Arylsulfur trifluorides: Improved method of synthesis and use as in situ deoxofluorination reagents

Article abstract of DOI:10.1016/j.jfluchem.2011.05.001

Building on recent results of Umemoto and Winter, an improved method of synthesis of arylsulfur trifluorides, including the excellent, new deoxofluorination reagent Fluolead, is hereby reported. The method utilizes Br₂ and KF as oxidizing and fluorinating reagents for efficient, high yield conversion of aryl disulfides and mercaptans to arylsulfur trifluorides. It has also been shown that both Fluolead and mesitylsulfur trifluoride may be generated in acetonitrile and used as in situ deoxofluorination reagents for conversion of either aldehydes or ketones to their respective gem-difluoro compounds. An analysis of the probable mechanism of action, including computational efforts, allows postulation of a rationale for the highly variable reactivities of different arylsulfur trifluorides as deoxofluorination reagents.

Full text of DOI:10.1016/j.jfluchem.2011.05.001

Journal of Fluorine Chemistry 132 (2011) 482–488
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Arylsulfur trifluorides: Improved method of synthesis and use as in situ
deoxofluorination reagents
*
Wei Xu, Henry Martinez, William R. Dolbier Jr
Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Building on recent results of Umemoto and Winter, an improved method of synthesis of arylsulfur
trifluorides, including the excellent, new deoxofluorination reagent Fluolead, is hereby reported. The
method utilizes Br2 and KF as oxidizing and fluorinating reagents for efficient, high yield conversion of
aryl disulfides and mercaptans to arylsulfur trifluorides. It has also been shown that both Fluolead and
mesitylsulfur trifluoride may be generated in acetonitrile and used as in situ deoxofluorination reagents
for conversion of either aldehydes or ketones to their respective gem-difluoro compounds. An analysis of
the probable mechanism of action, including computational efforts, allows postulation of a rationale for
the highly variable reactivities of different arylsulfur trifluorides as deoxofluorination reagents.
ß 2011 Elsevier B.V. All rights reserved.
Received 28 February 2011
Received in revised form 3 May 2011
Accepted 6 May 2011
Available online 12 May 2011
Keywords:
Deoxofluorination
Arylsulfur trifluorides
Synthetic fluorine chemistry
Fluolead
1. Introduction
Recently, two other broadly effective deoxofluorination reagents
have been reported, Xtal-Fluor (the E-version being derived from
Selective incorporation of fluorine into organic molecules
continues to be an important and ever-challenging component
in the design and synthesis of effective pharmaceuticals and
agrochemicals [1–4]. Considering the various techniques that are
utilized to accomplish such incorporation, deoxofluorination
reactions must be considered among the most important.
Deoxofluorination reactions include most notably the direct
conversion of alcohols to alkyl fluorides, ketones and aldehydes
to gem-difluoroalkanes and carboxylic acids to trifluoromethyl
groups.
DAST)[9]and Fluolead,acrystalline,thermallystable,highlyreactive
arylsulfur trifluoride [10–14]. Xtal-Fluor requires a fluoride source
such as Et3N-3HF to generate DAST-like reactivity whereas Fluolead
has been found to have broad and highly efficient reactivity with
alcohols, aldehydes, ketones and carboxylic acids, as exemplified in
Scheme 1 [10,14]. The excellent reactivity of Fluolead contrasts with
earlier reports regarding arylsulfur trifluorides, which have been
foundtobe relatively ineffective as deoxofluorination agents [14,15].
Interestingly, all of the above broadly effective, diverse deoxofluor-
ination reagents are fluorosulfur compounds.
The discovery that SF4 is an effective reagent for carrying out
such transformations [5,6] was a key factor in propelling the
emerging field of synthetic organofluorine chemistry into the main
stream of synthetic organic chemistry during the 1960s. In the
ensuing years other reagents, essentially derivatives of SF4,
emerged as safer, more convenient, and sometimes superior
deoxofluorination reagents. The best known, and most widely used
among them are DAST (diethylaminosulfur trifluoride) [7] and
Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) [8],
although there are many others that have more limited applica-
bility (Fig. 1)
According to Umemoto’s disclosures, Fluolead can be prepared
by treating an acetonitrile solution of precursor disulfide, 1a, with
3.5 equiv. of chlorine in the presence of 10 equiv. of anhydrous KF.
The Cl2 was slowly bubbled into the ice-bath-cooled solution over
a period of 2 h. After filtration and distillation, a yield of 68% of
Fluolead could be obtained (Scheme 2) [14].
The toxicity of gaseous Cl2 and control of its addition to the
reaction mixture can pose practical problems in the laboratory
synthesis of Fluolead. Moreover, when working with aryl disulfides
other than 1a, if the amount of Cl2 is not carefully controlled and
the reaction not carefully monitored, there is the possibility of
partial over-chlorination of the arylsulfur trifluorides to form
chlorotetrafluorosulfanyl compounds, such as 3 in Scheme 3.
Umemoto has demonstrated that such exhaustive chlorination of
arylsulfur trifluorides to form the aryl chlorotetrafluorosulfanyl
compounds can be put to good use, since intermediates such as 3
can be readily converted to the analogous aryl-SF5 compounds
(Scheme 3) [16,17].
* Corresponding author at: University of Florida, Department of Chemistry, PO
Box 117200, Gainesville, FL 32611-7200, USA. Tel.: +1 352 392 0591;
fax: +1 352 846 1962.
E-mail addresses: xuwei@chem.ufl.edu (W. Xu), hmg@chem.ufl.edu
(H. Martinez), wrd@chem.ufl.edu (W.R. Dolbier Jr).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.05.001

W. Xu et al. / Journal of Fluorine Chemistry 132 (2011) 482–488
483
Scheme 2. Umemoto synthesis of Fluolead.
Fig. 1. Major deoxofluorination reagents.
Recently Winter and Cook reported an efficient new method for
preparation of SF4, converting elemental sulfur to SF4 through
treatment with Br2 and KF (Eq. (1)) [18].
S þ 2Br2 þ 4KF ! SF4
(1)
Scheme 3. Example of the Umemoto process for synthesis of aryl-SF5 compounds.
Bromine is easier to handle and quantities are more readily
controlled than is the case for chlorine. Because of our past interest
in organic SF5 compounds [19,20], we considered the possibility of
applying the Winter/Cook chemistry to Umemoto’s approach to
aryl-SF5 compounds in the hope of enhancing his procedure. In our
hands the aryl-SF4Cl compounds, such as 3, were unstable and
difficult to handle and convert to the respective Ar-SF5 compounds,
and we thought that the respective bromides might provide some
advantage.
2. Results and discussion
Scheme 4. Initial experiments replacing chlorine with bromine.
2.1. Improved synthesis of arylsulfur trifluorides
compared to the chlorine-induced procedure of Umemoto. Indeed,
when this procedure was used to prepare. Fluolead, a 65% yield was
observed after 2 h at 0 8C, with 85% of Fluolead being obtained
upon stirring at room temperature for 4 additional hours. Further
study indicated that three equivalents of Br2 and six of KF were
sufficient to convert all of an aryl disulfide to the arylsulfur
trifluoride.
Aryl thiols could also be converted to their respective arylsulfur
trifluorides under similar conditions, as is exemplified for the
reaction of benzene thiol (Scheme 5).
What was in fact observed was that when phenyl disulfide (1b)
was allowed to react with excess Br2 and dry, excess KF in
acetonitrile, the reaction came to a complete stop with formation of
Ph-SF3 (Scheme 4). A 19F NMR spectrum of the reaction mixture
taken after 2 h at 0 8C (Fig. 2) indicates how clean this reaction is.
Only a small amount of phenyl sulfinyl fluoride (4), deriving from
not quite dry KF, contaminates the product mixture. This result
was disappointing with respect to possible use of these conditions
to prepare aryl-SF5 compounds, but it provided
a distinct
advantage for the synthesis of aryl-SF3 compounds when
Scheme 1. Typical Fluolead deoxyfluorinations.

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W. Xu et al. / Journal of Fluorine Chemistry 132 (2011) 482–488
Fig. 2. 19F NMR spectrum of the reaction mixture after 2 h at 0 8C.
Although Fluolead is an outstanding deoxofluorination reagent,
2.2. In situ use of Fluolead
with broad applicability, there are problems associated with its
preparation, storage and use. Fluolead, like all other arylsulfur
trifluorides, is corrosive to glass and moisture sensitive. The major
impurity in samples of Fluolead is the respective arylsulfinyl
fluoride compound (4). Sulfinyl fluoride 4 is derived from the
reaction of the Fluolead SF3 group with traces of water in the
reaction mixture, and its formation is very difficult to avoid. With
that in mind, effort must be made to use the driest possible KF in
the preparation of Fluolead. This sulfinyl fluoride is also the co-
product from Fluolead in its deoxofluorination reactions (Scheme
6), and it is itself corrosive to glass.
The corrosive natures of arylsulfur trifluorides and arylsulfinyl
fluorides do not appear to simply derive from HF that might be
generated from them. As noted by Sheppard in his early
preparation of phenylsulfur trifluoride [21,22], both of them
appear, even when pure, to slowly react with glass. Thus Fluolead
must be stored in flasks made of fluoropolymer, and reactions of
Fluolead are best carried out in fluoropolymer bottles or flasks.
Nevertheless, in spite of the above practical challenges, the ease
of synthesis of Fluolead, combined with its potential low cost and
its excellent reactivity characteristics with respect to its deoxo-
fluorination reactions might well make it the reagent of choice for
carrying out such transformations.
It was hypothesized that those problems associated with the
preparation and use of Fluolead might well be minimized or
alleviated by its generation and use in situ. In addition,
scrupulously dry KF would not be required, since one could
simply use a slight excess of reactants in order to compensate for
partial loss of Fluolead due to hydrolysis.
Indeed, it was found that the acetonitrile reaction mixture
containing prepared Fluolead can be used directly to carry out its
reactions with aldehydes and ketones. In the initial experiments,
10 equiv. of Br2 and dry KF were used per equivalent of disulfide.
After addition of Br2 at 0 8C was complete, the reaction was
warmed to RT and stirred for 2 h, at which time full conversion to
Fluolead was observed by fluorine NMR. Benzaldehyde
(0.75 equiv.) was then added and the mixture allowed to stir at
room temperature with no significant amount of product being
observed after 24 h. Umemoto had shown that the reaction of
Fluolead with aldehydes is complete at room temperature after
20 h when the reaction is carried out in 1,2-dichloroethane (DCE)
(Scheme 1) [14]. Thus the mixture of in situ-generated Fluolead in
acetonitrile is less reactive than that of pure Fluolead in DCE.
However, when the reaction mixture was then heated at reflux for
16 h, a very good (72%) yield of difluoromethylbenzene was
obtained.
Later, after some optimization of the in situ Fluolead reactions,
the minimum amounts of Br2 and KF (3 equiv. and 6 equiv.,
respectively) were found to be sufficient for reaction with disulfide
1a in acetonitrile at RT for 2 h, after which about 0.75 equiv. of
aldehyde or ketone were added and the mixture heated to reflux
for 16 h. Examination of the reaction mixtures by fluorine NMR at
that time indicated complete conversion of the respective
Scheme 5. Use of benzene thiol in preparation of phenylsulfur trifluoride.
Scheme 6. Formation of sulfinyl fluoride coproduct from Fluolead.

W. Xu et al. / Journal of Fluorine Chemistry 132 (2011) 482–488
485
Table 1
In situ generation and use of Fluolead.
Reactant
Product
Yield (%)
Benzaldehyde
PhCHF2
72a
80a
76a
70b
45b
49b
p-Bromobenzaldehyde
p-Tolualdehyde
Acetophenone
p-BrPhCHF2
p-MePhCHF2
PhCF2CH3
2-Butanone
CH3CH2CF2CH3
(CH3)2CHCF2H
Isobutyraldehyde
a
Isolated yield.
Scheme 9. In situ reactions of various arylsulfur trifluorides.
b
NMR yield.
and it reacts with water only slowly. These latter properties
become less important if one chooses to use the reagent in situ.
Thus, if simpler arylsulfur trifluorides were to exhibit similar in situ
reactivity, the lower cost of such reagents might then make them
preferred over Fluolead for an in situ process. Phenyl and mesityl
disulfides are readily available, either commercially or from
reduction of the respective sulfonylchlorides [23], and our Br2/
KF process proved successful for conversion of each to its
respective ArSF3 reagent (>70% yields for each).
When these reagents were used as in situ deoxofluorination
reagents, it was found that PhSF3 was ineffective as an in situ
reagent in acetonitrile, giving no observable difluoromethylben-
zene product after 24 h of reflux with benzaldehyde. This is
consistent with Umemoto’s finding that PhSF3 is considerably less
effective than Fluolead in its reactions in DCE [14]. The interesting
thing about the current results, however, is that PhSF3, under our in
situ reaction conditions in acetonitrile, appears to be essentially
untouched by the added benzaldehyde reactant. A fluorine NMR
spectrum of the reaction mixture shows the PhSF3 present and
unreacted. On the other hand, the mesityl reagent (2,4,6-
trimethylphenylsulfur trifluoride) exhibited reactivity with benz-
aldehyde that was very similar to that of Fluolead, giving an
unoptimized 62% yield of difluoromethylbenzene from benzalde-
hyde (Scheme 9).
substrates with the (unoptimized) yields of products indicated in
Table 1. Products were isolated after extraction by hexane and
hydrolysis of the sulfinyl fluoride co-product by treatment with
10% aq. NaOH.
Unfortunately, it was found that conversion of alcohols to
fluorides under the above-described in situ conditions was not
possible. No fluorinated products were able to be observed when
primary alcohols were used as substrates under the conditions
given in Scheme 7. The lack of fluoride product has been
demonstrated to derive from interception of the initially formed
intermediate (5) by bromide ion, in competition with fluoride ion
(Scheme 8). Bromide ion is much more nucleophilic than fluoride
ion, and it should also be present in much greater concentration
than fluoride ion. An interesting, still unanswered question
remains as to why bromide did not compete with fluoride during
the in situ reactions of ketones and aldehydes. In those reactions,
no significant amounts of bromofluoro products were observed by
fluorine NMR.
2.2.1. Alternative arylsulfur trifluorides
In addition to its high reactivity and thermal stability, Fluolead
has a number of other attributes which make it convenient and
safe to use. It is a crystalline solid, easy to handle, does not fume
Scheme 7. First attempt at in situ reaction with Fluolead.
Scheme 8. Reaction of alcohols with Fluolead under in situ conditions.

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W. Xu et al. / Journal of Fluorine Chemistry 132 (2011) 482–488
Scheme 10. First step of the mechanism of nucleophilic attack on Ar-SF3.
On the basis of these results, and those reported by Umemoto,
we concluded that the two ortho methyl substituents of Fluolead
were probably critical to allowing it to react in acetonitrile, which
implied that its p-t-butyl group should not necessarily be required
from a reactivity point of view. This hypothesis was further tested
by synthesizing 2,6-dimethylphenyl disulfide and examining its in
situ reactivity with benzaldehyde, which in the event was similar
to that of the mesityl system (Scheme 9).
Scheme 11. Interaction of nucleophilic solvent with ArSF3.
2.3. Mechanistic considerations
step (B) much faster than PhSF3. The octahedral complex (6) is a
more crowded environment than either ArSF3 or the following
intermediate 7, and therefore the ortho substituents on Fluolead
should destabilize this intermediate and accelerate its conversion
to 7, thus moving the overall deoxofluorination process forward.
The second issue that requires explanation is why the in situ
process, in acetonitrile, proceeds efficiently (albeit more slowly
than in DCE) when using the sterically hindered Fluolead, but no
reaction at all occurs when using PhSF3. It is proposed that both the
lack of reaction of PhSF3 and the diminished reactivity of Fluolead
derive from the variable extent of reversible, non-productive
complexation that they undergo with a nucleophilic solvent such
as acetonitrile (Scheme 11).
Based upon calculations discussed below, it is contended that
the equilibrium interaction of the solvent acetonitrile with PhSF3
depicted in Scheme 11 favors complex 8 to such an extent that
nucleophilic attack by the more nucleophilic alcohol and carbonyl
substrates is essentially kinetically prohibited. This conclusion is
supported by the experimental observation mentioned earlier that
All Ar-SF3 compounds exist as trigonal bipyramids with
fluorines always preferring the axial position and with the lone
pair in the equatorial position along with the aryl group. As
exemplified for the initial stages of the reaction of an alcohol with
Ar-SF3 (Scheme 10), in undergoing reaction its trigonal bipyramid
SF3 group is converted initially (Step A) to an octahedral complex 6,
which then eliminates HF (in Step B) to regenerate a trigonal
bipyramid species, intermediate 7 [24].
The mechanism of Scheme 10 should be able to allow us to
rationalize two reactivity issues. First, why are the ortho-
disubstituted ArSF3 reagents (i.e., Fluolead) more effective than
PhSF3 as deoxofluorination reagents? Both should be reactive with
respect to nucleophilic attack, but only Fluolead gives high yields
of fluorinated products. We believe that this disparity in
effectiveness can indeed be explained by Scheme 10. A reasonable
rationale is that although both PhSF3 and Fluolead participate in
the first step (A) (Fluolead probably slower than PhSF3), the
sterically-more-demanding Fluolead complex executes the second
˚
Fig. 3. Energies (kcal/mol) and N–S or O–S bond distances (angstroms, A) of complexes with acetonitrile and acetaldehyde.

W. Xu et al. / Journal of Fluorine Chemistry 132 (2011) 482–488
487
Fig. 4. Computed structures of complexes with acetonitrile and acetaldehyde.
PhSF3 remains unreacted and untouched by added benzaldehyde
when used under in situ conditions.
These calculations are consistent with our conclusion that
solvent (acetonitrile) binding to the SF3 group of Ph-SF3 is
sufficiently strong to prevent attack by a reactive nucleophile,
whereas Fluolead, having little if any interaction with solvent,
remains reactive, although with diminished reactivity.
2.4. Computational results and discussion
In order to provide additional evidence for these mechanistic
proposals, the structures of SF4, PhSF3 and mesityl-SF3 and the
structures and relative energies of their complexes with acetoni-
trile and acetaldehyde were examined computationally in the gas
phase at B3LYP/6-311G(d,p) levels of theory using the Gaussian 03
Rev. E01 package [25] (Fig. 3). Depictions of the computed
structures for the various species and their complexes are provided
in Fig. 4.
3. Conclusions
Building on the results of Umemoto and Winter, an improved
method of synthesis of arylsulfur trifluorides, including the
excellent, new deoxofluorination reagent Fluolead, has been
reported. The method utilizes Br2 and KF as oxidizing and
fluorinating reagents for efficient, high yield conversion of aryl
disulfides to arylsulfur trifluorides. It has also been shown that
both Fluolead and mesitylsulfur trifluoride may be generated in
acetonitrile and used as in situ deoxofluorination reagents for
conversion of either aldehydes or ketones to their respective gem-
difluoro compounds. An analysis of the probable mechanism of
action, including computational efforts, has allowed postulation of
a rationale for the highly variable reactivities of different arylsulfur
trifluorides as deoxofluorination reagents in acetonitrile. Further
details related to the specific relative efficiencies of various aryl
The calculations of
DE are consistent with acetonitrile binding
strongly to SF4 and somewhat strongly to Ph-SF3, while not binding
significantly to mesityl-SF3. The more nucleophilic acetaldehyde
binds much more strongly to both SF4 and Ph-SF3, and even shows
significant binding to mesityl-SF3. Comparing the combined van
˚
der Waals radii for S–N and S–O (3.35 and 3.33 A, respectively)
with the calculated bond distances for the various complexes
provides corroborating evidence of the relative binding within
these complexes.

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W. Xu et al. / Journal of Fluorine Chemistry 132 (2011) 482–488
sulfurtrifluorides as deoxofluorination reagents under in situ
conditions in solvents of variable nucleophilicities will be
addressed in future work.
with potassium fluoride (8.71 g, 150 mmol), disulfide 1a (9.67 g,
25 mmol) and anhydrous acetonitrile (50 mL) under nitrogen. The
mixture was cooled to 0 8C, and then bromine (12 g, 75 mmol) was
added dropwise over a period of 15 min. After addition, the cold
bath was removed and the reaction was stirred at room
temperature for 2 h, after which aldehyde (0.75 equiv. relative
to disulfide) was added in one portion. The mixture was heated to
reflux and stirred for 16 h, and then cooled to room temperature.
Then hexane (100 mL) was added, followed by 50 mL of water, and
the upper layer was separated and washed with brine. The hexane
extract was then stirred with 10% sodium hydroxide (50 mL) for
1 h. The upper layer was isolated and dried over sodium sulfate,
and then the product was purified by column chromatography or
by distillation.
4. Experimental
4.1. Preparation of aryl disulfides [26]
2,6-Dimethylphenyl disulfide (2d) was prepared in 40% yield
from 2-bromo-1,3-dimethylbenzene via its Grignard reagent, by
the method of Davis [27].
Mesityl disulfide (2c) was prepared in 70% yield via the sulfonyl
chloride [28], using the method of Umemoto [10,14].
4.2. Preparation of phenylsulfur trifluoride from phenyl disulfide
Acknowledgments
Into a flame-dried 500 mL three-necked flask equipped with a
reflux condenser and a dropping funnel was placed anhydrous
acetonitrile (120 mL) under nitrogen. Spray-dried potassium
fluoride (23.2 g, 400 mmol) was added with stirring, followed by
addition of phenyl disulfide (8.72 g, 40 mmol). The mixture was
cooled to 0 8C by an ice bath, and bromine (20 mL, 400 mmol) was
added dropwise. After addition, the mixture was stirred at 0 8C for
2 h and then warmed to room temperature slowly. Finally, the
mixture was heated to reflux and stirred for 4 h. The reaction
mixture was cooled to room temperature, and the solvent and
excess of bromine were removed under reduced pressure. Hexane
(200 mL) was added to the residue and stirred vigorously. The
mixture was filtered, the solid washed with hexane, and the
solvent removed. Then the residue was distilled under reduced
pressure to give a colorless liquid (65 8C/10 mm Hg) (10.0 g, 75%
The authors would like to thank the University of Florida High-
Performance Computing Center for providing computing time.
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4.4. Preparation of 2,6-dimethyl-4-t-butylphenylsulfur trifluoride
(Fluolead)
Into a flame-dried 500 mL round-bottomed flask equipped with
a dropping funnel was placed anhydrous acetonitrile (120 mL)
under nitrogen. Spray-dried potassium fluoride (29.1 g, 500 mmol)
was added with stirring, followed by addition of bis(2,6-dimethyl-
4-t-butylphenyl)disulfide (19.4 g, 50 mmol). The mixture was
cooled to 0 8C by an ice bath, and bromine (26 mL, 500 mmol)
was added dropwise. After addition, the mixture was stirred at 0 8C
for 2 h. The solvent and excess of bromine were removed under
reduced pressure at room temperature. After that, the product was
distilled under reduced pressure (178 8C/10 mm Hg) to give 17.5 g
of a pale white solid (70% yield): 19F NMR (CH3CN-d3):
d 50.9 (t,
J = 62.7 Hz, 2F), ꢀ58.4 (d, J = 62.7 Hz, 1F) [14].
4.5. Typical in situ deoxofluorination procedure
All glassware was flame dried and cooled under nitrogen. The
potassium fluoride was dried either by heating at 140 8C under
vacuum for 2 h, or by melting in a crucible, followed by grinding to
a powder under N2. Into a 250 mL three-necked flask was charged
[26] G.W. Kabalka, M.S. Reddy, M.-L. Yao, Tetrahedron Lett. 50 (2009) 7340–7342.
[27] F.A. Davis, R.H. Jenkins, S.W.A. Rizvi, S.G. Yocklovich, J. Org. Chem. 46 (1981)
3467–3474.
[28] W.S. Faber, J. Kok, B.d. Lange, B.L. Feringa, Tetrahedron 50 (1994) 4775–4794.