A R T I C L E S
Umemoto et al.
restrictions.7 Moreover, with DAST it is difficult to fluorinate
certain ketones such as non-enolizable ketones,8 and it does not
convert carboxylic acids to -CF3. An analogue, bis(methoxy-
ethyl)aminosulfur trifluoride (Deoxo-Fluor reagent, Air Products
and Chemicals, Inc.), with enhanced thermal stability, has been
developed.9,10 It is a liquid which fumes in air and has reactivity
similar to that of DAST. A continuous process using a
microreactor was recently developed for hazardous reactions
with DAST or Deoxo-Fluor.11 Most recently, crystalline di-
alkylamidodifluorosulfinium tetrafluoroborate ([R2N+dSF2]-
BF4-), which does not fume and is more thermally stable than
DAST and Deoxo-Fluor, has been recognized as a useful
deoxofluorinating agent when combined with triethylamine
tris(hydrogen fluoride) (Et3N(HF)3).12 However, the actual
reactive species might in fact be dialkylaminosulfur trifluoride,
which can be formed by the reaction of F- in Et3N(HF)3
[Et3NH+F-(HF)2] with the amidodifluorosulfinium salt, since
Et3N(HF)3 has a pH close to neutral and is a weak nucleophile
and fluoride donor.13,14
Many other deoxofluorinating agents are known. Fluoroamine
reagents such as Et2NCF2CFHCl (Yarovenko reagent),15
Et2NCF2CFHCF3 (Ishikawa reagent),16 2,2-difluoro-N,N′-di-
methylimidazolidine (DFI),17 1,1,2,2-tetrafluoroethyl-N,N-di-
methylamine,18 and N,N-diethyl-R,R-difluoro-(m-methylbenzyl)-
amine19 are useful for fluorination of alcohols. However, these
fluoroamine reagents have limited scope because of limited
applicability to the fluorinations of carbonyl functions. In
addition, Ph3PF220 and a method using n-perfluorobutanesulfonyl
fluoride/DBU21 have been developed for fluorination of alcohols.
In 1960, shortly after the report of fluorination with SF4, liquid
phenylsulfur trifluoride (PhSF3) was synthesized and its reactiv-
ity evaluated, showing that PhSF3 was useful for arylaldehydes
such as benzaldehyde but not effective for alkylaldehydes,
ketones, and carboxylic acids due to low reactivity and yields.22
Since the discovery of DAST as mentioned above, phenylsulfur
trifluoride has been mostly ignored, except for a report in 1981
that it fluorinated chlolesterol in good yield under certain limited
reaction conditions, as it proceeded via a specific homoallyl
cation intermediate.23 However, p-nitrophenylsulfur trifluoride
did not give any fluorinated products, but rather an ether
product.23
The recent developing need for a safe, reactive, and selective
fluorinating agent for use by non-fluorine organic chemists in
many areas stimulated us to develop a new deoxofluorinating
agent with both high reactivity and high stability, properties
which are generally in conflict. Thermal analysis studies of
DAST and related R2NSF3 compounds7b indicate that decom-
position of these aminosulfur trifluorides occurs in two stages.
A slow reaction is seen at 90 °C with evolution of gaseous SF4
and formation of a bis(dialkylamino)sulfur difluoride ((R2N)2-
SF2) by a disproportionation reaction. On heating to higher
temperatures, the samples explode or detonate, resulting in a
black tar and unidentified gaseous products. The enhanced
thermal stability of Deoxo-Fluor is rationalized on the basis of
conformational rigidity imposed by coordination of the alkoxyl
groups with the electron-deficient sulfur atom of the trifluoride.
However, the stability of Deoxo-Fluor is not significantly better
than that of DAST. The onset of decompostion is almost the
same for both compounds (∼140 °C), but DAST degrades much
more rapidly and with larger heat evolution (1700 vs 1100 J/g
for Deoxo-Fluor), and Deoxo-Fluor shows a more gradual
exotherm over a wider temperature range. These results indicate
that Deoxo-Fluor is more stable than DAST but without
significant improvements.
(7) (a) Cochran, J. Chem. Eng. News 1979, 57 (March 19), 4. (b) Messina,
P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42,
137–143.
In our attempt to develop new and upgraded deoxofluorinating
agents, we desired to prepare arylsulfur trifluorides that would
not yield significant gaseous byproducts on thermal decomposi-
tion. Compared to aminosulfur trifluoride, arylsulfur trifluorides
have several prominent advantages. First, the C-S bond (714
( 1.2 kJ/mol) is much stronger than the N-S bond (464 ( 21
kJ/mol).24 This would make arylsulfur trifluoride more stable
than aminosulfur trifluoride, as the N-S bond cleavage accounts
for the decomposition of aminosulfur trifluoride.7b Second,
arylsulfur trifluorides are more easily tunable by altering the
substituents on the aryl ring. The stability and reactivity of
arylsulfur trifluorides may be controlled by employing different
substituents on the phenyl ring. The reactivity of phenylsulfur
trifluoride may be increased with addition of electron-donating
substituents.
(8) (a) Chang, Y.; Tewari, A.; Adi, A.-I.; Bae, C. Tetrahedron 2008, 64,
9837–9842. (b) Kirsh, P.; Bremer, M.; Huber, F.; Lannert, H.; Ruhl,
A.; Lieb, M.; Wallmichrath, T. J. Am. Chem. Soc. 2001, 123, 5414–
5417. (c) Kiryanov, A. A.; Seed, A. J.; Sampson, P. Tetrahedron 2001,
57, 5757–5767.
(9) (a) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem.
Commun. 1999, 215–216. (b) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.;
Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999, 64, 7048–7054. (c)
Lal, G. S.; Lobach, E.; Evans, A. J. Org. Chem. 2000, 65, 4830–
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(10) For other papers, see ref S2 in the Supporting Information.
(11) Negi, D. S.; Ko¨ppling, L.; Lovis, K.; Abdallah, R.; Geisler, J.; Budde,
U. Org. Process Res. DeV. 2008, 12, 345–348.
(12) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.;
LaFlamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050–5053. (b)
L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.;
LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier,
M. J. Org. Chem. 2010, 75, 3401–3411.
(13) (a) Saluzzo, C.; Alvernhe, G.; Anker, D. J. Fluorine Chem. 1990, 47,
467–479. (b) McClinton, M. A. Aldrichimica Acta 1995, 28, 31–35.
(14) The 19F NMR peak of SF3 of DAST was not observed in the presence
of Et3N(HF)3 because of rapid equilibrium between conformations:
A broad peak at 26 ppm due to SF3 was observed in 19F NMR (300
MHz) of DAST in anhydrous CDCl3, but the broad peak was not
observed in 19F NMR of a 1:1 mole ratio mixture of DAST and
Et3N(HF)3 in anhydrous CDCl3.
This article now describes the clues that led us to the
discovery of a new, reactive deoxofluorinating agent and its
synthesis, high thermal stability, unexpected resistance to water,
high fluorinating capability, and extensive potential applications,
including direct conversion of carboxyl groups to trifluoromethyl
(15) Yarovenko, N. N.; Raksha, M. A.; Shemanina, V. N.; Vasileva, A. S.
J. Gen. Chem. USSR 1957, 27, 2246.
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18200 J. AM. CHEM. SOC. VOL. 132, NO. 51, 2010