Bis(2-methoxyethyl)aminosulfur trifluoride: A new broad-spectrum deoxofluorinating agent with enhanced thermal stability

Article abstract of DOI:10.1021/jo990566+

Bis(2-methoxyethyl)aminosulfur trifluoride, (CH₃OCH₂CH₂)₂NSF₃ (Deoxo-Fluor reagent), is a new deoxofluorinating agent that is much more thermally stable than DAST (C₂H₅)₂NSF₃ and its congeners. It is effective for the conversion of alcohols to alkyl fluorides, aldehydes/ketones to the corresponding gem-difluorides, and carboxylic acids to the trifluoromethyl derivatives with, in some cases, superior performance compared to DAST. The enhanced stability is rationalized on the basis of conformational rigidity imposed by a coordination of the alkoxy groups with the electron-deficient sulfur atom of the trifluoride.

Full text of DOI:10.1021/jo990566+

7048
J . Org. Chem. 1999, 64, 7048-7054
Bis(2-m eth oxyeth yl)a m in osu lfu r Tr iflu or id e: A New
Br oa d -Sp ectr u m Deoxoflu or in a tin g Agen t w ith En h a n ced Th er m a l
Sta bility
Gauri S. Lal,* Guido P. Pez, Reno J . Pesaresi, Frank M. Prozonic, and Hansong Cheng
Air Products and Chemicals Inc., 7201 Hamilton Boulevard, Allentown, Pennsylvania 18195-1501
Received March 30, 1999
Bis(2-methoxyethyl)aminosulfur trifluoride, (CH3OCH2CH2)2NSF3 (Deoxo-Fluor reagent), is a new
deoxofluorinating agent that is much more thermally stable than DAST (C2H5)2NSF3 and its
congeners. It is effective for the conversion of alcohols to alkyl fluorides, aldehydes/ketones to the
corresponding gem-difluorides, and carboxylic acids to the trifluoromethyl derivatives with, in some
cases, superior performance compared to DAST. The enhanced stability is rationalized on the basis
of conformational rigidity imposed by a coordination of the alkoxy groups with the electron-deficient
sulfur atom of the trifluoride.
In tr od u ction
R2NSF2NR2, presumably by a molecular disproportion-
ation mechanism. On heating to higher temperatures, the
samples exploded or detonated, resulting in a black char
and unidentified gaseous byproducts.
The introduction of fluorine into medicinal and agro-
chemical products can profoundly alter their biological
properties.1-4 Fluorine mimics hydrogen with respect to
steric requirements and contributes to an alteration of
the electronic properties of the molecule, often resulting
in favorable increased lipophilicity and oxidative stability
properties.5 In view of this, efforts aimed at the develop-
ment of simple, safe, and efficient methods for the
synthesis of organofluorine compounds have escalated in
recent years.6
A widely used synthetic technique involves the conver-
sion of carbon-oxygen to carbon-fluorine bonds (deoxo-
fluorination) by nucleophilic fluorinating sources. This
transformation has routinely been accomplished with the
dialkylaminosulfur trifluorides, mostly with DAST (NEt2-
SF3), in small laboratory scale reactions, usually at near-
ambient conditions.6 However, the use of DAST at more
forcing conditions and at a large scale has been severely
curtailed owing to its well-known thermal instability.7,8
Thermal analysis studies of DAST and related R2NSF3
compounds by Middleton et al.9 indicate that decomposi-
tion of these aminosulfur trifluorides occurs in two stages.
A slow reaction is seen at ∼90 °C with evolution of SF4
and formation of a bis(dialkylamino)sulfur difluoride,
In our attempts to arrive at more thermally stable and
safer deoxofluorinating reagents, we sought to prepare
aminosulfur trifluorides that primarily would not yield
significant gaseous byproducts on thermal decomposition.
Since such R2NSF3 reagents are expected to be a facile
source of fluoride, a very strong base, compounds in
which the R groups are relatively resistant to proton
abstraction were chosen. Perhaps more importantly, we
surmised that the presence of sterically hindered groups
in the vicinity of the reactive SF3 moiety would militate
against the postulated bimolecular disproportionation9
seen with DAST and hence lead to a more thermally
robust reagent. Such a sterically rigid entity could, in
principle, be realized by having very bulky groups on
nitrogen or preferably by employing electron-rich alkoxy
groups that could coordinate to the electron-deficient
sulfur atom. In this context, there was some indication
in the literature of a greater thermal stability of a cyclic
monoalkoxy aminosulfurane.10 Our efforts led to bis(2-
methoxyethyl)aminosulfur trifluoride, (CH3OCH2CH2)2-
NSF3, (Deoxo-Fluor reagent, 1) which was found to be
significantly more thermally stable than DAST with,
consequently, a greater range and scope of applicability.
We report here a synthesis of 1, results of thermal
analysis studies, and illustrations of the reagent’s sig-
nificant broad-spectrum utility, as in the conversion of
alcohols to alkyl fluorides, aldehydes/ketones to gem-
difluorides, and carboxylic acids to the corresponding
trifluoromethyl derivatives. A preliminary report of some
of this work has appeared.11
(1) Welch, J . T.; Eshwarakrishan, S. Fluorine in Bioorganic Chem-
istry; J ohn Wiley and Sons: New York, 1991.
(2) Filler, R.; Kirk, K. Biological Properties of Fluorinated Com-
pounds; Elliott, A. J . Fluorinated Pharmaceuticals; Lang, R. W.
Fluorinated Agrochemicals. In Chemistry of Organic Fluorine Com-
pounds II; Hudlicky, M., Pavlath, A. E., Eds.; ACS Monograph, 187,
American Chemical Society: Washington, DC, 1995.
(3) Cartwright, D. Recent Developments in Fluorine-Containing
Agrochemicals. In Organofluorine Chemistry, Principles and Com-
mercial Applications; Banks, R. E., Smart, B. E., Tatlow, J . C., Eds.;
Plenum Press: New York, 1994.
(4) Banks, R. E. Fluorine in Agriculture; Fluorine Technology
Limited: Sale, Chesire, U.K., 1995 (ISBN: 1-85957-033-X).
(5) Filler, R. Organofluorine Compounds in Medicinal and Biomedi-
cal Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.;
Elsevier Science Publishers: B. V. Amsterdam, The Nederlands, 1993.
(6) German, L., Zemskov, S., Eds. New Fluorinating Agents in
Organic Synthesis; Springer-Verlag: Berlin, Heidelberg, New York,
1989.
Resu lts
Syn th esis. The Deoxo-Fluor reagent 1 was obtained
in a manner analagous to that used for preparing DAST12
(10) Hahn, G.; Sampson, P. J . Chem. Soc., Chem. Commun. 1989,
1650.
(7) Cochran, J . Chem. Eng. News 1979, 57 (12), 4.
(8) Middleton, W. J . Chem. Eng. News 1979, 57 (21), 43.
(9) Messina, P. A.; Mange, K. C.; Middleton, W. J . J . Fluorine Chem.
1989, 42, 137.
(11) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M. J . Chem
Soc., Chem. Commun. 1999, 215.
(12) Hudlicky, M. Org. React. 1988, 25, 513.
10.1021/jo990566+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999

Bis(2-methoxyethyl)aminosulfur Trifluoride
J . Org. Chem., Vol. 64, No. 19, 1999 7049
F igu r e 2. Comparison of recorded pressure data from the
thermal decompositon of the Deoxo-Fluor (1), DAST, and
morpholino-DAST reagents in the Radex instrument.
F igu r e 1. Isothermal calorimetry of DAST and Deoxo-Fluor
(1) reagents.
by reacting the N-trimethylsilyl derivative of bis(2-
methoxyethyl)amine with SF4 in Et2O, followed by distil-
lation of the crude product at 71 °C (0.4 mmHg). It was
characterized by elemental and spectroscopic analyses:
1H NMR (CDCl3) δ 3.5 (t, J ) 5.30 Hz, 4H), 3.15 (t, J )
5.30 Hz, 4H), 3.05 (s, 6H); 19F NMR (CDCl3) δ 40 (s, br,
of 1 was investigated by calorimetry. Addition of a small
amount of 70% HF-pyridine (30 mg/2.5 g of 1) decreased
the time to maximum reaction rate at 90 °C by 1-2 h.
With a higher concentration (130 mg/3.0 g of 1), this time
decreased by about 6 h, but the maximum heat flux was
about the same with and without HF-pyridine. In both
cases however, the total heat evolved was about the same
as that measured for neat 1. Interestingly, the addition
of triethylamine (90 mg/3.0 g of 1) resulted in a greatly
accelerated decomposition of the reagent, with a maxi-
mum rate occurring at only 1-2 h after equilibration at
90 °C. Similar results were observed when triethylamine
was added to DAST; at 80 °C, the time to maximum
reaction rate decreased from 13 h to less than 2 h.
(b) Hea t Evolu tion a n d P r essu r e Rise Da ta on
Th er m a l Ra m p in g. Preliminary testing by DSC on very
small (∼3 mg) samples of DAST and 1 indicated that,
although both begin to decompose at about the same
temperature (∼140 °C), DAST releases more heat (1700
vs 1100 J /g) and does so at significantly higher rates (see
Figure 1 in ref 11). These results have now been
confirmed with larger samples (∼300 mg) utilizing the
Radex instrumentation.
Of equal importance to heat evolution is the rate of
formation of gaseous decomposition products, which
determines the size of emergency relief devices in process
vessels. In Figure 2 are summarized the pressure versus
temperature data obtained for DAST, morpholino-DAST,
and reagent 1, using the Radex instrument. DAST and
morpholino-DAST exhibit dramatic rates of gas evolution
on heating, as evidenced by the nearly vertical slope of
the pressure curves during their decomposition exo-
therms (∼130 and 150 °C, respectively). The Deoxo-Fluor
reagent (1) does not exhibit such a rapid increase in
pressure during decomposition. It is also interesting to
note that the cyclic alkoxy sulfurane, (S)-2-methoxy-
methyl-pyrrolidin-1-ylsulfur trifluoride10 showed a de-
composition profile similar to that of 1 up to ∼160 °C,
but somewhat higher pressures were recorded above this
temperature.
3F); with added fluoride scavenger, e.g., NEt2SiMe3,10 19
F
NMR (CDCl3) δ 55 (s, br, 2F), 28 (s, br, 1F). As prepared,
the reagent is a light yellow liquid, colorless after
distillation. It is currently commercially available.13
Th er m a l An a lysis Stu d ies. The thermal decomposi-
tion profiles of 1, of DAST, and in some cases, of mor-
pholino-DAST were examined by isothermal calorimetry,
differential scanning calorimetry (DSC), Radex, and
accelerating rate calorimetry (ARC). The instrumentation
and procedures are succinctly described in the Experi-
mental Section.
(a ) Isoth er m a l Hea t Evolu tion Mea su r em en ts. A
Setaram C80 calorimeter, operating in an isothermal
mode, was used to provide data on the decomposition
characteristics of reagent 1 and DAST. Results are
reported in Figure 1, which gives heat flow data (reaction
exotherms) for samples that were held isothermally at
90 and 80 °C for periods of hours to days. At 90 °C, DAST
decomposes within a few hours, with a high rate of heat
release (>160 mW). However, for 1 at 90 °C, the time to
maximum reaction rate is 25 h, about six times longer
than for DAST, and the maximum heat flow is substan-
tially lower (∼67 mW); both are indications of improved
thermal stability for 1. This is also the case at the lower
temperature (80 °C), where the DAST sample reaches
its maximum rate of decomposition (55 mW) in about 12
h, whereas 1 requires about 80 h (>3 days) to reach its
maximum (15 mW). Note that for the test with DAST at
80 °C the sample size was reduced from 3 to 1 g to avoid
over-ranging the calorimeter. This affects the magnitude
of the heat flow signal but not its position on the time
scale; as a result, rates of heat evolution cannot be
directly compared.
The data in Figure 1 also indicate that both materials
decompose by an autocatalytic mechanism, because the
maximum rate of heat evolution occurs after some
elapsed time. Clearly, the decomposition rate of both
compounds depends on the generation of some catalyst,
and this is hypothesized to be hydrogen fluoride. Because
HF is known to catalyze deoxofluorination reactions with
aminosulfur trifluorides,12 its effect on the decomposition
Further comparisons of DAST and 1 were provided by
ARC. Here temperature and pressure in the test cell are
measured as the sample undergoes runaway reaction at
near adiabatic conditions, and these signals can be
converted to rates of temperature and pressure rise. In
Figure 3, the log of the measured self-heating rate is
plotted versus inverse absolute temperature for DAST
and 1. A smaller sample size was used for DAST to
prevent rupture of the test cell by excessive pressure.
Exothermic activity is first detected at a slightly higher
temperature for 1 than for DAST (100 vs 85 °C); however,
(13) Aldrich Chemical Co., Milwaukee, WI, 53201 and Air Products
and Chemicals, Inc., 7201 Hamilton Blvd., Allentown, PA 18195-
1501: ref. to G. Saba, Tel: 610-481-7510, Fax: 610-481-3765, E-mail:
sabagt@apci.com.

7050 J . Org. Chem., Vol. 64, No. 19, 1999
Lal et al.
Ta ble 2. F lu or in a tion of Ald eh yd es a n d Keton es w ith 1
F igu r e 3. Accelerating rate calorimetry of DAST and Deoxo-
Fluor reagents.
Ta ble 1. F lu or in a tion of Alcoh ols w ith 1
menthol was more slowly fluorinated than ethyl lactate
under the same reaction conditions. The replacement of
the anomeric hydroxyls of both ribose and glucose deriva-
tives readily yielded the corresponding fluorides in virtu-
ally quantitative yields. This procedure for the anomeric
functionalization of carbohydrates, which has been per-
formed with DAST,14,15 should be more efficient than
previous reported methodologies, avoiding multistep
procedures.16
In reactions with some alcohols, better yields were
obtained with 1 than with DAST. For example, under
the same reaction conditions, fluorination of cyclooctanol
afforded an 85% yield of cyclooctyl fluoride with 1 and
only a 70% yield on reaction with DAST.17 This difference
can be attributed to a higher proportion of the olefin
elimination product (cyclohexene) in the DAST reaction.
Surprisingly, reaction of the earlier cited10 alkoxy amino-
sulfurane, (S)-2-(methoxymethyl)pyrrolidin-1-ylsulfur tri-
fluoride, with cyclooctanol was relatively unselective,
giving only a 17% yield of cyclooctyl fluoride and consid-
erable elimination byproducts under the same reaction
conditions. Thus, despite the apparent thermal stability
of this compound, its poor fluorinating ability coupled
with the relatively high cost and low availability of the
starting amine used in its preparation will likely limit
its synthetic utility.
heat generation rates are about an order of magnitude
higher for DAST at any temperature. The accompanying
rate of pressure increase data provided an even more
pronounced contrast in the thermal behavior of the two
reagents. For DAST, pressure generation rates of 1000
psi/min were recorded at 115 °C with a sample size of
<1 g. On the same scale, 1 exhibited a maximum
pressure rise rate of 50 psi/min, at a higher temperature
(160 °C).
F lu or in a tion Rea ction s w ith th e Deoxo-F lu or
Rea gen t (1). (a ) Alcoh ols. Alcohols are readily con-
verted to alkyl fluorides (Table 1). Excellent to moderate
yields were obtained with a variety of structurally diverse
substrates (1°, 2°, 3°, benzylic, and anomeric hydroxyl
groups). For most of the compounds examined, fluorina-
tion proceeded at -78 °C; however, in some cases it was
necessary to warm the reaction mixture to room temper-
ature to ensure a more rapid and complete conversion.
The rate of reaction was greatly dependent on the
structure of the compound with benzylic >2° > 3° > 1°.
Within any particular class of alcohol, the rate is con-
trolled by the steric hindrance of the compound; e.g.,
(b) Ald eh yd es a n d Keton es. The fluorination of
several structurally different aldehydes and ketones was
also investigated (Table 2). These reactions were con-
ducted in CH2Cl2 at room temperature in the presence
of 0.1 equiv of HF, generated in situ, with added EtOH.
Fluorination of benzaldehyde and terephthaldicarbox-
(14) Rosenbrook, W., J r.; Riley, D. A.; Lartez, P. A. Tettrahedron
Lett. 1985, 26 (1), 3.
(15) Posner, G. H.; Haines, S. R. Tettrahedron Lett. 1985, 26 (1), 5.
(16) Withers, S. G.; Rupitz, K.; Street, I. P. J . Biol. Chem. 1988,
263, 7929.
(17) Middleton, W. J . J . Org. Chem. 1975, 40, 574.

Bis(2-methoxyethyl)aminosulfur Trifluoride
J . Org. Chem., Vol. 64, No. 19, 1999 7051
Ta ble 3. F lu or in a tion of Ca r boxylic Acid s a n d Acid
Ch lor id e w ith 1
Ta ble 4. F lu or in a tion of Su lfid es, Su lfoxid es, a n d
Th ioester w ith 1
aldehyde proved to be surprisingly facile. The former
aldehyde afforded a 96% yield of benzal fluoride (3 h),
and the latter resulted in a 95% yield after 6 h of
refluxing. Deoxofluorination of the ketone 4-tert-butyl-
cyclohexanone afforded a mixture of 1-tert-butyl-4,4-
difluorocyclohexane and 4-tert-butyl-1-fluoro-1-cyclohex-
ene (5.25:1 ratio). Under the same conditions, DAST gave
a 2.03:1 ratio of difluoride to vinyl fluoride.17 A virtually
quantitative yield of the gem-difluoride was obtained on
fluorinating the straight chain ketone 3-phenoxy-2-
propanone. Good yields of products were also obtained
on fluorination of the keto-ester, ethyl benzoylformate
and the electron-deficient ketone, acetophenone. For the
fluorination of the latter, no reaction was seen at room
temperature and only ∼70% conversion was realized in
refluxing hexanes. However, using the neat reagent at
85 °C, there was an almost complete conversion to the
difluoride. This illustrates that it is possible to take
advantage of the greater thermal stability of 1 to
fluorinate relatively unreactive substrates.
(c) Ca r boxylic Acid s a n d Acid Ch lor id es. Trifluo-
romethylated compounds are an important class of
specialty chemicals that are usually prepared by fluoride
ion displacement reactions from the corresponding trichlo-
ride or via multistep processes.18 The direct conversion
of carboxylic acids to the trifluoromethyl derivatives by
SF4 (usually done at forcing conditions) is well-known.19
DAST has not generally been employed for the fluorina-
tion of carboxylic acids, and as far as we are aware only
the conversion of benzoic acid to benzotrifluoride in the
presence of NaF has been reported.20
We have found that 1 can be used for the synthesis of
trifluoromethyl-substituted aromatic and aliphatic com-
pounds from the corresponding carboxylic acid or acid
chloride (Table 3). A facile initial conversion to the
carbonyl fluoride is achieved by reaction of 1 with the
carboxylic acid or acid chloride at 0 °C. (The acid chloride
transformation can also be carried out using other
reagents, e.g., pyridine/HF.21) The monofluoro product is
then heated in neat 1 at 85 °C to obtain the trifluoro-
methyl derivative. This method proved to be useful for
aromatic and 1° alkyl-substituted carboxylic acids, but
only low yields (<10%) of products were obtained from
2° alkyl-substituted acids. In this conversion, the greater
thermal stability of 1 is again exploited for the fluorina-
tion of relatively unreactive compounds.
(d ) Su lfid es, Su lfoxid es, a n d Th ioester s. The R-flu-
orosulfides have proven to be important fluorinated
intermediates to â-lactams, amino acids, and other
medicinally active compounds.22 They are obtained in
moderate yields from sulfides by various electrochemical
processes or via the use of electrophilic fluorinating
agents.23 The reaction of DAST with sulfoxides and
sulfides bearing R-hydrogen atoms can also furnish these
compounds.24
Compound 1 reacts with sulfides in a manner analo-
gous to DAST to produce R-fluorosulfides (Table 4).
Excellent yields were obtained on fluorination of various
aryl-alkyl and dialkyl sulfides in CH2Cl2 containing 0.01
equiv of a SbCl3 catalyst. Most of the R-fluorosulfides are
not stable to standard purification techniques and were
oxidized to the sulfoxides or sulfone prior to isolation.
McCarthy and co-workers,25 as well as Robbins and
Wnuk,26 demonstrated the transformation of sulfoxides
to R-fluorosulfides using DAST, with or without Lewis
acid catalysis, via the Pummerer rearrangement mech-
anism. We have found that a similar conversion can be
effected with 1 (Table 4). This was applied to the simple
sulfoxide, phenyl methyl sulfoxide, as well as to the more
(22) (a) Sammes, P. G. Chem. Rev. 1976, 76, 113. (b) Hermann, P.
Organic Sulfur Chemistry; Friedlima, R., Skorova, A. E., Eds.; Perga-
mon Press: Oxford, 1981; p 51. (c) J arvi, E. T.; McCarthy, J . R.; Mehdi,
J . R.; Matthews, D. P.; Edwards, M. C.; Prakash, N. J .; Bowlin, T. L.;
Sunkara, P. S.; Bey, P. J . Med. Chem. 1991, 34, 647.
(23) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1748
and references therein.
(24) Robbins, M. J .; Wnuk, F. J . J . Org. Chem. 1993, 58, 3800.
(25) McCarthy, J . R.; Peet, N. P.; Le Tourneau, M. E.; Inbasekaran,
M. J . Am. Chem. Soc. 1985, 107, 735.
(18) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(19) Boswell, G. A., J r.; Ripka, W. C.; Scribner, R. M.; Tullock, C.
W. Org. React. 1974, 21, 1.
(20) Middleton, W. J . U.S. Patent 3,914,265, 1975.
(21) Olah, G. A.; Kuhn, S. J . J . Org. Chem. 1961, 26, 237
(26) Wnuk, S. F.; Robbins, M. J . J . Org. Chem. 1990, 55, 4757.

7052 J . Org. Chem., Vol. 64, No. 19, 1999
Lal et al.
Ta ble 5. Heter olytic C-H Bon d Dissocia tion En er gies
(k ca l/m ole) for Am in osu lfu r a n es a n d Dieth yla m in e
complicated 2′-aryl sulfoxide substituted nucleoside, 3′,5′-
di-O-acetyl-2′-S-(4-methoxyphenyl)-2′-sulfinyluridine. For
the latter, a higher yield (80%) of the fluorinated product
was obtained with 1 than was reported using DAST
(56%).27 The fluoronucleoside was obtained as a mixture
of diastereomers (2′ R/S ) 9:91 as determined by 19F
NMR) with stereoselectivity similar to that seen for the
reaction with DAST (2′ R/S ) 87:13).27
Although the geminal difluorination of the carbonyl
group of esters is generally too difficult to perform with
DAST12 or SF4,19 Bunnelle and co-workers28 demon-
strated a simple synthesis of R,R-difluoroethers by react-
ing thioesters with DAST. For example, methyl thiono-
benzoate obtained from methyl benzoate and the Lawes-
son reagent28 in refluxing toluene afforded the corre-
sponding difluoroether in an overall yield of ∼42%. When
the thionation was carried out at 150 °C in xylenes and
fluorination was done with 1 in the presence of a catalytic
amount of SbCl3 (0.01 equiv), a virtually quantitative
yield of the difluoride (48) was realized (Table 4).
with a 6-31G** basis set were carried out considering the
following structures:
Discu ssion
Sta bility of Rea gen t 1 Rela tive to Str u ctu r e. The
thermal analysis studies clearly point to an enhanced
thermal stability of the Deoxo-Fluor reagent 1 vis-a`-vis
DAST and even morpholino-DAST, which is cited as
being the most stable of the aminosulfur trifluorides.9
Under isothermal conditions at 80-90 °C, DAST decom-
poses much more rapidly and with greater heat evolution
than 1 (Figure 1). In the temperature ramping DSC,11
Radex, and ARC experiments, a similar contrast is seen
between 1 and DAST: the latter undergoes much more
rapid thermal degradation at generally lower tempera-
tures. Perhaps more important from a process safety
point of view, 1 surprisingly yields far less gaseous
byproducts on decomposition than DAST (Figure 2).
This enhanced stability of 1 was admittedly surprising,
and we attempted to rationalize it in terms of our starting
postulates relating to C-H bond acidities and steric
effects, now quantified by ab initio quantum-mechanical
calculations. Heterolytic bond dissociation energies for
specific C-H linkages in 1, DAST, morpholino-DAST,
and diethylamine as a reference molecule were calculated
using the Hartree-Fock method with a 6-31G** basis
set;29,30 these energies are collected in Table 5. It is
evident that the aminosulfuranes are generally in this
sense more acidic than Et2NH, but except perhaps for
the C-Hâ proton data, there is not a marked contrast
between 1 and DAST. This is consistent with the obser-
vation that the thermal decomposition of both of the
reagents is accelerated by triethylamine. The distinc-
tively higher acidities for DAST vis-a`-vis morpholino-
DAST may be an indication of the marginally greater
thermal stability of the latter.
The single ring structure (b) is calculated to be more
stable, in electronic energy terms, than the open molecule
(a) by 2.8 kcal/mol, while (c) is too sterically strained at
N to be energetically feasible. In (b) the optimized S-O
bond distance is 2.95 Å, indicating a weak bonding as a
result of the partial charge transfer from S to O. We thus
postulate that the single ring folded structure (b) stabi-
lizes 1 by shielding the reactive SF3 group with the ether
side chain, making the reagent less prone to decomposi-
tion by bimolecular disproportionation reactions, as
putatively occurs with DAST.9
DFT calculations done on (S)-2-methoxymethyl-pyrrol-
idin-1-ylsulfur trifluoride10 show that a five-membered
ring structure similar to (b) is the most stable conforma-
tion. However, the S-O bond with a bond distance of
3.15A° is much weaker than observed for 1 as a result of
steric hindrance around the -SF3 group.
Rea ctivity a n d Ap p lica tion s of th e Deoxo-F lu or
Rea gen t (1). The broad applicability of 1 as in the
fluorination of alcohols, aldehydes/ketones, carboxylic
acids, sulfides, sulfoxides and thioesters is evident from
the examples in Tables 1-4. The reagent’s reaction
chemistry generally parallels that of DAST, although in
some cases significantly higher selectivities for the
desired fluorinated compounds with concomitantly less
elimination products were realized. Pertinent examples
are the conversion of cyclooctanol to cyclooctyl fluoride
(Table 1) and of 4-tert-butylcyclohexanone to 1-tert-butyl-
4,4-difluorocyclohexane (Table 2). The most distinguish-
ing feature of 1 is its greater thermal stability, which
should encourage its use not only in larger scale processes
but also in reactions that require more forcing conditions,
as in the fluorination of electron-deficient ketones and
carboxylic acids, which are traditionally less reactive
substrates (Tables 2 and 3).
It appears, however, that the relatively greater stabil-
ity of 1 can be more satisfactorily rationalized on the
basis of conformational structures where there is bonding
between the ether oxygen and sulfur. Density functional
theory (DFT) calculations using the B3LYP functional29,30
(27) Robbins, M. J .; Mullah, K. B.; Wnuk, S. F.; Dalley, N. K. J .
Org. Chem. 1992, 57, 2357.
(28) Bunnelle, W. H.; McKinnis, B. R.; Narayanan, B. A. J . Org.
Chem. 1990, 55, 8.
(29) (a) Becke, A. D. J . Chem. Phys. 1993, 98, 1362. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(30) J aguar 3.5; Schrodinger Inc.: Portland, OR, 1998.
Exp er im en ta l Section
All of the substrates and bis(2-methoxyethyl)amine, SbCl3,
NBS, and MCPBA reagents were obtained from Aldrich and
used as received; the sulfoxide (45 in Table 4) was prepared

Bis(2-methoxyethyl)aminosulfur Trifluoride
J . Org. Chem., Vol. 64, No. 19, 1999 7053
by a standard literature method.27 Sulfur tetrafluoride was
acquired from Air Products and Chemicals, Inc.
dried (Na2SO4), filtered, and evaporated in vacuo. Flash
chromatography on silica gel in hexanes/Et2O afforded the
pure products: benzal fluoride17 (17, 1.22 g, 95%); R,R,R′,R′-
tetrafluoro-p-xylene32 (19, 1.67 g, 94%); 1,1-difluoro-4-tert-
butylcyclohexane33 (21, 1.50 g, 85%); 2,2-difluoroindan34 (23,
647 mg, 42%); 2,2-difluoro-1-phenoxypropane (25, 1.68 g, 98%).
1H NMR (CDCl3) δ 7.35 (t, J ) 7, 8.5 Hz, 2H), 7.05 (t, J ) 7
Hz, 1H), 6.90 (d, J ) 8.5 Hz, 2H), 4.10 (t, J ) 12 Hz, 2H), 1.80
(t, J ) 18 Hz, 3H). 19F NMR (CDCl3) δ - 102 (s, br). Elemental
analysis calculated for C9H10OF2: C, 62.88; H, 5.85; F, 22.07.
Found: C, 63.58; H, 5.88; F, 22.20. Ethyl 2-phenyl-2,2-
difluoroacetate35 (27, 1.62 g, 81%); 1,1-difluoroethylbenzene17
(29, 1.32 g, 92%).
1H and 19F NMR spectra were recorded at 300 and 282 MHz,
respectively. Chemical shifts were referenced to neat CFCl3
(19F) or neat TMS (1H). GC/MS were done using a GC with a
30 m × 0.25 mm SPB-5 column and a MS with an EI ionization
detector. Elemental analyses were done by Galbraith Labo-
ratories, Inc., Knoxville, TN.
The Hartree-Fock and DFT quantum chemistry calcula-
tions were done using the J aguar 3.5 package.30
CAUTION: Compound 1 reacts rapidly and exothermically
with water liberating HF. It is recommended that reactions
with neat 1 be carried out at <90 °C.
F lu or in a tion of Ca r boxylic Acid s. (a ) Ca r boxylic Acid
to Acyl F lu or id e. A solution of the carboxylic acid (10 mmol)
in CH2Cl2 (5.0 mL) was added to the aminosulfur trifluoride
1 (2.43 g, 11 mmol) under N2 and stirred for 16 h at room
temperature. The progress of the reaction was monitored by
GC/MS. On completion, the solution was poured into saturated
NaHCO3, and after CO2 evolution ceased it was extracted into
CH2Cl2 (3 × 15 mL), dried (Na2SO4), filtered, and evaporated
in vacuo. Flash chromatography on silica gel in hexanes/Et2O
afforded the pure products: benzoyl fluoride36 (31, 1.19 g, 96%);
dodecanoyl fluoride37 (33, 1.96 g, 97%).
Syn th esis of Bis(2-m eth oxyeth yl)a m in osu lfu r Tr iflu o-
r id e (1). A solution of bis(2-methoxyethyl)amine (3.3 g, 25
mmol) in hexane (12 mL) contained in a three-neck, 100 mL
round-bottom flask equipped with a N2 inlet tube, a rubber
septum and magnetic stirring bar was cooled to -78 °C and
treated with 2.5 M BuLi (10 mL, 25 mmol, in hexanes). The
mixture was brought to 0 °C and treated with chlorotrimeth-
ylsilane (2.72 g, 3.2 mL) dissolved in 10 mL of hexanes. After
30 min at 0 °C, the mixture was filtered, and the solvent was
evaporated in vacuo to obtain the silylamine, (CH3OCH2CH2)2-
1
NSi(CH3)3; H NMR (CDCl3) δ 3.25 (t, 4H), 3.25 (s, 6H), 2.95
(b) Acyl F lu or id e to th e Tr iflu or om eth yl Der iva tive.
The acyl fluoride (10 mmol) prepared as described above was
added to the aminosulfur trifluoride 1 (4.42 g, 20 mmol)
contained in a Teflon bottle equipped with a N2 inlet tube, and
the mixture was heated at 85 °C. The progress of the reaction
was monitored by GC/MS. On completion, the solution was
poured into saturated NaHCO3, and after CO2 evolution ceased
it was extracted into CH2Cl2 (3 × 15 mL), dried (Na2SO4),
filtered, and evaporated in vacuo. Flash chromatography on
silica gel in hexanes/Et2O afforded the pure products: R,R,R-
trifluorotoluene36 (35, 847 mg, 58%); 1,1,1-trifluorododecane38
(36, 1.41 g, 63%).
F lu or in a tion of Ben zoyl Ch lor id e. A solution of benzoyl
chloride (1.41 g, 10 mmol) in CH2Cl2 (5.0 mL) was added to 1
(2.43 g, 11 mmol) under N2 and stirred for 16 h at room
temperature. After workup as above, benzoyl fluoride36 (31,
1.18 g) was obtained in 95% yield.
F lu or in a tion of Su lfid es. A solution of the sulfide (10
mmol) in CH2Cl2 was added dropwise to a solution of 1 (3.09
g, 14 mmol) in CH2Cl2 (20 mL) under N2 in a three-neck, 50
mL, round-bottomed flask. This was followed by addition of
solid SbCl3 (114 mg, 0.5 mmol), and the mixture was stirred
at room temperature until GC/MS analysis indicated comple-
tion. The solution was poured into CH2CL2 (25 mL), washed
with saturated NaHCO3, dried, and filtered. The filtrate was
treated successively with MeOH (15 mL), H2O (1.5 mL), and
NBS (3.56 g, 20 mmol). After 30 min of stirring, the resulting
solution was washed with 0.1 M aqueous sodium thiosulfate
(25 mL), 5% H2SO4 (25 mL), saturated NaHCO3 (25 mL), dried
(Na2SO4), and evaporated in vacuo. The residue was purified
by flash chromatography on silica gel in hexane/ethyl acetate
to obtain the pure products: fluoromethyl phenyl sulfoxide24
(38, 1.48 g, 94%); p-chlorophenyl fluoromethyl sulfoxide39 (40,
1.82 g, 95%); p-methoxyphenyl fluoromethyl sulfide24 (42, 1.56
g, 83%) was isolated as such and not further oxidized.
F lu or in a tion of Su lfoxid es. A solution of the sulfoxide
(10 mmol) in CH2Cl2 (10 mL) was added to 1 (4.42 g, 20 mmol)
under N2. SbCl3 (0.1 mmol) was added, and the mixture was
stirred at room temperature for 16 h. The solution was
quenched with saturated NaHCO3 (25 mL). After CO2 evolu-
(t, 4H), 0.0 (s, 9H). This product was reacted with SF4 as
described below.
A 300 mL stainless steel Parr reactor, equipped with a
magnetic stirrer, was charged with the silylamine (5.05 g)
dissolved in Et2O (100 mL). The reactor vessel was cooled to
-30 °C and connected via an entry port to a vacuum/pressure
metal manifold, through which SF4 (37 mmol) was slowly
added. After the vessel was sealed, it was brought to 0 °C,
and the contents were stirred under autogenous pressure for
3 h. Gaseous volatiles were then removed by pumping through
a soda lime trap, and the remaining liquid contents of the
vessel were transferred to a 250 mL glass flask. Evaporation
in a vacuum resulted in 2.6 g (51% yield) of 1, as a light yellow
liquid. It was purified by distillation in glass at 71 °C (0.4
mmHg) to a colorless liquid. Elemental analysis calculated for
C6 H14 F3 NO2S: C, 32.57; H, 6.37; F, 25.76; N, 6.33; S, 14.49.
Found: C, 32.61, H, 6.46; F, 25.56; N, 6.44; S, 14.59. For NMR
see the Results section.
Gen er a l P r oced u r e for F lu or in a tion of Alcoh ols. The
alcohol (10 mmol) in dry CH2Cl2 (3.0 mL) was added at the
temperature indicated in Table 1, under N2, to a solution of
the aminosulfur trifluoride 1 (2.43 g, 11 mmol) in CH2Cl2 (2.0
mL) in a 50 mL, three-neck flask equipped with a N2 inlet tube,
septum, and a magnetic stirring bar. The reaction was
monitored by GC/MS for disappearance of the starting mate-
rial. On completion, the mixture was poured into saturated
NaHCO3 (25 mL), and after CO2 evolution ceased it was
extracted into CH2Cl2 (3 × 15 mL), dried (Na2SO4), filtered,
and evaporated in vacuo. Flash chromatography on silica gel
in hexane/ethyl acetate afforded the pure products: 2-fluoro-
ethylbenzene17 (3, 1.05 g, 85%); benzyl fluoride17 (5, 1.05 g,
96%); 1-fluoro-2-isopropyl-5-methylcyclohexane17 (7, 695 mg,
44%); ethyl 2-fluoropropionate17 (9, 876 mg, 73%); ethyl
2-fluoro-2-methylpropionate31 (11, 1.19 g, 89%); 1-fluoro-2,3,5-
tri-O-benzyl-D-arabinofuranose14 (13, 4.13 g, 98%, R/â ) 9:91);
1-fluoro-2,3,4,6-tetra-O-benzyl-D-glucopyranose15 (15, 5.32 g,
98%, R/â ) 28:72).
F lu or in a tion of Ald eh yd es a n d Keton es. A solution of
aldehyde (16, 18) or ketone (20, 22, 24, 26) (10 mmol) in
CH2Cl2 (3.0 mL), contained in a 25 mL Teflon bottle equipped
with a N2 inlet tube and stirring bar, was treated with a
solution of 1 (3.76 g, 17 mmol) in CH2Cl2 (2.0 mL) at room
temperature. EtOH (92 mg, 116 µL, 2 mmol) was added, and
the mixture was stirred at room temperature. The progress
of the reaction was monitored by GC/MS. On completion, the
solution was poured into saturated NaHCO3, and after CO2
evolution ceased it was extracted into CH2Cl2 (3 × 15 mL),
(32) Fuqua, S. A.; Parkhurst, R. M.; Silverstein, R. M. Tetrahedron
1964, 20, 1625.
(33) Boswell, G., J r. U.S. Patent 4212815, 1980.
(34) Adcock, W.; Compton, B. D.; Khor, T. C. Aust. J . Chem. 1976,
29, 2571.
(35) Hagele, G.; Haas, A. J . Fluor. Chem. 1996, 15.
(36) Middleton, W. J . U.S. Patent 3,914,265, 1975.
(37) Rozen, S.; David, B. J . Fluor. Chem. 1996, 76, 145.
(38) Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J . Am. Chem.
Soc. 1960, 82, 543.
(31) Cost, D. J .; Boutin, N. E.; Reiss, J . G. Tetrahedron 1974, 30,
3793.
(39) Lal, G. S. J . Org. Chem. 1993, 58, 2791.

7054 J . Org. Chem., Vol. 64, No. 19, 1999
Lal et al.
tion ceased, the CH2Cl2 extract was dried (Na2SO4), filtered,
and evaporated in vacuo. Flash chromatography on silica gel
in ethyl acetate/hexanes afforded the pure products: fluoro-
methyl phenyl sulfide24 (44, 1.15 g, 82%); 3′,5′-di-O-acetyl-2′-
fluoro-2′-S-(4-methoxyphenyl)-2′-thiouridine27 (46, 3.75 g, 80%,
R/S ) 9/91).
were heated at 2 °C per minute from 30 to 350 °C. Relatively
small (∼300 mg) samples were used to avoid overpressuriza-
tion of the stainless steel cell. Either Viton or ethylene-
propylene (EP) O-rings were used for the flange closure.
The Setaram C80 (Setaram/SFIM, Inc.; Grand Prairie, TX)
is a high sensitivity heat-flux (Calvet-type) calorimeter. Its
standard high pressure 316 stainless steel cells (8 cm3 internal
volume) were used, with a Teflon O-ring seal. The calorimeter
was heated to operating temperature (usually 80 or 90 °C,
nominal) and allowed to stabilize before insertion of the test
cell.
Typically, the ARC instrument (Arthur D. Little, Inc.;
Cambridge, MA) operates in a “heat-wait-search mode”, i.e.,
it heats the sample to a predetermined temperature, waits for
thermal transients to subside, then searches for exothermic
activity at a detection limit of 0.02 °C per minute of self-
heating. Accumulation of heat causes the system temperature
to rise, which results in an increase in the rate of reaction.
Acceleration of the rate continues exponentially. The typical
heat-wait-search profiles were done from 50 to 350 °C, using
5 °C steps and 15-20 min wait times. The thermal inertia
factor (φ) cited in Figure 3 is the ratio of the heat capacity of
the cell plus sample to that of the sample alone and indicates
the amount of heat lost to the test cell relative to that
generated by the sample.
F lu or in a tion of Th ioester . Lawesson reagent (4.04 g, 10
mmol) was added under N2 to a solution of methyl benzoate
(1.3 mL, 10 mmol) in xylenes (15 mL) contained in a three-
neck, round-bottom flask equipped with a N2 inlet tube,
septum, and a magnetic stirring bar. The mixture was heated
at 150 °C for 16 h. On cooling to room temperature, the
mixture was treated with hexane (35 mL), the resulting
precipitate was filtered, and the filtrate was evaporated in
vacuo. The thioester thereby obtained was dissolved into
CH2Cl2 (5.0 mL) and transferred to a three-neck, round-bottom
flask under N2. This solution was then treated with SbCl3 (114
mg, 0.5 mmol) and the aminosulfur trifluoride 1 (3.09 g, 14
mmol) and stirred for 3 h. The solution was quenched with
saturated NaHCO3 (25 mL). After CO2 evolution ceased, the
mixture was extracted with CH2Cl2 (2 × 25 mL), dried
(Na2SO4), filtered, and evaporated in vacuo. Flash chroma-
tography on silica gel in diethyl ether/hexanes afforded the
pure product: R,R-difluorobenzyl methyl ether28 (48, 1.52 g,
96%).
Th er m a l An a lysis P r oced u r es. The Radex Thermal
Hazards Screening System (Astra Scientific International, Inc.;
Pleasanton, CA) is similar in principle to a heat-flux dif-
ferential scanning calorimeter but uses larger sample sizes and
is equipped with a transducer to monitor pressure inside the
test cell (8 cm3 internal volume). For the Radex tests, samples
Ack n ow led gm en t. We are grateful to G. Saba and
Air Products and Chemicals, Inc. for support of this
work.
J O990566+