ORGANIC
LETTERS
2004
Vol. 6, No. 23
4315-4317
Nucleophilic Difluoromethylation of
Primary Alkyl Halides Using
Difluoromethyl Phenyl Sulfone as a
Difluoromethyl Anion Equivalent
G. K. Surya Prakash,* Jinbo Hu, Ying Wang, and George A. Olah
Loker Hydrocarbon Research Institute and Department of Chemistry, UniVersity of
Southern California, Los Angeles, California 90089-1661
Received September 10, 2004
ABSTRACT
A facile and efficient nucleophilic difluoromethylation of primary alkyl halides has been disclosed through a novel nucleophilic substitution
reductive desulfonylation strategy, using difluoromethyl phenyl sulfone as a difluoromethyl anion (“CF2H ”) equivalent.
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Selective introduction of difluoromethyl group (CF2H) into
organic molecules is of great importance due to its ability
to contribute special biological properties to those molecules.
CF2H functionality has been known to be isosteric and
isopolar to hydroxyl (OH) group and behaves as a hydrogen
donor through hydrogen bonding.1-5 Moreover, CF2H group
has similar high lipophilicity as the trifluoromethyl group,
which is useful in applications where a more lipophilic
hydrogen bond donor other than OH is required.3 As a result,
CF2H group has been frequently incorporated into various
biologically active compounds (such as enzyme inhibitors,6
sugars,7 pesticides,8 and herbicides9) and materials (such as
liquid crystals10 and fluoropolymers11). Many CF2H-contain-
ing compounds have also been used as anesthetics, including
well-known desflurane and isoflurane.12
Several methods have been developed for the preparation
of CF2H-containing compounds, including the deoxofluori-
nation of aldehydes using SF4, DAST, or SeF4,13 nucleophilic
fluorination of gem-bistriflates using TBAF,14 fluorination
of 1,2- or 1,3-dithianes using BrF3 and other in situ-generated
halogen fluorides,5,15 addition of CF2Br2 into double bonds,16
(7) (a) Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 1993, 58,
2302. (b) Houlton, S. J.; Motherwell, W. B.; Ross, B. C.; Tozer, M. J.;
Williams, D. J.; Slawin, A. M. Z. Tetrahedron 1993, 49, 8087.
(8) (a) Otaka, K.; Oohira, D.; Takaoka, D. WO 2004006677, 2004. (b)
Markl, M.; Schaper, W.; Ort, O.; Jakobi, H.; Braun, R.; Krautstrunk, G.;
Sanft, U.; Bonin, W.; Stark, H.; Pasenok, S.; Cabrera, I. WO 2000007998,
2000; Chem. Abstr. 2000, 132, 166248.
(1) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan, S.,
Eds; Wiley: New York, 1991.
(2) Modern Fluoroorganic Chemistry; Kirsch, P., Ed.; Wiley-VCH:
Weinheim, 2004.
(9) Groure, W. F.; Leschinsky, K. L.; Wratten, S. J.; Chupp, J. P. J.
Agric. Food Chem. 1991, 39, 981.
(10) Kondou, T.; Matsui, S.; Miyazawa, K.; Takeuchi, H.; Kubo, Y.;
Takeshita, F.; Nakagawa, E. WO 9813324, 1998; Chem. Abstr. 1998, 128,
302171.
(11) Fluorine-containing Molecules. Structure, ReactiVity, Synthesis and
Applications; Liebman, J. F., Greenberg, A., Dolbier, W. R., Jr., Eds.;
VCH: New York, 1988.
(12) Rozov, L. A.; Huang, C.; Halpern, D. F.; Vernice, G. G. U.S. Patent
5,283,372, 1994; Halpern, D. F.; Robin, M. L., U.S. Patent 4,996,371, 1991.
(13) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (b) Olah, G. A.;
Nojima, M.; Kerekes, I. J. Am. Chem. Soc. 1974, 96, 925.
(14) Martinez, G. A.; Barcina, O. J.; Rys, A. Z.; Subramanian, L. R.
Tetrahedron Lett. 1992, 33, 7787.
(3) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.;
Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572 and references cited therein.
(4) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
(5) Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769 and
references cited therein.
(6) (a) Chen, Y.; Freskos, J. N.; Gasiecki, A. F.; Grapperhaus, M. L.;
Hansen, D. W., Jr.; Heintz, R. M.; Khanna, I. K.; Kolodziej, S. A.;
Mantegani, S.; Massa, M. A.; McDonald, J. J.; Mischke, D. A.; Nagy, M.
A.; Perrone, E.; Schmidt, M. A.; Spangler, D. P.; Talley, J. J.; Trivedi, M.;
Wynn, T. A.; Becker, D. P.; Rico, J. G., WO 2004000811, 2004; Chem.
Abstr. 2004, 140, 59663. (b) Parker, M. F.; McElhone, K. E.; Mate, R. A.;
Bronson, J. J.; Gai, Y.; Bergstrom, C. P.; Marcin, L. R.; Macor, J. E. WO
2003053912, 2003; Chem. Abstr. 2003, 139, 85645.
(15) (a) Sondej, S. C.; Katzenellenbogen, J. A. J. Org. Chem. 1986, 51,
3508. (b) Synthetic Fluorine Chemistry; Olah, G. A., Chambers, R. D.,
Prakash, G. K. S., Eds.; Wiley: New York, 1992.
10.1021/ol048166i CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/13/2004