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

Article abstract of DOI:10.1039/a808517j

Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is effective for the conversion of alcohols to alkyl fluorides, aldehydes/ketones to the corresponding gem-difluorides and also for the transformation of carboxylic acids to their trifluoromethyl derivatives; it is a less thermally sensitive, broader-spectrum alternative to the traditional dialkylaminosulfur trifluoride (DAST) deoxofluorination reagents.

Full text of DOI:10.1039/a808517j

Bis(2-methoxyethyl)aminosulfur trifluoride: a new broad-spectrum
deoxofluorinating agent with enhanced thermal stability
Gauri S. Lal,* Guido P. Pez, Reno J. Pesaresi and Frank M. Prozonic
Air Products and Chemicals Inc, 7201, Hamilton Boulevard, Allentown, PA 18195-1501, USA.
E-mail: lalgs@apci.com
Received (in Corvallis, OR, USA) 2nd November 1998, Accepted 7th December 1998
Bis(2-methoxyethyl)aminosulfur
trifluoride
(Deoxo-
yellow oil in 70% yield [dH(CDCl3) 3.5 (t, 4H), 3.15 (t, 4H),
3.05 (s, 6H); dF(CDCl3) 55 (s, br, 2F), 28 (s, br, 1F]. A
comparison of the thermal stability of Deoxo-Fluor and DAST,
as determined by differential scanning calorimetry (DSC), is
illustrated in Fig. 1. While the onset of decomposition is almost
the same for both compounds ( ~ 140 °C), DAST degrades
much more rapidly and with somewhat larger heat evolution
(1700 vs. 1100 J g21 for 1). Deoxo-Fluor showed a much more
gradual exotherm over a wider temperature range. These
preliminary results indicate that the latter should be safer to use
than DAST on a larger, practical scale.
The broad applicability of 1 for the deoxofluorination of
organic substrates is illustrated by its reaction chemistry, as
shown in Table 1. Primary, secondary and tertiary alcohols react
at relatively low temperatures (278 °C to ambient), giving
moderate to excellent yields of the corresponding alkyl
fluorides. Fluorination of the anomeric hydroxy group of the
sugar was particularly effective, giving the desired compound in
95% yield. The fluorination of aldehydes and ketones con-
Fluor™) is effective for the conversion of alcohols to alkyl
fluorides, aldehydes/ketones to the corresponding gem-
difluorides and also for the transformation of carboxylic
acids to their trifluoromethyl derivatives; it is a less
thermally sensitive, broader-spectrum alternative to the
traditional dialkylaminosulfur trifluoride (DAST) deoxo-
fluorination reagents.
In view of the importance of organofluorine compounds in the
pharmaceutical and agrochemical industries, efforts aimed at
the development of simple, safe and efficient methods for their
synthesis have escalated in recent years.1–5 The conversion of
carbon–oxygen to carbon–fluorine bonds by nucleophilic
fluorinating sources (deoxofluorination) represents one such
technique which has been widely used for the selective
introduction of fluorine into organic molecules.6 This trans-
formation has been accomplished routinely with the dialkylami-
nosulfur trifluorides, such as DAST (NEt2SF3), for laboratory
scale reactions.7 However, utilization of DAST for larger scale
applications has been limited by its well known thermal
instability.8,9 DAST and related dialkylaminosulfur trifluorides
are said to undergo catastrophic decomposition (explosion or
detonation) with gas evolution on heating to > 90 °C.10
We now report on bis(2-methoxyethyl)aminosulfur tri-
fluoride (Deoxo-Fluor) 1, a new deoxofluorinating agent which
is a less thermally sensitive and very effective alternative to
DAST. It permits the facile conversion of alcohols to alkyl
fluorides, aldehydes/ketones to the corresponding gem-di-
fluorides, and also the transformation of carboxylic acids to the
corresponding trifluoromethyl derivatives with, in some cases,
superior performance to DAST.
Deoxo-Fluor reagent is obtained in a manner analogous to
that of DAST9 by reacting the N-trimethylsilyl derivative of
bis(2-methoxyethyl)amine with SF4 in Et2O at 230 °C. The
crude product is distilled (60 °C, 0.1 mmHg) to afford a light
Fig. 1 DSC plots for the thermal decomposition of DAST and Deoxo-Fluor
1 (ref. 13). Samples were in hermetically sealed gold pans; scan rate 10 °C
min21
.
Table 1 Fluorination of model compounds with the Deoxo-Fluor reagent 1
Substrate
1/equiv.
Solvent
T/°C
t/h
Product
Yield (%)
PhCH2CH2OH
MeCH(OH)CO2Et
Me2C(OH)CO2Et
1.1
1.1
1.1
CH2Cl2
CH2Cl2
CH2Cl2
room temp.
room temp.
room temp.
16
3
8
PhCH2CH2F
MeCHFCO2Et
Me2CFCO2Et
85
73
89
O
OH
F
BnO
BnO
1.1
CH2Cl2
0
0.5
95a
OBn
OBn
OBn
OBn
PhCHO
1.7
1.7
1.7
1.5
1.1
1.1
2.0
2.0
CH2Cl2
CH2Cl2
CH2Cl2
neat
CH2Cl2
CH2Cl2
neat
reflux
room temp.
room temp.
85
0
0
85
85
16
16
16
16
0.5
0.5
48
48
PhCHF2
95
85
98
92
96
96
58
63
4-tert-butylcyclohexanone
PhOCH2COMe
PhCOMe
PhCO2H
Me(CH2)8CO2H
PhCOF
1-tert-butyl-4,4-difluorocyclohexane
PhOCH2CF2Me
PhCF2Me
PhCOF
Me(CH2)8COF
PhCF3
Me(CH2)8COF
neat
Me(CH2)8CF3
a Ratio a:b = 9:91.
Chem. Commun., 1999, 215–216
215

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Hudlicky and A. E. Pavlath, ACS Monograph 187, American Chemical
Society, Washington, DC, 1995.
ducted in CH2Cl2 at room temperature in the presence of 0.1
equiv. of HF, generated in situ with added EtOH, afforded
excellent yields of the corresponding gem-difluoro products
from both aliphatic and aromatic carbonyl compounds. The
relatively greater thermal stability of 1 was exploited for the
fluorination of electron-deficient ketones and carboxylic acids,
which are traditionally less reactive substrates. As illustrated in
Table 1, 1 reacted readily with carboxylic acids, giving acyl
fluorides. These were subsequently converted to the tri-
fluoromethyl derivatives on heating for an extended period in
the neat reagent at 90 °C. DAST has not been generally
employed for the fluorination of carboxylic acids and we are
only aware of one report of such an application.11
The broad-spectrum reactivity of the Deoxo-Fluor reagent
coupled with its potentially greater margin of safety in use and
commercial availability12should lead to its widespread applica-
tion for the synthesis of specialty organofluorine compounds.
Detailed studies of its thermal behavior and reactivity with a
wider range of functional groups are in progress.
3 D. Cartwright, Recent Developments in Fluorine-Containing Agro-
chemicals, in Organofluorine Chemistry, Principles and Commercial
Applications, ed. R. E. Banks, B. E, Smart and J. C. Tatlow, Plenum,
New York, 1994.
4 R. Filler, in Organofluorine Compounds in Medicinal and Biomedicinal
Applications, ed. R. Filler, Y. Kobayashi and L. M. Yagupolskii,
Elsevier, Amsterdam, The Nederlands, 1993.
5 New Fluorinating Agents in Organic Synthesis, ed. L. German and S.
Zemskov, Springer-Verlag, Heidelberg, New York, 1989.
6 M. Hudlicky, Fluorination with Diethylaminosulfur Trifluoride and
related Aminosulfuranes, in Org. React.,, 1988, 25, 513.
7 W. J. Middleton, J. Org. Chem., 1975, 40, 574.
8 J. Cochran, Chem. Eng. News, 1979, 57, 4.
9 W. J. Middleton, Chem. Eng. News, 1979, 57, 43.
10 P. A. Messina, K. C. Mange and W. J. Middleton, J. Fluorine Chem.,
1989, 42, 137.
11 PhCF3 was reportedly produced in 50% yield by heating in situ prepared
PhCOF with excess DAST in diglyme for 20 h at 80 °C: W. J.
Middleton, US Pat. 3,914,265 (1975).
12 From Aldrich Chemical Co, Milwaukee, WI 53201 and Air Products
and Chemicals, Inc. 7201 Hamilton Boulevard, Allentown, PA, USA
18195-1501.
Notes and references
13 The exotherm peak for DAST appears skewed, as the sample heats faster
than the furnace, then cools to readjust to the temperature program.
1 J. T. Welch and S. Eshwarakrishan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991.
2 R. Filler and K. Kirk, Biological Properties of Fluorinated Compounds,
A. J. Elliott, Fluorinated Pharmaceuticals and R. W. Lang, Fluorinated
Agrochemicals in Chemistry of Organic Fluorine Compounds II, ed. M.
Communication 8/08517J
216
Chem. Commun., 1999, 215–216
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