J . Org. Chem. 2002, 67, 997-1000
997
Rea ctivity of Sta ble Tr iflu or oa ceta ld eh yd e Hem ia m in a ls. 2.
Gen er a tion a n d Syn th etic P oten tia lities of F lu or in a ted Im in iu m s
Thierry Billard* and Bernard R. Langlois*
Laboratoire SERCOF (UMR CNRS 5622), Universite´ Claude Bernard - Lyon 1,
Baˆt. Chevreul, 43, Bd du 11 novembre 1918, 69622 Villeurbanne, France
billard@univ-lyon1.fr
Received November 5, 2001
Under Lewis acid activation, hemiaminals of trifluoroacetaldehyde and related (fluoroalkyl)-
aldehydes generate iminium species that can react with various nucleophiles to provide fluorinated
amines.
Ch a r t 1. Silyla ted Hem ia m in a l of F lu or a l
Interest in fluorine-containing compounds is continu-
ously growing1 since fluorinated organic products present
unique properties2 that are of great interest for a variety
of applications3-5 and, in particular, for the design of
bioactive compounds.3 Thus, because of this tremendous
interest, research for new methodologies to prepare
fluorinated compounds, by the shortest route, is still a
challenge.
Generally speaking, synthetic routes involving imini-
ums species are useful strategies for amino compound
functionalization.6 Following this concept, Fuchigami et
al.7-9 and Dolbier et al.10 have demonstrated the ef-
fectiveness of trapping in situ generated trifluoromethy-
lated iminiums by various nucleophiles. However, the
trifluoroacetaldehyde N,O-acetals7-9 or N,N-aminals10
they used suffer from a difficult access and a lack of
variety in amino moieties.
We have recently shown that the easy accessible (even
on a multigram scale11) silylated hemiaminal of trifluo-
roacetaldehyde 1a (Chart 1) is a very efficient precursor
of the corresponding iminium salt under Lewis acid
activation.12
Furthermore, a lot of bioactive substances bearing a
piperazino group13 are described in the literature, and
several of them led to commercial drugs.14 Thus, we
focused our interest on the use of our iminium strategy
for the synthesis of fluorinated compound bearing a
piperazino moiety and studied the reactivity of 1, under
Lewis acid activation, toward various nucleophiles. The
first ones we envisaged were heteronucleophiles as
alcohols and amines (Table 1).
This reaction generally provides satisfactory yields
which, however, are lower with secondary alcohols (Table
1, entry 3) because they are probably more sensitive to
Lewis acids and lead to side reactions. Such side re-
actions are especially important with sugar derivatives
(Table 1, entry 5) that are poly-oxygenated reagents.
Indeed, under usual conditions (see the Experimental
Section), no 2a e was obtained, but this target sub-
strate can be successfully synthesized when 1a is pre-
chelated with the Lewis acid before introduction of
the carbohydrate. Tertiary alcohols have not been
tested because of their high sensitivity toward Lewis
acids.
This strategy provides more elaborated N,O-acetals of
fluoral than previously described and constitutes the
unique possibility to reach such compounds since the
standard O-alkylation of fluoral hemiaminolate under
basic conditions failed in our hands.
As we previously described the preparation of other
fluorinated hemiaminals,12 they were reacted in the same
way to deliver the corresponding N,O-acetals (Table 1,
entries 6 and 7).
(1) Schofield, H. J . Fluorine Chem. 1999, 100, 7-11.
(2) Smart, B. E. J . Fluorine Chem. 2001, 109, 3-11.
(3) Filler, R.; Kobayashi, Y.; Yagulpolskii, Y. L. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications;
Elsevier: Amsterdam, 1993.
(4) Banks, R. E.; Smart, B. E.; Tatlow, J . C. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press:
New York, 1994.
(5) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine
Compounds II. A critical Review; ACS Monograph 187; American
Chemical Society: Washington, DC, 1995.
(6) Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000, 56, 3817-
3856.
(7) Fuchigami, T.; Ichikawa, S.; Konno, A.; Nonaka, T. Chem. Lett.
1989, 1987-1988.
(8) Fuchigami, T.; Ichikawa, S.; Kandeel, Z. E.; Konno, A.; Nonaka,
T. Heterocycles 1990, 31, 415-417.
(9) Fuchigami, T.; Ichikawa, S. J . Org. Chem. 1994, 59, 607-615.
(10) Xu, Y.; Dolbier, W. R., J r. J . Org. Chem. 2000, 65, 2134-2137.
(11) Billard, T.; Langlois, B. R.; Blond, G. Tetrahedron Lett. 2000,
41, 8777-8780.
(12) Blond, G.; Billard, T.; Langlois, B. R. J . Org. Chem. 2001, 66,
4826-4830.
The reaction with sulfur-centered nucleophiles is under
study in our laboratory and will be reported in due
course.
Then, to create C-C bonds, we turned our attention
to carbon nucleophiles. However, carbon-centered anions,
like Grignard’s reagents or organolithium derivatives,
failed to give the expected products, certainly because of
their high affinity toward Lewis acid. To circumvent this
disappointing result, neutral carbon nucleophiles were
engaged. In this respect, allylsilane was very efficient and
provided fluoroalkylated homoallylic amines at room
temperature (Table 2).
(13) The Merk Index, 12th ed.; Merck & Co., Inc.: Rahway, NJ , 1996.
(14) Index Nominum: International drug directory, 16th ed.; Swiss
Pharmaceutical Society, Ed.; MedPharm Scientific Publishers: Stut-
tgart, 1995.
10.1021/jo016265t CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/11/2002