corresponding â-fluoroamines.9 Taking into account the interest
in difluorinated building blocks of high synthetic value, we
would like to report the behavior of alkyne nitrogen substrates
as potential precursors of â-gem-difluoroamino derivatives in
acidic and/or superacidic conditions.
gem-Difluorination of Aminoalkynes via Highly
Reactive Dicationic Species in Superacid
HF-SbF5: Application to the Efficient Synthesis
of Difluorinated Cinchona Alkaloid Derivatives
The gem-difluorination of alkynes has been described by
Olah10 using HF/pyridine and by Henne11 with hydrogen fluoride
to give the corresponding gem-difluoroalkanes. Recently, Klumpp
reported the reactivity of aminoalkynes and proposed for the
first time the possible formation of dicationic electrophiles (or
superelectrophiles) in the Brønsted superacid CF3SO3H (triflic
acid) which form new products in Friedel-Crafts-type reac-
tions.12
In the following note, we describe our studies of the
superacid-catalyzed HF-SbF5 chemistry of alkynes bearing an
N-heterocycle or amine functional groups and their ability to
regioselectively form new â-gem-difluoro nitrogen compounds.
Starting materials 1-9 were easily synthesized in one step by
direct alkylation of the corresponding amines under basic
conditions (2, 5, 6, and 9: NaH, THF;13 3 and 4: K2CO3,
acetone;14 7: Cs2CO3, DMF;15 1 and 8: K2CO3, 18-crown-6,
benzene16) in the presence of alkynylic bromide in variable
yields (19-89%).
Initial experiments were performed using pure HF (0 °C, 5
h). The expected addition of hydrogen fluoride by an electro-
philic mechanism with Markovnikov’s rule orientation on
piperidine 2 afforded the difluoro derivative 12 as the sole
product. Under the same conditions of acidity and temperature,
phthalimide 1 yielded a gem-difluoro compound 10 as the major
product (Table 1) and minor amounts of methylketone 11.
Surprisingly, all propargylic amino derivatives 3-9 remained
unchanged under these conditions. It may be assumed that the
basic nitrogen atom must be irreversibly protonated, thus
decreasing the nucleophilicity of the adjacent triple bond and
completely deactivating it toward electrophilic reagents. The
use of more acidic conditions (HF-SbF5) was then considered.
In optimized conditions (HF-SbF5: 7/1 molar ratio, -40 to
-60 °C), the starting materials were fully transformed within
2 to 15 min. Results are summarized in Table 2. Under these
conditions, primary, secondary, tertiary, and aromatic amines
afforded the corresponding â-gem-difluoroamines in good yields
Anne-Ce´line Cantet, He´le`ne Carreyre, Jean-Pierre Gesson,
Marie-Paule Jouannetaud, and Brigitte Renoux*
Laboratoire “Synthe`se et Re´actiVite´ des Substances Naturelles”,
UniVersity of Poitiers, CNRS, 40 AVenue du Recteur Pineau,
F-86022 Poitiers Cedex, France
brigitte.renoux@uniV-poitiers.fr
ReceiVed NoVember 14, 2007
A variety of alkynylated amines, amides, and imides are
reacted in the superacid system HF-SbF5 to give regiose-
lectively new â-gem-difluoroamines. The reaction, which is
not observed in pure HF, is consistent with the formation of
a dicationic intermediate (i.e., both vinylic and adjacent
protonated N-ammonium cations). Application to the regi-
oselective and efficient synthesis of difluorinated cinchona
alkaloid derivatives is described.
As the most important electronegative element, fluorine has
played a key role in recent pharmaceutical, agrochemical, and
materials science.1 The introduction of fluorine atoms in a given
molecule often dramatically alters its chemical properties and
its pharmacological profile in the case of biologically active
compounds.2 Recently, we have developed in our laboratory a
powerful fluorinating methodology in superacid. Under these
conditions (HF-SbF5), unusual reactivity of functionalized
organic substrates is observed.3-7 While attempting to synthesize
potentially new bioactive fluorinated compounds, Jacquesy et
al. previously reported a novel oxidative gem-difluorination of
vinca alkaloids in superacid HF-SbF5, in the presence of either
N-bromosuccinimide (NBS) or chloromethanes (CHCl3 or CCl4).
This resulted in the preparation of vinflunine,8 a new difluoro
derivative which has shown promising antitumor activity and
is currently in phase III clinical trials. More recently, hydrof-
luorination of these substrates was investigated to afford the
(8) (a) Fahy, J.; Duflos, A.; Ribet, J. P.; Jacquesy, J. C.; Berrier, C.;
Jouannetaud, M. P.; Zunino, F. J. Am. Chem. Soc. 1997, 119, 8576-8577.
(b) Jacquesy, J. C.; Berrier, C.; Jouannetaud, M. P.; Zunino, F.; Fahy, J.;
Duflos, A.; Ribet, J. P. J. Fluorine Chem. 2002, 114, 139-141. (c) Jacquesy,
J. C.; Fahy, J. Biomedical Chemistry: Applying Chemical Principles to
the Understanding and Treatment of Disease; Wiley-Interscience: New
York, 2000; pp 227-245.
(9) Thibaudeau, S; Martin-Mingot, A.; Jouannetaud, M. P.; Karam, O.;
Zunino, F. Chem. Commun. 2007, 3198-3200.
(1) Dolbier, W. R., Jr. J. Fluorine Chem. 2005, 126, 157-163.
(2) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11. (b) Shimizu,
M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214-231.
(3) Berrier, C.; Jacquesy, J. C.; Jouannetaud, M. P.; Lafitte, C.; Vidal,
Y.; Zunino, F.; Fahy, J.; Duflos, A. Tetrahedron 1998, 54, 13761-13770.
(4) Gesson, J. P.; Jacquesy, J. C.; Jacquesy, R. Tetrahedron Lett. 1971,
49, 4733-4736.
(10) Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 779.
(11) (a) Henne, A. L.; Zimmerschied, W. J. J. Am. Chem. Soc. 1947,
69, 281-283. (b) Henne, A. L.; Plueddeman, E. P. J. Am. Chem. Soc. 1943,
65, 587-589.
(12) Klumpp, D. A.; Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.;
Dang, H. J. Org. Chem. 2004, 69, 8108-8110.
(13) Anwar, U.; Casaschi, A.; Grigg, R.; Sansano, J. M. Tetrahedron
2001, 57, 1361-1367.
(5) Martin, A.; Jouannetaud, M. P.; Jacquesy, J. C. Tetrahedron Lett.
1996, 37, 2967-2970.
(14) Kundu, N. G.; Nandi, B. J. Org. Chem. 2001, 66, 4563-4575.
(15) Perrez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Gonzalez-Perez,
P.; Perez-Castells, J. Synthesis 2002, 13, 1810-1812.
(6) Debarge, S.; Violeau, B.; Bendaoud, N.; Jouannetaud, M. P.;
Jacquesy, J. C. Tetrahedron Lett. 2003, 44, 1747-1750.
(7) Moine, A.; Thibaudeau, S.; Martin, A.; Jouannetaud, M. P.; Jacquesy,
J. C. Tetrahedron Lett. 2002, 43, 4119-4122.
(16) Cousson, A.; Gazeau, C.; Gesson, J. P.; Jacquesy, J. C.; Rambaud,
D.; Renoux, B. Bull. Soc. Chim. Fr. 1994, 131, 95-104.
10.1021/jo702441p CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/04/2008
J. Org. Chem. 2008, 73, 2875-2878
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