ORGANIC
LETTERS
2006
Vol. 8, No. 21
4767-4770
Direct Electrophilic
Imines: Efficient Synthesis of Mono-
and Difluoroimines
r-Fluorination of
Guido Verniest,§ Eva Van Hende, Riccardo Surmont, and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering,
Ghent UniVersity, Coupure Links 653, B-9000 Ghent, Belgium
Received July 13, 2006
ABSTRACT
A mild and efficient procedure to synthesize
were successfully monofluorinated using NFSI (N-fluorobenzenesulfonimide) in a mixture of CH3CN and DMF at 0
procedure without DMF gave rise to difluorinated imines when performed at room temperature. The obtained - and
were subsequently reduced to give the corresponding -fluoro- and -difluoroamines in good yield.
r
-fluoro- and
r
,
r
-difluoroimines was developed. Various N-alkylimines derived from acetophenones
C. Alternatively, the same
-difluorinated imines
°
r
r,r
â
â,â
The growing interest in site-specific fluorinated compounds
in medicinal and agricultural chemistry is a result of the
undisputed biological importance of a fluorine substituent
at relevant positions in bioactive compounds.1,2 The presence
of a fluorine atom alters the electronic distribution of the
molecule drastically without major changes concerning the
steric properties of the compound and, as a consequence,
can lead to improved bioactivities.3,4 In this regard, there
exists an increasing demand for generally applicable fluo-
rination methods, especially concerning the fluorination of
ketones and imines as these building blocks play an important
role in heterocyclic chemistry. In contrast to the significant
number of methodologies to introduce fluorine next to
ketones and aldehydes,1,2,5-7 no fluorinated imines have been
prepared via electrophilic fluorination of imines. Imines
bearing one or two fluorine atoms at the R-position not only
can be used directly in the synthesis of fluorinated azahet-
erocyclic compounds but also permit a mild and efficient
synthesis of â-fluorinated amines, which are of interest in
medicinal and agricultural chemistry.1 Although enamines
and enamides proved useful as intermediates in the synthesis
(5) (a) Wilkinson, J. A. Chem. ReV. 1992, 92, 505. (b) Rozen, S. In
Synthetic Fluorine Chemistry; Olah, G. O., Chambers, R. D., Surya Prakash,
G. D., Eds.; John Wiley & Sons: New York, 1992.
(6) (a) Sankar Lal, G.; Pez, G. P.; Syvret, R. G. Chem. ReV. 1996, 96,
1737. (b) Davis, F. A.; Kasu, P. V. N. Org. Prep. Proced. Int. 1999, 31,
125. (c) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619. (d)
Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.;
Tomita, K. J. Am. Chem. Soc. 1990, 112, 8563. (e) Banks, R. E.; Du
Boisson, R. A.; Tsiliopoulos, E. J. Fluorine Chem. 1986, 32, 461. (f)
Barnette, W. E. J. Am. Chem. Soc. 1984, 106, 452. (g) Differding, E.; Lang,
R. W. HelV. Chim. Acta 1989, 72, 1248. (h) Muniz, K. Angew. Chem., Int.
Ed. 2001, 40, 9. (i) Stavber, G.; Zupan, M.; Jereb, M.; Stavber, S. Org.
Lett. 2004, 6, 4973. (j) Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C.
L. Tetrahedron Lett. 1986, 27, 2715. (k) Stavber, S.; Jereb, M.; Zupan, M.
Synthesis 2002, 17, 2609. (l) Rozen, S.; Brand, M. Synthesis 1985, 6/7,
665. (m) Differding, E.; Ofner, H. Synlett 1991, 3, 187. (n) Meddleton, W.
J.; Bingham, E. M. J. Am. Chem. Soc. 1980, 102, 4845. (o) Stavber, S.;
Zupan, M. Tetrahedron Lett. 1996, 37, 3591.
* To whom correspondence should be addressed. Phone: +32(0)9 264
59 51. Fax: +32(0)9 264 62 43.
§ Postdoctoral Fellow of the Research FoundationsFlanders (FWOs
Vlaanderen).
(1) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
John Wiley & Sons: New York, 1991.
(2) Baasner, B.; Hageman, H.; Tatlow, J. C. Organo-Fluorine Com-
pounds. In Houben-Weyl Methods of Organic Chemistry, additional and
supplementary vol. to the 4th ed.; Georg Thieme-Verlag: Stuttgart, New
York, 1999; Vol. E10a-c.
(3) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(4) O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645.
(7) (a) Enders, D.; Hu¨ttl, M. R. M. Synlett 2005, 6, 991. (b) Beeson, T.
D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826. (c) Marigo,
M.; Fielenbach, D.; Braunton, A.; Kjoersgaard, A.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 3703.
10.1021/ol061720z CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/15/2006