Efficient protocol for the SO2F2-mediated deoxyfluorination of aliphatic alcohols

Article abstract of DOI:10.1016/j.jfluchem.2021.109888

Alkyl fluorides are prevalent in both the pharmaceutical and agrochemical industries. As such, there has been significant interest over the past 40 years in the development of new synthetic methods to access these important fluorinated motifs. Herein we report the sulfuryl fluoride-mediated deoxyfluorination of alcohols using room temperature reaction conditions in only an hour. A wide range of primary aliphatic alcohols were efficiently converted to the corresponding fluoride in 46-70% isolated yields. Secondary alcohols were also effectively deoxyfluorinated in 50–92% yields. Chiral secondary alcohols were cleanly converted to the corresponding alkyl fluoride with only a minor deterioration of the enantioenrichment. A steroid derivative also underwent deoxyfluorination in 50% yield and 5.9:1 dr, with the major product resulting from net inversion of the stereocenter.

Full text of DOI:10.1016/j.jfluchem.2021.109888

Journal Pre-proof
Efficient Protocol for the SO2F2-Mediated Deoxyfluorination of
Aliphatic Alcohols
Cayo Lee , Joey Lai , Maxim Epifanov , Cindy Xinyun Wang ,
Glenn M. Sammis
PII:
S0022-1139(21)00166-4
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2021.109888
FLUOR 109888
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Journal of Fluorine Chemistry
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Revised date:
Accepted date:
14 July 2021
31 August 2021
2 September 2021
Please cite this article as: Cayo Lee , Joey Lai , Maxim Epifanov , Cindy Xinyun Wang ,
Glenn M. Sammis , Efficient Protocol for the SO2F2-Mediated Deoxyfluorination of Aliphatic Alcohols,
Journal of Fluorine Chemistry (2021), doi: https://doi.org/10.1016/j.jfluchem.2021.109888
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Efficient Protocol for the SO2F2-Mediated Deoxyfluorination of Aliphatic Alcohols
Cayo Lee, Joey Lai, Maxim Epifanov, Cindy Xinyun Wang, and Glenn M. Sammis*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia
V6T 1Z1, Canada
Graphical abstract
Highlights




New, mild SO2F2-mediated deoxyfluorination reaction.
Efficient for both primary and secondary alcohols.
The alkyl fluorides can be accessed at room temperature in an hour.
Net inversion of configuration is observed with only minor deterioration of the ee.
Abstract:
Alkyl fluorides are prevalent in both the pharmaceutical and agrochemical industries. As such,
there has been significant interest over the past 40 years in the development of new synthetic
methods to access these important fluorinated motifs. Herein we report the sulfuryl fluoride-
mediated deoxyfluorination of alcohols using room temperature reaction conditions in only an
hour. A wide range of primary aliphatic alcohols were efficiently converted to the corresponding
fluoride in 46-70% isolated yields. Secondary alcohols were also effectively deoxyfluorinated in
50-92% yields. Chiral secondary alcohols were cleanly converted to the corresponding alkyl
fluoride with only a minor deterioration of the enantioenrichment. A steroid derivative also
underwent deoxyfluorination in 50% yield and 5.9:1 dr, with the major product resulting from
net inversion of the stereocenter.
Keywords
Sulfur(VI) fluorides, sulfuryl fluoride, alkyl fluoride, deoxyfluorination, ex situ gas generation.
1. Introduction
Fluorine incorporation into pharmaceuticals and agrochemicals is a common method to
modulate and tune a molecule’s physicochemical properties, including lipophilicity, acidity,[1]
and metabolic stability.[2] Because of the utility of organofluorine molecules, they are now

prevalent in both industries. Between 1991 and 2019, 18% of all pharmaceuticals on the market
contained fluorine, [3] including three out of the five top-selling drugs. [4] For pesticides alone,
16% are fluorine-containing agrochemicals. [5] While many different fluorinated motifs are
utilized in both of these industries, alkyl fluorides are prevalent (Fig. 1). The importance of these
fluoroalkyl motifs has motivated the development of numerous methods for their synthesis. Of
particular interest are the methods that promote the direct deoxyfluorination of alcohols in a
single synthetic step. Numerous nitrogen-, [6–8] carbon-, [9] and sulfur-based reagents [10–17]
have been developed over the past forty years to effect deoxyfluorinations, but there are
limitations with many of the aforementioned methods, such as long reaction times, harsh reaction
conditions, and high reagent expense.
Fig. 1. Representative examples of fluoroalkyl pharmaceuticals and agrochemicals.
We were intrigued by the possibility of developing a general method for the
deoxyfluorination of alcohols using sulfuryl fluoride (SO2F2), a commodity chemical that is
widely used as a fumigant but has not been extensively applied to organic synthesis. Sulfuryl
fluoride is an attractive reagent as it can either be directly purchased or readily synthesized on-
demand. [18–20] Furthermore, the by-products of sulfuryl fluoride-based methods are typically
sulfates that can readily be removed. There are few patents by Ishii and coworkers that describe
SO2F2-promoted deoxyfluorination. [21–27] Unfortunately, this method has several
disadvantages, such as requiring low temperatures (–40 to –78 ˚C), moderate to high pressures
(up to 2 MPa), long reaction times (20 to 40 h), and highly variable yields. Our goal was to
develop a more efficient and mild protocol for SO2F2-mediated deoxyfluorination.
2. Results and discussion
Our study began by applying our previously developed aliphatic alcohol activation methods
for deoxyfluorination,[19,20] but nether provided high yields of the desired product. We then
investigated different bases in the SO2F2-mediated deoxyfluorination of primary alcohols (Table

1). 3-Phenyl-1-propanol (1a) was selected as a model substrate as the alcohol is not activated,
and the corresponding alkyl fluoride (2a) has a sufficiently high molecular weight that it is not
highly volatile. We started by examining the reaction with 1.5 equivalents of 1,8-
diazabicyclo(5.4.0)undec-7-ene (DBU) with sulfuryl fluoride in DMF, which afforded the
desired alkyl fluoride (2a) in only 26% isolated yield (entry 1). Increasing the amount of DBU
resulted in a modest decrease in the isolated yield (entry 2). Replacing DBU with the weaker
bases triethylamine (Et3N) or N,N-diisopropylethylamine (DIPEA) resulted in 30% (entry 3) and
6% isolated yield (entry 4), respectively.
The addition of catalytic amounts of 4-
dimethylaminopyridine (DMAP) or tetrabutylammonium iodide (TBAI) had a negligible effect
on the reaction yield (entries 5-7). While tetrabutylammonium fluoride (TBAF) did not improve
the reaction with DIPEA (entry 8), it led to a significant increase in yield when DBU was utilized
(entry 9). Changing the fluoride source to KF led to a slight decrease in yield (entry 10), but
addition of KF and 18-crown-6 with sulfuryl fluoride and DBU afforded 2a in 52% isolated yield
(entry 11).
Table 1
Base and additive optimization of sulfuryl fluoride-mediated deoxyfluorinations.a
entry variation from standard conditions
NMR yield of 2a (%)
1
DBU (1.5 equiv.)
26
18
30
6
2
DBU (4 equiv.)
3
Et3N (4 equiv.)
4
DIPEA (4 equiv.)
5
DIPEA (4 equiv.), DMAP (0.1 equiv.)
DIPEA (4 equiv.), TBAI (0.1 equiv.)
DBU (4 equiv.), TBAI (0.1 equiv.)
DIPEA (4 equiv.), TBAF (in THF, 1 equiv.)
DBU (4 equiv.), TBAF (in THF, 1 equiv.)
DBU (2 equiv.), KF (3 equiv.)
DBU (2 equiv.), KF (3 equiv.), 18-crown-6 (3 equiv.)
12
12
20
12
49
32
52
6
7
8
9
10
11
aReaction conditions: To a solution of the base, 3-phenyl-1-propanol (0.6 mmol), and DMF (1.8
mL) was bubbled ex situ-generated SO2F2 (general procedure A). The yield was determined by
19F NMR spectroscopy using trifluorotoluene as an internal standard.

Despite extensive subsequent optimization, the isolated yields of 2a never exceeded 52%. We
hypothesized that the problem may be due to the competing reaction of alcohol 1 with the key
reactive intermediate, fluorosulfate 3 (Fig. 2) to form dialkyl sulfate 4, which is known to be less
reactive towards substitution.[28,29] This hypothesis was confirmed as analysis of the crude
1
reaction mixture using H NMR spectroscopy revealed that a significant amount of dialkyl
sulfate 4 (Fig. 2) was forming under the reaction conditions and, once formed, it did not react
with fluoride in solution. Thus, disfavoring the dialkyl sulfate pathway is essential to achieve
high yields of the desired alkyl fluoride product (2).
Fig. 2. One-pot deoxyfluorination mediated by SO2F2 (blue; top) and the associated undesired
reaction pathway to the formation of dialkylsulfate 4 (red; bottom).
One strategy to disfavor the formation of dialkyl sulfate 4 is to keep the concentration of
alcohol low compared to sulfuryl fluoride. This increases the likelihood of the desired reaction
between fluorosulfate 3 and fluoride compared to the reaction of 3 with the alcohol (1). To
minimize the concentration of alcohol during the course of the reaction, we examined reverse
addition conditions, where the alcohol was slowly added to a pre-saturated solution of SO2F2
(Table 2). [30] After a brief screen, THF was identified as the most promising solvent for the
reversed addition conditions.[31] The desired alkyl fluoride (2a) was obtained in 39% and 41%
yields (Table 2, entries 1 and 2), which is notably higher than the 32% yield that was achieved
using the former protocol (Table 1, entry 9). Increasing the amount of KF to 3 equivalents gave
48% of the target product 2a. The reaction afforded either comparable or modestly higher yields
when CsF, tetramethylammonium fluoride (TMAF), or potassium bifluoride were used as
fluoride additives (Table 2, entries 4-6). The addition of 18-crown-6 led to a slight increase in
yield for both CsF and KF (entries 7,8). We selected KF over KHF2 for further optimization as
18-crown-6 is more commonly utilized in conjunction with KF. Increasing the amount of the
KF/18-crown-6 to 4 equivalents led to 70% yield of the desired alkyl fluoride (entry 9), but
further increasing the amount of fluoride did not influence the reaction (entry 10).
Table 2
Optimization of the fluoride additive using reversed addition conditionsa

entry fluoride
DBU (equiv.) fluoride (equiv.) NMR yield (%)
1
2
3
4
5
6
7
8
9
10
KF
1
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
5
39
41
48
45
54
54
54
55
70
69
KF
KF
CsF
TMAF
KHF2
CsF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
aReaction conditions: To a solution of the sulfuryl fluoride in THF (6 mL) was added base, 3-
phenyl-1-propanol (0.3 mmol), and the fluoride additive (general procedure B). The yield was
determined by 19F NMR spectroscopy using trifluorotoluene as an internal standard.
With optimized conditions in hand, we next examined the substrate scope with primary
alcohols (Table 2). The reaction with 3-phenyl-1-propanol on both 0.6 mmol and 1 mmol scales
afforded the desired alkyl fluoride (2a) in 66% isolated yield. The reaction with 3-phenyl-1-
propanol on a gram-scale provided 2a in 73% isolated yield. The reaction was insensitive to
bromine on the arene, with both ortho- and meta-bromophenethyl alcohols converted to the
corresponding fluorides (2b and 2c) in 68% isolated yields. The optimized conditions led to
significant elimination of nitro derivative 1d to 1-nitro-4-vinylbenzene. However, when the
amount of DBU was decreased to 1 equivalent, the desired alkyl fluoride could be isolated in
66% yield. The reaction was also compatible with electron-donating groups on the arene, with
para-(benzyloxy)phenethyl alcohol (1e) and dimethoxy derivative 1f both converted to 2e and 2f
in 57% isolated yields. Trimethyl derivative 1g was effective under the reaction conditions,
affording 2g in 79% NMR yield. The reaction was not significantly impacted when extra steric
bulk was added to the beta-position as alkyl fluoride 2h was isolated in 68% yield. Phthalimides
and esters were also tolerated under the reaction conditions, with 2i and 2j isolated in 63% and
58% yield, respectively. Linear primary aliphatic alcohols 1m-1p were successfully converted to
the corresponding alkyl fluorides (2m-2p) in good yields. Notably, 2n was obtained in 21% yield
under Ishii’s conditions [27] while our protocol afforded the same substrate in 54% yield.
Alkyne-containing primary alkyl alcohol derivative 1q was only converted to the corresponding
alkyl fluoride in 46% NMR yield, presumably due to elimination of the fluorosulfate
intermediate (3). Two other alkyne-containing primary alkyl alcohol derivatives, 1r and 1s,

afforded 2r and 2s in 54% and 75% NMR yields. Allylic alcohol gave 3-fluoroprop-1-ene (2t) in
46% NMR yield.
Benzyl alcohols were generally not effective under these reaction conditions, possibly due to
the competing reaction between the base and activated fluorosulfate intermediate 3.[32] Only a
benzyl alcohol derivative with an electron withdrawing group, trifluoromethyl derivative 1k, was
converted to the corresponding benzylic fluoride (2k). Pyridinyl derivative 1l was converted to
the corresponding alkyl fluoride (2l) in 20% NMR yield. Under the optimized conditions, steroid
2u was isolated in a low yield due to the formation of 2u’. By decreasing the amount of base to 1
equivalent, 2u could be isolated in 66% yield and only 13% yield of the undesired side product
was obtained. The reaction is not expected to be tolerant of phenols or carboxylic acids as they
are known to rapidly convert to fluorosulfates [33] and acyl fluorides, [34] respectively, in the
presence of SO2F2.
Table 3
Deoxyfluorination substrate scope for primary alcohols.

a
Isolated yields of acyl fluorides are reported using 0.6 mmol of alcohol 1 following the
reversed addition protocol (general procedure C). 19F NMR yields are reported in parentheses. 1
mmol scale. c1 gram-scale (10 mmol). dDue to the volatility of the product, some residual solvent
remained after purification. The reported yield has been corrected for these minor impurities. e1
equiv. of base.
b
We next examined the scope of secondary alcohols using our new deoxyfluorination
methodology. Gratifyingly, cyclopentanol (1v) was efficiently transformed into the volatile alkyl
fluoride 2v in 73% NMR yield. Linear secondary alcohol 1w could also be converted to the
corresponding alkyl fluoride (2w) in 65% NMR yield. Secondary benzylic alcohol 1x was also
an effective substrate, affording corresponding alkyl fluoride 2x in 79% NMR yield.
We next examined whether stereodefined secondary alcohols were viable substrates for the
optimized reaction conditions. Chiral secondary alcohol 1y could be converted to the
corresponding alkyl fluoride 2y in very high yield relative to 2w. Similarly, the reaction with
enantiopure alcohol 1z afforded very high yields of alkyl fluoride 2z in 98:2 er. A more complex
substrate, 3β-hydroxy-5-cholestene (1za), afforded the desired alkyl fluoride 2za in 50% isolated
yield and 5.9:1 dr. Comparison to the literature confirms that the major product results from net
inversion of the stereocenter.[35]
Table 4
Deoxyfluorination substrate scope for secondary alcohols.a
a Isolated yields of acyl fluorides are reported using 0.6 mmol of alcohol 1 following the reversed
addition protocol (general procedure C). 19F NMR yields are reported in parentheses.
3. Conclusion
We have developed a practical SO2F2-mediated deoxyfluorination methodology that affords
good to high yields of the desired alkyl fluoride products at room temperature under atmospheric
pressure in only an hour. This study is complementary to our previously developed methods,
which did not work well for deoxyfluorination.[19,20] The critical aspect of this new work is a

combination of the reversed addition conditions and the specific choice of fluoride salt. The
reverse addition strategy, where the alcohol was slowly added to a pre-concentrated solution of
sulfuryl fluoride, effectively promoted the deoxyfluorination of primary alcohols with a range of
functionalities. Furthermore, the reaction was successfully applied to both symmetric and chiral
secondary alcohols, with the latter formed in good enantioselectivity and a net inversion of
configuration. Finally, the method was applied to a steroid derivative, which afforded good yield
and 5.9:1 dr with the major product resulting from net inversion of the stereocenter.
4. Experimental
4.1. General information
All chemicals were from commercial sources AK Scientific, Alfa Aesar, Fisher Chemical,
Oakwood Chemical, Sigma-Aldrich, and Tokyo Chemical Industry (TCI). All reactions were
performed in flame-dried disposable scintillation 3.70 mL (15 x 45 mm), 20 mL (28 x 61 mm),
or 30 mL (25 x 95 mm) glass vials under nitrogen atmosphere. 1,1’-sulfonyldiimidazole (SDI)
was prepared to synthesize sulfuryl fluoride (SO2F2) following the procedure reported by De
Borggraeve. [18] Screw caps and PTFE/Silicone septa (13 mm x 0.060” and 22 mm x 0.060”)
were from Chemglass Life Sciences. Polyethylene tubing 100 ft (I.D. 1.57 mm, O.D. 1.14 mm)
was from Becton Dickinson. KDS 100 Legacy Single Syringe Infusion Pump was from KD
Scientific. Disposable 1 mL syringes (I.D. 4.69 mm), 3 mL Syringes (I.D. 9.65 mm), 5 mL
Syringes (I.D. 12.45 mm), and 10 mL Syringes (I.D. 15.9 mm) were from Norm-Ject.
Tetrahydrofuran (THF) was obtained from Sigma-Aldrich, dried by a solvent purification system
(SPS), or distilled over sodium and benzophenone. N,N-Dimethylformamide (DMF), dioxane,
and ethyl acetate (EtOAc) were dried over 4 Å molecular sieves. Acetonitrile (ACN) and
dichloromethane (DCM) were obtained from a solvent purification system (SPS)
Flash column chromatography was performed using Silicycle F60 silica: 230-400 mesh (40-63
μm) silica. TLC’s were run on Merck Kieselgel 60 F254 aluminum sheets and visualized by UV
fluorescence (254 nm) then one of the following: KMnO4, ninhydrin, p-anisaldehyde,
bromocresol green.
Infrared (IR) spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer or a Perkin
Elmer Frontier FT-IR. The spectra are reported in cm−1.
High resolution mass spectra (HRMS) were recorded on a Waters or Micromass LCT
spectrometer or a JEOL AccuTOF-GC spectrometer.
Chiral high performance liquid chromatography (HPLC) analysis was performed using an
Agilent 1260 infinity LC system with commercially available Daicel Chiralcel® OD-3 (250 x
4.6 mm) chiral columns, with products detected using UV absorbance at 210 nm.
Optical rotations were measured on a Jasco P-2000 polarimeter. The reported value [훼]퐷23
(concentration in g/100 mL, CHCl3) was the average of five runs.

1
NMR spectra were obtained on a Bruker AV-300 or AV-400 spectrometer. H, 13C, and 19F
NMR chemical shifts are reported in parts per million (ppm) relative to the residual solvent peak
1
(CDCl3, H: δ = 7.26 ppm, 13C: δ = 77.16 ppm). 19F NMR chemical shifts were referenced to
19
19
Trichlorofluoromethane (CFCl3, F: δ = 0.00 ppm). NMR yields were determined by F NMR
using a relaxation delay (or recycle delay) of 40 seconds to ensure complete relaxation of all
fluorine nuclei. α,α,α-Trifluorotoluene (PhCF3, 19F: δ = -63.72 ppm) was used as an internal
standard, unless otherwise specified. The aliquot is diluted with CDCl3 in the quantitative NMR
1
analysis. H and 19F multiplicities are reported as follows: singlet (s), doublet (d), triplet (t),
multiplet (m), doublet of triplets (dt), doublet of quartets (dq), triplet of doublets (td), triplet of
triplets (tt), triplet of quartets (tq) and doublet of doublet of triplets (ddt). Coupling constants (J)
are reported in Hz. Assignment of peaks was done based on the chemical shifts, multiplicities,
and integrals of the peaks. Note: Impurities in the 0.8-1.3 ppm range are visible on the spectra.
CAUTION: Sulfuryl fluoride is a toxic gas and must always be handled with care in a well
ventilated fumehood. The excess sulfuryl fluoride can be quenched by passing it through a basic
aqueous medium.
4.2. Base and additive optimization of sulfuryl fluoride-mediated deoxyfluorinations
General procedure A: Two 20 mL vials equipped with magnetic stir-bars were capped
with septum-fitted vial caps connected by a polyethylene tube. Vial A was charged with SDI
(2.64 mmol, 4.4 equiv) and anhydrous KF (7.02 mmol, 11.7 equiv). To vial B was added 3-
Phenyl-1-propanol 1a (0.6 mmol, 1 equiv), DBU (0.9 mmol, 1.5 equiv), DMF (1.8 mL), and
additives. The polyethylene tube in vial B was immersed into the solution and then to vial A was
added TFA (1.5 mL). Vigorous bubbling of SO2F2 and fuming were observed in vial B for a few
minutes and when the bubbling subsided, vial B was vented via a needle for 1-2 minutes (this
triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed
and the mixture in vial B was allowed to stir at ambient temperature for 10 minutes. An aliquot
was taken for quantitative 19F NMR analysis. Caution: Reaction vials can become pressurized
during the generation of SO2F2. Note: we have not observed a difference in reactivity when
different needle diameters were utilized. As the density of SO2F2 is about 3 times larger than the
density of air, any air seepage had a minimal impact on the reaction.
4.3. Optimization of the fluoride additive using reversed addition conditions
General procedure B: A 3.7 mL vial A and a 30 mL vial B were equipped with
magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene
tube. Under nitrogen, Vial A was charged with SDI (2.77 mmol, 9.22 equiv) and anhydrous KF
(7.36 mmol, 24.5 equiv). To vial B was added THF (6 mL). A 3 mL syringe filled with excess of
TFA (1.50 mL, 19.6 mmol) was added into the vial A at a rate of 9 mL/hr by a syringe pump.
The tube in vial B was immersed into the solution after the first bubbles of SO2F2 appeared.
Once bubbling of SO2F2 subsided, into vial B was inserted an empty balloon to increase the
bubbling rate. When the bubbling had almost stopped, 6M NaOH (1.5 mL) was slowly added
into vial A. After completing generation of SO2F2, the tube was removed. Without opening the

vial B, trifluorotoluene (1 equiv) was added by a syringe into vial B as an internal standard.
Without opening the vial B, an aliquot was taken by a syringe for quantitative 19F NMR analysis
to confirm no TFA contaminant and quantify the amount of SO2F2 (Note: the chemical shift of
the two equivalent fluorines of SO2F2 appear at 33.8 ppm. Typically, about 1.5 to 2.5 equivalents
of SO2F2 were calculated to be in THF prior to addition of the other reagents). KF (4 equiv) and
18-crown-6 (4 equiv) were added into vial B. A reaction mixture of 3-Phenyl-1-propanol 1a (0.3
mmol, 1 equiv), THF (2.0 mL), and DBU (0.9 mmol, 3 equiv) were added into vial B at 4 mL/hr
19
by a syringe pump. An aliquot was taken for quantitative F NMR analysis after stirring for one
hour (note: the amount of the aliquot is less than 0.1 mL which is less than 2% of the reaction
solution). Caution: Reaction vials can become pressurized during the generation of SO2F2. Note:
Picture of the assembly is available in the SI.
4.4. 0.6 mmol scale one-pot deoxyfluorination of alcohols
General procedure C: A 20 mL vial A and a 30 mL vial B were equipped with magnetic
stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Under
nitrogen, Vial A was charged with SDI (5.53 mmol, 9.22 equiv) and anhydrous KF (14.7 mmol,
24.5 equiv). To vial B was added THF (12 mL). A 3 mL syringe filled with excess of TFA (3.0
mL, 39.2 mmol) was added into the vial A at a rate of 9 mL/hr by a syringe pump. The tube in
vial B was immersed into the solution after the first bubbles of SO2F2 appeared. Once bubbling
of SO2F2 subsided, into vial B was inserted an empty balloon to increase the bubbling rate. When
the bubbling had almost stopped, 6M NaOH (3.0 mL) was slowly added into vial A. After
completing generation of SO2F2, the tube was removed. Without opening the vial B,
trifluorotoluene (1 equiv) was added by a syringe into vial B as an internal standard. Without
opening the vial B, an aliquot was taken by a syringe for quantitative 19F NMR analysis to
confirm no TFA contaminant and quantify the amount of SO2F2 (Note: the chemical shift of the
two equivalent fluorines of SO2F2 appear at 33.8 ppm. Typically, about 1.5 to 2.5 equivalents of
SO2F2 were calculated to be in THF prior to addition of the other reagents). KF (4 equiv) and 18-
crown-6 (4 equiv) were added into vial B. A reaction mixture of 3-Phenyl-1-propanol 1a (0.6
mmol, 1 equiv), THF (4.0 mL), and DBU (1.8 mmol, 3 equiv) were added into vial B at 4 mL/hr
19
by a syringe pump. An aliquot was taken for quantitative F NMR analysis after stirring for one
hour (note: the amount of the aliquot is less than 0.1 mL which is less than 1% of the reaction
solution). Caution: Reaction vials can become pressurized during the generation of SO2F2. Note:
Picture of the assembly is available in the SI.
(3-fluoropropyl)benzene (2a)
Compound 2a was prepared on 0.6 mmol, 1.0 mmol and 10 mmol scale following the
general procedure C. The crude product was purified by column chromatography on silica (100%
pentane as eluent) to leave (3-fluoropropyl)benzene as a colorless liquid (55.0 mg, 66% for 0.6
mmol scale and 91.1 mg, 66% for 1.0 mmol scale, 100.8 mg, 73% for 10 mmol scale). The
1
spectroscopic data were consistent with those previously published. [36] H NMR (300 MHz,
Chloroform-d) δ 7.36 – 7.27 (m, 2H), 7.25 – 7.14 (m, 3H), 4.54 (t, J = 6.0 Hz, 1H), 4.38 (t, J =
6.0 Hz, 1H), 2.81 – 2.69 (m, 2H), 2.13 – 1.90 (m, 2H).13C{1H} NMR (75 MHz, Chloroform-d) δ
141.3, 128.6, 128.6, 126.2, 83.3 (d, J = 164.7 Hz), 32.2 (d, J = 19.8 Hz), 31.5 (d, J = 5.4 Hz). 19F
NMR (282 MHz, Chloroform-d) δ -220.4 (tt, J = 47.4, 25.2 Hz).

1-Bromo-2-(2-fluoroethyl)benzene (2b)
Compound 2b was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (100% petroleum ether as eluent)
to leave 1-bromo-2-(2-fluoroethyl)benzene as a colorless liquid (85.3 mg, 70% yield
contaminated with approx. 2% petroleum ether leading to 82.8 mg, 68% corrected yield). The
1
spectroscopic data were consistent with those previously published. [37] H NMR (300 MHz,
Chloroform-d) δ 7.56 (d, J = 7.5 Hz, 1H), 7.34 – 7.23 (m, 2H), 7.18 – 7.06 (m, 1H), 4.66 (dt, J =
47.0, 6.5 Hz, 2H), 3.18 (dt, J = 22.5, 6.5 Hz, 2H). 13C{1H} NMR (75 MHz, Chloroform-d) δ
136.5 (d, J = 6.3 Hz), 133.1, 131.5, 128.6, 127.7, 124.7, 82.6 (d, J = 169.2 Hz), 37.2 (d, J = 21.0
Hz). 19F NMR (282 MHz, Chloroform-d) δ -217.2 (td, J = 46.9, 23.0 Hz).
1-bromo-3-(2-fluoroethyl)benzene (2c)
Compound 2c was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (100% petroleum ether as eluent)
to leave 1-bromo-3-(2-fluoroethyl)benzene as a colorless liquid (85.1 mg, 70%).1H NMR (300
MHz, Chloroform-d) δ 7.43 – 7.34 (m, 2H), 7.23 – 7.13 (m, 2H), 4.62 (dt, J = 47.0, 6.4 Hz, 2H),
13
2.98 (dt, J = 24.2, 6.3 Hz, 2H). C{1H} NMR (75 MHz, Chloroform-d) δ 139.7 (d, J = 5.4 Hz),
19
132.1, 130.2, 130.0, 127.8, 122.7, 83.7 (d, J = 169.6 Hz), 36.6 (d, J = 20.7 Hz). F NMR (282
MHz, Chloroform-d) δ -216.5 (td, J = 47.2, 23.6 Hz). HRMS-EI (m/z) calculated for C8H8BrF:
201.9793. Found: 201.9799. IR (cm−1): 3064, 2966, 1568, 1473, 1428.
1-(2-fluoroethyl)-4-nitrobenzene (2d)
Compound 2d was prepared on 0.6 mmol scale following a modification to general
procedure C (1 equiv of base). The crude product was purified by column chromatography on
silica (5% ethyl acetate in petroleum ether as eluent) to leave 1-(2-fluoroethyl)-4-nitrobenzene as
a pale yellow solid (78.9 mg, 57%). The spectroscopic data were consistent with those
1
previously published. [38] H NMR (300 MHz, Chloroform-d) δ 8.24 – 8.13 (m, 2H), 7.47 –
7.36 (m, 2H), 4.77 (t, J = 6.0 Hz, 1H), 4.61 (t, J = 6.0 Hz, 1H), 3.16 (t, J = 6.0 Hz, 1H), 3.08 (t, J
= 6.0 Hz, 1H).13C{1H} NMR (75 MHz, Chloroform-d) δ 147.1, 145.2 (d, J = 4.0 Hz), 130.0,
123.9, 83.2 (d, J = 170.3 Hz), 36.8 (d, J = 20.7 Hz). 19F NMR (282 MHz, Chloroform-d) δ -
217.4 (tt, J = 47.0, 25.8 Hz).
1-(benzyloxy)-4-(2-fluoroethyl)benzene (2e)
Compound 2e was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (100% petroleum ether as eluent)
1
to leave 1-(benzyloxy)-4-(2-fluoroethyl)benzene as a colorless liquid (78.9 mg, 57%). H NMR
(300 MHz, Chloroform-d) δ 7.55 – 7.34 (m, 5H), 7.28 – 7.15 (m, 2H), 7.07 – 6.94 (m, 2H), 5.11
(s, 2H), 4.65 (dt, J = 47.2, 6.6 Hz, 2H), 3.02 (dt, J = 22.8, 6.6 Hz, 2H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 157.9, 137.3, 130.2, 129.6 (d, J = 6.6 Hz), 128.8, 128.2, 127.7, 115.2, 84.5 (d, J
19
= 168.9 Hz), 70.2, 36.3 (d, J = 20.3 Hz). F NMR (282 MHz, Chloroform-d) δ -215.1 (td, J =
47.0, 23.0 Hz). HRMS-EI (m/z) calculated for C15H15FO: 230.1107. Found: 230.1097. IR (cm−1):
3035, 2919, 2247, 1610, 1455, 1237.
4-(2-fluoroethyl)-1,2-dimethoxybenzene (2f)

Compound 2f was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (10% ethyl acetate in petroleum
ether as eluent) to leave 4-(2-fluoroethyl)-1,2-dimethoxybenzene as a colorless liquid (62.8 mg,
1
57%). The spectroscopic data were consistent with those previously published. [32] H NMR
(300 MHz, Chloroform-d) δ 6.91 – 6.60 (m, 3H), 4.61 (dt, J = 47.2, 6.6 Hz, 2H), 3.87 (d, J = 4.7
Hz, 6H), 2.96 (dt, J = 23.3, 6.6 Hz, 2H). 13C{1H} NMR (75 MHz, Chloroform-d) δ 149.1, 148.0,
129.8 (d, J = 6.4 Hz), 121.0, 112.4, 111.5, 84.4 (d, J = 168.8 Hz), 56.0, 56.0, 36.6 (d, J = 20.2
Hz). 19F NMR (282 MHz, Chloroform-d) δ -215.4 (tt, J = 47.0, 23.4 Hz).
2-(2-fluoroethyl)-1,3,5-trimethylbenzene (2g)
Compound 2g was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (100% petroleum ether as eluent)
1
to leave 2-(2-fluoroethyl)-1,3,5-trimethylbenzene as a colorless liquid (46.1 mg, 46%). H NMR
(300 MHz, Chloroform-d) δ 6.89 (s, 2H), 4.52 (dt, J = 47.2, 7.5 Hz, 2H), 3.10 (dt, J = 17.2, 7.5
Hz, 2H), 2.34 (s, 6H), 2.28 (s, 3H). 13C{1H} NMR (75 MHz, Chloroform-d) δ 137.1, 136.3,
19
130.0 (d, J = 9.5 Hz), 129.2, 82.5 (d, J = 170.4 Hz), 30.5 (d, J = 20.5 Hz), 21.0, 20.0. F NMR
(282 MHz, Chloroform-d) δ -213.3 (tt, J = 47.2, 17.1 Hz). HRMS-EI (m/z) calculated for
C11H15F: 166.1158. Found: 166.1155. IR (cm−1): 3004, 2966, 2920, 1613, 1447.
(1-fluoropropan-2-yl)benzene (2h)
Compound 2h was prepared on 0.6 mmol scale following the general procedure C. The crude
product was purified by column chromatography on silica (100% petroleum ether as eluent) to
leave (1-fluoropropan-2-yl)benzene as a colorless liquid (60.5 mg, 73% yield contaminated with
approx. 5% petroleum ether leading to 56.4 mg, 68% corrected yield). The spectroscopic data
were consistent with those previously published. [39] 1H NMR (300 MHz, Chloroform-d) δ 7.41
– 7.31 (m, 2H), 7.31 – 7.19 (m, 3H), 4.67 – 4.32 (m, 2H), 3.17 (dq, J = 16.7, 6.9 Hz, 1H), 1.37
(dd, J = 7.0, 1.2 Hz, 3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 142.2 (d, J = 6.2 Hz),
128.6, 127.4, 126.9, 88.1 (d, J = 173.0 Hz), 40.4 (d, J = 18.9 Hz), 16.9 (d, J = 5.7 Hz). 19F NMR
(282 MHz, Chloroform-d) δ -217.3 (td, J = 47.3, 16.5 Hz).
2-(4-fluorobutyl)isoindoline-1,3-dione (2i)
Compound 2i was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (15% ethyl acetate in petroleum
ether as eluent) to leave 2-(4-fluorobutyl)isoindoline-1,3-dione as a white solid (83.3 mg, 63%).
The spectroscopic data were consistent with those previously published. [40] 1H NMR (400 MHz,
Chloroform-d) δ 7.92 – 7.77 (m, 2H), 7.77 – 7.63 (m, 2H), 4.47 (dt, J = 47.7, 5.7 Hz, 2H), 3.73 (t,
13
J = 6.8 Hz, 2H), 1.87 – 1.65 (m, 4H). C{1H} NMR (101 MHz, Chloroform-d) δ 168.5, 134.1,
132.2, 123.4, 83.5 (d, J = 165.3 Hz), 37.6, 27.9 (d, J = 20.2 Hz), 24.7 (d, J = 4.9 Hz). 19F NMR
(282 MHz, Chloroform-d) δ -219.2 (tt, J = 48.3, 24.6 Hz).
3-fluoropropyl 3,4-dimethylbenzoate (2j)
Compound 2j was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (3% ethyl acetate in petroleum

ether as eluent) to leave 3-fluoropropyl 3,4-dimethylbenzoate as a colorless liquid (73.5 mg,
58%). 1H NMR (300 MHz, Chloroform-d) δ 7.65 (s, 2H), 7.19 (s, 1H), 4.62 (dt, J = 47.0, 5.5 Hz,
13
2H), 4.44 (t, J = 6.0 Hz, 2H), 2.36 (s, 6H), 2.17 (dt, J = 25.5, 5.8 Hz, 2H). C{1H} NMR (75
MHz, Chloroform-d) δ 166.9, 138.2, 134.8, 130.1, 127.4, 80.8 (d, J = 165.4 Hz), 60.9 (d, J = 5.5
Hz), 30.1 (d, J = 20.1 Hz), 21.3. 19F NMR (282 MHz, Chloroform-d) δ -222.4 (tt, J = 47.0, 25.5
Hz). HRMS-EI (m/z) calculated for C12H15FO2: 210.1056. Found: 210.1059. IR (cm−1): 3014,
2969, 1716, 1609, 1455, 1308, 1209.
1-(fluoromethyl)-4-(trifluoromethyl)benzene (2k)
Compound 2k was prepared on 1.0 mmol scale following the general procedure C. The
19F NMR spectroscopy yield of the desired product was 42%. The spectroscopic data were
19
consistent with those previously published. [41] F NMR (377 MHz, Chloroform-d) δ -65.8, -
216.0 (t, J = 47.2 Hz).
4-(fluoromethyl)pyridine (2l)
Compound 2k was prepared on 0.6 mmol scale following the general procedure C. The
19F NMR spectroscopy yield of the desired product was 20%. The spectroscopic data were
consistent with those previously published.[42] 19F{1H} NMR (282 MHz, Chloroform-d) δ -
222.5.
1-bromo-9-fluorononane (2m)
Compound 2m was prepared on 0.6 mmol scale following the general procedure C. The crude
product was purified by column chromatography on silica (100% petroleum ether as eluent) to
leave 1-bromo-9-fluorononane as a colorless liquid (77.3 mg, 57%). The spectroscopic data were
consistent with those previously published.[43] 1H NMR (300 MHz, Chloroform-d) δ 4.43 (dt, J
= 47.4, 6.2 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 1.85 (p, J = 6.9 Hz, 2H), 1.67 (ddt, J = 24.9, 8.0,
6.1 Hz, 2H), 1.48 – 1.24 (m, 10H). 13C{1H} NMR (75 MHz, Chloroform-d) δ 84.3 (d, J = 164.1
Hz), 34.1, 32.9, 30.5 (d, J = 19.3 Hz), 29.4, 29.2, 28.8, 28.3, 25.3 (d, J = 5.5 Hz). 19F NMR (282
MHz, Chloroform-d) δ -218.5 (tt, J = 47.2, 25.0 Hz).
1-fluorodecane (2n)
Compound 2n was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (100% petroleum ether as eluent)
to leave 1-fluorodecane as a colorless liquid (52.3 mg, 54%). The spectroscopic data were
1
consistent with those previously published. [44,45] H NMR (300 MHz, Chloroform-d) δ 4.43
(dt, J = 47.4, 6.2 Hz, 2H), 1.68 (dt, J = 24.6, 6.9 Hz, 2H), 1.44 – 1.26 (m, 14H), 0.89 (m, 3H).
13C{1H} NMR (75 MHz, Chloroform-d) δ 84.4 (d, J = 164.0 Hz), 32.0, 30.7, 30.4 (d, J = 1.9 Hz),
29.6, 29.4 (d, J = 3.9 Hz), 25.3 (d, J = 5.6 Hz), 22.8, 22.7, 14.2. 19F NMR (282 MHz,
Chloroform-d) δ -218.4 (tt, J = 48.0, 24.6 Hz).
1-fluorooctadecane (2o)
Compound 2o was prepared on 0.6 mmol scale following the general procedure C. The crude
product was purified by column chromatography on silica (100% petroleum ether as eluent) to
leave 1-fluorooctadecane as a white solid (98.3 mg, 60%). The spectroscopic data were
1
consistent with those previously published. [9] H NMR (300 MHz, Chloroform-d) δ 4.44 (dt, J

= 47.4, 6.2 Hz, 2H), 1.68 (ddt, J = 24.8, 8.0, 6.2 Hz, 2H), 1.48 – 1.14 (m, 30H), 0.93 – 0.84 (m,
3H). 13C{1H} NMR (75 MHz, Chloroform-d) δ 84.4 (d, J = 164.0 Hz), 32.1, 30.5 (d, J = 19.3
Hz), 29.8, 29.8, 29.8, 29.7, 29.7, 29.5, 29.4, 25.3 (d, J = 5.5 Hz), 22.8, 14.2. 19F NMR (282 MHz,
Chloroform-d) δ -218.3 (tt, J = 47.5, 24.6 Hz).
11-fluoroundec-1-ene (2p)
Compound 2p was prepared on 0.6 mmol scale following the general procedure C. The crude
product was purified by column chromatography on silica (100% petroleum ether as eluent) to
leave 11-fluoroundec-1-ene as a colorless liquid (48.1 mg, 51%). The spectroscopic data were
consistent with those previously published. [46] 1H NMR (300 MHz, Chloroform-d) δ 5.81 (ddt,
J = 16.9, 10.2, 6.7 Hz, 1H), 5.14 – 4.83 (m, 2H), 4.44 (dt, J = 47.4, 6.2 Hz, 2H), 2.13 – 1.97 (m,
2H), 1.80 – 1.61 (m, 2H), 1.43 – 1.28 (m, 10H). 13C{1H} NMR (75 MHz, Chloroform-d) δ 139.3,
114.3, 84.4 (d, J = 164.0 Hz), 33.9, 30.5 (d, J = 19.3 Hz), 29.5, 29.3, 29.1, 29.0, 25.3 (d, J = 5.6
Hz). 19F NMR (282 MHz, Chloroform-d) δ -218.1 – -218.8 (m).
4-fluorobut-1-yne (2q)
Compound 2q was prepared on 0.6 mmol scale following the general procedure C. The 19F NMR
spectroscopy yield of the desired product was 46%. 19F{1H} NMR (377 MHz, Chloroform-d) δ -
216.5.
3-fluoroprop-1-yne (2r)
19
Compound 2r was prepared on 0.6 mmol scale following the general procedure C. The F NMR
spectroscopy yield of the desired product was 54%. The spectroscopic data were consistent with
those previously published.[47] 19F{1H} NMR (377 MHz, Chloroform-d) δ -218.7.
5-fluoropent-1-yne (2s)
19
Compound 2s was prepared on 0.6 mmol scale following the general procedure C. The F NMR
spectroscopy yield of the desired product was 75%. The spectroscopic data were consistent with
those previously published.[48] 19F{1H} NMR (377 MHz, Chloroform-d) δ -222.9.
3-fluoroprop-1-ene (2t)
19
Compound 2t was prepared on 0.6 mmol scale following the general procedure C. The F NMR
spectroscopy yield of the desired product was 46%. The spectroscopic data were consistent with
those previously published.[47] 19F{1H} NMR (377 MHz, Chloroform-d) δ -216.9.
(8R,9S,10R,13S,14S,17R)-17-(2-fluoroacetyl)-17-hydroxy-10,13-dimethyl-
1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (2u)
Compound 2u was prepared on 0.6 mmol scale following the general procedure C. The crude
product was purified by column chromatography on silica (10% ethyl acetate in dichloromethane
as eluent) to leave (8R,9S,10R,13S,14S,17R)-17-(2-fluoroacetyl)-17-hydroxy-10,13-dimethyl-
1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one as
a
white solid (65.5 mg, 31%). Using 1 equivalent base, a white solid (137.1 mg, 66%) was
obtained. The spectroscopic data were consistent with those previously published. [49] 1H NMR
(300 MHz, Chloroform-d) δ 5.73 (s, 1H), 5.36 (dd, J = 47.9, 17.0 Hz, 1H), 5.09 (dd, J = 47.7,

17.0 Hz, 1H), 2.82 – 2.68 (m, 1H), 2.51 – 2.23 (m, 4H), 2.09 – 1.99 (m, 1H), 1.94 – 1.28 (m,
13
12H), 1.19 (s, 3H), 1.13 – 0.91 (m, 2H), 0.74 (s, 3H). C{1H} NMR (75 MHz, Chloroform-d) δ
206.1 (d, J = 13.0 Hz), 199.7, 171.0, 124.1, 90.0, 85.2 (d, J = 181.0 Hz), 53.4, 50.6, 48.6, 38.7,
35.9, 35.7, 35.0, 34.0, 32.9, 32.1, 30.5, 23.8, 20.7, 17.5, 15.1. 19F NMR (282 MHz, Chloroform-d)
δ -231.4 (t, J = 47.8 Hz).
(8R,9S,10R,13S,14S,17R)-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-
dodecahydrospiro[cyclopenta[a]phenanthrene-17,2'-oxetane]-3,3'(2H)-dione (2u’)
Compound 2u’ was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (10% ethyl acetate in
dichloromethane as eluent) to leave (8R,9S,10R,13S,14S,17R)-17-(2-fluoroacetyl)-17-hydroxy-
10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-
cyclopenta[a]phenanthren-3-one as a white solid (101.7 mg, 52%). Using 1 equivalent base, a
white solid (26.2 mg, 13%) was obtained. The spectroscopic data were consistent with those
1
previously published. [49] H NMR (300 MHz, Chloroform-d) δ 5.71 (s, 1H), 5.03 (d, J = 14.7
Hz, 1H), 4.91 (d, J = 14.7 Hz, 1H), 2.43 – 2.22 (m, 5H), 2.14 – 1.99 (m, 2H), 1.89 – 1.79 (m,
2H), 1.72 – 1.53 (m, 4H), 1.49 – 1.21 (m, 4H), 1.17 (s, 3H), 1.13 – 0.93 (m, 2H), 0.86 (s, 3H).
13C{1H} NMR (75 MHz, Chloroform-d) δ 206.3, 199.5, 170.8, 124.1, 118.6, 85.8, 53.2, 50.3,
48.5, 38.7, 35.8, 35.5, 34.0, 33.4, 32.8, 32.0, 30.5, 24.5, 20.5, 17.6, 13.9. HRMS-EI (m/z)
calculated for C21H28O3: 328.2038. Found: 328.2051.
fluorocyclopentane (2v)
Compound 2v was prepared on 0.6 mmol scale following the general procedure C. The
19F NMR spectroscopy yield of the desired product was 73% with, while 65% was obtained
without using KF and 18-crown-6. The spectroscopic data were consistent with those previously
published. [35,50] 19F{1H} NMR (377 MHz, Chloroform-d) δ -170.9.
2-fluoropentane (2w)
Compound 2w was prepared on 0.6 mmol scale following the general procedure C. The 19F
NMR spectroscopy yield of the desired product was 65%. The spectroscopic data were consistent
with those previously published. [47] 19F{1H} NMR (377 MHz, Chloroform-d) δ -173.5.
(fluoromethylene)dibenzene (2x)
Compound 2x was prepared on 0.6 mmol scale following the general procedure C. The
19F NMR spectroscopy yield of the desired product was 79%. The spectroscopic data were
19
consistent with those previously published. [51–53] F{1H} NMR (377 MHz, Chloroform-d) δ
-166.7.
(R)-(3-fluorobutyl)benzene (2y)
Compound 2y was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (100% petroleum ether as eluent)
to leave (R)-(3-fluorobutyl)benzene as a colorless liquid (83.8 mg, 92%). The spectroscopic data
1
were consistent with those previously published. [45,54] H NMR (300 MHz, Chloroform-d) δ
7.34 – 7.26 (m, 2H), 7.20 (dt, J = 9.8, 3.1 Hz, 3H), 4.84 – 4.49 (m, 1H), 2.89 – 2.59 (m, 2H),
13
2.12 – 1.68 (m, 2H), 1.35 (dd, J = 23.9, 6.2 Hz, 3H). C{1H} NMR (75 MHz, Chloroform-d) δ

141.6, 128.6, 126.1, 90.2 (d, J = 164.9 Hz), 38.8 (d, J = 20.9 Hz), 31.5 (d, J = 4.8 Hz), 21.1 (d, J
19
= 22.7 Hz). F NMR (282 MHz, Chloroform-d) δ -174.3 – -175.0 (m). [훼]2퐷3 = –16.3 (c 1.4,
CHCl3, 94% ee) HPLC: Chiralcel® OD-3, Hexane = 100%, Flow rate = 0.6 mL/min, UV = 210
nm, tR (minor) = 12.5 min and tR (major) = 12.8 min.
(R)-((2-fluoropropoxy)methyl)benzene (2z)
Compound 2z was prepared on 0.6 mmol scale following the general procedure C. The
crude product was purified by column chromatography on silica (30% dichloromethane in
petroleum ether as eluent) to leave (R)-((2-fluoropropoxy)methyl)benzene as a colorless liquid
(88.2 mg, 87%). The spectroscopic data were consistent with those previously published. [55] 1H
NMR (300 MHz, Chloroform-d) δ 7.40 – 7.27 (m, 5H), 5.00 – 4.70 (m, 1H), 4.60 (d, J = 1.2 Hz,
2H), 3.74 – 3.45 (m, 2H), 1.35 (dd, J = 23.6, 6.4 Hz, 3H). 13C{1H} NMR (75 MHz, Chloroform-
d) δ 138.1, 128.6, 127.9, 127.8, 89.7 (d, J = 168.2 Hz), 73.6, 73.2 (d, J = 21.9 Hz), 17.6 (d, J =
19
22.4 Hz). F NMR (282 MHz, Chloroform-d) δ -179.8 (tq, J = 47.3, 23.7 Hz). [훼]2퐷3 = –3.2 (c
1.2, CHCl3, 95% ee) HPLC: Chiralcel® OD-3, Hexane : Propan-2-ol = 97% : 3%, Flow rate =
1.0 mL/min, UV = 210 nm, tR (major) = 5.1 min and tR (minor) = 6.5 min.
3α-Fluoro-5α-cholestane (2za)
Compound 2za was prepared on 0.6 mmol scale following the general procedure C. The crude
product was purified by column chromatography on silica (100% petroleum ether as eluent) to
leave 3α-Fluoro-5α-cholestane as a white solid (117.9 mg, 51%). The spectroscopic data were
consistent with those previously published. [35] 1H NMR (300 MHz, Chloroform-d) δ 4.80 (d, J
= 48.5 Hz, 1H), 2.01 – 1.90 (m, 1H), 1.90 – 1.84 (m, 1H), 1.84 – 1.77 (m, 1H), 1.70 – 1.61 (m,
2H), 1.53 (s, 7H), 1.41 – 1.19 (m, 10H), 1.11 (td, J = 14.0, 12.9, 6.8 Hz, 6H), 1.05 – 0.96 (m,
3H), 0.89 (d, J = 6.5 Hz, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.77 (s, 3H), 0.64 (s, 3H). 13C{1H}
NMR (75 MHz, Chloroform-d) δ 89.7 (d, J = 165.6 Hz), 56.6, 56.4, 54.2, 42.7, 40.1, 39.7, 39.5,
36.3, 35.9, 35.8, 35.6, 34.1 (d, J = 21.1 Hz), 32.5, 32.1, 28.5, 28.4, 28.1, 27.2 (d, J = 22.1 Hz),
24.3, 24.0, 23.0, 22.7, 20.9, 18.8, 12.2, 11.3. 19F NMR (282 MHz, Chloroform-d) δ -178.7 – -
183.6 (m).
4.4. Synthesis of alcohols
2-(4-hydroxybutyl)isoindoline-1,3-dione (1i)
4-amino-1-butanol (10 mmol, 1 equiv.), phthalimide (20 mmol, 2 equiv.) and iron (III)
nitrate nonahydrate (0.5 mmol, 0.05 equiv.) were suspended in toluene (10 mL). The resulting
reaction mixture was stirred under reflux for 17 hours, then allowed to cool down, diluted with
ethyl acetate (20 mL) and filtered through celite. The filtrate was concentrated under reduced
pressure and the resulting residue was diluted with 3% MeOH/DCM. The undissolved solid
(phthalimide) was filtered off and the product 1i was isolated by flash column chromatography
(3% to 5% MeOH/DCM) as a straw-coloured solid (1.69 g, 76% yield). The spectroscopic data
match a literature report. [56] 1H NMR (300 MHz, CDCl3) δ 7.91 – 7.79 (m, 2H), 7.78 – 7.66 (m,
2H), 3.80 – 3.65 (m, 4H), 1.88 – 1.73 (m, 2H), 1.71 (s, 1H), 1.69 – 1.55 (m, 2H). 13C{1H} NMR
(75 MHz, CDCl3) δ 168.6, 134.0, 132.2, 123.3, 62.3, 37.8, 29.9, 25.2.
3-hydroxypropyl 3,5-dimethylbenzoate (1j)

A solution of propane-1,3-diol (45 mmol, 3 equiv.) and Et3N (30 mmol, 2 equiv.) in
DCM (75 mL) was cooled down to 0 °C. To the mixture was added 3,5-dimethylbenzoyl
chloride (15 mmol, 1 equiv.) dropwise over 5 minutes. The mixture was warmed up to room
temperature and allowed to stir for 17 hours. The solution was transferred to a separatory funnel,
diluted with 75 mL of water and the layers were separated. The aqueous layer was extracted with
DCM (3 x 50 mL) and the combined organics were washed with brine (75 mL), dried over
Na2SO4 and concentrated under reduced pressure. The product 1j was isolated via flash column
1
chromatography (50% ethyl acetate/hexanes) as a clear oil (1.73 g, 55% yield). H NMR (300
MHz, CDCl3) δ 7.62 (s, 2H), 7.15 (s, 1H), 4.43 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H), 2.89
(bs, 1H), 2.32 (s, 6H), 1.98 (p, J = 6.2 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 167.4, 138.0,
134.7, 129.9, 127.3, 61.8, 59.0, 31.9, 21.1. LRMS-ESl (m/z): 231.2 [M+Na] +.
Corresponding Author
Glenn M. Sammis − Department of Chemistry, University of British Columbia, Vancouver,
British Columbia V6T 1Z1, Canada; orcid.org/0000-0002-8204-8571; Email:
gsammis@chem.ubc.ca
Author Contributions
Cayo Lee − Department of Chemistry, University of British Columbia, Vancouver, British
Columbia V6T 1Z1, Canada; orcid.org/0000-0002-0743-6187
Joey Lai − Department of Chemistry, University of British Columbia, Vancouver, British
Columbia V6T 1Z1, Canada;
Maxim Epifanov − Department of Chemistry, University of British Columbia, Vancouver, British
Columbia V6T 1Z1, Canada;
Cindy Xinyun Wang − Department of Chemistry, University of British Columbia, Vancouver,
British Columbia V6T 1Z1, Canada;
Declaration of Competing Interest
The authors declare no competing financial interest.
Funding
Research reported in this publication was supported by the University of British Columbia
(UBC), and the Natural Sciences and Engineering Resource Council of Canada (2020- RGPIN-
04653).
Acknowledgments
G.M.S., C.L., M.E., J.L. and C.W. thank the University of British Columbia (UBC), and the
Natural Sciences and Engineering Resource Council of Canada (NSERC) for funding.
Supplementary materials
Supplementary material associated with this article can be found, in the online version

References
[1] M. Morgenthaler, E. Schweizer, A. Hoffmann-Röder, F. Benini, R.E. Martin, G. Jaeschke,
B. Wagner, H. Fischer, S. Bendels, D. Zimmerli, J. Schneider, F. Diederich, M. Kansy, K.
Müller, Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine
Basicities, ChemMedChem. 2 (2007) 1100–1115.
doi:https://doi.org/10.1002/cmdc.200700059.
[2] G. Theodoridis, Chapter 4 Fluorine-Containing Agrochemicals: An Overview of Recent
Developments, in: A.B.T.-A. in F.S. Tressaud (Ed.), Fluor. Environ., Elsevier, 2006: pp.
121–175. doi:https://doi.org/10.1016/S1872-0358(06)02004-5.
[3] M. Inoue, Y. Sumii, N. Shibata, Contribution of Organofluorine Compounds to
Pharmaceuticals, ACS Omega. 5 (2020) 10633–10640. doi:10.1021/acsomega.0c00830.
[4] J. Wang, M. Sánchez-Roselló, J.L. Aceña, C. del Pozo, A.E. Sorochinsky, S. Fustero, V.A.
Soloshonok, H. Liu, Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs
Introduced to the Market in the Last Decade (2001–2011), Chem. Rev. 114 (2014) 2432–
2506. doi:10.1021/cr4002879.
[5] Y. Ogawa, E. Tokunaga, O. Kobayashi, K. Hirai, N. Shibata, Current Contributions of
Organofluorine Compounds to the Agrochemical Industry, IScience. 23 (2020) 101467.
doi:https://doi.org/10.1016/j.isci.2020.101467.
[6] A. Takaoka, H. Iwakiri, N. Ishikawa, F-Propene-Dialkylamine Reaction Products as
Fluorinating Agents, Bull. Chem. Soc. Jpn. 52 (1979) 3377–3380.
doi:10.1246/bcsj.52.3377.
[7] G. Bellavance, P. Dubé, B. Nguyen, Tetramethylfluoroformamidinium
Hexafluorophosphate (TFFH) as a Mild Deoxofluorination Reagent, Synlett. 2012 (2012)
569–574.
[8] F. Sladojevich, S.I. Arlow, P. Tang, T. Ritter, Late-Stage Deoxyfluorination of Alcohols
with PhenoFluor, J. Am. Chem. Soc. 135 (2013) 2470–2473. doi:10.1021/ja3125405.
[9] L. Li, C. Ni, F. Wang, J. Hu, Deoxyfluorination of alcohols with 3,3-difluoro-1,2-
diarylcyclopropenes, Nat. Commun. 7 (2016) 13320. doi:10.1038/ncomms13320.
[10] W.C. Smith, The Chemistry of Sulfur Tetraflouride, Angew. Chemie Int. Ed. English. 1
(1962) 467–475. doi:https://doi.org/10.1002/anie.196204671.
[11] W.J. Middleton, New fluorinating reagents. Dialkylaminosulfur fluorides, J. Org. Chem.
40 (1975) 574–578. doi:10.1021/jo00893a007.
[12] G.S. Lal, G.P. Pez, R.J. Pesaresi, F.M. Prozonic, H. Cheng, Bis(2-
methoxyethyl)aminosulfur Trifluoride:ꢀ A New Broad-Spectrum Deoxofluorinating Agent
with Enhanced Thermal Stability, J. Org. Chem. 64 (1999) 7048–7054.
doi:10.1021/jo990566+.
[13] F. Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F. LaFlamme, A. L’Heureux,

Aminodifluorosulfinium Tetrafluoroborate Salts as Stable and Crystalline
Deoxofluorinating Reagents, Org. Lett. 11 (2009) 5050–5053. doi:10.1021/ol902039q.
[14] T. Umemoto, R.P. Singh, Y. Xu, N. Saito, Discovery of 4-tert-Butyl-2,6-
dimethylphenylsulfur Trifluoride as a Deoxofluorinating Agent with High Thermal
Stability as Well as Unusual Resistance to Aqueous Hydrolysis, and Its Diverse
Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation , J. Am. Chem. Soc.
132 (2010) 18199–18205. doi:10.1021/ja106343h.
[15] A. Baranczak, Y. Liu, S. Connelly, W.-G.H. Du, E.R. Greiner, J.C. Genereux, R.L.
Wiseman, Y.S. Eisele, N.C. Bradbury, J. Dong, L. Noodleman, K.B. Sharpless, I.A.
Wilson, S.E. Encalada, J.W. Kelly, A Fluorogenic Aryl Fluorosulfate for Intraorganellar
Transthyretin Imaging in Living Cells and in Caenorhabditis elegans, J. Am. Chem. Soc.
137 (2015) 7404–7414. doi:10.1021/jacs.5b03042.
[16] P.A. Champagne, J. Desroches, J.-D. Hamel, M. Vandamme, J.-F. Paquin,
Monofluorination of Organic Compounds: 10 Years of Innovation, Chem. Rev. 115 (2015)
9073–9174. doi:10.1021/cr500706a.
[17] J. Guo, C. Kuang, J. Rong, L. Li, C. Ni, J. Hu, Rapid Deoxyfluorination of Alcohols with
N-Tosyl-4-chlorobenzenesulfonimidoyl Fluoride (SulfoxFluor) at Room Temperature,
Chem. – A Eur. J. 25 (2019) 7259–7264. doi:https://doi.org/10.1002/chem.201901176.
[18] C. Veryser, J. Demaerel, V. Bieliunas, P. Gilles, W.M. De Borggraeve, Ex Situ
̅
Generation of Sulfuryl Fluoride for the Synthesis of Aryl Fluorosulfates, Org. Lett. 19
(2017) 5244–5247. doi:10.1021/acs.orglett.7b02522.
[19] J.Y. Mo, M. Epifanov, J.W. Hodgson, R. Dubois, G.M. Sammis, One-Pot Substitution of
Aliphatic Alcohols Mediated by Sulfuryl Fluoride, Chem. – A Eur. J. 26 (2020) 4958–
4962. doi:https://doi.org/10.1002/chem.202000721.
[20] M. Epifanov, J.Y. Mo, R. Dubois, H. Yu, G.M. Sammis, One-Pot Deoxygenation and
Substitution of Alcohols Mediated by Sulfuryl Fluoride, J. Org. Chem. 86 (2021) 3768–
3777. doi:10.1021/acs.joc.0c02557.
[21] A. Ishi, T. Ootsuka, M. Yasumoto, H. Tsuruta, K. Inomiya, K. Ueda, K. Mogi, Process for
the preparation of fluoro compounds from alcohols using sulfuryl fluoride. EP 1842841
B1, 2013.
[22] A. Ishii, H. Tsuruta, T. Ootsuka, Y. Kuriyama, M. Yasumoto, K. Inomiya, K. Ueda,
Process for the preparation of optically active α-fluorocarboxylic ester derivatives.
US 20080103327 A1, 2008.
[23] A. Ishii, T. Yamazaki, M. Yasumoto, Process for preparation of optically active
fluoroamines. US 8426645 B2, 2013.
[24] A. Ishii, M. Yasumoto, Process for preparation of halogenated α-fluoroethers. US
8304576 B2, 2012.
[25] A. Ishii, M. Yasumoto, K. Ueda, Method for manufacturing hydroxyl group substitution
product. US 20110251403 A1, 2011.

[26] A. Ishii, M. Yasumoto, Method for the preparation of fluorosulfuric acid ester. US
8835669 B2, 2014.
[27] A. Ishii, T. Otsuka, M. Yasumoto, H. Tsuruta, K. Inomiya, K. Ueda, K. Motegi,
Dehydroxylating fluorinating agent and fluorination of hydroxy compounds using said
agent. US 8058412 B2, 2011.
[28] M. Epifanov, P.J. Foth, F. Gu, C. Barrillon, S.S. Kanani, C.S. Higman, J.E. Hein, G.M.
Sammis, One-Pot 1,1-Dihydrofluoroalkylation of Amines Using Sulfuryl Fluoride, J. Am.
Chem. Soc. 140 (2018) 16464–16468. doi:10.1021/jacs.8b11309.
[29] P.J. Foth, F. Gu, T.G. Bolduc, S.S. Kanani, G.M. Sammis, New sulfuryl fluoride-derived
alkylating reagents for the 1,1-dihydrofluoroalkylation of thiols, Chem. Sci. 10 (2019)
10331–10335. doi:10.1039/c9sc03570b.
[30] C. Lee, N.D. Ball, G.M. Sammis, One-pot fluorosulfurylation of Grignard reagents using
sulfuryl fluoride, Chem. Commun. 55 (2019) 14753–14756. doi:10.1039/C9CC08487H.
[31] We have screened different solvents, including ACN, DMF, DCM, EtOAc, and toluene,
but the yields were lower than THF (See SI for details).
[32] M.K. Nielsen, C.R. Ugaz, W. Li, A.G. Doyle, PyFluor: A Low-Cost, Stable, and Selective
Deoxyfluorination Reagent, J. Am. Chem. Soc. 137 (2015) 9571–9574.
doi:10.1021/jacs.5b06307.
[33] R. Lekkala, R. Lekkala, B. Moku, K.P. Rakesh, H.-L. Qin, Applications of sulfuryl
fluoride (SO2F2) in chemical transformations, Org. Chem. Front. 6 (2019) 3490–3516.
doi:10.1039/C9QO00747D.
[34] P.J. Foth, T.C. Malig, H. Yu, T.G. Bolduc, J.E. Hein, G.M. Sammis, Halide-Accelerated
Acyl Fluoride Formation Using Sulfuryl Fluoride, Org. Lett. 22 (2020) 6682–6686.
doi:10.1021/acs.orglett.0c02566.
[35] M. González-Esguevillas, J. Miró, J.L. Jeffrey, D.W.C. MacMillan, Photoredox-catalyzed
deoxyfluorination of activated alcohols with Selectfluor®, Tetrahedron. 75 (2019) 4222–
4227. doi:https://doi.org/10.1016/j.tet.2019.05.043.
[36] G.K.S. Prakash, S. Chacko, H. Vaghoo, N. Shao, L. Gurung, T. Mathew, G.A. Olah,
Efficient Nucleophilic Fluoromethylation and Subsequent Transformation of Alkyl and
Benzyl Halides Using Fluorobis(phenylsulfonyl)methane, Org. Lett. 11 (2009) 1127–1130.
doi:10.1021/ol8029627.
[37] L. Zhang, W. Zhang, J. Liu, J. Hu, C−F Bond Cleavage by Intramolecular SN2 Reaction
of Alkyl Fluorides with O- and N-Nucleophiles, J. Org. Chem. 74 (2009) 2850–2853.
doi:10.1021/jo802819p.
[38] N.J. Taylor, E. Emer, S. Preshlock, M. Schedler, M. Tredwell, S. Verhoog, J. Mercier, C.
Genicot, V. Gouverneur, Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic
Positron Emission Tomography Radioligands, J. Am. Chem. Soc. 139 (2017) 8267–8276.
doi:10.1021/jacs.7b03131.
[39] S. Ventre, F.R. Petronijevic, D.W.C. MacMillan, Decarboxylative Fluorination of

Aliphatic Carboxylic Acids via Photoredox Catalysis, J. Am. Chem. Soc. 137 (2015)
5654–5657. doi:10.1021/jacs.5b02244.
[40] Z. Li, Z. Wang, L. Zhu, X. Tan, C. Li, Silver-Catalyzed Radical Fluorination of
Alkylboronates in Aqueous Solution, J. Am. Chem. Soc. 136 (2014) 16439–16443.
doi:10.1021/ja509548z.
[41] J. Zhu, M. Pérez, D.W. Stephan, C−C Coupling of Benzyl Fluorides Catalyzed by an
Electrophilic Phosphonium Cation, Angew. Chemie Int. Ed. 55 (2016) 8448–8451.
doi:https://doi.org/10.1002/anie.201603627.
[42] W. Ying, D.D. DesMarteau, Y. Gotoh, N-fluoro-bis[(trifluoromethyl)sulfonyl]imide:
Electrophilic fluorination of imines and some methyl-substituted pyridines, Tetrahedron.
52 (1996) 15–22. doi:https://doi.org/10.1016/0040-4020(95)00884-B.
[43] K.-Y. Kim, B.C. Kim, H.B. Lee, H. Shin, Nucleophilic Fluorination of Triflates by
Tetrabutylammonium Bifluoride, J. Org. Chem. 73 (2008) 8106–8108.
doi:10.1021/jo8015659.
[44] D. Albanese, D. Landini, M. Penso, Hydrated Tetrabutylammonium Fluoride as a
Powerful Nucleophilic Fluorinating Agent, J. Org. Chem. 63 (1998) 9587–9589.
doi:10.1021/jo981522o.
[45] X. Ma, M. Diane, G. Ralph, C. Chen, M.R. Biscoe, Stereospecific Electrophilic
Fluorination of Alkylcarbastannatrane Reagents, Angew. Chemie Int. Ed. 56 (2017)
12663–12667. doi:https://doi.org/10.1002/anie.201704672.
[46] M. Janjetovic, A.M. Träff, G. Hilmersson, Mild and Selective Activation and Substitution
– A Eur. J. 21 (2015) 3772–3777.
doi:https://doi.org/10.1002/chem.201406097.
[47] F.J. Weigert, Fluorine magnetic resonance spectra of monofluoro- and difluoro-substituted
hydrocarbons, J. Org. Chem. 45 (1980) 3476–3483. doi:10.1021/jo01305a022.
[48] S.H. Hausner, J. Marik, M.K.J. Gagnon, J.L. Sutcliffe, In Vivo Positron Emission
Tomography (PET) Imaging with an αvβ6 Specific Peptide Radiolabeled using 18F-
“Click” Chemistry: Evaluation and Comparison with the Corresponding 4-
[18F]Fluorobenzoyl- and 2-[18F]Fluoropropionyl-Peptides, J. Med. Chem. 51 (2008)
5901–5904. doi:10.1021/jm800608s.
[49] C.G. Bergstrom, P.B. Sollman, R.T. Nicholson, R.M. Dodson, 21-Halo-17-
acyloxyprogesterones, J. Am. Chem. Soc. 82 (1960) 2322–2327.
doi:10.1021/ja01494a055.
[50] H.-J. Schneider, W. Gschwendtner, D. Heiske, V. Hoppen, F. Thomas, 13C-19F couplings
and 19F NMR shifts of cycloalkyl, bicycloalkyl and steroid monofluoro compounds11Part
XIV: 13C NMR Spectroscopical and Stereochemical Investigations; Part XIII: H.-J.
Schneider and L. Sturm, Angew. Chem. 88, 574 (1976); Int. Ed. 15, 545 , Tetrahedron. 33
(1977) 1769–1773. doi:https://doi.org/10.1016/0040-4020(77)84058-1.
[51] J.-B. Xia, C. Zhu, C. Chen, Visible Light-Promoted Metal-Free C–H Activation:
Diarylketone-Catalyzed Selective Benzylic Mono- and Difluorination, J. Am. Chem. Soc.

135 (2013) 17494–17500. doi:10.1021/ja410815u.
[52] X. Wu, C. Meng, X. Yuan, X. Jia, X. Qian, J. Ye, Transition-metal-free visible-light
photoredox catalysis at room-temperature for decarboxylative fluorination of aliphatic
carboxylic acids by organic dyes, Chem. Commun. 51 (2015) 11864–11867.
doi:10.1039/C5CC04527D.
[53] I. Mallov, A.J. Ruddy, H. Zhu, S. Grimme, D.W. Stephan, C−F Bond Activation by
Silylium Cation/Phosphine Frustrated Lewis Pairs: Mono-Hydrodefluorination of PhCF3,
PhCF2H and Ph2CF2, Chem. – A Eur. J. 23 (2017) 17692–17696.
doi:https://doi.org/10.1002/chem.201705276.
[54] D.E. Sood, S. Champion, D.M. Dawson, S. Chabbra, B.E. Bode, A. Sutherland, A.J.B.
Watson, Deoxyfluorination with CuF2: Enabled by Using a Lewis Base Activating Group,
Angew. Chemie Int. Ed. 59 (2020) 8460–8463.
doi:https://doi.org/10.1002/anie.202001015.
[55] A.M. Träff, M. Janjetovic, G. Hilmersson, C–F bond substitution via aziridinium ion
intermediates, Chem. Commun. 51 (2015) 13260–13263. doi:10.1039/C5CC04723D.
[56] E.A. Wappes, K.M. Nakafuku, D.A. Nagib, Directed β C–H Amination of Alcohols via
Radical Relay Chaperones, J. Am. Chem. Soc. 139 (2017) 10204–10207.
doi:10.1021/jacs.7b05214.