Selective synthesis of gem -chlorofluorinated nitrogen-containing derivatives after superelectrophilic activation in superacid HF/SbF5

Article abstract of DOI:10.1021/jo102225w

The first direct selective synthesis of novel gem-chlorofluorinated nitrogen-containing building blocks in superacid is reported. The dramatic role of the chlorine atom on the reaction is shown by in situ NMR experiments and allows the involvement of a novel original superelectrophilic activation process in superacid HF/SbF₅ to be postulated.(Figure Presented)

Full text of DOI:10.1021/jo102225w

pubs.acs.org/joc
SCHEME 1. Selective Synthesis of gem-Chlorofluorinated or
gem-Difluorinated Nitrogen-Containing Derivatives in HF/SbF5
Selective Synthesis of gem-Chlorofluorinated
Nitrogen-Containing Derivatives after
Superelectrophilic Activation in Superacid HF/SbF5
†
Fei Liu, Agnes Martin-Mingot,
†
ꢀ
Marie-Paule Jouannetaud,† Christian Bachmann,‡
Gilles Frapper,‡ Fabien Zunino,§
effect,5 with a concomitant effect on the conformation and
basicity of the amines. In addition, their ability to be used as
precursors of fluorinated nitrogen-containing functionalized
building blocks6 make them excellent candidates for SAR
studies. However, their synthesis has been scarcely studied to
date.7 Herein, we report the first direct selective synthesis of
gem-chlorofluorinated nitrogen-containing derivatives after
reaction in HF/SbF5.
,†
ꢁ
and Sebastien Thibaudeau*
†Laboratoire “Syntheꢀse et Reꢁactiviteꢁ des Substances
Naturelles”, UMR 6514, 40 avenue du Recteur Pineau,
F-86022 Poitiers Cedex, France, ‡UMR 6503,
40 avenue du Recteur Pineau, F-86022 Poitiers Cedex, France,
and §@rtMolecule, 40 avenue du Recteur Pineau,
F-86022 Poitiers Cedex, France
In the course of the synthesis of the difluorinated antic-
ancer agent vinflunine (Javlor),8 we recently proposed that
the gem-difluorination of unsaturated amines in superacid is
strongly based on the ability to form superelectrophilic9 am-
monium-R-chloronium intermediates.10 Despite the very weak
nucleophilic character of the solvated fluorine in the poly-
meric anionic form SbnF5nþ1- of the superacidic medium,11
it was postulated that the ammonium ion plays a critical role
in activating the nearby electrophilic site, allowing its fluor-
ination and subsequent formation of the difluorinated pro-
duct. On the basis of these previous investigations, we postu-
lated that ammonium-R-chloronium intermediates A should
easily be formed in superacid starting from chlorinated
olefins 1 (Scheme 1).
By modification of the reaction conditions and especially
the cationic and anionic composition of the superacid me-
dium,11 gem-chlorofluorinated and/or gem-difluorinated de-
rivatives 2 and/or 3 should be selectively obtained (Table 1).
With substrate 1a as a model substrate, the first attempt
confirmed our initial hypothesis, with the formation of a
mixture of products 2a and 3a (Table 1, entry 1). When per-
formed at 0 °C, the reaction led to the selective formation of
difluorinated product 3a (Table 1, entry 2). Decreasing the
temperature afforded chlorofluorinated product 2a selec-
tively, but the reaction was not complete in this case (Table 1,
entry 3). The influence of the acidity of the medium11 on the
selectivity of the reaction was dominant and allowed the
selective formation of product 2a (Table 1, entry 4).
sebastien.thibaudeau@univ-poitiers.fr
Received November 10, 2010
The first direct selective synthesis of novel gem-chloro-
fluorinated nitrogen-containing building blocks in super-
acid is reported. The dramatic role of the chlorine atom
on the reaction is shown by in situ NMR experiments and
allows the involvement of a novel original superelectro-
philic activation process in superacid HF/SbF5 to be
postulated.
The importance of fluorine in medicinal chemistry,1 which
is mainly due to a fluorine atom’s unique properties, is well-
recognized.2 Among fluorine substitution consequences, the
strong inductive withdrawing effect of fluorine on the acidity
or basicity of neighboring functional groups is especially
evident,3 making the incorporation of nitrogen-containing
organofluorine cores very popular in medicinal chemistry.4
While gem-difluorinated amines have been exploited, sur-
prisingly little attention has been given to gem-chlorofluori-
nated analogues. The intriguing combination of the two
different geminal halogens might interfere with both the
(6) Shibatomi, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 5796.
(7) To the best of our knowledge, only two articles have reported the
synthesis of gem-chlorofluorinated amines. See: (a) Verniest, G.; Colpaert,
F.; Van Hende, E.; De Kimpe, N. J. Org. Chem. 2007, 72, 8569. (b) Van
Hende, E.; Verniest, G.; Surmont, R.; De Kimpe, N. Org. Lett. 2007, 9, 2935.
(8) (a) Fahy, J.; Duflos, A.; Ribert, J.-P.; Jacquesy, J.-C.; Berrier, C.;
Jouannetaud, M.-P.; Zunino, Z. J. Am. Chem. Soc. 1997, 119, 8576.
(b) Jacquesy, J.-C. J. Fluorine Chem. 2006, 127, 1484.
(9) Olah, G. A.; Klumpp, D. In Superelectrophiles and Their Chemistry;
John Wiley and Sons: New York, 2008.
(10) Zunino, F.; Liu, F.; Berrier, C.; Martin-Mingot, A.; Thibaudeau, S.;
Jouannetaud, M.-P.; Jacquesy, J.-C.; Bachmann, C. J. Fluorine Chem. 2008,
129, 775.
gauche fluorine effect and the NH FC dipole orientation
3 3 3
ꢁ
ꢁ
(1) (a) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (b) Begue, J.-P.;
Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992. (c) Purse, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(3) Morgenthaler, M.; Schweiser, E.; Hoffman-Roder, F.; Benini, F.;
Martin, R. E.; Jaeschke, G.; Wagner, B.; Fisher, H.; Bendels, S.; Zimmerili,
D.; Schneider, J.; Hiedrich, F.; Kansy, M.; Muller, K. ChemMedChem 2007,
2, 1100.
(11) (a) Bonnet, B.; Mascherpa, G. Inorg. Chem. 1980, 19, 785. (b) Mootz,
D.; Bartmann, K. Angew. Chem., Int. Ed. Engl. 1988, 27, 391. (c) Culmann,
J.-C.; Sommer, J. J. Am. Chem. Soc. 1990, 112, 4057. (d) Culmann, J.-C.;
Fauconet, M.; Jost, R.; Sommer, J. New J. Chem. 1999, 23, 863. (e) Sommer,
J.; Canivet, P.; Schwartz, S.; Rimmelin, P. New J. Chem. 1981, 5, 45.
(4) Hagmann, W. H. J. Med. Chem. 2008, 51, 4359.
(5) Buissonneaud, D. Y.; van Mourik, T.; O’Hagan, D. Tetrahedron 2010,
66, 2196 and references cited therein.
1460 J. Org. Chem. 2011, 76, 1460–1463
Published on Web 01/20/2011
DOI: 10.1021/jo102225w
r
2011 American Chemical Society

Liu et al.
JOCNote
a
TABLE 1. Substrate 1a Behavior in HF/SbF5
TABLE 2. Synthesis of gem-Chlorofluorinated and gem-Difluorinated
Nitrogen-Containing Compounds in Superacid HF/SbF5
entry acidity (mol % SbF5) temperature (°C)
product (yield)b
1
2
3
4
13.6
13.6
13.6
3.8
-20
0
-50
-20
2a (40)
2a (0)
2a (45)
2a (74)
3a (24)
3a (70)
3a (0)c
3a (0)
aReaction conditions: substrate (1 mmol), HF/SbF5 (3 mL), 10 min.
bYield obtained after flash chromatography. cStarting material remain-
ing.
SCHEME 2. Proposed Mechanism for the Fluorination Process
To explain these preliminary results, we postulated the
mechanism shown in Scheme 2. Protonation of the amine
and the double bond in superacid should give dication A,
which after fluorination should give ammonium B, the
precursor of the chlorofluoro product. After 10 min of
reaction in HF/SbF5 (13.6 mol % SbF5) at 0 °C starting from
chlorofluorinated amine 2a, product 3a was formed quanti-
tatively, confirming that ion B could be considered as an
intermediate in the difluorination process. After protona-
tion of ion B and HCl elimination, R-fluoronium intermedi-
ate C, a precursor of difluorinated ammonium D (ion D
could also come from B via an SN2-type mechanism) should
be formed to give the difluorinated product 3a after hydro-
lysis.
To an approximation, superelectrophilic activation de-
creases with increasing separation of the charge centers.9 To
verify the ability to use ammonium-R-chloronium super-
electrophilic activation as a new synthetic tool, a scope and
limitations study focused on the influence of the distance
between the charge centers on the reaction course was needed
(Table 2).
Through the use of reaction conditions A or B, gem-
chlorofluorinated or gem-difluorinated amines, amides, imi-
des, or sulfonamides were selectively obtained in good yields
(Table 2, entries 1-12). Increasing the distance between the
amino group and the chlorine atom allowed the formation of
γ,γ-chlorofluorinated and -difluorinated amines (Table 2,
entries 13-15). It also should be noted that the reaction of
substrate 1i led to a complex mixture of compounds, regard-
less of the conditions used. At this stage, the behavior of
substrates 1e and 1f intrigued us. In a previous study,12 we
showed that dicationic carboxonium-carbenium ions B1
and B2 are not superelectrophilic enough to react with fluo-
ride ions (Scheme 3).
aReaction conditions A: SbF5 (3.8 mol %), 10 min, T (°C). Reaction
conditions B: SbF5 (13.6 mol %), 10 min, T (°C). bYield obtained after
flash chromatography. cReaction time = 1 min. dComplex mixture.
character, should prevent them from fluorination. To under-
stand and verify this intriguing effect of chlorine substitution
on the reactivity of amides and imides, a screening of various
substrates was investigated (Table 3).
Under difluorination conditions (conditions B), we
showed above that imide 1e and amide 1f led exclusively to
difluorinated products (Table 2, entries 10 and 12). However,
starting from amide 1f, oxazole 4f was selectively synthesized
after reaction at 0 °C (Table 3, entry 1). Increasing the
distance between the imide function and the chlorine atom
led to the formation of carbonyl compounds 4j and 4k
(Table 3, entries 2 and 4). To form the corresponding difluo-
rinated product 3j, a longer reaction time was needed, and
only a small amount of the desired product could be
synthesized (Table 3, entry 3). The limit of the reaction
was found with the formation of a complex mixture of
compounds after reaction of substrate 1m in superacid
(Table 3, entry 6). The exclusive formation of oxazole 4f
In R-chloronium ions, the chlorine atom becomes both a
π- and σ-donor substituent.13 As a consequence, we could
have expected that the stabilizing effect of the chlorine atom
in intermediates C1 and C2, which reduces their electrophilic
(12) Thibaudeau, S.; Martin-Mingot, A.; Jouannetaud, M.-P.; Karam,
O.; Zunino, F. Chem. Commun. 2007, 3198.
(13) Christe, K. O.; Zhang, X.; Ban, R.; Hegge, J.; Olah, G. A.; Prakash,
G. K. S.; Sheety, J. A. J. Am. Chem. Soc. 2000, 122, 481.
J. Org. Chem. Vol. 76, No. 5, 2011 1461

Liu et al.
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SCHEME 3. Reaction of Amides and Imides in Superacidic HF/
SbF5
SCHEME 4. Proposed Reaction Mechanism Involving Cyclic
Carboxonium Ions
SCHEME 5. Results from Low-Temperature (-20 °C) 13
C
NMR Studies of Amides 10f and 1f and Imide 1j Dissolved in HF/
SbF5 (Compared to Theoretical Values in ppm)
TABLE 3. Reactivity of Unsaturated Imides and Amidesa
imides were dissolved in HF/SbF5 (21.6 mol % SbF5) and
studied by 13C NMR and DEPT experiments at -20 °C.
To compare experimental NMR chemical shift values with
those from theory, model calculations on the postulated
intermediates were also performed at the B3LYP/cc-pVTZ
level.16 For example, the cyclic carboxonium ions F, G, and
H are the sole intermediates respectively detected from low-
temperature 13C NMR studies of amides 10f and 1f and imide
1j dissolved in superacid (Scheme 5).
The observed signals at 170.9 and 181.1 ppm in addition
to the CH signals observed respectively at 88.5 and 98.8 ppm
for F and H confirmed the presence of CH groups that
are strongly deshielded and proximal to carboxonium ions,
consistent with the proposed cyclic carboxonium ions.17 Inter-
estingly, the quaternary carbon at 157.1 ppm and a CH signal
at 116.7 ppm proved the presence of a formed double bond
after reaction of 1f under these conditions (21.6 mol % SbF5).
These observations, combined with the shielded conjugated
carboxonium ion (159.4 ppm), are in accordance with the
structure of oxazolinium ion G. It should be noted that for all
of the postulated intermediates, the observed chemical shift
values are in good agreement with the calculated data.16 On
the basis of this study, the involvement of the cyclic carbox-
onium ions shown in Scheme 6 can be postulated. Whereas
five-membered-ring carboxonium ion F is not electrophilic
enough to be fluorinated, the withdrawing effect of the chlo-
rine atom in G0 makes possible the superelectrophilic acti-
vation,18 and fluorination occurs. Interestingly, the effect of
the cyclic shape of the chlorinated cyclic carboxonium ions
on the fluorination process is dramatic. Whereas five- and
seven-membered-ring carboxonium ions (intermediates I
and K) give fluorinated products, making them superelec-
trophiles, the corresponding six-membered rings (intermedi-
ates H and J) cannot be fluorinated (or are fluorinated very
slowly in the case of dication H) and cannot be considered
as superelectrophiles. To the best of our knowledge, this is
the first time that the relative superelectrophilic character of
polycationic intermediates has been shown to be influen-
ced by their geometry in addition to charge repulsion. In
aReaction conditions B: SbF5 (13.6 mol %), 10 min. bYield obtained
after flash chromatography. cReaction time = 24 h. dComplex mixture.
after reaction of amide 1f at 0 °C and the observed nonlinear
effect of the distance between the function and the reactive
double bond on the reactivity of the substrates encouraged
us to postulate the mechanism shown in Scheme 4.
Amides and imides exist as neutral and O-protonated
forms in strongly acidic solutions.14 If a fast equilibrium
between these species in superacid and potent intramolecular
participation of the carbonyl group in the stabilization of the
formed carbenium ion are assumed,15 carboxonium ions of
type E could be considered as the reactive intermediates in
the reactions of chlorinated amides and imides. To confirm
the involvement of these novel monocationic superelectro-
philic intermediates in the fluorination process, amides and
(14) (a) Cox, R. A.; Druet, L. M.; Klausner, A. E.; Modro, T. A.; Wan, P.;
Yates, K. Can. J. Chem. 1981, 59, 1568. (b) Perrin, C. L.; Lollo, C. P.;
Johnston, E. R. J. Am. Chem. Soc. 1984, 106, 2749. (c) Olah, G. A.;
Schlosberg, R. H. J. Am. Chem. Soc. 1968, 90, 6464. (d) Prakash, G. K. S.;
Mathew, T.; Hoole, D.; Esteves, P. M.; Wang, Q.; Rasul, G.; Olah, G. A.
J. Am. Chem. Soc. 2004, 126, 15770. (e) Bagno, A.; Bujnicki, B.; Bertrand,
S.; Comuzzi, C.; Dorigo, F.; Janvier, P.; Scorrano, G. Chem.;Eur. J. 1999,
5, 523.
(16) Please see the Supporting Information.
(15) Similar intramolecular stabilization in superacid has already been
postulated. Please see: Thibaudeau, S.; Martin-Mingot, A.; Jouannetaud,
M.-P.; Jacquesy, J.-C. Tetrahedron 2002, 58, 6643 and references cited
therein.
(17) Olah, G. A.; Laali, K. K.; Wang, Q.; Prakash, G. K. S. In Onium Ions;
Wiley-Interscience: New York, 1998.
(18) In superacid HF/SbF5 (21.6 mol % SbF5), after protonation and HCl
elimination, G0 gives oxazolinium G.
1462 J. Org. Chem. Vol. 76, No. 5, 2011

Liu et al.
JOCNote
SCHEME 6. Cyclic Carboxonium Ions Involved in Superacid
SCHEME 7. Synthetic Applications of Chlorofluorinated De-
rivatives
organic molecules that will prove to be useful building blocks
for many applications in the life sciences. As already proved
by the recent development of Javlor, such a process could
also be used on more elaborated substrates.
addition, even if it should be recognized that “electrophilic
assistance” (solvation, association) by the superacidic med-
ium could occur in this context,19 the involvement of a mono-
cationic intermediate such as cyclic carboxonium ion G0 has
not been reported to date in a superelectrophilic activation
process.
Experimental Section
The authors draw the reader’s attention to the dangerous
features of superacid chemistry. Handling of hydrogen fluoride
and antimony pentafluoride must be done by experienced chem-
ists with all of the necessary safety arrangements in place.
Synthesis of gem-Chlorofluorinated Compounds. Optimized
Procedure: Conditions A. To a HF/SbF5 mixture (3 mL,
3.8 mol % SbF5) was added substrate (1 mmol). The mixture
was magnetically stirred at the same temperature for 10 min of
reaction time, after which the reaction mixture was neutralized
with water/ice/Na2CO3 until pH 9 was attained and then ex-
tracted with dichloromethane (ꢀ3). The combined organic
phases were dried (MgSO4) and concentrated in vacuo. Pro-
ducts were isolated by column chromatography over silica gel.
Compound 2a: 1-(4-(2-Chloro-2-fluoropropyl)piperazin-1-yl)-
ethanone. The optimized procedure (maintained at -20 °C) was
followed. Purification by flash column chromatography [99.5/
0.5 dichloromethane/NH3(aq)] gave 164 mg of the title com-
pound (74%).
We next turned our attention to the synthetic opportunity
provided by these new gem-chlorofluorinated derivatives
(Scheme 7). First, a new chlorofluorinated amine building
block 5 was synthesized in 62% yield after treatment of
phtalimide 2e with hydrazine. Alternatively, imide 2e could
also be used to access original fluoroenimide 6 after basic
elimination. Interestingly, Woodward recently reported an
elegant synthesis of β-functionalized hydroxylamines via the
Owari rearrangement of β-chloro-N-oxides.20 With chloro-
fluorinated amines, we thought that the strongly inductive
withdrawing effect of the fluorine atom in the geminal posi-
tion should activate this transformation. Gratifyingly, after
in situ formation of the corresponding N-oxide, ring closure,
and nucleophilic ring opening with the formed benzoate,
fluorinated N-oxide 7 could be obtained in 77% yield under
optimized conditions. It should be pointed out that no C-F
bond cleavage occurred under our conditions.21
In summary, we have described a new, selective, one-
step synthetic route to novel gem-chlorofluorinated and
gem-difluorinated nitrogen-containing compounds starting
from easily accessible starting materials. In addition, for the
first time, we have proved the involvement of a monoca-
tionic superelectrophile in a fluorination reaction in super-
acid. Furthermore, the cyclic shape of the cyclic chlorinated
carboxonium ions has been proved to be crucial for this new
superelectrophilic activated fluorination process in the
superacid HF/SbF5. We believe that this novel, powerful
synthetic methodology, which is based on cationic R-chloro-
nium ion activation, allows access to a new class of fluorinated
1H NMR (300 MHz, CDCl3, ppm): 1.93 (d, 3JH-F = 19.4 Hz,
3H, H-300), 2.06 (s, 3H, H-2), 2.57 (m, 4H, H-30), 2.78 (dd, 3JH-F
= 24.2 Hz, 2JH-H = 14.3 Hz, 1H, H-100), 2.94 (dd, 3JH-F = 14.3
Hz, 2JH-H = 14.3 Hz, 1H, H-100), 3.42 and 3.57 (2 m, 4H, H-20).
13C NMR (75 MHz, CDCl3, ppm): 21.7 (s, CH3, C-2), 28.4 (d,
2JC-F = 25 Hz, CH3, C-300), 41.9 and 46.8 (2 s, 2CH2, C-20), 54.4
2
and 54.6 (s, CH2, C-30), 67.8 (d, JC-F = 22 Hz, CH2, C-100),
1
114.3 (d, JC-F = 243 Hz, 1C, C-200), 169.3 (s, C-1). 19F {1H}
NMR (282 MHz, CDCl3, ppm): -99.3. MS (GCT, CIþ) m/z
(relative intensity %): 222 (2), 224 (5), 187 (80). HRMS (ESI) m/
z: calcd for C9H16N2OF 35Cl, 222.0935; found, 222.0930.
Acknowledgment. We thank the region Poitou-Charentes
(grant to F.L.), the CNRS, and the University of Poitiers for
financial support.
(19) Olah, G. A. In A Life of Magic Chemistry; John Wiley and Sons:
New York, 2001.
(20) Wefelscheid, U. K.; Woodward, S. J. Org. Chem. 2009, 74, 2254.
(21) Intramolecular nucleophilic substitution of alkyl fluorides was re-
cently achieved with phenolate ions. Please see: Zhang, L.; Zhang, W.; Liu,
J.; Hu, J. J. Org. Chem. 2009, 74, 2850.
Supporting Information Available: Experimental proce-
dure, characterization of products, computational data, and
copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 5, 2011 1463