One-pot preparation of (RSe)2CF2 and (RS)2CF2 compounds via insertion of TMSCF3-derived difluorocarbene into diselenides and disulfides

Article abstract of DOI:10.1016/j.tet.2019.04.042

A method for the first direct insertion of difluorcarbene, generated from TMSCF₃, into diselenides and disulfides is disclosed, producing novel difluoromethyl diselenoacetals and difluoromethyl dithioacetals. The reaction conditions tolerate a range of synthetically useful and biologically relevant functional groups. The process is scalable, with two representative compounds prepared at a gram-scale in good yields, and it utilizes cheap and available reagents.

Full text of DOI:10.1016/j.tet.2019.04.042

Accepted Manuscript
One-pot preparation of (RSe) CF and (RS) CF compounds via insertion of
2
2
2
2
TMSCF -derived difluorocarbene into diselenides and disulfides
3
Colby Barrett, Vinayak Krishnamurti, Artur Pratas Oliveira, G.K. Surya Prakash
PII:
S0040-4020(19)30454-5
https://doi.org/10.1016/j.tet.2019.04.042
TET 30287
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 March 2019
Revised Date: 13 April 2019
Accepted Date: 16 April 2019
Please cite this article as: Barrett C, Krishnamurti V, Oliveira AP, Prakash GKS, One-pot preparation of
(RSe) CF and (RS) CF compounds via insertion of TMSCF -derived difluorocarbene into diselenides
2
2
2
2
3
and disulfides, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.042.
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One-pot preparation of (RSe)2CF2 and
(RS)2CF2 compounds via insertion of
TMSCF3-derived difluorocarbene into
diselenides and disulfides
Leave this area blank for abstract info.
Colby Barrett, Vinayak Krishnamurti, Artur Pratas Oliveira, and G. K. Surya Prakash
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los
Angeles, California 90089-1661, United States

1
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Tetrahedron
journal homepage: www.elsevier.com
One-pot preparation of (RSe)2CF2 and (RS)2CF2 compounds via insertion of
TMSCF3-derived difluorocarbene into diselenides and disulfides
Colby Barrett +, Vinayak Krishnamurti +, Artur Pratas Oliveira a, and G. K. Surya Prakash
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States
+These authors contributed equally to this work
aUndergraduate research participant
Dedicated to Professor. John Hartwig as a joint recipient of the 2018 Tetrahedron Prize for Creativity in Organic Chemistry.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method for the first direct insertion of difluorcarbene, generated from TMSCF3, into
diselenides and disulfides is disclosed, producing novel difluoromethyl diselenoacetals and
difluoromethyl dithioacetals. The reaction conditions tolerate a range of synthetically useful and
biologically relevant functional groups. The process is scalable, with two representative
compounds prepared at a gram-scale in good yields, and it utilizes cheap and available reagents.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
difluorocarbene
TMSCF3
insertion
diselenides
disulfides
CF2Br2.27–29
.
1. Introduction
been
synthesized
from
thiolates
and
Bromodifluoromethyl selenoethers are prepared through reaction
of selenols with CF2Br2.30 The only reported synthesis of
difluoromethyl thioacetals is from the reaction TMSCF2H with
Fluorofunctionalization is an effective means of tuning the
lipophilicity, bioavailability, and metabolic stability of
molecules.1–7 Direct introduction of a -CF2- group is a highly
sought after transformation8 due to the heightened biological
activity of some -CF2- derivatives over their parent
compounds.9,10 In this context, the generation and utilization of
difluorocarbene from fluoroalkylsilanes has emerged as a
powerful tool for the difluoromethylation of nucleophilic
substrates.11,12 TMSCF2Br has been widely used as
a
difluorocarbene source for CF2 incorporation into various
nucleophiles.13,14 The Ruppert-Prakash reagent (TMSCF3) is
arguably the cheapest source of CF2 carbene (Figure 1). It has
been employed in the difluoromethylation of olefins and alkynes
to afford difluorocyclopropanes and difluorocyclopropenes
respectively.15 Mikami and co-workers have reported the
siladifluoromethylation of carbon16,17 and boron18 nucleophiles.
Our group has previously disclosed difluoromethylation reactions
on various nucleophiles including imidazoles,19 thiols,20
phosphonates and phosphine oxides,21 and stannyl hydrides.22
Figure 1. Reported difluoromethylation reactions using TMSCF3.
disulfides.31 No analogous transformation has been performed on
diselenides to afford difluoromethyl selenoacetals. The reported
strategy utilizes TMSCF2H to transfer CF2H- to disulfides,
forming a difluoromethyl thioether, which attacks another
equivalent of disulfide upon deprotonation to form
difluoromethyl thioacetal (Figure 2). Conducting an analogous
Difluoromethyl thioethers have been prepared through
nucleophilic23
and
electrophilic24
difluoromethylation,
a
difluorocarbene reaction with thiols,14,20,25 and direct C(sp3)-H
fluorination26 of thioethers. Bromodifluoromethyl thioethers have
———
transformation using TMSCF3 would be desirable, since
Corresponding author. e-mail: gprakash@usc.edu

2
Tetrahedron
ACCEPTED MANUSCRIPT
TMSCF2H is prepared from TMSCF3 and is not nearly as cost-
contrast, fluoride’s weaker bond with the softer K+ allows for its
effective or available as TMSCF3. Considering this, and our
previous experience with CF2 insertion reactions, we set out to
develop a direct CF2 insertion reaction into chalcogen-chalcogen
bonds. We believe that access to such sulfur and selenium
compounds would provide potentially useful building blocks for
recombination with CF2 carbene (Figure 3 eq.3).33 The
persistence34 of and preference for CF3- explains the selectivity
for trifluoromethylation with KOtBu. Finally, substituting
TMSCF2Br in place of TMSCF3 afforded no favorable amount of
the desired product. It is likely that when using TMSCF2Br under
these conditions, the difluorocarbene generation is too fast, which
results in carbene dimerization or oligomerization products.
the
molecules.
fluorofunctionalization-thio/selenolation
of
organic
Figure 3. Effect of the cation on CF2 carbene formation.
Figure 2. Prior art on the synthesis of difluoromethyl dithioacetals from
TMSCF2H and this work from TMSCF3.
The optimized conditions were then applied to a series of
diselenides (Figure 4). 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 bulk
of the methoxy group, and its inability to donate significantly by
resonance when in the meta position, 2b, 2d, and 2f were isolated
in near-identical yields (80%, 80%, and 82%, respectively),
indicating that substituent position may not significantly
influence the difluorocarbene insertion. Both 2a and 2b were
prepared at a 1 g scale in good yields, showing the potential for
scalability. 1-naphthyl derivative 2c could also be isolated in high
yield (96%). The yield was lower (63%) in the case of a 2-
dimethylamino substituent (2e). This may be due to strong
coordination of the N-lone pair with Li+ in the system, which
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, producing the corresponding
Se-CF3 compound. Difluoromethyl diselenoacetal 2g, with a 4-Cl
substituent, was obtained in excellent isolated yield, which
provides a handle for further functionalization. However, 4-OCF3
2. Results/Discussion
Reaction optimization (Table 1) 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.21,32
Conveniently, our first trial with LiOtBu, LiCl and TMSCF3
yielded 95% of 2a. In the absence of LiCl, a slightly diminished
Table 1. Optimization trials on 1a.
Entrya
Activator (equiv)
Silane (equiv)
Yield %
2a
95
89
83
4
3a
1
LiOtBu (1.0)
LiOtBu (1.0)
NaOtBu (1.0)
KOtBu (1.0)
LiOtBu (1.0)
TMSCF3 (2.0)
TMSCF3 (2.0)
TMSCF3 (2.0)
TMSCF3 (2.0)
TMSCF2Br (2.0)
5
2b
3b
4b
5
6
8
50
5c
1
aReactions performed with 0.5 mmol of 2a, in 0.63 mL of DMF, with 1.2
equiv LiCl. Yields provided were determined by 19F NMR using PhF (0.5
mmol) as internal standard. bNo LiCl added. cyield of PhSeCF2Br
.
yield was observed. Performing the reaction with NaOtBu in
place of LiOtBu decreased the conversion of 2a. KOtBu provided
no reasonable conversion to 2a, with a 50% conversion to 3a
(100% consumption of 1a), clearly demonstrating the effect of
the cation in directing the chemoselectivity of the transformation.
This cation dependence stems from the identity of the fluoride
salt (Figure 3). Li+ and Na+ both form very strong bonds with
fluoride. Effectively, this makes the reactions irreversible
(Figure 3 eq.1, eq.2). Lithium and sodium cations are both hard
Lewis acids that bind strongly to hard Lewis bases, such as F-. In
Figure 4: Products of difluorocarbene insertion into Se-Se and S-S bonds.
All reactions performed at 0.5 mmol scale, with isolated yields shown outside
parentheses. Yields provided in parentheses were determined by 19F NMR
spectroscopy using PhF as internal standard.

3
substituted product 2h could not be isolated and was only
observed by 19F NMR. The diminished conversion and instability
may be attributed to the good leaving group ability of -OCF3,
N2 and stored over activated 3 Å molecular sieves in a Strauss
ACCEPTED MANUSCRIPT
flask. Where applicable, flash column chromatography was
performed to isolate the compounds. Solid starting materials
were dried under high vacuum (< 0.1 Torr) with a P2O5 trap for at
-
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
19F 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(sp3)-H bond,
followed by elimination of a phenyl selenolate and a phenyl
selenoaldehyde moiety may be responsible for the loss of starting
material.35
least 12 hours prior to use. H, 13C, and 19F NMR spectra were
1
recorded on 400 MHz or 500 MHz Varian NMR spectrometers.
All chemical shifts are given in units of ppm relative to an
internal standard. 1H NMR chemical shifts were determined
relative to CHCl3 at δ 7.26. 13C NMR shifts were determined
relative to CDCl3 at δ 77.16. 19F NMR chemical shifts were
determined relative to CFCl3 at δ 0.00. Mass spectral data were
recorded on a high-resolution mass spectrometer, EI or ESI
mode.
5.2. Starting materials
Having tested the reaction conditions on diselenides, attempts
to extend the conditions to disulfides were made. The optimized
conditions for diselenides did not furnish the desired
difluoromethyl dithioacetals 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, would react more readily with the hard nucleophile,
CF3-, as opposed to the analogous reaction with diselenides
(wherein the Se atom would likely be a softer electrophile). To
circumvent this problem, a higher loading of LiOtBu (3 equiv)
was used to increase the Li+ concentration. This should 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 a 3-F and 4-Me substituent, could also be
produced in good yields. Finally, product 2l was obtained, albeit
in lower yield, showing compatibility with pyridyl moieties.
Figure 5: Proposed reaction pathway.
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.
1b: 1,2-Bis(2-methoxyphenyl) diselenide
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). 1H 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.36
The first step of the reaction pathway (Figure 5) is likely the
activation of TMSCF3 by LiOtBu, forming lithium (tert-
butyloxy)(trifluoromethyl)trimethylsilicate (I), which would
liberate lithium trifluoromethide (LiCF3) and TMS-OtBu. Due to
the inherent electrophilicity of the chalcogen center,
trifluoromethylation to form trifluoromethyl selenoether 3 is a
non-constructive pathway. Decomposition of LiCF3 gives LiF
and CF2 carbene. The CF2 carbene could be trapped by the
diselenide, generating a difluoromethyl selenonium ylide (II).
Rearrangement of the ylide would afford product 2. The same
reaction pathway can be envisioned with disulfides in place of
diselenides.
1c: 1,2-Di(naphthalen-1-yl) diselenide
3. Conclusion
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 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)
In
summary,
we
have
developed
a
novel
difluoromethylenation of diselenides and disulfides, yielding
difluoromethyl diselenoacetals and dithioacetals. The method
tolerates a number of commonly encountered functional groups.
The transformation is scalable, with 2a and 2b having been
prepared in good yields on a 1-gram scale.
4. Acknowledgements
The authors would like to thank the Loker Hydrocarbon
Research Institute for funding.
5. Experimental section
5.1. General
Unless otherwise mentioned, all the chemicals were purchased
from commercial sources and used without further purification.
N,N-dimethylformamide (DMF) was distilled from CaH2 under

4
Tetrahedron
ACCEPTED MANUSCRIPT
from aqueous HCl (0.15 M, 150 mL). The combined organic
The combined organic layer was washed with brine (75 mL, one
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
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). 1H
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.38
1
was obtained in 74% yield (1.53 g) was a pale-yellow solid. 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.37
1f: 1,2-Bis(3-methoxyphenyl) diselenide
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-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.39
1d: 1,2-Bis(4-methoxyphenyl) diselenide
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 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
1g: 1,2-Bis(4-chlorophenyl) diselenide
1
pale-yellow solid. 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
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
matches previous reports.36
1e: 1,2-Bis(4-(N,N-dimethylamino)phenyl) diselenide
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
extracted with CHCl3 (50 mL, three times) from water (150 mL).

5
hours at room temperature. The solution was concentrated under
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.40
addition of TMSCF3 (1.0 mmol, 2 equiv, 148 µL). The solution
ACCEPTED MANUSCRIPT
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 2b in 80% isolated yield
(218 mg) as a pale-yellow solid. 1H 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). 13C 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. 19F 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.
1h: 1,2-Bis(4-(trifluoromethoxy)phenyl) diselenide
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.40
2c: Difluorobis(naphthalen-1-ylselanyl)methane
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. 1H 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). 13C
NMR (100 MHz, 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).
19F 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.
5.3. Products (2)
2a: Difluorobis(phenylselanyl)methane
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.
1H 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). 13C NMR
(101 MHz, Chloroform-d) δ 137.0, 129.9, 129.4, 126.4, 119.1 (t,
J = 347.1 Hz). 19F 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.
2d: Difluorobis((4-methoxyphenyl)selanyl)methane
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
2b: Difluorobis((2-methoxyphenyl)selanyl)methane
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
1
(77 mg) as a yellow solid. H NMR (399 MHz, Chloroform-d) δ
7.8 – 7.4 (m, 4H), 7.0 – 6.5 (m, 4H), 3.8 (s, 6H). 13C 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. 19F NMR (376 MHz,

6
Tetrahedron
ACCEPTED MANUSCRIPT
Chloroform-d) δ -45.5. FT-IR (cm-1) 3067, 2969, 2942, 2889,
EtOAc (5 mL) and poured into aqueous HCl (12 mL, 1 M
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.
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
2e: 2,2'-((Difluoromethylene)bis(selanediyl))bis(N,N-
dimethylaniline)
1
2g in 84% isolated yield (181 mg) as a colorless solid. H NMR
(399 MHz, Chloroform-d) δ 7.64 – 7.57 (m, 1H), 7.38 – 7.30 (m,
1H). 13C 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).
19F NMR (376 MHz, Chloroform-d) δ -44.1. FT-IR (cm-1) 3084,
2923, 2851, 2761, 2645, 2359, 1909, 1645, 1579, 1558, 1470,
1435, 1387, 1350, 1291, 1267, 1084, 1023, 1009, 951, 801, 732,
486.
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
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
2i: Difluorobis(phenylthio)methane
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. 1H NMR (399 MHz, Chloroform-d)
δ 7.66 – 7.56 (m, 4H), 7.49 – 7.43 (m, 2H), 7.43 – 7.36 (m, 4H).
13C NMR (100 MHz, Chloroform-d) δ 136.3, 132.4 (t, J = 312.4
Hz), 130.3, 129.2, 127.4. 19F NMR (376 MHz, Chloroform-d) δ -
49.5. The NMR data matches previous reports.31
1
(141 mg) as a pale-yellow oil. 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). 13C 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.
19F 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.
2f: Difluorobis((3-methoxyphenyl)selanyl)methane
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 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
2j: Difluorobis((3-fluorophenyl)thio)methane
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, 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. 1H
NMR (399 MHz, Chloroform-d) δ 7.4 – 7.3 (m, 6H), 7.2 (m,
2H). 13C 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). 19F NMR (376 MHz, Chloroform-d) δ -49.2, -
110.5 – -113.3 (m). HRMS (M-H+) 303.0011.
1
(174 mg) as a pale-yellow oil. 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). 13C 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.
19F 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.
2g: Bis((4-chlorophenyl)selanyl)difluoromethane
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
2k: Difluorobis(p-tolylthio)methane
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

7
19. Prakash, G. K. S.; Krishnamoorthy, S.; Ganesh, S. K.; Kulkarni,
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. 1H NMR (399 MHz, Chloroform-
d) δ 7.51 (d, J = 8.2 Hz, 4H), 7.27 – 7.18 (m, 4H), 2.40 (s, 6H).
13C 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.
19F NMR (376 MHz, Chloroform-d) δ -50.2. HRMS (M-H+)
295.0436.
ACCEPTED MANUSCRIPT
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2l: Difluorobis(pyridin-2-ylthio)methane
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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,
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2l in 25% isolated yield (34 mg) as a light-brown oil. H NMR
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ACCEPTED MANUSCRIPT