4830
J . Org. Chem. 2000, 65, 4830-4832
F lu or in a tion of Th ioca r bon yl Com p ou n d s w ith
Bis(2-m eth oxyeth yl)a m in osu lfu r Tr iflu or id e (Deoxo-F lu or
Rea gen t): A F a cile Syn th esis of gem -Diflu or id es
Gauri S. Lal,* Elyse Lobach,† and Ann Evans†
Air Products and Chemicals Inc., 7201 Hamilton Boulevard, Allentown, Pennsylvania 18195-1501
lalgs@apci.com
Received J anuary 8, 2000
A variety of thiocarbonyl derivatives (thioketone, thioester, thioamide, dithioester, and dithiocar-
bamate) were converted to the corresponding gem-difluorides in excellent yields on reaction with
the fluorinating agent, bis(2-methoxyethyl)aminosulfur trifluoride, in the presence of SbCl3.
In tr od u ction
philic halonium species in the presence of fluoride ions.13
The synthesis of R,R-difluoroethers from the reaction of
thioesters with diethylaminosulfur trifluoride (DAST)14
is the only report of a thiocarbonyl to gem-difluoride
conversion using aminosulfur trifluorides.
We recently reported on the preparation and the
general synthetic utility of bis(2-methoxyethyl)amino-
sulfur trifluoride (Deoxo-Fluor Reagent, 1)15 a compound
that has been found to be significantly more thermally
stable and therefore of broader applicability than DAST.
Herein, we describe a simple, efficient route to a variety
of gem-difluorides by the reaction of thioketones, thio-
esters, thioamides, dithioesters, and dithiocarbamates
with 1. These compounds are not readily accessible
directly from their carbonyl precursors.
The introduction of fluorine into organic compounds
can profoundly alter their chemical, physical, and biologi-
cal properties.1-5 As a result, there has been a consider-
able interest in the development of pharmaceuticals and
plant protection agents that contain fluorine in their
structures. 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
The direct transformation of the carbonyl group of
aldeydes and ketones into the gem-difluoride can in many
cases be accomplished with reagents such as SF4 and
7
aminosulfur trifluorides8 with relative ease. However,
extreme conditions are required and low yields are
obtained when similar transformations are conducted
with electron-deficient ketones, esters, and amides.7
Alternative methods involve the reaction of carbonyl-
derived hydrazones9 and diazo compounds10 with the
strong oxidative fluorinators, iodine monofluoride or
fluorine. gem-Difluorides can also be prepared by the
oxidative desulfurization-fluorination of ortho thioesters,11
dithiolanes,12 and thiocarbonyl derivatives with electro-
Resu lts a n d Discu ssion
The direct conversion of benzophenone to the gem-
difluoride with SF4 is known to be quite difficult. It takes
place only at 180 °C in the presence of a large excess of
HF.16 Alternatively, the product can be obtained by
reacting the dithiolane derivative with excess DBH in
HF-pyridine12a or with I2/F2.12b We observed no reaction
when benzophenone was heated with neat 1 at 90 °C for
16 h. However, we found that the thiono derivative of
bezophenone obtained from the reaction of benzophenone
† Air Products and Chemicals Inc. summer interns (1998 and 1999,
respectively) from Cedar Crest College, Allentown, PA.
(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. Organofluorine Chemistry, Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J . C., Eds.; Plenum
Press: New York, 1994.
17
with P4S10 reacted readily with 1 in CH2Cl2 in the
presence of a catalytic amount of SbCl3 (Table 1) to
produce the difluoride in excellent yield.
(11) (a) Patrick, T. B.; Hudson, C. M. Heteroat. Chem. 1999, 10, 1.
(b) Matthews, D. P.; Whitten, J . P.; McCarthy, J . R.; Tetrahedron Lett.
1986, 27, 4861.
(12) Katzenellenbogen, J . A.; Sondej, S. C. J . Org. Chem. 1986, 51,
3508. (b) Chambers, R. D.; Sandford, G.; Sparrowhawk, M. E.;
Atherton, M. J . J . Chem. Soc., Perkins Trans. 1 1996, 1941.
(13) (a) Kuroboshi, M.; Hiyama, T. Chem. Lett. 1992, 827. (b)
Kuroboshi, M.; Hiyama, T. Tett. Lett. 1994, 35, 3983. (c) Kuroboshi,
M.; Suzuki, K.; Hiyama, T. Tett. Lett. 1992, 33, 4173. (d) Kuroboshi,
M.; Hiyama, T. Tetrahedron Lett. 1992, 33, 4177. (e) Rozen, S.; Mishani,
E. J . Chem. Soc., Chem. Commun. 1994, 2081. (f) Kanie, K.; Mizuno,
K.; Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc. J pn. 1998, 71, 1973.
(14) Bunnelle, W. H.; McKinnis, B. R.; Narayanan, B. A. J . Org.
Chem. 1990, 55, 8.
(4) Banks, R. E. Fluorine in Agriculture; Fluorine Technology
Limited: Sale, Chesire, U.K., 1995.
(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 Netherlands, 1993.
(6) German, L., Zemskov, S. Eds. New Fluorinating Agents in
Organic Synthesis; Springer-Verlag: Berlin, Heidelberg, New York,
1989.
(7) Boswell, G. A., J r.; Ripka, W. C.; Scribner, R. M.; Tullock, C. W.
Org. React. 1974, 21, 1.
(8) Hudlicky, M. Org. React. 1988, 25, 513.
(9) Rozen, S.; Brand, M.; Zamir, D.; Hebel, D. J Am. Chem. Soc.
1987, 109, 896.
(15) (a) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M.; Cheng,
H. J . Org. Chem. 1999, 71, 7048 (b) Lal, G. S.; Pez, G. P.; Pesaresi, R.
J .; Prozonic, F. M. J . Chem. Soc., Chem. Commun. 1999, 215.
(16) Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J . Am. Chem.
Soc. 1960, 82, 543.
(10) Patrick, T. B.; Schiebel, J . J .; Cantrell, G. L. J . Org. Chem. 1981,
46, 3917.
(17) Scheeren, J . W.; Ooms, P. J . H.; Nivard, R. J . P. Synthesis 1973,
149.
10.1021/jo000020j CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/11/2000