (101 MHz, Chloroform-d) δ 130.6 (d, J = 1.8 Hz), 130.2 (d, J = 1.8 Hz), 93.5 (d, J
= 299.5 Hz), 84.1 (d, J = 305.1 Hz), 34.3 (d, J = 9.0 Hz), 32.1 (d, J = 11.6 Hz), 27.8 (d, J = 10.2
Hz), 25.4 (d, J = 9.7 Hz), 12.8 (d, J = 1.3 Hz), 7.5 (d, J = 6.9 Hz). FT-IR l (cm
-1
) 3058, 3031,
2927, 1600, 1496, 1446, 1400, 1234, 1188, 1145, 1087, 960, 867, 764, 694, 509. HRMS data not
obtained due to compound decomposition.
((1S,2S)-3-bromo-3-fluorocyclopropane-1,2-diyl)dibenzene and ((1R,2R)-3-bromo-3-
fluorocyclopropane-1,2-diyl)dibenzene (2p)
Prepared from trans-stilbene following General Procedure Br. A known quantity of
trifluoromethoxybenzene was added after reaction completion, and
19
F NMR analysis of the neat
reaction mixture showed 61% yield of 2p as a single signal, presumably arising from a racemic
89
mixture of indistinguishable enantiomers (Figure 3.8.6.3). The compound was not isolated due to
instability.
((1R,2S)-3-bromo-3-fluorocyclopropane-1,2-diyl)dibenzene (2q)
Prepared from cis-stilbene following General Procedure Br. A known quantity of
trifluoromethoxybenzene was added after reaction completion, and
19
F NMR analysis of the neat
reaction mixture showed 24% yield of 2q as a single diastereomer (Figure 3.8.6.4). The compound
was not isolated due to instability.
((2-bromo-2-fluorocyclopropyl)methyl)trimethylsilane (2r)
Prepared from allyltrimethylsilane following General Procedure Br. Isolated by column
chromatography (hexanes) as a colorless oil in 94% yield (106 mg).
1
H NMR (400 MHz,
Chloroform-d) δ [1.64 (ddd, J = 18.1, 11.2, 7.3 Hz), 1.52 – 1.30 (m), 1.09 – 0.91 (m), 0.91 – 0.74
(m), 0.68 (ddd, J = 15.0, 7.3, 1.4 Hz), 0.48 (ddd, J = 14.8, 8.8, 2.5 Hz) S5H], [0.08 (s), 0.07 (s),
S9H].
19
F NMR (470 MHz, Chloroform-d) δ -127.2 (td, J = 19.1, 7.2 Hz), -148.3 (dd, J = 17.3,
7.4 Hz).
13
C NMR (126 MHz, Chloroform-d) δ 90.1 (d, J = 300.0 Hz), 83.1 (d, J = 302.2 Hz),
25.7 (d, J = 11.5 Hz), 24.3 (d, J = 10.9 Hz), 23.9 (d, J = 9.6 Hz), 22.4 (d, J = 9.5 Hz), 19.2 (d, J =
1.6 Hz), 14.6 (d, J = 3.2 Hz), -1.4, -1.5. FT-IR l (cm
-1
) 2954, 2897, 1423, 1249, 1188, 1145, 1084,
1026, 972, 945, 906, 841, 733, 698, 498. Anal. Calcd. For C7H14BrFSi: C, 37.34; H, 6.27. Found
C, 37.67; H, 6.28.
(2-bromo-2-fluorocyclopropyl)(phenyl)sulfane (2s)
Prepared from phenyl(vinyl)sulfane following General Procedure Br. Isolated by column
chromatography (hexanes) as a colorless oil in 81% yield (100 mg).
1
H NMR (500 MHz,
Chloroform-d) δ [7.42 – 7.37 (m), 7.34 (td, J = 7.8, 1.9 Hz), 7.25 – 7.20 (m), S5H], [2.95 – 2.76
(m), 2.11 (ddd, J = 16.4, 11.0, 8.1 Hz), 1.89 (dt, J = 10.0, 8.0 Hz), 1.68 (dt, J = 15.2, 7.6 Hz), 1.38
90
(q, J = 8.0 Hz), S3H].
19
F NMR (470 MHz, Chloroform-d) δ -128.1 (td, J = 16.3, 8.0 Hz), -146.4
(dd, J = 15.6, 7.6 Hz).
13
C NMR (126 MHz, Chloroform-d) δ 135.6, 135.0, 129.2, 129.1, 128.0,
127.9, 126.4, 126.3, 86.8 (d, J = 300.9 Hz), 79.8 (d, J = 303.6 Hz), 29.3 (d, J = 12.6 Hz), 27.3 (d,
J = 12.5 Hz), 24.3 (d, J = 10.8 Hz), 23.9 (d, J = 10.9 Hz). FT-IR l (cm
-1
) 3062, 3008, 2919, 2854,
1581, 1477, 1427, 1303, 1218, 1137, 1068, 948, 817, 736. HRMS (ESI) m/z: [M - Br]
+
Calcd for
C9H8FS
+
167.0325; Found 167.0319 (3.59 ppm).
20 mmol scale: The same procedure was followed for a 20 mmol scale reaction. All masses and
volumes were multiplied by 40. The reaction mixture was allowed to stir for 4 hours prior to work
up in place of the standard 2.5 hours. The product was obtained in 81% yield (3.99 g).
1-bromo-1-fluoro-2-isobutoxycyclopropane (2t)
Prepared from isobutyl vinyl ether following General Procedure Br. A known quantity of
trifluoromethoxybenzene was added after reaction completion, and
19
F NMR analysis of the neat
reaction mixture showed 71% yield of 2t as a 1.37 : 1 mixture of syn : anti diastereomers (Figure
3.8.6.5). The compound was not isolated due to volatility.
1-(2-bromo-2-fluorocyclopropyl)pyrrolidine-2-one (2u)
Prepared from N-vinyl-2-pyrrolidinone following General Procedure Br. A known
quantity of trifluoromethoxybenzene was added after reaction completion, and
19
F NMR analysis
of the neat reaction mixture showed 62% yield of 2u as a 3.13 : 1 mixture of syn : anti
diastereomers (Figure 3.8.6.6). The compound was not isolated due to decomposition.
4-(2-chloro-2-fluorocyclopropyl)-1,1'-biphenyl (3e)
Prepared from 4-vinyl-1,1’-biphenyl following General Procedure Cl. Isolated by column
chromatography (hexanes) as a white solid in 70% yield (104 mg). m.p. 71 – 73°C.
1
H NMR (500
MHz, Chloroform-d) δ [7.64 – 7.53 (m), 7.48 – 7.40 (m), 7.38 – 7.27 (m), S9H], [2.92 (ddd, J =
91
16.0, 11.9, 8.5 Hz), 2.76 (t, J = 9.8 Hz), 2.03 (ddd, J = 14.8, 11.3, 7.4 Hz), 1.90 (dt, J = 16.2, 8.0
Hz), 1.81 (dt, J = 10.6, 7.7 Hz), 1.67 (q, J = 7.5 Hz), S3H].
19
F NMR (470 MHz, Chloroform-d)
δ -128.8 (td, J = 16.3, 4.8 Hz), -149.2 (dd, J = 16.0, 6.9 Hz).
13
C NMR (100 MHz, Chloroform-d)
δ 140.7 (d, J = 4.4 Hz), 140.4, 133.6, 132.8 (d, J = 1.4 Hz), 129.0 (d, J = 2.0 Hz), 128.9, 128.8 (d,
J = 1.2 Hz), 127.5, 127.3, 127.2, 94.9 (d, J = 288.1 Hz), 92.1 (d, J = 287.6 Hz), 32.2 (d, J = 11.1
Hz), 30.2 (d, J = 11.8 Hz), 21.8 (d, J = 10.8 Hz), 21.1 (d, J = 11.1 Hz). FT-IR l (cm
-1
) 3059, 3035,
1488, 1433, 1250, 1161, 1139, 988, 939, 856, 833, 762, 726, 690, 577. HRMS (ESI) m/z: [M -
Cl]
+
Calcd for C15H12F
+
211.0918; Found 211.0913 (2.37 ppm).
((2-chloro-2-fluoro-1-methylcyclopropyl)methyl)benzene (3k)
Prepared from (2-methylallyl)benzene following General Procedure Cl. Isolated by
column chromatography (hexanes) as a colorless oil in quantitative yield (101 mg).
1
H NMR (500
MHz, Chloroform-d) δ [7.36 – 7.29 (m), 7.29 – 7.21 (m), S5H], [2.90 (d, J = 15.3 Hz), 2.87 (s),
2.78 (d, J = 14.7 Hz), 1.47 (dd, J = 17.4, 7.2 Hz), 1.33 – 1.25 (m), 1.15 – 1.14 (m), 1.08 (t, J = 7.2
Hz), S7H].
19
F NMR (470 MHz, Chloroform-d) δ -138.9 (bd, J = 16.8 Hz), -140.7 (bd, J = 16.2
Hz).
13
C NMR (126 MHz, Chloroform-d) δ 138.6, 138.4, 129.2, 129.2 (d, J = 1.6 Hz), 128.6,
128.5, 126.7, 126.6, 99.2 (d, J = 288.5 Hz), 98.9 (d, J = 289.9 Hz), 41.7 (d, J = 1.8 Hz), 27.4 (dd,
J = 15.2, 10.5 Hz), 20.2 (d, J = 1.8 Hz), 16.8 (d, J = 9.0 Hz). FT-IR l (cm
-1
) 3030, 2929, 1748,
1604, 1496, 1454, 1384, 1208, 1132, 1095, 1068, 1044, 1025, 978, 921, 845, 759, 724, 698, 566,
521, 485. Anal. Calcd. for C11H12ClF: C, 66.50; H, 6.09. Found: C, 66.25; H, 5.90.
4,4'-(2-chloro-2-fluorocyclopropane-1,1-diyl)bis(chlorobenzene) (3m)
Prepared from 4,4'-(ethene-1,1-diyl)bis(chlorobenzene) 1m following General Procedure
Cl.

Isolated by column chromatography (hexanes) as a colorless solid in 90% yield (141 mg). m.p.
75 – 78°C.
1
H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.27 (m, 8H), 2.21 (dd, J = 16.3, 7.7 Hz,
92
1H), 2.08 (dd, J = 7.7, 7.0 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -132.4 (dd, J = 16.3,
6.9 Hz).
13
C NMR (101 MHz, Chloroform-d) δ 138.3 (d, J = 2.6 Hz), 137.4 (d, J = 2.5 Hz), 133.7,
133.7, 130.6 (d, J = 0.6 Hz), 130.3 (d, J = 1.9 Hz), 129.1, 129.0, 95.0 (d, J = 291.3 Hz), 41.7 (d, J
= 10.8 Hz), 28.2 (d, J = 10.4 Hz). FT-IR l (cm
-1
) 3023, 2927, 2850, 1720, 1612, 1488, 1430,
1315, 1272, 1226, 1122, 1091, 1010, 944, 914, 833, 755, 532. Anal. Calcd. for C15H10Cl3F: C,
57.09; H, 3.19. Found: C, 57.42; H, 3.24.
5 mmol scale: The same procedure was followed for a 5 mmol scale reaction. All masses and
volumes were multiplied by 10. The product was obtained in 84% yield (1.32 g).
1-(2-chloro-2-fluoro-3-methylcyclopropyl)-4-methoxybenzene (3n)
Prepared from (E)-1-methoxy-4-(prop-1-en-1-yl)benzene following General Procedure
Cl. Isolated by column chromatography (hexanes) as a colorless oil in 97% yield (104 mg).
1
H
NMR (500 MHz, Chloroform-d) δ 7.17 – 7.11 (m, 2H), 6.87 – 6.85 (m, 2H), [3.80 (s), 3.80 (s),
Σ3H], [2.36 (dd, J = 18.2, 8.2 Hz), 2.19 – 2.16 (m), Σ1H], [1.94 – 1.83 (m), 1.81 – 1.73 (m), Σ1H],
[1.40 (d, J = 6.0 Hz), 1.37 (d, J = 6.4 Hz), Σ3H].
19
F NMR (470 MHz, Chloroform-d) δ -142.6 (d,
J = 19.8 Hz), -143.2 (d, J = 18.2 Hz).
13
C NMR (126 MHz, Chloroform-d) δ 158.9, 158.9, 129.5
(d, J = 1.9 Hz), 129.3 (d, J = 1.3 Hz), 127.1, 126.2 (d, J = 1.9 Hz), 114.0, 113.9, 97.7 (d, J = 292.2
Hz), 97.6 (d, J = 289.2 Hz), 55.4, 55.4, 38.3 (d, J = 11.2 Hz), 36.2 (d, J = 10.7 Hz), 27.8 (d, J =
11.2 Hz), 26.2 (d, J = 9.7 Hz), 14.5, 11.9 (d, J = 6.4 Hz). FT-IR l (cm
-1
) 2934, 2838, 2358, 1742,
1669, 1612, 1514, 1459, 1290, 1247, 1177, 1155, 1118, 1101, 1038, 1027, 1002, 981, 815, 756,
647, 553, 514, 482. Anal. Calcd. for C11H12ClFO: C, 61.55; H, 5.63. Found: C, 61.43; H, 5.42.
(2-chloro-2-fluorocyclopropyl)(phenyl)sulfane (3s)
Prepared from phenyl(vinyl)sulfane following General Procedure Br. Isolated by column
chromatography (hexanes) as a colorless oil in 50% yield (51 mg).
1
H NMR (400 MHz,
93
Chloroform-d) δ 7.41 – 7.30 (m, 4H), 7.25 – 7.20 (m, 1H), [2.97 (dddt, J = 15.5, 12.2, 7.4, 1.0 Hz),
2.82 (ddd, J = 10.2, 7.1, 0.8 Hz), 2.18 – 1.97 (m), 1.92 – 1.78 (m), 1.73 – 1.61 (m), 1.37 (q, J = 7.4
Hz), Σ3H].
19
F NMR (470 MHz, Chloroform-d) δ -131.1 (td, J = 15.0, 6.0 Hz), -148.2 (dd, J =
14.0, 6.3 Hz).
13
C NMR (101 MHz, Chloroform-d) δ 135.6, 135.2 (d, J = 1.7 Hz), 129.3, 129.3,
128.0, 126.5, 126.5, 95.9 (d, J = 286.9 Hz), 91.7 (d, J = 289.0 Hz), 28.6 (d, J = 13.1 Hz), 27.1 (d,
J = 13.2 Hz), 23.2 (d, J = 11.6 Hz), 23.1 (d, J = 11.4 Hz). FT-IR l (cm
-1
) 3062, 3006, 2921, 2851,
1584, 1480, 1440, 1315, 1227, 1151, 1093, 1067, 1058, 1046, 1040, 1026, 989, 946, 919, 830,
736, 687. HRMS (ESI) m/z: [M - Cl]‾ Calcd for C9H8FS‾ 167.0336; Found 167.0330 (3.59 ppm).
3.8.5 Post functionalization procedures and related information
Homogeneous reduction of 2s to 4s

Scheme 3.8.5.1 Homogeneous reduction of 2s to 4s
Procedure was adapted from previous reports.
32–34
A oven dried glass crimp top vial
equipped with a magnetic stir bar and sealed with a septum cap was charged with (2-bromo-2-
fluorocyclopropyl)(phenyl)sulfane 2s (37 µL, 1 equiv, 0.15 mmol) and freshly distilled THF (0.75
mL, 0.2 M) under an atmosphere of nitrogen. The solution was cooled to -78°C for the dropwise
addition of n-BuLi (150 µL, 2.5 equiv, 0.375 mmol, as 2.5 M solution in hexanes). The resultant
brown solution was warmed to -20°C and stirred for an additional 1 h. The reaction mixture was
then quenched with TFA (0.5 mL, 43.5 equiv, 6.53 mmol). A known quantity of
19
F NMR standard
PhF was added, and the mixture was analyzed by
19
F NMR. 78% yield of 4s was observed as a
mixture of diastereomers. It was not isolated. 4s has not been reported in the literature, but given
94
the characteristic coupling of the
19
F NMR signals (Figure 3.8.6.7) and their similarities to a
report
35
of similar compounds, we are confident in our identification.
Oxidation of sulfide 2s to sulfone 5s

Scheme 3.8.5.2 Oxidation of sulfide 2s to sulfone 5s
Procedure was adapted from a previous report.
28
An oven dried glass 20 mL crimp top vial
equipped with magnetic stir bar was charged with (2-bromo-2-fluorocyclopropyl)(phenyl)sulfane
2s (1.000 g, 1 equiv, 4.046 mmol), ammonium molybdate tetrahydrate (250.1 mg, 0.050 equiv,
202.3 µmol), and EtOH (4.0 mL, 1.0 M). The mixture was stirred in a r.t. water bath for the slow
addition of aqueous hydrogen peroxide (1.950 g, 1.756 mL, 30.0% Wt, 4.250 equiv, 17.20
mmol). The reaction vial was sealed with a crimp cap and allowed to stir at r.t. for 18 h. The
temperature was then increased to 50°C (oil bath) for an additional 30 h of stirring, at which point
reaction completion was confirmed by
19
F NMR based on full consumption of starting
material. The reaction mixture was then quenched with aqueous sodium sulfite (~10 mL), and
then it was vacuum filtered, washing with water (3 x 8 mL). The residual solid material was
redissolved in CHCl3 and concentrated in vacuo to give ((2-bromo-2-
fluorocyclopropyl)sulfonyl)benzene 5s (947 mg, 3.39 mmol, 84%) as a light tan solid. m.p. 61 –
65°C.
1
H NMR (500 MHz, Chloroform-d) δ 8.02 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H),
7.75 – 7.69 (m, 1H), 7.61 (td, J = 7.7, 1.9 Hz, 2H), [3.18 – 3.06 (m), 2.68 (dt, J = 16.7, 8.1 Hz),
2.27 – 2.18 (m), 2.01 (dt, J = 10.5, 8.1 Hz), S3H].
19
F NMR (470 MHz, Chloroform-d) δ -125.2
(td, J = 14.9, 10.7 Hz), -148.3 (dd, J = 17.2, 7.4 Hz).
13
C NMR (126 MHz, Chloroform-d) δ 140.1,
139.5, 134.4, 134.4, 129.7, 129.6, 128.4, 127.9 (d, J = 1.7 Hz), 75.8 (d, J = 298.0 Hz), 74.8 (d, J =
95
308.5 Hz), 46.3 (d, J = 11.9 Hz), 43.5 (d, J = 12.5 Hz), 22.8 (d, J = 10.9 Hz), 22.5 (d, J = 11.7 Hz).
FT-IR l (cm
-1
) 3105, 3035, 2920, 2854, 1142, 1412, 1308, 1227, 1149, 1084. Anal. Calcd. for
C9H8BrFO2S: C, 38.73; H, 2.89; S, 11.49. Found: C, 38.77; H, 3.20; S, 11.80.
3.8.6 Additional NMR data
Our proposed mechanism predicts the generation of diethyl carbonate (Scheme 3.3.1).
1
H
NMR evidence of diethyl carbonate presence supports our mechanism (Figure 3.8.6.1).

Figure 3.8.6.1
1
H NMR of an impure sample of 2r containing diethyl carbonate
We noticed that 2,3-disubstituted products decomposed over time. Given below (Figure 3.8.6.2)
is an excerpt from the NMR spectrum of 2n. The
19
F NMR signals obtained are consistent with
those of vinyl fluorides, as predicted by the proposed decomposition mechanism (Scheme 3.4.2).
96

Figure 3.8.6.2
19
F NMR of partially decomposed sample of 2n
The following figures (Figure 3.8.6.3, Figure 3.8.6.4, Figure 3.8.6.5, Figure 3.8.6.6, and Figure
3.8.6.7) are excerpts of the reaction mix
19
F NMR spectra for products 2p, 2q, 2t, 2u, and 4s,
respectively. It should be noted that the first four spectra exhibit significant signal broadening due
in large part to the fact that the reaction mixes were rather viscous suspensions. As a result, the
fine coupling was not fully resolved, so broad singlets and multiplets were observed. The reaction
mixture
19
F NMR of compound 4s in Figure 3.8.6.7 did exhibit resolved fine coupling, with the
expected dddd multiplicity patterns.
97

Figure 3.8.6.3
19
F NMR of 2p reaction mixture, referenced to PhOCF3 at -58.3 ppm

Figure 3.8.6.4
19
F NMR of 2q reaction mixture, referenced to PhOCF3 at -58.3 ppm
98

Figure 3.8.6.5
19
F NMR of 2t reaction mixture, referenced to PhOCF3 at -58.3 ppm

Figure 3.8.6.6
19
F NMR of 2u reaction mixture, referenced to PhOCF3 at -58.3 ppm
99

Figure 3.8.6.7
19
F NMR of 4s reaction mixture, referenced to PhF at -113.4 ppm; isomers
tentatively assigned

100
3.9 References
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–H Compounds with TMSCF3: Route to P
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–CF2– Transfer
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104
Chapter 4: Accessing azidofifluoromethide (N3CF2¯ ) from azide and difluorocarbene:
A marriage that just clicks
4.1 Introduction
Azides have a complicated reputation in chemistry. Typically, the mention of the word
azide will evoke one of three immediate associations within the listener’s mind. First: explosive.
This long-standing connection is not entirely without merit, but it is arguable that this “azido-
anxiety” is quite overblown (for lack of a better term). Second: strong nucleophile, weak base.
This listener has likely taken an undergraduate organic chemistry course recently, in which they
were taught about the azide anion as a prototypical SN2 nucleophile. Third: click chemistry. Given
its prevalence in synthesis and biochemistry, and its recent recognition in the awarding of the 2022
Nobel Prize in chemistry,
1
click chemistry may now be the most common association with azide.
Going from dangerous to useful in popular perception is quite an upgrade.
From the first synthesis of phenyl azide in 1864, to the most modern applications today,
organic azides have been made and utilized in many creative ways.
2–7
Fluorinated analogues have
also been synthesized. Of particular interest are those containing an azidodifluoromethyl group
(-CF2N3) because of their demonstrated utility in making fluoroalkyltriazoles among other
valuable products.
8
The synthesis of these compounds generally follows one of four main
approaches (Scheme 4.1.1). The first approach involves a formal nucleophilic substitution reaction
of azide with a halodifluoromethyl group, -CF2X (Scheme 4.1.1-a). With bromides (X = Br) and
chlorides (X = Cl), the reaction follows the traditional SN2-type path.
9–20
Trifluoromethyl groups
(X = F) can also undergo this, but the necessary C-F activation step requires more sophisticated
conditions or specialized substrates.
21,22
The second approach requires difluoroolefin substrates,
to which azide performs nucleophilic addition. The remediation method of the consequent charge
105
differs among the reports, but many either follow an SN2’ pathway, with loss of a leaving group to
give vinyl azidodifluoromethane derivatives, or they perform nucleophilic additions to
electrophiles via the carbon adjacent to the azidodifluoromethyl group (Scheme 4.1.1-b).
23–40
The
third approach starts with generation of a nucleophilic R-CF2¯ upon deprotonation or
desilylation,
41
or in the form of a Grignard reagent,
42
which then adds to an electrophilic azide
source (Scheme 4.1.1-c). Xihi Bi and coworkers have reported on another approach involving
generation of vinyl azides from alkynes and subsequent electrophilic fluorination reaction with in
situ-generated PhIF2 in the presence of HF. In most cases, the reaction produces b,b-difluorinated
azides rather than the a-derivatives discussed here; however, the reaction proceeds via an
intermediate which, dependent upon the migratory aptitude of the R group, can favor the path
toward azidodifluoromethyl compounds (Scheme 4.1.1-d).
43,44

Scheme 4.1.1 Known approaches for the synthesis of azidodifluoromethyl compounds

106
This method’s selectivity issues and the hazardous reagents required serve as limitations for its
broad application in the synthesis of these compounds.
All but the last of these approaches rely on the introduction of the azido group to a
prefunctionalized difluoromethylene (or difluoromethylidene) moiety. This reliance can be quite
restrictive in that it limits the potential generality and diversity of the products. Thus, we set our
sights on the direct installation of the azidodifluoromethyl group. We envisioned a multi
component reaction similar to those developed independently by Dilman
45–47
and Hu,
48
in which
we could generate a nucleophilic azidodifluoromethide (¯CF2N3) in situ from difluorocarbene and
N3¯ for addition to electrophiles (Scheme 4.1.2).

Scheme 4.1.2 Prior in situ XCF2¯ work and our approach

107
4.2 Optimization
With our plan set, we chose 4-fluorobenzaldehyde as our model substrate and performed
an extensive set of optimization trials. Table 4.2.1 serves as a summary of our key observations.

entry
b
deviations from standard conditions yield 2a (%)
b

1 none 68
2 LiCl (1 equiv) added 48
3 KOTf (1 equiv) added 70
4 halved conc. (0.1 M) 38
5 TMSCF2Br added at r.t. 29
6 TMSCF2Br added 10 s/drop at r.t. 31
7 TMSCF2Br added 10 s/drop 64
8 2 equiv. NaN3 used 58
9 4 equiv. NaN3 used 68
10 30 min reaction time, doubled conc. (0.4 M) 77
a
All reactions were carried out under inert gas (Ar or N2) with anhydrous solvent.
b
Yields were
determined by
19
F NMR of the reaction mixture using an internal standard (PhOCF3).
Table 4.2.1 Summary of findings from optimization trials
We found that 2a could be obtained in 68% yield by
19
F NMR using 3 equivalents of NaN3 in
DMF at 0.2 molar concentration (w.r.t. 1a), followed by slow addition of TMSCF2Br at 0˚C and
then stirring for 2 hours at room temperature. In contrast to what we observed with our previous
work using TMSCF3 to generate difluorocarbene,
49,50
lithium salt additives like LiCl were actually
detrimental to reaction efficiency (entry 1). Potassium salt additives had little to no effect (entry
2). Concentration sensitivity was observed. Decreasing the concentration to 0.1 molar led to a
considerable drop in yield (entry 4). We found it was essential to add the TMSCF2Br slowly and
at lower temperature. Addition at room temperature dramatically decreased the yield (entry 5),
108
even with a slower addition rate (entry 6). This slower addition rate when applied to the standard
0˚C addition gave slightly diminished yields from standard conditions (entry 7). No benefit was
seen from altering the loading of sodium azide (entries 8, 9). Entry 10 shows that the reaction is
complete after 30 minutes and can be performed at higher concentration, though there is one
important consideration with the higher concentration conditions. We found that the reaction
mixture for with 0.4 M conditions were very thick suspensions and were quite sensitive to the need
for effective stirring, without which the results were inconsistent. With strong, steady stirring,
these conditions produced the best and most consistent results, with near perfect selectivity for the
O-silyl ether product 2a.
4.3 Scope of aldehyde azidodifluoromethylation
Having determined the optimized reaction conditions, we were eager to explore the
behavior of other substrates (Scheme 4.3.1). The products from 4-fluoro-, 3-fluoro-, and 2-
fluorobenzaldehyde (2a, 2b, and 2c, respectively) all gave very similar good yields by
19
F NMR,
though the isolated yields had a bit of a split. A series of para-substituted benzaldehyde derivatives
were then tested. Electron rich aryls were not advantageous for this reaction, as evidenced by the
low yields of 2d and 2e. Electron deficient substrates, however, worked quite well with both
resonance withdrawing examples (2f, 2g, and 2h-H) and inductively withdrawing examples (2i
and 2j) giving moderate to high yields of corresponding products 2. It is worth noting that 4-
(methylsulfonyl)benzaldehyde (1h) was isolated solely as the alcohol product 2h‑H. Similarly, 2-
nitroaryl 2k-H was isolated as the alcohol. In both cases, the
19
F NMR yields were quite good,
but the final yield of the isolated alcohols were significantly lower due to losses in the workup and
purification steps. It is unclear why, but these examples seem more prone to desilylation than
other examples. Perhaps in the concentrated form, the Lewis basic oxygens of the sulfonyl and
109
nitro groups can somehow assist in the desilylation process. Steric hindrance at the ortho position
is reasonably well tolerated, as exemplified by comparisons of the sets of ortho/para isomers
(2f/2k-H, 2i/2n, 2j/2o). By
19
F NMR, 2f and 2k were generated in almost identical yields, though
as discussed previously, the latter was obtained in low yield as 2k-H.

Scheme 4.3.1 Substrate scope of azidodifluoromethylation
110
The large trifluoromethyl group in 2j and 2o did effect a moderate drop in yield at the ortho
position (2o), despite the stronger inductive withdrawal. The similar
19
F NMR yields of 2i and 2n
in spite of the large iodide substituent also serve as evidence that the reaction is only modestly
affected by sterics. An ortho phenylethynyl group was also tolerated, giving 66% yield of 2l, in
spite of the well documented reactivity of alkynes with our intermediate difluorocarbene.
51

Notably, in spite of their close proximity, no reactivity was observed between the azido and alkynyl
moieties at ambient conditions. The very electron deficient 3,5-bis(trifluoromethyl)benzaldehyde
(1p) was successfully converted to azidodifluoromethylated 2p, though in lower yield than
anticipated (51%). 2-bromo 2m was successfully prepared in 66% yield at 5 mmol scale.
Satisfyingly, trans-2-nitrocinnamaldehyde was converted to 2q in good yield (83% by
19
F NMR),
showing substrate compatibility beyond benzaldehyde derivatives. Heteroaryl aldehydes
generally gave lower yields; only 47% of thiophene-containing 2r was detected by
19
F NMR.
Acidic substrates were particularly problematic. Our intermediate azidodifluoromethyl anion,
¯CF2N3 is not only a strong nucleophile, it is also a strong base. Phenylacetaldehyde (1s) with its
acidic a-protons and 2-ethynylbenzaldehyde (1t) with its acidic C(sp)-H proton were both largely
incompatible with this method. In both cases, significant increases were observed in the quantities
of H-CF2N3 present after the reaction, clearly demonstrating that the nucleophile which we
painstakingly generated is simply being quenched by the acidic protons of these substrates.
However, also in both cases, some of the desired product was indeed formed. Attempts to isolate
2s were unsuccessful, as the product decomposed during the work up to a complex mixture of
unidentified fluorinated products.

111
4.4 Proposed mechanism
Based on our observations, we propose the mechanism shown in Scheme 4.4.1. The
reaction is likely initiated by a nucleophilic attack of azide on TMSCF2Br.

Scheme 4.4.1 Proposed mechanism of N3CF2¯ generation and addition to aldehydes
TMSN3 is then generated, along with bromodifluoromethide, ¯CF2Br. Elimination of bromide
from the latter gives difluorocarbene, which is quickly taken up by the excess azide to form our
azidodifluoromethide intermediate, N3CF2¯. This nucleophile adds to the aldehyde to give the
intermediate secondary alkoxide. The alkoxide oxygen is then silylated by addition to one of two
species, TMSCF2Br or TMSN3, to give the final azidodifluoromethyl O-silyl ether 2.
4.5 Cycloadditions – demonstrating utility
As discussed in Section 4.1, one of the main synthetic applications of organic azides is in
click chemistry, azide-alkyne [3+2] cycloadditions. To demonstrate the utility of our products we
performed both intermolecular and intramolecular click reactions to make valuable a,a-
difluorinated triazoles (Scheme 4.5.1). We treated 2m with ethyl propiolate under standard copper
catalyzed azide-alkyne coupling conditions,
52,53
and 3m was generated as a 3:1 mixture of isomers.
112
The major isomer was isolated. This shows the potential of our methodology in generating
fluorinated “clickable” tags for biochemical labeling studies. We also targeted 2l as an example
with both azido and alkynyl groups to determine if it could undergo an intramolecular click
reaction. Gratifyingly, upon simple thermal conditions, 3l was furnished. This novel, complex
scaffold was synthesized in three easy steps (including aldehyde synthesis) from simple, accessible
materials. It is worth noting that in both cases, the conditions tolerated the silyl ether moiety.

Scheme 4.5.1 [3+2] Click reactions with synthesized products 2
4.6 Conclusions
We have successfully developed a method for the direct installation of azidodifluoromethyl
groups into aldehydes via in situ-generation of N3CF2¯ from TMSCF2Br and sodium azide. These
valuable scaffolds can be accessed using safe and inexpensive reagents and without the need for
specialized, prefunctionalized starting materials. The method is expedient, operationally simple,
scalable, and the products are simple to purify. We were able to access complex triazole structures
via simple click reactions with alkynes, demonstrating the potential synthetic and biochemical
113
utility of our products. This approach also has potential for extension to other electrophilic
systems, though attempts so far have been unsuccessful.
4.7 Experimental
4.7.1 General experimental information
Unless otherwise specified, all materials were purchased from commercial sources and
used without further purification. Sodium azide purchased from Millipore Sigma as an “ultra dry”
variant (product number: 769320). Distilled DMF or anhydrous DriSolv® DMF (Millipore Sigma)
was used unless otherwise specified. Where applicable, flash column chromatography on silica gel
was performed with either a manual column or a Biotage autocolumn with UV detector (254 nm
and 280 nm detection) for product isolation with a hexanes/EtOAc eluent system.
1
H,
13
C, and
19
F
spectra were recorded on 400 MHz, 500 MHz, or 600 MHz Varian NMR spectrometers.
1
H NMR
chemical shifts were determined relative to CHCl3 as the internal standard at 7.26 ppm.
13
C NMR
shifts were determined relative to CDCl3 at 77.16 ppm.
19
F NMR chemical shifts were determined
relative to CFCl3 at 0.00 ppm. Multiplicity abbreviations (e.g. s, d, t) preceded by “b” denotes
those signals as being broad, and as such their finer coupling may be masked. NMR yields were
determined via
19
F spectral analysis of neat reaction mixture aliquots after adding a known quantity
of a fluorinated internal standard: PhF, PhCF3, or PhOCF3. Mass spectral data were recorded on a
high-resolution mass spectrometer (QTOF) in either EI or ESI mode. Elemental analyses were
performed on a Flash 2000 CHNS elemental analyzer. IR data were recorded on a JASCO FT/IR
spectrometer. Melting points are uncorrected.
Notes:
1. Solid starting materials were added to the reaction vial along with sodium azide in an
argon glovebox. Liquid starting materials were added by syringe after
114
2. With some substrates, during the addition of TMSCF2Br at 0˚C the suspension would
freeze and inhibit stirring; however, despite the reaction’s sensitivity to efficient
stirring, this was not an issue. After removing the ice bath, the suspension would thaw
and begin stirring again.
3. Combining acids or transition metal salts with inorganic azides can generate potentially
explosive species. Care must be taken to avoid such contact, and any azide-containing
waste must be handled accordingly. This includes segregation from general waste into
a designated azide waste container that is labeled to reflect its contents.
4. During purification by column chromatography, the crude samples should be wet
loaded onto silica, as dry loading can lead to desilylative decomposition.
4.7.2 Synthesis of products 2
General procedure
A 5 mL vial equipped with magnetic stir bar was charged with sodium azide (49 mg, 3
equiv, 0.75 mmol) in an argon glovebox. The vial was then sealed with a crimp-top septum cap
and removed from the glovebox. At 0˚C in an ice bath DMF (0.625 mL) was added, followed by
the starting aldehyde (0.25 mmol). TMSCF2Br (78 μL, 2 equiv, 0.5 mmol) was then added slowly
dropwise (1 drop every 5 seconds). After full addition, the ice bath was removed, and the reaction
mixture was stirred at room temperature for 30 minutes. The vial was then opened, and hexanes
(4 mL) was added to the vial. After agitation, two layers formed. The top (hexanes) layer was
decanted, and the DMF layer was extracted twice more with hexanes (2 x 4 mL). The hexanes
layers were washed individually with 12 M phosphoric acid (15 mL) to remove any DMF. The
combined hexanes layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The
115
crude material was usually quite clean at this point, but for further purification the material was
subjected to column chromatography on silica gel, generally eluting in hexanes or pentane.
(2-azido-2,2-difluoro-1-(4-fluorophenyl)ethoxy)trimethylsilane 2a
Prepared from 4-fluorobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as a yellow liquid in 74% yield (54 mg).
1
H NMR (400
MHz, Chloroform-d) δ 7.45 – 7.37 (m, 2H), 7.06 (t, J = 8.7 Hz, 2H), 4.87 (t, J = 6.7 Hz, 1H), 0.11
(s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -84.96 (dd, J = 183.1, 6.2 Hz), -88.09 (dd, J =
183.0, 7.2 Hz), -113.33 – -113.45 (m). Anal. Calcd. for [C11H14F3N3OSi]: C, 45.66; H, 4.88; N,
14.52. Found: C, 45.32; H, 5.11; N, 14.32.
(2-azido-2,2-difluoro-1-(3-fluorophenyl)ethoxy)trimethylsilane 2b
Prepared from 3-fluorobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as a colorless liquid in 67% yield (48 mg).
1
H NMR (400
MHz, Chloroform-d) δ 7.33 (td, J = 8.1, 5.8 Hz, 1H), 7.22 – 7.15 (m, 2H), 7.06 (td, J = 8.3, 2.4
Hz, 1H), 4.88 (t, J = 6.6 Hz, 1H), 0.13 (s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -84.55 (dd,
J = 183.2, 6.0 Hz), -87.78 (dd, J = 183.3, 6.9 Hz), -113.20 – -113.47 (m).
13
C NMR (100 MHz,
Chloroform-d) δ 162.78 (d, J = 246.2 Hz), 138.68 (dd, J = 7.2, 2.7 Hz), 129.82 (d, J = 8.0 Hz),
123.58 – 123.36 (m), 120.80 (dd, J = 269.2, 265.6 Hz), 116.09 (d, J = 21.1 Hz), 114.84 (dt, J =
23.0, 1.2 Hz), 75.51 (td, J = 32.5, 2.0 Hz), -0.17. FT-IR l (cm
-1
) 2957, 2924, 2857, 2148, 1743,
1616, 1544, 1450, 1447, 1353, 1253, 1186, 1146, 1110, 1053, 1028, 938, 874, 843. Anal. Calcd.
for [C11H14F3N3OSi]: C, 45.55; H, 4.88, N, 14.52. Found: C, 45.88; H, 5.73, N, 14.34.
(2-azido-2,2-difluoro-1-(2-fluorophenyl)ethoxy)trimethylsilane 2c
Prepared from 2-fluorobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as a colorless liquid in 82% yield (59 mg).
1
H NMR (400
116
MHz, Chloroform-d) δ 7.63 (t, J = 7.5 Hz, 1H), 7.38 – 7.31 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.05
(ddd, J = 9.8, 8.3, 1.2 Hz, 1H), 5.32 (t, J = 6.6 Hz, 1H), 0.11 (s, 9H).
19
F NMR (376 MHz,
Chloroform-d) δ -85.40 (dt, J = 182.5, 5.8 Hz), -88.96 (dt, J = 182.5, 8.0 Hz), -118.82 (ddt, J =
15.4, 10.2, 5.5 Hz).
13
C NMR (101 MHz, Chloroform-d) δ 160.21 (d, J = 247.8 Hz), 130.74 (d, J
= 8.4 Hz), 129.55 (dt, J = 3.1, 1.1 Hz), 124.32 (d, J = 3.6 Hz), 123.62 (dd, J = 13.0, 2.3 Hz), 120.96
(ddd, J = 269.5, 267.5, 2.1 Hz), 115.26 (d, J = 22.1 Hz), 68.84 (td, J = 33.8, 3.5 Hz), -0.28. FT-
IR l (cm
-1
) 2960, 2932, 2832, 2857, 2358, 2149, 1779, 1617, 1591, 1490, 1458, 1301 1254, 1232,
1182, 1652, 1122, 1080, 1053, 877, 843. Anal. Calcd. for [C11H14F3N3OSi]: C, 45.66; H, 4.88;
N, 14.52. Found: C, 45.39; H, 4.55; N, 14.15.
(2-azido-2,2-difluoro-1-(4-methoxyphenyl)ethoxy)trimethylsilane 2d
Prepared from 4-methoxybenzaldehyde following the general procedure. Isolated by
column chromatography (eluting in hexanes) as a colorless liquid in 31% yield (23 mg).
1
H NMR
(400 MHz, Chloroform-d) δ 7.35 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.84 (t, J = 6.8 Hz,
1H), 3.82 (s, 3H), 0.11 (s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -85.01 (dd, J = 182.8, 6.4
Hz), -88.14 (dd, J = 182.8, 7.2 Hz).
13
C NMR (101 MHz, Chloroform-d) δ.
13
C NMR (101 MHz,
Chloroform-d) 13C NMR (100 MHz, cdcl3) δ 160.24, 129.08 (t, J = 1.2 Hz), 128.2 (d, J = 2.7 Hz),
113.76, 76.36 – 74.88 (m), 55.41, 1.21, -0.05. FT-IR l (cm
-1
) 2998, 2960, 2927, 2854, 2854, 2854,
2831, 2149, 1613, 1587, 1513, 1464, 1305, 1249, 1173, 1152, 1100, 1097, 1029, 876, 841, 751.
Anal. Calcd. for [C12H17F2N3O2Si]: C, 47.83; H, 5.60; N, 13.94. Found: C, 47.45; H, 5.25; N,
14.20.
(2-azido-2,2-difluoro-1-(p-tolyl)ethoxy)trimethylsilane 2e
Prepared from 4-methylbenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as a yellow oil in 20% yield (14 mg).
1
H NMR (400 MHz,
117
Chloroform-d) δ 7.31 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 4.86 (t, J = 6.8 Hz, 0H), 2.36
(s, 2H).
19
F NMR (470 MHz, Chloroform-d) δ -84.75 (dd, J = 182.9, 6.3 Hz), -87.95 (dd, J =
182.8, 7.2 Hz). FT-IR l (cm
-1
) 2954, 2924, 2854, 2145, 1457, 1264, 1053, 878, 737. Anal. Calcd.
for [C12H17F2N3OSi]: C, 50.51 H, 6.00, N, 14.73. Found: C, 50.9 H, 5.73, N, 14.34.
(2-azido-2,2-difluoro-1-(4-nitrophenyl)ethoxy)trimethylsilane 2f
Prepared from 4-nitrobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in pentane) as an orange oil in 81% yield (64 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 8.24 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 4.97 (t, J = 6.5 Hz, 1H), 0.15
(s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -84.35 (dd, J = 183.1, 6.1 Hz), -87.08 (dd, J =
182.8, 6.9 Hz).
13
C NMR (101 MHz, Chloroform-d) δ148.52, 143.20 (d, J = 2.6 Hz), 128.80 (t, J
= 1.3 Hz), 123.55, 120.65 (dd, J = 270.8, 267.7 Hz), 75.23 (t, J = 32.5 Hz), -0.14. FT-IR l (cm
-1
)
2923, 2857, 2185, 2151, 1609, 1523, 1346, 1254, 1201, 1053, 1015, 873, 843. Anal. Calcd. for
[C11H14F2N4O3Si]: C, 41.77; H; 4.46, N, 17.71. Found: C, 41.98; H, 4.142; N, 14.57.
4-(2-azido-2,2-difluoro-1-((trimethylsilyl)oxy)ethyl)benzonitrile 2g
Prepared from 4-cyanobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as a pale yellow oil in 70% yield (52 mg).
1
H NMR (400
MHz, Chloroform-d) δ 7.68 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 4.92 (t, J = 6.5 Hz, 1H),
0.13 (s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -84.39 (dd, J = 183.1, 6.1 Hz), -87.24 (dd, J
= 183.1, 6.8 Hz). FT-IR l (cm
-1
) 2961, 2893, 2230, 2149, 1739, 1612, 1503, 1414, 1253, 1203,
1853, 1253, 1853, 1052, 868, 843. Anal. Calcd. for [C12H14F2N4OSi]: C, 48.64; H, 4.76; N, 18.91.
Found: C, 49.01; H, 4.42; N, 18.59.

118
2-azido-2,2-difluoro-1-(4-(methylsulfonyl)phenyl)ethan-1-ol 2h-H
Prepared from 4-(methylsulfonyl)benzaldehyde following the general procedure. Isolated
by column chromatography (eluting in hexanes) as a colorless liquid in 43% yield (30 mg).
1
H
NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 5.04 (t, J =
7.4 Hz, 1H), 3.34 (bs, 1H), 3.05 (s, 3H).
19
F NMR (376 MHz, Chloroform-d) δ -84.18 (d, J = 6.9
Hz), -84.67 (d, J = 6.8 Hz), -85.73 (d, J = 8.1 Hz), -86.22 (d, J = 7.7 Hz). FT-IR l (cm
-1
) (OTMS
product) 2957, 2923, 2153, 2037, 1408, 1314, 1255, 1200, 1152, 1088, 916, 877, 845. Anal.
Calcd. for [C12H17F2N3O3SSi]: C, 41.25; H, 4.90; N, 12.03; S, 9.17. Found: C, 41.42 ; H, 5.18;
N, 12.13; S, 9.19.
(2-azido-2,2-difluoro-1-(4-iodophenyl)ethoxy)trimethylsilane 2i
Prepared from 4-iodobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as a pale yellow liquid in 50% yield (50 mg).
1
H NMR (400
MHz, Chloroform-d) δ 7.71 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.82 (t, J = 6.6 Hz, 1H),
0.12 (s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -84.72 (dd, J = 183.0, 6.2 Hz), -87.81 (dd, J
= 183.0, 7.0 Hz). FT-IR l (cm
-1
) 3060, 2957, 2935, 2146, 1569, 1467, 1253, 1199, 1127, 1051,
1012, 873, 843, 751. Anal. Calcd. for [C11H14F2IN3OSi]: C, 33.26; H, 3.55; N, 10.58. Found: C,
33.65; H, 3.25; N, 10.28.
(2-azido-2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethoxy)trimethylsilane 2j
Prepared from 4-(trifluoromethyl)benzaldehyde following the general procedure. Isolated
by column chromatography (eluting in hexanes) as a colorless oil in 91% yield (77 mg).
1
H NMR
(400 MHz, Chloroform-d) δ 7.64 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 4.94 (t, J = 6.6 Hz,
1H), 0.13 (s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -63.20, -84.48 (dd, J = 183.2, 6.1 Hz), -
87.54 (dd, J = 183.2, 6.9 Hz).
13
C NMR (101 MHz, Chloroform-d) δ.139.92, 131.1 (d, J = 32.4),
119
128.02, 125.14 (q, J = 3.8 Hz), 122.9 (d, J = 73.6 Hz), 119.3 (d, J = 270.5 Hz), 75.36 (t, J = 32.4
Hz), -0.3 δ. FT-IR l (cm
-1
) 2957, 2929, 2150, 1622, 1419, 1323, 1254, 1122, 1066, 1019, 869,
843. Anal. Calcd. for [C12H14F5N3OSi]: C, 42.27; H, 4.16; N, 12.38. Found: C, 42.57; H, 4.06;
N, 12.07.
2-azido-2,2-difluoro-1-(2-nitrophenyl)ethan-1-ol 2k-H
Prepared from 2-nitrobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as an orange oil in 23% yield (14 mg). FT-IR l (cm
-1
)
3419,2923, 2854, 2151, 1607, 1512, 1455, 1228, 1159, 1183, 1055, 1015, 845, 811, 777. Anal.
Calcd. for [C13H16F2N4O3Si]: C, 45.61; H, 4.71; N: 16.36. Found: C, 45.93; H, 4.51; N, 17.02.
(2-azido-2,2-difluoro-1-(2-(phenylethynyl)phenyl)ethoxy)trimethylsilane 2l
Prepared from 2-(phenylethynyl)benzaldehyde following the general procedure. Isolated
by column chromatography (eluting in pentane) as a colorless liquid in 66% yield (61 mg).
1
H
NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 7.7 Hz, 1H), 7.56 – 7.51 (m, 3H), 7.43 – 7.32 (m,
5H), 5.66 (t, J = 7.1 Hz, 1H), 0.12 (s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -84.79 (dd, J =
182.1, 6.9 Hz), -88.22 (dd, J = 182.0, 7.4 Hz).
13
C NMR (101 MHz, Chloroform-d) δ 137.78 (d, J
= 1.9 Hz), 131.95, 131.65, 128.89, 128.77, 128.63, 128.37, 123.08, 123.05, 121.26 (dd, J = 269.5,
268.3 Hz), 94.35, 86.66, 73.41 (t, J = 32.6 Hz), -0.15. FT-IR l (cm
-1
) 3064, 2959, 2926, 2146,
1601, 1494, 1442, 1253, 1191, 1152, 1051, 877, 843, 753. Anal. Calcd. for [C19H19F2N3OSi]: C,
61.44; H, 5.16; N, 11.31. Found: C, 61.824; H, 5.25; N, 11.23.
(2-azido-1-(2-bromophenyl)-2,2-difluoroethoxy)trimethylsilane 2m
Prepared from 2-bromobenzaldehyde via modified procedure at 5 mmol scale. A 20 mL
vial equipped with magnetic stir bar was charged with sodium azide (975 mg, 3 equiv, 15 mmol)
in an argon glovebox. The vial was then sealed with a crimp-top septum cap and removed from
120
the glovebox. At 0˚C in an ice bath DMF (12.5 mL) was added, followed by 2-bromobenzaldehyde
(584 µL, 925 mg, 5 mmol). TMSCF2Br (1.56 mL, 2 equiv, 10 mmol) was then added by syringe
pump (26 µL/min). After full addition, the ice bath was removed, and the reaction mixture was
stirred at room temperature for 1 hour. The vial was then uncapped and transferred to a separatory
funnel with hexanes (60 mL). The layers were mixed and allowed to settle, and the hexanes layer
was collected. The DMF layer was extracted again with hexanes (2 x 60 mL). [Note: the emptied
separatory funnel had a yellow gooey residue. This was washed out completely with DI water
prior to the next step to avoid acid contact with any residual azide.] The combined hexanes layers
were washed with 12 M phosphoric acid (3 x 50 mL) and water (60 mL), dried over sodium sulfate,
and filtered. This solution was concentrated to give a yellow liquid, which by NMR was mostly
clean apart from some DMF. After further purification by column chromatography on silica gel
(eluting in pentane), the product was obtained as a colorless liquid in 66% yield (1.15 g).
1
H NMR
(400 MHz, Chloroform-d) δ 7.67 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz,
1H), 7.22 (t, J = 7.7 Hz, 1H), 5.48 (t, J = 6.8 Hz, 1H), 0.10 (s, 9H).
19
F NMR (376 MHz,
Chloroform-d) δ -84.75 (dd, J = 182.5, 6.3 Hz), -88.27 (dd, J = 182.6, 7.4 Hz).
13
C NMR (101
MHz, Chloroform-d) δ 135.78 (d, J = 1.9 Hz), 132.70, 130.58, 130.45 (t, J = 1.3 Hz), 127.62,
123.81, 121.14 (t, J = 269.9 Hz), 74.33 (dd, J = 33.2, 32.0 Hz), -0.18. FT-IR l (cm
-1
) 3068, 2956,
2924, 2147, 1570, 1470, 1441, 1253, 1192, 1101, 1051, 1025, 878, 843. Anal. Calcd. for
[C11H14BrF2N3OSi]: C, 37.72; H, 4.03; N, 12.00. Found: C, 37.33; H, 3.64; N, 12.35.
(2-azido-2,2-difluoro-1-(2-iodophenyl)ethoxy)trimethylsilane 2n
Prepared from 2-iodobenzaldehyde following the general procedure. Isolated by column
chromatography (eluting in hexanes) as a pale yellow liquid in 59% yield (58 mg).
1
H NMR (400
MHz, Chloroform-d) δ 7.83 (dd, J = 7.9, 1.3 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.42 – 7.36 (m,
121
1H), 7.09 – 7.01 (m, 1H), 5.32 (t, J = 6.9 Hz, 1H), 0.11 (s, 9H).
19
F NMR (376 MHz, Chloroform-
d) δ -84.37 (dd, J = 182.4, 6.6 Hz), -87.78 (dd, J = 182.4, 7.3 Hz). FT-IR l (cm
-1
) 3060, 2957,
2935, 2146, 1569, 1467, 1253, 1199, 1127, 1051, 1012, 873, 843, 751. Anal. Calcd. for
[C11H14F2IN3OSi]: C, 33.26; H, 3.55; N, 10.58. Found: C, 32.91; H, 3.15; N, 10.46.
(2-azido-2,2-difluoro-1-(2-(trifluoromethyl)phenyl)ethoxy)trimethylsilane 2o
Prepared from 2-(trifluoromethyl)benzaldehyde following the general procedure. Isolated
by column chromatography (eluting in hexanes) as a pale yellow liquid in 63% yield (53 mg).
1
H
NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.0 Hz, 0H), 7.66 (d, J = 7.9 Hz, 0H), 7.62 (t, J =
7.7 Hz, 0H), 7.48 (t, J = 7.7 Hz, 0H), 5.39 (t, J = 6.2 Hz, 0H), 0.08 (s, 1H).
19
F NMR (376 MHz,
Chloroform-d) δ -57.60 (t, J = 6.8 Hz), -83.08 (dt, J = 184.0, 6.0 Hz), -88.84 (dt, J = 183.7, 7.3
Hz). FT-IR l (cm
-1
) 2957, 2925, 2854, 2287, 2192, 2185, 2046, 1971, 1311, 1278, 1133, 875,
748, 714. Anal. Calcd. for [C12H14F5N3OSi]: C, 42.27; H, 4.16; N, 12.38. Found: C, 42.83; H,
4.16; N,12.08.
(2-azido-1-(3,5-bis(trifluoromethyl)phenyl)-2,2-difluoroethoxy)trimethylsilane 2p
Prepared from 3,5-bis(trifluoromethyl)benzaldehyde following the general procedure.
Isolated by column chromatography (eluting in hexanes) as a yellow liquid in 51% yield (52 mg).
13
C NMR (101 MHz, Chloroform-d) δ. 138.8 (d, J = 2.7 Hz), 131.7 (q, J = 33.8 Hz), 127.82,
124.44, 123.0 (p, J = 3.8 Hz), 121.73, 120.47, 119.01, 117.77, 74.7 (t, J = 32.4 Hz), -0.33 FT-IR
l (cm
-1
) 2961, 2896, 2153, 1628, 1382, 1352, 1276, 1257, 1172, 1130, 1104, 1055, 904, 874, 843.
Anal. Calcd. for [C13H13F8N3OSi]: C, 36.74 ; H, 2.57; N, 10.71. Found: C, 36.85; H, 2.18; N,
11.04.

122
(E)-((1-azido-1,1-difluoro-4-(2-nitrophenyl)but-3-en-2-yl)oxy)trimethylsilane 2q
Prepared from (E)-3-(2-nitrophenyl)acrylaldehyde following the general procedure.
Isolated by column chromatography (eluting in hexanes) as a brown solid.
1
H NMR (400 MHz,
Chloroform-d) δ 7.99 (d, J = 8.2 Hz, 1H), 7.62 – 7.57 (m, 2H), 7.45 (dt, J = 8.7, 4.1 Hz, 1H), 7.26
(d, J = 15.8 Hz, 1H), 6.14 (dd, J = 15.7, 5.7 Hz, 1H), 4.60 (q, J = 6.0 Hz, 1H), 0.24 (s, 9H).
19
F
NMR (376 MHz, Chloroform-d) δ -84.41 (dd, J = 183.8, 6.0 Hz), -87.71 (dd, J = 183.8, 6.2 Hz).
FT-IR l (cm
-1
) 2957, 2925, 2855, 2148, 1608, 1573, 1524, 1344, 1254, 1155, 1075, 967, 913,
878. Anal. Calcd. for [C13H16F2N4O3Si]: C, 45.61; H, 4.71; N, 16.36. Found: C, 45.61; H, 4.34;
N, 16.53.
(2-azido-1-(5-bromothiophen-2-yl)-2,2-difluoroethoxy)trimethylsilane 2r
Prepared from 5-bromothiophene-2-carbaldehyde following the general procedure.
Product was observed by
19
F NMR but was not isolated.
((1-azido-1,1-difluoro-3-phenylpropan-2-yl)oxy)trimethylsilane 2s
Prepared from phenylacetaldehyde following the general procedure. Product was observed
by
19
F NMR but was not isolated.
(2-azido-1-(2-ethynylphenyl)-2,2-difluoroethoxy)trimethylsilane 2t
Prepared from 2-ethynylbenzaldehyde following the general procedure. Product was
observed by
19
F NMR but was not isolated.
4.7.3 Synthesis of triazoles 3
ethyl 1-(2-(2-bromophenyl)-1,1-difluoro-2-((trimethylsilyl)oxy)ethyl)-1H-1,2,3-triazole-4-
carboxylate 3m
Adapted from a reported procedure.
53
A vial equipped with magnetic stir bar was charged
with (2-azido-1-(2-bromophenyl)-2,2-difluoroethoxy)trimethylsilane (175 mg, 0.500 mmol) and
123
ethyl propiolate (60.8 μL, 58.9 mg, 1.2 equiv, 0.6 mmol). Water (1.00 mL) and t-BuOH (1.00 mL)
were added, followed by L-sodium ascorbate (9.91 mg, 50.0 μL, 1.00 molar, 0.100 equiv, 0.05
mmol) (as 1 M aqueous solution) and copper(II) sulfate pentahydrate (2.50 mg, 33.3 μL, 0.30
molar, 0.020 equiv, 0.01 mmol) (as 0.3 M aqueous solution). The vial was then sealed, and the
suspension was stirred vigorously at r.t. for 70 h. The mixture was transferred to an 8 dram vial
with DI water (~10 mL), and it was extracted with diethyl ether (4 x 5 mL). Each portion of ether
was individually washed with DI water (~15 mL), dried over Na2SO4, and filtered through a plug
of cotton. The combined organics were concentrated in vacuo to give 3m.
5,5-difluoro-1-phenyl-6-((trimethylsilyl)oxy)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquinoline
3l
(2-azido-2,2-difluoro-1-(2-(phenylethynyl)phenyl)ethoxy)trimethylsilane 2l (92.9 mg,
0.25 mmol) and toluene (1.8 mL) were added to a vial with a magnetic stir bar, and the vial was
sealed. The reaction was stirred at 110˚C for 18 h. The contents were then concentrated in vacuo
to give the crude product. Purification by column chromatography on silica gel (eluting in pentane)
provided 3l.
124
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Abstract (if available)

Abstract This dissertation is focused on the development of methods to install fluorinated single carbon moieties into organic molecules. In particular these involve the generation and capture of reactive intermediate singlet carbenes.
Chapter 1 covers the advancements in the use of common silicon based reagents, like TMSCF2Br, including those involving an intermediate singlet difluorocarbene.
In Chapter 2, siladifluoromethylation of benzeneselenol with TMSCF3 is discussed, along with how this exploration led us to our discovery of an unprecedented difluoromethylene insertion reaction with diphenyl diselenide. The generation of difluorocarbene with TMSCF3 under basic conditions in the presence of diaryl diselenides yielded the product difluoromethylene diselenoethers in good to excellent yields. The method was also extended to the synthesis of the sulfur analogues, starting with diaryl disulfides.
In Chapter 3, the development of an efficient and operationally simple synthesis of gem-bromofluorocyclopropanes under mild conditions is discussed. The method employs ethyl dibromofluoroacetate as an accessible and inexpensive source of the bromofluorocarbene (:CFBr) intermediate. The protocol provides the bromofluorocyclopropane products in excellent yields, including examples synthesized in multigram scales. The chlorinated ester, ethyl dichlorofluoroacetate, is also utilized to make the analogous gem-chlorofluorocyclopropanes.
In Chapter 4, the first nucleophilic azidodifluoromethylation of aldehydes is discussed. This involves the in situ generation of intermediate azidodifluoromethide from sodium azide and TMSCF2Br-derived difluorocarbene. The O-silyl ether products are valuable as synthetic building blocks and have potential in biochemical protein labeling as fluorinated tags using click chemistry.

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University of Southern California Dissertations and Theses

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Creator Barrett, Colby (author)

Core Title Singlet halofluorocarbenes: Modes of generation and their reactions with alkenes and various heteroatom nucleophiles

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Degree Conferral Date 2023-05

Publication Date 05/04/2023

Defense Date 01/27/2023

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag 2+1,3+2,azide,azidodifluoromethylation,bromofluorocarbene,carbene,chlorofluorocarbene,click chemistry,cycloaddition,cyclopropane,difluorocarbene,fluorine,fluorine chemistry,fluoroalkylation,halofluorocarbene,OAI-PMH Harvest,organofluorine methodology,selenium,silane,silicon,singlet carbene,sulfur,TMSCF2Br,TMSCF₃,triazole

Format theses (aat)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Prakash, G.K. Surya (committee chair), Ershaghi, Iraj (committee member), Narayan, Sri (committee member)

Creator Email colbybar@usc.edu,colbybarrett@live.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC113099679

Unique identifier UC113099679

Identifier etd-BarrettCol-11776.pdf (filename)

Legacy Identifier etd-BarrettCol-11776

Document Type Dissertation

Format theses (aat)

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