New sulfuryl fluoride-derived alkylating reagents for the 1,1-dihydrofluoroalkylation of thiols

Article abstract of DOI:10.1039/c9sc03570b

Herein, we report a new method for the one-pot synthesis of 1,1-dihydrofluoroalkyl sulfides by bubbling sulfuryl fluoride (SO₂F₂) through a solution of the corresponding alcohol and thiol. The reaction proceeds through a new class of bis(1,1-dihydrofluoroalkyl) sulfate reagents, to afford the desired 1,1-dihydrofluoroalkyl sulfides in 55-90% isolated yields. The bis(1,1-dihydrofluoroalkyl) sulfates are highly chemoselective for thiol alkylation, and are unreactive with competing, unprotected nucleophiles, including amines, alcohols, and carboxylic acids.

Full text of DOI:10.1039/c9sc03570b

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DOI: 10.1039/C9SC03570B
ARTICLE
New Sulfuryl Fluoride-Derived Alkylating Reagents for the 1,1-
Dihydrofluoroalkylation of Thiols
Paul J. Fotha, Frances Gua, Trevor G. Bolduca, Sahil S. Kanania, Glenn M. Sammis*a
Received 00th January 20xx,
Accepted 00th January 20xx
ABSTRACT: Herein, we report a new method for the one-pot synthesis of 1,1-dihydrofluoroalkyl sulfides by bubbling sulfuryl
fluoride (SO2F2) through a solution of the corresponding alcohol and thiol. The reaction proceeds through a new class of
bis(1,1-dihydrofluoroalkyl) sulfate reagents, to afford the desired 1,1-dihydrofluoroalkyl sulfides in 55-90% isolated yields.
The bis(1,1-dihydrofluoroalkyl) sulfates are highly chemoselective for thiol alkylation, and are unreactive with competing,
unprotected nucleophiles, including amines, alcohols, and carboxylic acids.
DOI: 10.1039/x0xx00000x
Sulfuryl fluoride (SO2F2) has been utilized since the 1960s as an fluoride is bubbled through a solution of the requisite oxygen
industrial fumigant,1 but it has only recently attracted nucleophile and
base, which is usually N,N-
a
significant attention as a reagent for organic synthesis.1b,2 diisopropylethylamine (DIPEA), triethylamine, or a carbonate
Studies have demonstrated that oxygen nucleophiles, such as salt.1b,2-7 Despite the expansion of the use of sulfuryl fluoride,
alcohols (1),3,4 phenol derivatives (2),1b,5 oximes (3),6 and the only reactive intermediates that have been identified are
carboxylic acids (4),7 react with sulfuryl fluoride to form fluorosulfate derivatives (5), and no other sulfuryl fluoride-
fluorosulfate derivatives (Scheme 1).2 The addition of a second derived reactive intermediates have been explored.10
equivalent of the oxygen nucleophile is kinetically slow, which
We previously reported that bubbling sulfuryl fluoride
allows fluorosulfate 5 to undergo subsequent transformations.8 through a solution of 2,2,2-trifluoroethanol (1a) and an amine
Fluorosulfates (5) have been utilized as key reactants in a base, such as DIPEA or triethylamine, afforded trifluoroethyl
diverse range of reactions, including metal-catalyzed cross fluorosulfate (5a, R” = CH2CF3) in >90% yield.3a,11 Following up
couplings,5c,9
click
reactions,1b,5d
deoxyfluorinations,5b on the synthesis and reactivity of fluorosulfate 5a in new
alkylations,3a,4 nitrile syntheses,6 and the formation of amide transformations, we serendipitously discovered that even
bonds.7a
moderately more basic reagents,12 such as 1,8-
All current synthetic methods rely on a very similar protocol diazabicyclo[5.4.0]undec-7-ene (DBU) with a pKaH of 12,13
for the formation of the fluorosulfate intermediate. Sulfuryl afforded bis(trifluoroethyl) sulfate (6a) as the major product,
and only trace amounts of fluorosulfate 5a were detected by 19
F
Previous work: representative SO2F2-derived fluorosulfate intermediates.
NMR spectroscopy. Bis(trifluoroethyl) sulfate (6a) is an
intriguing species as there are only two previous methods for its
synthesis,14–16 and there are no studies investigating its
reactivity.17
SO2F2
Base
SO2F2
Base
R'
N
Rf
OH
OH
1
3
R
O
O
O
SO2F2
Base
SO2F2
Base
Ar
We elected to study the reactivity of this new
bis(trifluoroethyl) sulfate intermediate (6a) for the 1,1-
dihydrofluoroalkylation of thiols for two reasons: (1) the
resulting fluoroalkyl sulfides are important fluorinated motifs in
pharmaceuticals and agrochemicals,18–20 and (2) the more
common sulfuryl fluoride-derived reagent, trifluoroethyl
fluorosulfate 5a, is not an effective intermediate for thiol
alkylation. Previous studies by Shreeve and coworkers indicated
that the reaction between methane thiol (7), triethylamine, and
5a afforded the corresponding fluoroalkyl sulfide (8) in only 31%
yield and a 2.2:1 preference for reactivity at carbon compared
to sulfur (Scheme 2, A).14
OH
R"
S
O
F
R
OH
2
5
4
This work: new SO2F2-derived bis(1,1-dihydrofluoroalkyl) sulfate intermediates.
O
O
SO2F2
DBU
S
Rf
O
O
Rf
Rf
OH
1
6
1a: Rf = CF3
6a: Rf = CF3
1b: Rf = CF2CF3
6b: Rf = CF2CF3
Scheme 1 Representative examples of sulfuryl fluoride-mediated processes that utilize
fluorosulfate reactive intermediates (5) and a new bis(trifluoroalkyl) sulfate (6).
a. Department of Chemistry, University of British Columbia, 2036 Main Mall,
Vancouver, British Columbia V6T 1Z1, Canada
* Corresponding authors
To examine the viability of bis(trifluoroethyl) sulfate (6a) as a
thiol alkylating reagent, we treated a solution of 6a and DBU
with benzyl mercaptan (9a), which led to a 99% 19F NMR yield
of 1,1-dihydrofluoroalkylated product 10a (Scheme 2, B). The
Email: gsammis@chem.ubc.ca
Electronic Supplementary Information (ESI) available: [Experimental procedures,
methods, and optimization data; NMR, IR, and MS data including 1H, 13C, and 19F
NMR spectra]. See DOI: 10.1039/x0xx00000x
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A. Reactivity of fluorosulfate 5a with methane thiol.14
Table 1 Optimization of the one-pot, 1,1-dihydrofluoroalkylation of benzyl mercaptan
View Article Online
DOI: 10.1039/C9SC03570B
(9a).
O
O
CH3SH (7), NEt3
S
H3C
F
O
CF3
S
CF3
SO2F2
DBU
–196 °C to rt
5a
8
31%
SH
9a
S
CF3
trifluoroethanol (1a)
B. Reactivity fo bis(trifluoroethyl) sulfate (6a) with benzyl mercaptan.
10a
conditions
then
SH
SO2F2
DBU
O
O
entry
solvent
DMF
DMF
DMF
THF
temp (°C)
19F NMR yielda (%)
9a
S
S
CF3
1a
CF3
O
O
CF3
1
2
3
4
5
6
7
8
25
40
60
40
40
40
40
40
71
86
85
81
77
75
67
38
DMF
99%
10a
6a
C. Reactivity fo fluorosulfate 5a with benzyl mercaptan.
then
SH
ACN
SO2F2
DIPEA
O
O
9a
S
S
CF3
hexane
benzene
DCM
1a
F
O
CF3
DMF
52%
10a
5a
ref 14a
All reactions were carried out following a one-pot procedure on 0.30 mmol scale
Scheme
2
Investigations into thiol alkylation using fluorosulfate (5a) and
a
of 9a and a 1:1 v/v trifluoroethanol:solvent ratio. Yield after 20 minutes, as
determined by 19F NMR spectroscopy using trifluorotoluene as an internal
standard.
bis(trifluoroethyl) sulfate (6a). The yields in B and C were determined by 19F NMR
spectroscopy using trifluorotoluene as an internal standard.
analogous reaction with a solution of DIPEA and fluorosulfate
5a with 9a afforded only 52% yield of 10a (Scheme 2, C), which
is comparable to the result reported by Shreeve and
coworkers.14 The addition of DBU and benzyl mercaptan to a
solution of DIPEA and 5a improved the yield; however, the
reaction led to an increase in the amount of free
trifluoroethanol in solution, presumably resulting from
nucleophilic attack at sulfur.21
This initial result is noteworthy as it represents the first
example of the direct conversion of an unactivated 1,1-
dihydrofluoroalcohol to the corresponding fluoroalkyl sulfide in
a one-pot process. Thiol 1,1-dihydrofluoroalkylation can be
achieved through nucleophilic displacement of activated
trifluoroalkyl moieties,14,22 copper-catalyzed reactions with
trifluoroalkyl iodide23 or trifluorodiazoalkanes,24 or reductive
trifluoroalkylthiolations.25 All previous work relies on activated
trifluoroalkyl moieties. This is particularly problematic for
select activated trifluoroethyl derivatives and longer chain 1,1-
dihydrofluoroalkyl groups that are only available from the
corresponding alcohols, and thus require additional synthetic
steps to activate.
With an established protocol for a one-pot, sequential
reaction, investigations next focused on a one-step process,
where the alkylation proceeds by bubbling sulfuryl fluoride
through a solution of trifluoroethanol (1a), benzyl mercaptan
(9a), and DBU. At room temperature, the reaction proceeded
efficiently to afford desired trifluoroethylated product 10a in
71% yield (Table 1, entry 1). The yield increased at 40 °C (entry
2), but there was no further improvement when the reaction
was run at 60 °C (entry 3). We next examined the reaction
performance in different solvents (entries 4-8).26 Overall, the
reaction was robust in a range of solvents, providing good yield
in both polar aprotic (entries 4 and 5) and nonpolar solvents
(entries 6 and 7). DCM was not as effective for this
transformation, with product 10a observed in only 38% yield
(entry 8).27
The one-pot reaction generally affords high yields of the
desired thioalkylated product regardless of the steric bulk or the
electronics of the thiol (Scheme 3). Benzyl mercaptan (9a) and
furfuryl mercaptan (9b) were both efficiently trifluoroethylated
to form the corresponding sulfides 10a and 10b in good yields.
1-Decanethiol (9c), 2-phenylethanethiol (9d), methyl
thiolglycolate (9e), and 1,9-nonanedithiol (9f) were effective
substrates for this transformation, affording mono- and
dialkylated products 10c-10f in 58% to 73% isolated yields. The
reaction was insensitive to steric bulk alpha to the thiol, with
both cyclohexyl mercaptan (9g) and triphenylmethanethiol (9h)
alkylated in comparable yields (10g and 10h, respectively).
Electron rich and electron poor thiophenol derivatives were
well tolerated, regardless of the position of the substituents
(10i-q). Importantly, longer chain 1,1-dihydrofluoroalcohols,
such as 2,2,3,3,3-pentafluoropropanol (1b), were viable starting
materials; however extended reaction times were required. The
isolated yields of 11a and 11c were increased to 90% and 89%,
respectively, by conducting the reaction in a sequential one-pot
manner,28 where sulfuryl fluoride was first bubbled through a
solution of DBU and trifluoroethanol followed by the addition
of the requisite thiol.
We next examined the functional group tolerance of this
new thiol 1,1-dihydrofluoroalkylation (Scheme 4). In substrates
in which there is competition between alcohol and thiol
alkylation, the reaction cleanly afforded good yields of the
desired thiol 1,1-dihydrofluoroalkylation products (10r and
11r). Carboxylic acids were also tolerated, with good isolated
yields of thiol alkylated product 10s using either the standard
one-pot or the sequential one-pot protocols. The reaction was
selective for the thiol over potential competing reactivity at the
nitrogen atom of aniline and pyridine derivatives (10t, 11t, and
10u). As primary nitrogen derivatives were competent
nucleophiles in reactions with trifluoroalkyl fluorosulfate, we
next examined the reaction of L-cysteine ethyl ester. Under our
sequential one-pot conditions, reactivity was only observed at
sulfur to give 10v in 63% isolated yield.29
2 | J. Name., 2012, 00, 1-3
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ARTICLE
HO
Rf
HO
Rf
View Article Online
RfDOI: 10.1039/C9SC03570B
SO2F2, DBU
SO2F2, DBU
RSH
RS
Rf
RSH
RS
DMF, 40 °C
20 min
DMF, 40 °C
20 min
9
10: Rf = CF3
11: Rf = CF2CF3
9
10: Rf = CF3
11: Rf = CF2CF3
HO
O
HO
HO
S
CF3
S
10a
CF3
S
CF3
S
CF3
S
CF3
S
CF2CF3
8
S
CF3
O
10r
11r
10s
10b
10c
10d
70%a
76% (84%)
59% (93%)
58% (86%)
60%a (85%)
67% (87%)
66% (84%)
sequential one-pot: 75%
H2
N
H2
N
N
Ph
Ph
Ph
MeO2
C
S
CF3 CF3
S
S
CF3
S
CF3
S
CF3
S
CF3
S
CF2CF3
S
CF3
7
10e
10f
73%b
10g
10h
10t
11t
10u
60%a (82%)
62%a (79%)
(80%)c
72% (79%)
sequential one-pot: 63% (94%)b
73% (78%)
CF3
O
AcHN
Cl
O
S
NH2
O
O
O
EtO
H
N
S
CF3
S
CF3
S
CF3
S
CF3
HO
N
H
OH
S
CF3
10i
10j
10k
10l
NH2 HCl
O
10v
sequential one-pot: 63%b
10w
79% (92%)
78% (93%)
60% (78%)
57% (99%)
sequential one-pot: 59%c (92%)
CF3
Scheme 4 Functional group tolerance of the 1,1-dihydrofluoroalkylation reaction.
Reaction conditions: SO2F2 (2.9 equiv) was bubbled through a solution of 9 (1 equiv), DBU
(5.9 equiv) in 1:1 TFE/DMF (v/v), at 40 ˚C for 3 minutes, and then the reaction was stirred
for an additional 17 min. All reactions were run on a 1 mmol scale unless otherwise
indicated. Isolated yields for the one-pot reaction are reported, with 19F NMR yields
(using trifluorotoluene as the internal standard) provided in parentheses. aThe one-pot
reaction was stirred for 2 hours. bThe sequential, one-pot reaction was stirred for 30
minutes after addition of thiol. cThe product was converted to an HCl salt, and the
reported yield has been corrected for solvent impurities.
S
CF3
F
S
CF3
Cl
S
CF3
S
CF3
F
10m
10n
10o
10p
78% (93%)
61% (76%)
48% (99%)
80% (96%)
S
CF2CF3
S
CF2CF3
8
S
CF3
Me
10q
11a
11c
83%a (95%)
standard one-pot: 44% (67%)d
sequential one-pot: 90%e
standard one-pot: 78%d
sequential one-pot: 89%e
Scheme 3 Substrate scope for the 1,1-dihydrofluoroalkylation of thiols. Reaction
conditions: SO2F2 (2.9 equiv) was bubbled through a solution of 9 (1 equiv), DBU (5.9
equiv) in 1:1 TFE/DMF (v/v), at 40 ˚C for 3 minutes, and then the reaction was stirred for
an additional 17 min. All reactions were run on 1 mmol scale of thiol unless otherwise
indicated. Isolated yields for the one-pot reaction are reported, with 19F NMR yields
(using trifluorotoluene as the internal standard) provided in parentheses. aThe isolated
yield has been corrected to account for disulfide or solvent impurities. See the
Supplementary Information for details. bThe reaction was conducted on 0.5 mmol scale.
cThe product was not isolated due to volatility. dThe reaction was stirred for 2 hours.
ePentafluoropropanol:DMF (1:2 v/v) was used to form the reagent, and then the thiol
was added to the reaction mixture. The reaction was stirred for 30 minutes.
A. Trifluoroethyl fluorosulfate (5a) reactivity.
O
O
S
F
O
CF3
5a
NH
N
CF3
+
+
+
Ph
SH
Ph
S
CF3
1a
DIPEA
DMF, 20 min
9a
12
10a
13
1 equiv 5a:
37%
30%
5%34
B. Trifluoroethyl fluorosulfate (5a) reactivity with added DBU.
O
O
S
Finally, we investigated whether we could achieve selective
F
O
CF3
5a
NH
N
CF3
1,1-dihydrofluoroalkylation
using
glutathione
(9w).
+
+
+
Ph
SH
Ph
S
CF3
1a
DIPEA, DBU
DMF, 20 min
Glutathione is a challenging substrate as it has two carboxylic
acids, an amine, and two amides that may interfere with the
desired thiol fluoroalkylation. Gratifyingly, under our
sequential, one-pot reaction conditions, the thiol was
selectively alkylated in 92% 19F NMR yield and 59% isolated
yield. Under similar reaction conditions, trifluoroethyl triflate
only afforded moderate yields of 10w.
9a
12
10a
13
75%
80%
3%
10%
16%34
18%34
1.1 equiv 5a:
1.5 equiv 5a:
C. Bis(trifluoroethyl) sulfate (6a) reactivity.
O
O
S
CF3
O
O
CF3
6a
NH
N
CF3
+
+
Ph
SH
Ph
S
CF3
Intrigued by the chemoselectivity of the bis(trifluoroethyl)
sulfate reagent (6a), we next investigated its selectivity
compared to trifluoroethyl fluorosulfate (5a)30 in a competition
experiment between benzyl mercaptan (9a) and piperidine
(12)31 (Scheme 5).32 Addition of 9a and 12 to a preformed
solution of trifluoroethyl fluorosulfate and DIPEA afforded only
DBU
DMF, 20 min
9a
12
10a
13
1.1 equiv 6a:
1.5 equiv 6a:
90%
>97%
<3%
<3%
D. Bis(trifluoroethyl) sulfate (6a) reactivity using pyrrolidine as the competition substrate.
O
O
S
CF3
O
O
CF3
a
slight preference for thiol alkylation (Scheme 5, A).
6a
+
+
Ph
SH
NH
Ph
S
CF3
N
CF3
Trifluoroethanol (1a) was liberated in the course of the reaction,
which is likely the result of the addition of thiol to the sulfur
center of the fluorosulfate reagent.33,34 Better selectivity for
thiol versus amine alkylation could be achieved by adding DBU
with 9a and 12;35 however, there was also a concomitant
increase in the amount of 1a (Scheme 5, B). Increasing the
DBU
DMF, 20 min
9a
14
10a
15
1.0 equiv 6a:
84%
<3%
Scheme 5 Competition experiments with sulfur and nitrogen nucleophiles.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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5
For representative examples, see: (a) W. C. J. FiVrietwh,ArJt.icPleoOlynlmine.
amount of fluorosulfate reagent 5a resulted in more amine
alkylated product (13), but did not lead to a significantly better
yield of 10a. In contrast, formation of bis(trifluoroethyl) sulfate
(6a) followed by addition of 9a and 12 led to 90% yield of thiol
alkylated product 10a, and only trace amounts of 13 and
trifluoroethanol (Scheme 5, C). Further increasing the
equivalents of the alkylating reagent led to near quantitative
yield of 10a (>97%). Even when pyrrolidine (14), a more
nucleophilic amine,36 was used in a competition experiment,
trifluoroethyl sulfide 10a was obtained almost exclusively
(Figure 5, D).37
Overall, we have developed a new method for the 1,1-
dihydrofluoroalkylation of thiols using a previously unexplored,
sulfuryl fluoride derived bis(trifluoroethyl) sulfate reagent (6a).
This protocol enables the one-pot activation and thiolation of
1,1-dihydrofluoroalcohols to afford industrially relevant
moieties in high yields, regardless of the sterics or electronics of
the starting thiol. In-situ generated bis(trifluoroethyl) sulfate
(6a) is highly selective for thiols, even in the presence of
unprotected alcohols, carboxylic acids, or amines, allowing for
possible late-stage functionalization. Compared to trifluoro-
ethyl fluorosulfate, the new bis(trifluoroethyl) sulfate reagent
displays superior thiol alkylation chemoselectivity over both
competing amine alkylation and reactivity at the sulfate center.
Efforts to further explore this new class of bis(1,1-
dihydrofluoroalkyl) reagents in the context of other reactions
are currently underway.
Sci. B, 1972, 10, 637 – 641. (b) S. D. Schimler, M. A. Cismesia,
DOI: 10.1039/C9SC03570B
P. S. Hanley, R. D. J. Froese, M. J. Jansma, D. C. Bland, M. S.
Sanford J. Am. Chem. Soc., 2017, 139(4), 1452-1455. (c) P. S.
Hanley, M. S. Ober, A. L. Krasovskiy, G. T. Whiteker, W. J.
Kruper, ACS Catal., 2015, 5(9), 5041-5046. (d) J. Dong, K. B.
Sharpless, L. Kwisnek, J. S. Oakdale, V. V. Fokin, Angew. Chem.
Int. Ed., 2014, 53(36), 9466–9470.
(a) J. Gurgar, J. Baker, V. V. Fokin, Chem. Eur. J., 2019, 25(8),
1906-1909. (b) W. -Y. Fang, H. -L. Qin, J. Org. Chem. 2019,
84(9), 5803–5812.
6
7
For representative examples, see: (a) S. -M. Wang, C. Zhao, X.
Zhang, H. -L. Qin, Org. Biomol. Chem., 2019, 17, 4087-4101.
(b) A. Ishii, M. Yasumoto, U. Koji, JP Pat. 155 248, 2009.
For an early report on the stability of aryl fluorosulfates, see
ref 5a.
8
9
A. Ishii, T. Ishimaru, T. Yamazaki, JP Pat. 001 653 A, 2013.
10 While other minor sulfuryl fluoride-derived products have
been observed (see ref 3a), they have only been detected in
<10% yield.
11 When non-fluorinated alcohols are used, the corresponding
alkyl fluorosulfate is highly reactive and leads to numerous
degradation products. The 1,1-dihydrofluoroalkyl group
makes the corresponding fluorosulfate more stable and less
prone to degradation. For a study on the effect of halides
alpha to the electrophilic center of SN2 reactions, see: J. Hine,
W. H. Brader Jr. J. Am. Chem. Soc., 1953, 75(16), 3964 – 3966.
12 Stronger bases, such as KO-tBu and KHMDS, provide
comparable results as DBU. Presumably, this is because more
alkoxide is formed in the reaction, thus accelerating the
conversion of 5a to 6a. For full base optimization, see the
Supplementary Information.
13 D. Granitza, M. Beyermann, H. Wenschuh, H. Haber, L. A.
Carpino, G. A. Truran, M. Bienert, J. Chem. Soc., Chem.
Commun., 1995, 21, 2223–2224.
14 Shreeve et al. synthesized fluorosulfate 5a in two separate
steps using SOCl2 followed by ClF. Fluorosulfate 5a could be
converted to the corresponding bis(trifluoroethyl) sulfate (6a)
by running the reaction under solvent-free conditions using
triethylamine and warming the reaction from -196 °C to room
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
temperature.
No subsequent reactivity studies were
performed on 6a. S. A. Kinkead, R. C. Kumar, J. M. Shreeve, J.
Am. Chem. Soc., 1984, 106(24), 7496–7500.
This work was supported by the University of British Columbia
(UBC), the Natural Sciences and Engineering Research Council
of Canada (NSERC), the NSERC CREATE Sustainable Synthesis
Program for support for PJF, an NSERC CGSM scholarship for
TGB, and a UBC Work Learn International Undergraduate
Research Award to SSK.
15 For a synthesis of bis(trifluoroethyl) sulfate (6a) from
trifluoroethanol and sulfuryl chloride, see: W. V. Cohen, J.
Org. Chem., 1961, 26(10), 4021–4026.
16 We have previously detected the formation of
bis(trifluoroethyl) sulfate (6a) as a minor byproduct in the
formation of trifluoroethyl fluorosulfate (5a). See ref 3a.
17 While a SciFinder® search indicates that bis(trifluoroethyl)
sulfate (6a) was reported (WO Pat. 066 559, 2000), the
reagent is not mentioned in this patent.
Notes and references
18 For selected reviews on fluoroalkyl sulfides see: (a) S.
Swallow, Prog. Med. Chem., 2015, 54, 65–133. (b) F. Leroux,
P. Jeschke, M. Schlosser, Chem. Rev., 2005, 105(3), 827–856.
19 For selected patents containing trifluoroethyl sulfur
compounds see: (a) A. Adrien EP Kohler, B. Alig, A. Becker, A.
Voerste, U. Gorgens, R. Fischer, W. A. Moradi, S. Cerezo-
Galvez, J. Neumann, K. Ilg, H. -G. Schwarz, T. Gomibuchi, M.
Ito, D. Yamazaki, K. Shibuya, E. Shimojo, WO Pat. 092 350,
2013. (b) F. Setsu, E. -J. Umemura, K. Sasaki, K. Tadauchi, T.
Okutomi, K. Ohtsuka, S. Takahata, WO Pat. 042 188, 2003. (c)
F. Kaiser, S. Gross, J. Langewald, A. Narine, WO Pat. 030 262,
2013. (d) B. Alig, S. Cerezo-Galvez, R. Fischer, A. Koehler, J. J.
Hahn, K. Ilg, P. Loesel, O. Malsam, D. Portz, WO Pat. 004 028,
2015.
1
(a) E. E. Kenaga, J. Econ. Entomol., 1957, 50(1), 1–6. (b) J.
Dong, L. Krasnova, M. G. Finn, K. B. Sharpless, Angew. Chem.
Int. Ed., 2014, 53(36), 9430–9448. (c) Dow AgroSciences
Technical Bulletin, “Sulfuryl Fluoride Gas Fumigant,” April
2002.
For a representative review, see: L. Revathi, L. Ravindar, J.
Leng, K. P. Rakesh, H. -L. Qin, Asian J. Org. Chem., 2018, 7(4),
662–682.
For select examples of 1,1-dihydrofluoroalcohol activation,
see: (a) M. Epifanov, P. J. Foth, F. Gu, C. Barrillon, S. S. Kanani,
C. S. Higman, J. E. Hein, G. M. Sammis, J. Am. Chem. Soc., 2018,
140(48), 16464–16468. (b) M. R. Johnson, WO Pat. 124 456,
2014.
For a representative example, see: A. Ishii, T. Yamazaki, M.
Yasumoto, (Central Glass Company, Ltd.). US Pat. 8 426 645B2,
2013.
2
3
4
20 For the effect of fluoroalkyl moieties on the properties in a
molecule, as well as the importance of fluorine in the
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ARTICLE
pharmaceutical and agrochemical industries, see: (a) W. A. 36 T. Kanzian, T. A. Nigst, A. Maier, S. Pichl, H. Mayr, Eur. J. Org.
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Manteau, S. Pazenok, J. -P. Vors, F. R. Leroux, J. Fluorine 37 The competition experiment was run using an equimolar
Chem., 2010, 131, 140–158. (c) C. Ni, M. Hu, J. Hu, Chem. Rev.,
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amount of benzyl mercaptan (9a) and pyrrolidine, and 1.0
equiv. of sulfate 6a. No amine alkylation product was
detected by 19F NMR spectroscopy using trifluorotoluene as
an internal standard. See the Supplementary Information for
full reaction details.
21 See the Supplementary Information for full reaction details.
22 For representative examples, see: (a) Z. -Y. Long, Q. -Y. Chen,
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26 The reaction also works well using 1:2 and 1:4 TFE/DMF
solvent ratios, which correlates to approximately 13 and 8
equivalents of TFE, respectively. For optimization of the
amount of trifluoroethanol relative to solvent, see the
Supplementary Information.
27 The alkylation step is slower in DCM than in more polar
solvents, such as DMF.
28 Under the standard one-pot conditions, sulfuryl fluoride can
react with the thiol, which leads to disulfides, among other
products. The sequential, one-pot conditions prevent this
side reaction from occurring. For a discussion of this disulfide,
see the Supplementary Information.
29 19F NMR spectroscopic analysis of the crude reaction mixture
indicated that no amine 1,1-dihydrofluoroalkylation products
were observed.
30 Reactivity was compared to fluoroalkyl fluorosulfates, such as
5a, because they are the only other sulfuryl fluoride-derived
reagent that can be generated from any 1,1-
dihydrofluoroalcohol, and used in a one-pot process.
31 Piperidine was selected for the competition experiment as it
was an effective substrate for amine trifluoroethylation (see
ref 3a).
32 For full reactions conditions, see the Supplementary
Information.
33 As attack at the sulfur atom with nitrogen was not typically
seen under these conditions (see ref 3a), the reagent
degradation is likely to be due to thiol attack at sulfur.
34 The amount of trifluoroethanol is due to nucleophile-
mediated degradation of the alkylating reagent. Therefore,
the percentage of trifluoroethanol was calculated relative to
the total amount of benzyl mercaptan.
35 Similar moderate selectivity for S- versus N-trifluoroalkylation
was observed with trifluoroethyl triflate. See the
Supplementary Information for details.
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