Substitution effect on the cylization/fluorination reaction of N-dienes in superacid

Article abstract of DOI:10.1021/jo900881f

(Chemical Equation Presented) The novel cyclization/fluorination reaction of N-dienes in superacid was extended to substituted substrates. The influence of the substitution on superelectrophilic character of dicationic intermediates was shown and its dram

Full text of DOI:10.1021/jo900881f

pubs.acs.org/joc
Substitution Effect on the Cylization/Fluorination Reaction of N-Dienes
in Superacid
†
Emilie Vardelle, Agnes Martin-Mingot, Marie-Paule Jouannetaud,
†
†
ꢀ
Christian Bachmann, Jerome Marrot, and Sebastien Thibaudeau*
‡
§
,†
ꢁ ^
ꢁ
†
ꢁ
ꢀ
ꢁ
ꢁ
Universite de Poitiers-UMR 6514-Laboratoire ”Synthese et Reactivite des Substances Naturelles”, 40,
avenue du Recteur Pineau, F-86022 Poitiers Cedex, France, ‡Universiteꢁde Poitiers-UMR 6503-Laboratoire
de Catalyse en Chimie Organique, 40, avenue du Recteur Pineau, F-86022 Poitiers Cedex, France, and
§Institut Lavoisier de Versailles, UMR 8180, Universiteꢁ de Versailles, 45 avenue des Etats Unis, F-78035
Versailles Cedex, France
sebastien.thibaudeau@univ-poitiers.fr
Received May 12, 2009
The novel cyclization/fluorination reaction of N-dienes in superacid was extended to substituted
substrates. The influence of the substitution on superelectrophilic character of dicationic intermedi-
ates was shown and its dramatic effect on the synthesis of fluoropiperidines was studied. On the basis
of new dicationic R-chloronium ammonium intermediates, starting from halogen-substituted dienes,
high-valued fluorinated piperidines were synthesized.
Introduction
fluoride (DAST) or derivatives.4 However, this methodology
suffers from the formation of rearranged and/or dehydrated
products which greatly diminish the yields of fluoroanalo-
gues.5 The encountered rearrangement is usually due to the
anchimeric assistance of an electron-rich group present at a
vicinal position of the reacting alcohol. Starting from proli-
nol derivatives, this rearrangement has been recently ele-
gantly applied to the synthesis of 3-fluoropiperidines.6 Other
methods, such as ring-opening of aziridines7 or Prins cycliza-
tion of aldehydes with protected amines in ionic liquid
hydrogen fluorine salts,8 have also been employed to access
N-protected fluoropiperidines. However, these methods
Fluorine can be highly advantageous in pharmaceutical
and agrochemical compounds. Only one or just a few atoms
in an organic molecule can dramatically alter its chemical
and biological nature, including its stability, lipophilicity,
and bioavailability,1 this being mainly due to the properties
of the fluorine atom.2 Among fluorocompounds, heterocyc-
lic nitrogen-containing compounds and especially fluori-
nated piperidines are currently largely used in SAR
studies.3 Despite the general relevance of fluorinated piper-
idines, few methods currently exist for their synthesis. Fluor-
opiperidines are usually prepared by dehydroxyfluorination
of hydroxylated amines by using (diethyl)aminosulfurtri-
(4) (a) Singh, R. P.; Shreeve, J. M. J. Fluorine Chem. 2002, 116, 23–26. (b)
Ye, C.; Shreeve, J. M. J. Fluorine Chem. 2004, 125, 1869–1872.
(5) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574–578. (b) Hallett, D.
J.; Gerhard, U.; Goodacre, S. C.; Hitzel, L.; Sparey, T. J.; Thomas, S.;
Rowley, M.; Ball, R. G. J. Org. Chem. 2000, 65, 4984–4993. (c) van Niel, M.
B.; Collins, I.; Beer, M. S.; Broughton, H. B.; Cheng, S. K. F.; Goodacre, S.
G.; Heald, A.; Locker, K. L.; MacLoed, A. M.; Morrisson, D.; Moyes, C. R.;
O’Connor, D.; Pike, A.; Rowley, M.; Russel, M. G. N.; Sohal, B.; Stanton, J.
A.; Thomas, S.; Verrier, H.; Watt, A. P.; Castro, J. L. J. Med. Chem. 1999, 42,
2087–2104.
*To whom correspondence should be addressed. Fax: 33-549453501.
Phone: 33-549453702.
(1) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303–319.
ꢁ
ꢁ
Begue, J. P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012.
Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029. Purser, S.; Moore, P. M.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330. Kirk, K. L.
Org. Process Res. Dev. 2008, 12, 305–321.Hagmann, W. K. J. Med. Chem.
2008, 51 (15), 4359-4369 and references cited therein.
ꢁ
(6) Dechamps, I.; Pardo, D. G.; Cossy, J. Eur. J. Org. Chem. 2007, 4224–
4234.
(2) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308-319 and references cited
therein.
(3) For a recent example please see: Shipe, W. D.; Barrow, J. C.; Yang, Z.-
Q.; Lindsley, C. W.; Yang, F. V.; Schlegel, K. S.; Shu, Y.; Rittle, K. E.; Bock,
M. G.; Hartman, G. D.; Tang, Q.; Ballard, J. E.; Kuo, Y.; Adarayan, E. D.;
Prueksaritanont, T.; Zrada, M. M.; Uebele, V. N.; Nuss, C. E.; Connolly, T.
M.; Doran, S. M.; Fox, S. V.; Kraus, R. L.; Marino, M. J.; Kuzmick
Graufelds, V.; Vargas, H. M.; Bunting, P. B.; Hasbun-Manning, M.; Evans,
R. M.; Koblan. K. S.; Renger. J. J. J. Med. Chem. 2008, 51 (13), 3692-3695.
(7) (a) Alvernhe, G.; Laurent, A.; Touhami, K.; Bartnik, R.; Mloston, G.
J. Fluorine Chem. 1985, 29, 363–384. (b) Hu, X. E. Tetrahedron Lett. 2002, 43,
5315–5318. (c) Hu, X. E.; Kim, N. K.; Ledoussal, B.; Colson, A. O.
Tetrahedon Lett. 2002, 43, 4289–4293.
(8) (a) Kishi, Y.; Nagura, H.; Inagi, S.; Fuchigami, T. Chem. Commun.
2008, 3876–3878. (b) Kishi, Y.; Inagi, S.; Fuchigami, T. Eur. J. Org. Chem.
2009, 103–109.
DOI: 10.1021/jo900881f
r
Published on Web 07/09/2009
J. Org. Chem. 2009, 74, 6025–6034 6025
2009 American Chemical Society

Vardelle et al.
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TABLE 1. N-Substituent Effect on Reaction in Superacida
aStandard conditions: HF/SbF5 molar ratio 8/1, 5 min, -30 °C. bComplex mixture. cReaction performed at -50 °C. dSide products formation.
SCHEME 1. Cyclization/Fluorination Reaction in Superacid
require starting materials that are not readily available and
lack generality and substrate scope. Carrying on our research
work on the synthesis of fluorinated nitrogen-containing
compounds in superacid HF/SbF5,9,10 we recently developed
a new cyclization/fluorination reaction starting from nitro-
gen-containing dienes as a new route to 3- and 4-fluoropi-
peridines.11 This reaction is based on the double protonation
of a N-allylic group to form a superelectrophilic dicationic
intermediate.12 This superelectrophilic intermediate can un-
dergo intramolecular nucleophilic attack by the double
bond, leading to the formation of fluorinated piperidines
after isomerization and fluorination (Scheme 1).
tions of the cyclization/fluorination reaction in superacid
HF/SbF5. In this paper we describe the dramatic influence of
substitution (nitrogen or double bond substitutions) on the
reaction. In addition, the compatibility of halogen-substi-
tuted starting material with the reaction is demonstrated,
making it an alternative method to synthesize gem-chloro-
fluoro or difluoropiperidines.
Considering the increased interest in fluorinated piperi-
dine synthesis and the few methods existing to access such
structural units, we set out to explore the scope and limita-
Results and Discussion
(9) (a) Jacquesy, J. C.; Berrier, C.; Jouannetaud, M. M.; Zunino, F.;
Fahy, J.; Duflos, A.; Ribet, J. P. J. Fluorine Chem. 2002, 114, 139–141. (b)
Debarges, S.; Thibaudeau, S.; Violeau, B.; Martin-Mingot, A.; Jouannetaud,
M. P.; Jacquesy, J. C.; Cousson, A. Tetrahedron 2005, 61, 2065–2073. (c)
Moine, A.; Thibaudeau, S.; Martin, A.; Jouannetaud, M. P.; Jacquesy, J. C.
Tetrahedron Lett. 2002, 43, 4119–4122.
(10) Thibaudeau, S.; Martin-Mingot, A.; Jouannetaud, P. P.; Karam, O.;
Zunino, F. Chem. Commun. 2007, 3198–3200.
(11) Vardelle, E.; Gamba-Sanchez, D.; Martin-Mingot, A.; Jouannetaud,
M. P.; Thibaudeau, S.; Marrot, J. Chem. Commun. 2008, 1473–1475.
(12) Olah, G. A.; Klumpp, D. Superelectrophiles and their chemistry;
John Wiley and Sons: New York, 2008.
N-Substitution Effect. First, we investigated the ability to
perform cyclization/fluorination starting from elaborated
substrates such as amino alcohols, amino esters, or amino
nitriles (Table 1).
In a previous study, we showed that the potential partici-
pation of an aromatic ring could influence the reaction
course in superacid.11 Whereas N-benzoyl diallylamine 1a
led to the formation of a complex mixture of compounds
after reaction in standard conditions, deactivation of the
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SCHEME 2. Reaction Mechanism for Substrates 1c-e
SCHEME 3. Reaction Mechanism for 2h Formation
aromatic ring by a nitro group (entry 2) allowed the forma-
tion of the desired fluoropiperidine 2b. These results sug-
gested that a side reaction occurred between the formed
dication and the aromatic ring. In the same way, we also
described the intramolecular trapping of dicationic species
by neutral oxygen (alcohol,13 carbonyl14) in superacid HF/
SbF5. To evaluate the influence of a potential chelating
group on the reaction, amino alcohol (protected or not),
amino esters, and amino nitriles were subjected to the reac-
tion. Substrate 1c gave a complex mixture of compounds
whatever conditions were used. On the basis of the hypoth-
esis of a participation of nonprotonated alcohol to the
stabilization of the dicationic intermediate, alcohol was
protected. Whereas ether protection was not successful to
prevent oxygen participation (entry 4), it was better to add
ester function, as shown by the formation of desired fluori-
nated piperidine 2e in 50% yield starting from substrate 1e
(entry 5). During his famous work on protonation studies in
superacid, Olah observed an equilibrium between diproto-
nated (protonation of acid and amine functions) and mono-
protonated (protonation of nitrogen atom) amino acids in
superacid.15 On the basis of this observation and postulating
a similar behavior of the amino esters, we propose the
potential formation of a tricationic intermediate starting
from substrate 1e (Scheme 2).
For amino alcohol 1c and amino ether 1d, the proximal
distance between functions disallowed the protonation of
oxygen, and dicationic species A1 should be the intermediate
of the reaction. The potential formation of a six-membered
ammonium-oxonium dication by intramolecular quenching,
leading to a less electrophilic dication, prevents substrates
from undergoing the cyclization/fluorination process. This
intra- or intermolecular participation could explain the ab-
sence of selectivity starting from these substrates. For sub-
strate 1e, the distance between the nitrogen atom and the
carbonyl group of the ester function as well as the conjugation
in the protonated ester group should allow protonation on
both sites, followed by double bond protonation to give the
intermediate B1. No chelating effect of the function can occur
and the cyclization/fluorination process can take place. To
access valuable fluorinated building blocks, we focused our
work on the reactivity of N-diallylic amino esters. Unfortu-
nately it appeared that the amino ester function was not
compatible with the reaction (entries 6 and 7). The result
obtained starting from substrate 1h is in accordance with the
postulated hypothesis (entry 8). Substrate 1h led to the for-
mationof the bicyclicproduct2hand thisresultencouragedus
to postulate the following mechanism (Scheme 3).
After protonation, carbocation A2 can be trapped by a
double bond, leading to the formation of intermediate B2.
Then, we postulate that such β-ammonium-carbenium dica-
tion can act as an hydride abstracting agent14 to form tertiary
carbocation C2. After intramolecular quenching with the
carbonyl group in neutral form, the more stable cyclic carbox-
onium ion D2 is formed as precursor of product 2h. We
suppose that both formation of a more stable carbocation
C2, and subsequent intramolecular quenching leading to a
five- membered-ring carboxonium ion D2 probably act as
driving forces for this process. It should also be mentioned
that because of the low yield and side products formation, we
cannot rule out a potential hydride abstraction in an inter-
molecular way and/or an intermolecular quenching of carbo-
cation C2. To the best of our knowledge, such reaction
involving an ammonium-carbenium dicationic intermediate
as hydride abstracting agent has not been reported before.
Besides the originality of the result, the formation of product
2h, resulting from the hydrolysis of a probably less electro-
philic ammonium-carboxonium dication, emphasizes the
potential participation of the ester function on the stabiliza-
tion of ammonium-carbenium dications starting from amino
esters. To confirm this hypothesis, the reactivity of nitrile 1i
(more basic) was tested. After reaction in superacid HF/SbF5
at -50 °C, amino nitrile 1i led to 3-fluoropiperidine 2i in 45%
yield. Besides product 2i, we could separate and identify a
small amount of the linear difluorinated mixture of diaster-
eoisomers 2i0 showing a limited undesired effect of nitrile in
this case. The formation of a 3-fluoropiperidine at -50 °C was
in accordance with already observed similar effects of tem-
perature on reaction course.11 At higher temperature, the
reaction became less selective.
Double Bond Substitution Effect. To investigate the influ-
ence of the double bond substitution on the formation of a
potential ammonium-carbenium superlectrophilic inter-
mediate, and thus, on the cyclization/fluorination reaction,
the reactivity of substrates 3a-i was tested (Table 2).
(13) Thibaudeau, S.; Violeau, B.; Martin-Mingot, A.; Jouannetaud, M.
P.; Jacquesy, J. C. Tetrahedron. Lett. 2002, 43, 8773–8775.
(14) (a) Thibaudeau, S.; Martin-Mingot, A.; Jouannetaud, M. P.; Jac-
quesy, J. C. Tetrahedron 2002, 58, 6643–6649. (b) Martin, A.; Jouannetaud,
M. P.; Jacquesy, J. C. Tetrahedron. Lett. 1996, 37, 2967–2970.
(15) Olah, G. A.; Brydon, D. L.; Porter, R. D. J. Org. Chem. 1970, 35,
317–328.
We had previously showed11 that the reaction of methyl-
substituted (entries 1 and 2) or homoallylic substrates led to
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TABLE 2. Double Bond-Substituted N-Dienes Reaction in Superacida
aStandard conditions: HF/SbF5 molar ratio 8/1, 3 min, 0 °C. bComplex mixture. cSole product detected by 1H NMR of the crude mixture.
fluorinated pyrrolydine 4a. After working on this alternative
of the cyclization/fluorination process, and based on the
amount of formed pyrrolidine depending on starting materi-
al, we propose the mechanism in Scheme 4.
selectivity (yield) depending on substrate. Phenyl substitu-
tion (entries 3 and 4) was not compatible with the cyclization/
fluorination process. Starting from phenyl-substituted sub-
strates, whatever reaction conditions used, a mixture of
compounds was obtained. The absence of selectivity could
be explained by a competition between the desired reaction
and a potential intra- or intermolecular Friedel-Crafts-type
reaction. Deactivation of the double bond by an electron-
withdrawing group, like an ester function (on protonated or
nonprotonated form in superacid), prevented the substrate
from undergoing the desired reaction (entries 5-8, 10). Start-
ing from 3e, a monohydroxylated product 4e was obtained in
41% yield after purification and no other compounds were
detected in the crude. Modification of the substituent on the
After successive protonations, 3a gives dication A3, which
undergoes cylization to B3. After isomerization toward the
more stable ion C3 (less repulsion of charges), the isomeriza-
tion process through protonated cyclopropane could give the
more stable dication E3 (less repulsion of charges and
inductive donating effect), precursor of the fluorinated pro-
duct. The formation of A3 requires two steps (protonation
followed by isomerization) or one step, depending on the
substrate. In addition, intermediate A03 might be subjected to
potential side reactions, which could explain the difference of
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SCHEME 4. Formation of Pyrrolidine 4a
TABLE 3. Cyclization/Fluorination Reaction of Halogen-Substituted
Substratesa
temp
(°C)
products
(yield %c)
d
entry
R
X
6/7/70
b
b
b
b
1
2
3
4
5
6
7
8
9
5a p-NO2Bz Br
5b p-NO2Bn Br
0
0
0
0
0
/
/
/
/
5c Me
Br
5d p-NO2Bz Cl
5e p-NO2Bn Cl
6e (57) 7e (0) 70e (0)
5e p-NO2Bn Cl -50 6e (0) 7e/70e (73)
0/90/10
6f (25) 7f (0) 70f (0) 94/6/0
Cl -30 6f 7f 51/40/9
70f
Cl -50 6f (0) 7f (26) 70f (6) 14/71/15
Cl -78 6f 7f 9/79/12
70f
Cl
6g (33) 7g (0) 70g (0) 97/3/0
Cl -50 6g (0) 7g (29) 70g (8) 27/60/12
5f Me
5f Me
5f Me
Cl
0
10 5f Me
11 5g iPr
12 5g iPr
0
nitrogen atom allowed the formation of tetrahydroisoquino-
lines 4g-i (entries 7-10) or fluorinated product 4f (entry 6).
The observed effect of the function on the reactivity of the
substrate is in accordance with the influence of the distance
between charges on the electrophilic character of the formed
dicationic intermediate.10 Starting from substrate 3h, fluori-
nated and hydroxylated products 4h and 4h0 were obtained in
33% and 20% yields, respectively. This original dehydro-
fluorination/fluorination process seems to come from the
intramolecular Friedel-Crafts reaction, followed by dehy-
drofluorination (rearomatization)/fluorination. As Friedel
Crafts alkylation of polyfluorobenzenes requires relatively
harsh conditions,16 to support our hypothesis, the reactivity
of substrate 3h0 was tested. In similar conditions, the fluori-
nated isoquinoline 4h00 was formed in 41% yield (entry 9).
Interestingly, these results emphasize the superelectrophilic
character of the ammonium-carbenium dication, as it can be
trapped by a very poor nucleophile such as a polyfluorinated
aromatic.
aStandard conditions: HF/SbF5 molar ratio 8/1, 3 min. bComplex
c
mixture. Yield of isolated product. dRelative abundances were deter-
mined by 1H, 19F NMR and confirmed by GC analysis of the crude
reaction mixture (excepted for entry 6 by HPLC analysis).
SCHEME 5. Reaction of Substrate 5e
conformer with both methyl group and N-substituent in
equatorial positions, the structure was determined by
NMR experiments and confirmed by X-ray crystallogra-
phy.18 Under milder conditions (-50 °C, entry 6) substrate
5e led to the formation of gem-chlorofluoroderivatives 7e
and 70e in good overall yield. As observed for the difluoro-
product 6e, the more stable conformations present both the
methyl group and the N-substituent in equatorial
positions. Interestingly chlorofluoroderivatives 7e and 70e
were obtained as a mixture of diastereoisomers with a 9/1
ratio in favor of an axial fluorine mixture of enantiomers
(7e). This ratio was determined by 1H, 19F NMR experiments
and confirmed by HPLC analysis of the crude. A proposed
mechanism to explain the reaction of chlorinated dienes is
depicted in Scheme 5.
Halogen-Substituted Double Bond. In our ongoing work
on the fluorination reaction in superacid, we recently showed
a dramatic effect of halonium ions on difluorination.17
Encouraged by these results, we studied the halogen-sub-
stitution influence on the cyclization/fluorination reaction
(Table 3).
First, the reactivity of brominated substrates 5a-c was
tested. Unfortunately, whatever reaction conditions, the
reaction was not selective and no products resulting from
the cyclization/fluorination process could be identified. The
formation of a cyclic bromonium ion after protonation of
the double bond and the absence of regioselectivity for its
opening by intra- or intermolecular nucleophilic attack
could explain the formation of a mixture of compounds.
Then, chlorinated substrates were submitted to reaction.
Starting from chlorinated amines 5d-g, except for p-NO2-
benzoyl protection (substrate 5d), in all cases difluoropiper-
idines and/or chlorofluoroanalogues were obtained in
good yields. Starting from amine 5e, after reaction at 0 °C
difluorinated piperidine 6e was obtained selectively in
57% yield. The product observed experimentally was the
After successive protonations, superelectrophile A4 is
formed and undergoes intramolecular cyclization to give R-
chloronium ion B4.19 Dication B4 is then fluorinated to give
ammonium C4 precursor of chlorofluoro products. Elimina-
tion of HCl after protonation leads to the formation of R-
fluoronium ion D4,19 precursor of the difluorinated product.
(16) Beckert, W. F.; Lowe, J. U., Jr. J. Org. Chem. 1967, 32, 582–584.
(17) Zunino, F.; Liu, F.; Berrier, C.; Martin-Mingot, A.; Thibaudeau, S.;
Jouannetaud, M. P.; Jacquesy, J. C.; Bachmann, C. J. Fluorine Chem. 2008,
129, 775–780.
(18) See Supporting Information, section I.
(19) 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, 481-487 and references
cited therein.
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SCHEME 6. Reaction of Dichlorinated Substrate 5h
This hypothesis, based on the formation of chlorofluoroder-
ivative as intermediate, was confirmed by submitting a
mixture of compounds 7e/70e to superacid at 0 °C. Starting
from chlorofluoroderivatives, difluoroproduct 6e was
formed quantitatively. To know if the reaction could be
influenced by the substituent on the nitrogen atom, we
evaluated N-methyl substrate 5f (entries 7-10) and N-iso-
propyl amine 5g behaviors (entries 11 and 12). Analogously
to substrate 5e, difluorinated piperidines were formed at
0 °C (entries 7 and 11) and chlorofluoro analogues at -50 °C
(entries 9 and 12). The obtained low yields could be the fact
of the high volatility of the products as no other compounds
were detected in the crude mixture. As shown by GC analysis
of the crude mixtures, no notable influence of nitrogen atom
substituent on diastereoisomers ratio was shown. For all
substrates, the mixture of enantiomers with fluorine atom in
the axial position was predominant. The relative stereochem-
istry of gem-chlorofluoroproducts was assigned by NMR
experiments and confirmed by X-ray crystallography.18 In
summary, at low temperature chlorofluoroderivatives were
formed with a diastereoselective excess in favor of axial
fluorine atom diastereoisomers and at higher temperature
(0 °C) difluorinated analogues could be obtained. On the
basis of the postulated mechanism, the remarkable diaster-
eoselectivity of the fluorination step prompted us to carry
out theoretical studies to determine whether the fluorination
was under kinetic or thermodynamic control.20 For example,
the products 7f and 70f obtained experimentally are the more
stable, but the relative energies between their more stable
conformation are within 0.5 kcal mol-1 of each other and do
not explain the observed diastereoselectivity. In addition,
product ratios do not change over time under reaction
conditions. To evaluate the thermodynamic control hypoth-
esis, we also submitted a mixture of minor enantiomers
(product 70g) to superacid at 0 °C. Difluorinated product
6g was obtained besides the remaining 70g, a mixture of
enantiomers 7g was not observed in crude mixture. These
results seemed to indicate that the fluorination step was
under kinetic control. To confirm this hypothesis, we carried
out theoretical calculations on R-chloronium-ammonium
dication B4.20 The calculations showed that the structure
with the Nþ-H bond in the axial position and the methyl in
the equatorial position is the most stable conformer. It is
likely to evaluate the approach of fluoride ion source (pro-
bably SbF6- or Sb2F11- in our conditions)21 to the cationic
center in this conformation. Two hypotheses can be consid-
ered. Fluorination could occur on the less hindered face of
the pseudochair conformation (axial face). On the basis of
the absence of considerable steric hindrance we propose a
second hypothesis based on recent observations formulated
on fluorinated cyclic ammonium ions.22 On β-fluorinated
piperidinium ions, intramolecular β-fluorine-ammonium
interaction has been shown to be similar to that of a good
hydrogen bond. Analogously, we postulate similar intermo-
lecular ammonium-fluorine interaction between the axial
Nþ-H bond of the ammonium ion and one of the fluorine
atoms of the antimony hexafluoride ion. Such interaction
could explain a favorable approach of fluorinating agent by
the upper face of the chloronium ion (Nþ-H bond face of the
ammonium ion). Further experimental and theoretical
works are currently underway to confirm this hypothesis.
To evaluate the scope of this novel alternative of the
cyclization/fluorination process, dichloro substrate 5h was
submitted to superacid (Scheme 6). After reaction at -50 °C,
5h led to a mixture of compounds. After purification, five
compounds were separated and identified as products com-
ing from a cyclization process in superacid. Two major
products were piperidines containing three halogen atoms
(compounds 6h and 6h0). Besides, three minor products,
probably coming from further elimination in the media, were
obtained. The equatorial position of methyl and axial posi-
tions of fluorine atoms in 6h and 6h0 were assigned by NMR
experiments and confirmed by X-ray crystallography.18
These preliminary results confirm a potent diastereoselective
fluorination step as mentioned before. This recent result
shows that cyclization/fluorination reaction could be applied
to disubstituted (halogenated) nitrogen-containing dienes
and further extends the scope of this reaction to high-valued
polyhalogenated piperidines.
In conclusion, we have studied the scope and limitations of
the recent cyclization/fluorination reaction of N-dienes in
superacid. After showing a potential chelating effect of
nitrogen substituent on the reaction, a dramatic double bond
substitution effect on dicationic ammonium-carbenium
intermediates reactivity has been showed. We have also
studied the ability to use this reaction starting from haloge-
nated substrates. On the basis of the formation of super-
lectrophilic novel dicationic R-chloronium ammonium
intermediates in the media, this work has allowed the for-
mation of high-valued gem-chlorofluoro- and difluoropiper-
idines in one step starting from easily accessible starting
materials. In addition, stereoselective fluorination in super-
acid has been shown, which opens future innovative devel-
opment for this particular chemistry.
Experimental Section
The authors draw the reader’s attention to the dange-
rous features of superacidic chemistry. Handling of hydrogen
(20) See the Supporting Information, section H.
(22) (a) Sun, A.; Lankin, D. C.; Hardcastle, K.; Snyder, J. P. Chem.;Eur.
J. 2005, 11, 1579–1591. (b) Gooseman, N. E. J.; O’Hagan, D.; Slawin, A. M.
Z.; Teale, A. M.; Tozer, D. J.; Young, R. J. Chem. Commun. 2006, 3190–
3192.
(21) (a) Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids; Wiley
Interscience: New York, 1985. (b) Culmann, J. C.; Fauconet, M.; Jost, R.;
Sommer, J. New J. Chem. 1999, 23, 863–867.
6030 J. Org. Chem. Vol. 74, No. 16, 2009

Vardelle et al.
JOCArticle
fluoride and antimony pentafluoride must be done by experienced
chemists with all the necessary safety arrangements in place.
Optimized Procedure in Superacidic Media. To a mixture of
HF/SbF5 (3 mL, 8/1 molar ratio) maintained at the indicated
temperature was added nitrogen derivative (1 mmol). The
mixture was magnetically stirred at the same temperature for
the reaction time. The reaction mixture was then neutralized
with water-ice-Na2CO3 and extracted with dichloromethane
(3ꢀ). The combined organic phases were dried (MgSO4) and
concentrated in vacuo. Products were isolated by column chro-
matography over silica gel.
Compound 2b: 4-fluoro-4-methyl-1-(4-nitrobenzoyl)piperidine:
The optimized procedure (-30 °C, 5 min reaction time) was
followed, starting from 500 mg of 1b (2.03 mmol). Purification
by flash column chromatography (70/30: petroleum ether/ethyl
acetate) afforded 296 mg of the title compound as a colorless
Compound 2i0: 3-(bis(2-fluoropropyl)amino)propanenitrile: 1H
3
NMR (300 MHz, CDCl3, ppm) δ 1.32 (dd, JH-F =23.6 Hz,
3JH-H=6.3 Hz, 3H, H-10 and H-100); 2.48 (m, 2H, H-3); 2.62
(m, 4H, H-30 and H-300); 2.90 (m, 2H, H-2); 4.79 (dm, 2JH-F
=
49.3 Hz, 2H, H-20 and H-200). 13C NMR (75 MHz, CDCl3, ppm)
δ 17.5 (CH2, C-2); 19.0 (d, 2JC-F=24 Hz, 2 CH3, C-10 and C-100);
52.2 and 52.3 (2s, CH2, C-3); 60.1 and 60.9 (2d, 2JC-F=21 Hz,
CH2, C-30 and C-300); 90.5 and 90.9 (2d, 1JC-F=167 Hz, 2 CH,
C-20 and C-200); 119.3 (C-1). 19F{1H} NMR (282 MHz, CDCl3,
external standard C6F6 (δF -162.90 ppm), ppm) -175,95 and
-176,07. MS (EI, 70 eV) m/z (rel intensity, %) 190 (5), 150 (18),
143 (100), 102 (7), 90 (10), 43 (25). HRMS (ESI) calcd for
C9H16N2F2 190.12816, found 190.1293.
Then, dichloromethane/methanol/NH3(aq) 98/1/1 afforded
205 mg of compound 2i (45%).
Compound 2i: 3-(3-fluoro-3-methylpiperidine-1-yl)propaneni-
trile: 1H NMR (300 MHz, CDCl3, ppm) δ 1.35 (d, 3JH-F = 21.6
Hz, 3H, H-100); 1.55 (m, 2H, H-50); 1.81 (m, 2H, H-40); 2.30 (m,
2H, H-20 and H-60); 2.50 (t, 3JH-H=7.2 Hz, 2H, H-3); 2.67 (m,
1
powder (55%). H NMR (300 MHz, CDCl3, ppm) δ 1.43 (d,
3JH-F = 21.4 Hz, 3H, H-6); 1.79 (m, 4H, H-3); 3.19 (m, 1H) and
4.55 (m, 1H, H-2); 3.36 (m, 2H, H-2); 7.58 (d, 3JH-H = 8.7 Hz,
2H, H-20); 8.28 (d, JH-H = 6.8 Hz, 2H, H-30). 13C NMR (75
2H, H-20 and H-60); 2.77 (t, 3JH-H=7.2 Hz, 2H, H-2). 13C NMR
3
MHz, CDCl3, ppm) δ 27.0 (d, 2JC-F = 24 Hz, CH3, C-6); 35.9
(d, 2JC-F = 22 Hz, CH2) and 36.8 (d, 2JC-F = 23,3 Hz, CH2, C-
3); 38.8 and 43.6 (2 CH2, C-2); 92.0 (d, 1JC-F = 168 Hz, C-4);
123.9 (2 CH, C-30); 127.9 (2 CH, C-20); 142.5 (C-10) ; 148.3 (C-40);
170.0 (C-5). 19F{1H} NMR (282 MHz, CDCl3, external stan-
dard C6F6 (δF -162.90 ppm) ppm) -154.72. MS (EI, 70 eV) m/z
(rel intensity, %) 266 (6), 247 (28), 150 (100), 104 (78), 83 (80).
HRMS (ESI) calcd for C13H14N2O3F 265.09885, found
265.0987. Mp 145 °C.
(75 MHz, CDCl3, ppm) δ 15.9 (CH2, C-2); 22.1 (d, JC-F
=
3
4 Hz, CH2, C-50); 25.3 (d, 2JC-F=24 Hz, CH3, C-100); 35.1 (d,
2JC-F=23 Hz, CH2, C-40); 52.6 (CH2, C-60); 53.6 (CH2, C-3);
61.9 (d, 2JC-F=23 Hz, CH2, C-20); 92.5 (d, 1JC-F=171 Hz, C-
30); 119.1 (C-1). 19F{1H} NMR (282 MHz, CDCl3, external
standard C6F6 (δF -162.90 ppm), ppm) -147,58. MS (EI,
70 eV) m/z (rel intensity, %) 170 (4), 130 (46), 110 (8), 97 (4),
70 (5), 59 (18), 43 (32), 32 (25), 28 (100), 18 (25). HRMS (ESI)
calcd for C9H15N2F 170.12193, found 170.1210.
Compound 2e: 2-(4-fluoro-4-methylpiperidine-1-yl)ethyl acet-
ate: The optimized procedure (-30 °C, 5 min reaction time) was
followed, starting from 310 mg of 1e. Purification by column
chromatography (dichloromethane/methanol/NH3(aq) 98/1/1)
Compound 4a: (3-(2-fluoropropan-2-yl)pyrrolidin-1-yl)(4-nitro-
phenyl)methanone: The optimized procedure (0 °C, 3 min reac-
tion time) was followed, starting from 300 mg of 3a. Purification
by column chromatography (dichloromethane/methanol 99/1)
1
1
afforded 173 mg of the title compound (50%). H NMR (300
MHz, CDCl3, ppm) δ 1.33 (d, 3JH-F = 21.4 Hz, 3H, H-50); 1.75
afforded 240 mg of the title compound (86%). H NMR (300
=
3
MHz, CDCl3, ppm) δ 1.28, 1.35, 1.40, and 1.41 (4d, JH-F
(m, 4H, H-30); 2.06 (s, 3H, H-200); 2.38 (m, 2H, H-20ax); 2.66
20.8, 21.0, 21.4, and 21.3 Hz), 6H, H-10; 1.96 (m, 2H, H-4); 2.39
(m, 1H, H-3); 3.47 (m, 3H, H-5 and H-2); 3.82 (m, 1H, H-2); 7.65
3
(m, 4H, H-20eq and H-2); 4.19 (t, JH-H = 6.0 Hz, 2H, H-1).
13C NMR (75 MHz, CDCl3, ppm) δ 21.4 (CH3, C-200); 27.3 (d,
(d, JH-H =8.8 Hz) and 7.67 (d, JH-H =8.8 Hz, 2H, H-200);
3
3
2
3
3
2JC-F = 24 Hz, CH3, C-50); 36.8 (d, JC-F = 21 Hz, 2 CH2,
8.25 (d, JH-H=8.8 Hz) and 8.27 (d, JH-H=8.8 Hz, 2H, H-
300). 13C NMR (75 MHz, CDCl3, ppm) δ 25.3 and 27.2 (d, CH2,
3JC-F=4 Hz, C-4); 25.6 (d, CH3, 2JC-F=24.6 Hz) and 25.8 (d,
CH3, 2JC-F=24.7 Hz) and 26.3 (d, CH3, 2JC-F=26.2 Hz) and
26.7 (d, CH3, 2JC-F = 24.8 Hz), C-10; 46.7 and 49.8 (CH2, C-5);
47.2 (d, CH, 2JC-F=22.7 Hz) and 49.0 (d, CH, 2JC-F = 22.2 Hz,
C-30); 50.0 (2 CH2, C-20); 57.0 (CH2, C-2); 62.4 (CH2, C-1); 92.3
1
(d, JC-F = 167 Hz, C-40); 171.4 (C-100). 19F{1H} NMR (282
MHz, CDCl3, external standard C6F6 (δF -162.90 ppm), ppm)
-151.71.MS (EI, 70 eV) m/z (rel intensity, %) 203 (4), 143 (5),
130 (100), 110 (23), 70 (7), 43 (11). HRMS (ESI) calcd for
C10H18NO2F 203.13216, found 203.1331.
3
C-3); 47.3 and 49.9 (d, 2 CH2, JC1-F = 4.8 Hz, C-2); 94.0
1
Compound 2h: dihydro-5,5-dimethyl-3-(3-methylpiperidin-1-
yl)furan-2(3H)-one: The optimized procedure (-50 °C, 10 min
reaction time) was followed, starting from 250 mg of 1h.
Purification by column chromatography (petroleum ether/ethyl
(d, JC-F = 168.9 Hz) and 94.2 (d, JC-F =168.3 Hz), C-20;
123.6 and 123.7 (2 CH, C-300); 128.1 (2 CH, C-200); 142.5
and 142.7 (C-100); 148.4 (C-400); 167.3 and 167.4 (CdO).
19F{1H} NMR (282 MHz, CDCl3, external standard C6F6 (δF
-162.90 ppm), ppm) -151.41 and -151.31. MS (EI, 70 eV) m/z
(rel intensity %) 168 (35), 150 (61), 73 (88), 59 (100). HRMS
(ESI) calcd for C14H17N2O3F 280.12232, found 280.1220.
Mp 69 °C.
1
acetate 95/5) afforded 32 mg of the title compound (15%). H
NMR (300 MHz, CDCl3, ppm) δ 0.83 (m, 1H, H-40); 0.84 (d,
3JH-H = 6.4 Hz, 3H, H-70); 1.35 (s, 3H, H-6); 1.44 (s, 3H, H-6);
1.63 (m, 4H, H-30, H-40 and H-50); 1.85 (t, 3JH-H = 10.4 Hz, 1H,
H-20ax); 2.10 (m, 3H, H-50 and H-4); 2.48 (dt, 2JH-H = 10.9 Hz,
3JH-H = 3.3 Hz, 1H, H-60ax); 2.68 (m, 1H, H-60eq); 2.93 (m, 1H,
H-20eq); 3.75 (dd, 3JH-H = 11.2 Hz, 3JH-H = 9.0 Hz, 1H, H-3).
13C NMR (75 MHz, CDCl3, ppm) δ 19.5 (CH3, C-7); 25.4 and
25.6 (CH2, C-40); 27.4 (CH3, C-6); 29.0 (CH3, C-6); 31.1 and 31.3
(CH, C-30); 32.7 (CH2, C-50 or C-4); 35.6 and 35.8 (CH2, C-50 or
C-4); 49.8 and 50.2 (CH2, C-60); 57.5 and 57.9 (CH2, C-20); 64.4
(CH, C-3); 79.8 (C-5); 174.5 (C-2). MS (EI, 70 eV) m/z (rel
intensity, %) 211 (11); 168 (23); 152 (89); 124 (100); 98 (29).
HRMS (ESI) calcd for C12H21NO2 211.5723, found 211.580.
Mp 50 °C.
Compound 4e: ethyl 2-((N-(2-hydroxypropyl)-4-nitrobenza-
mido)methyl)acrylate: The optimized procedure (0 °C, 3 min
reaction time) was followed, starting from 200 mg of 3e.
Purification by column chromatography (petroleum ether/ethy-
lacetate 60/40) afforded 86 mg of the title compound (41%). 1H
NMR (300 MHz, CDCl3, ppm) δ 1.26 (t, 3JH-H = 5.4 Hz, 3H,
3
H-7); 1.39 (d, JH-H = 6.3 Hz, 3H, H-40); 2.85 (m, 2H, H-20);
3.50 (s, 2H, H-2); 4.19 (q, 3JH-H = 7.2 Hz, 2H, H-6); 5.29 (m,
1H, H-30); 5.72 (s, 1H, H-4); 6.24 (s, 1H, H-4); 8.20 (d, 3JH-H
=
8.8 Hz, 2H, H-200); 8.29 (d, JH-H = 6.8 Hz, 2H, H-300). 13C
NMR (75 MHz, CDCl3, ppm) δ 14.5 (CH3, C-7); 18.4 (CH3, C-
40); 50.8 (CH2, C-2); 53.4 (CH2, C-20); 61.1 (CH2, C-6); 72.7 (CH,
C-30); 123.8 (CH, C-300); 126.5 (CH2, C-4); 131.0 (CH, C-200);
136.3 (C-3 or C-100 or C-400); 138.7 (C-3 or C-100 or C-400); 150.8
(C-3 or C-100 or C-400); 164.6 (C-5 or C-8); 166.9 (C-5 or C-8). MS
3
Compounds 2i and 2i0. The optimized procedure (-50 °C, 60
min reaction time) was followed, starting from 400 mg of 1i.
Purification by column chromatography (dichloromethane/
methanol 99/1) afforded 34 mg of compound 2i0 (7%).
J. Org. Chem. Vol. 74, No. 16, 2009 6031

Vardelle et al.
JOCArticle
and HRMS analyses were not performed on this compound due
to its high instability.
(300 MHz, CDCl3, ppm) δ 1.29 (t, 3JH-H=7.1 Hz, 3H, H-60);
1.66 (s, 3H, H-11); 2.60 (d, JH-H = 11.7 Hz, 1H, H-3a);
2
2
2.77 (d, JH-H =11.7 Hz, 1H, H-3b); 3.05 (s, 1H, OH); 3.42
Compound 4f: ethyl 2-((N-(methyl)(2-fluoropropyl))methyl)-
acrylate: The optimized procedure (0 °C, 3 min reaction time)
was followed, starting from 90 mg of 3f. Purification by column
chromatography (dichloromethane/NH3(aq) 99/1) afforded
58 mg of the title compound (58%). 1H NMR (300 MHz, CDCl3,
ppm) δ 1.28 (dd, 3JH-F=23.5 Hz, 3JH-H=6.3 Hz, 3H, H-40);
1.28 (t, 3JH-H = 7.1 Hz, 3H, H-7); 2.28 (s, 3H, H-8); 2.55 (m,
2H, H-20); 3.25 (s, 2H, H-2); 4.19 (q, 3JH-H=7.1 Hz, 2H, H-6);
4.81 (dm, 2JH-F = 49.4 Hz, 1H, H-30); 5.74 (s, 1H, H-4); 6.23 (s,
1H, H-4). 13C NMR (75 MHz, CDCl3, ppm) δ 14.5 (CH3, C-7);
19.6 (d, 2JC-F = 22 Hz, CH3, C-40); 43.2 (CH3, C-8); 58.7 (CH2,
C-2); 61.0 (CH2, C-6); 62.8 (d, 2JC-F = 22 Hz, CH2, C-20); 89.6
(d, 1JC-F = 167 Hz, CH, C-30); 126.8 (CH2, C-4); 138.2 (C-3);
167.2 (C-5). 19F{1H} NMR (282 MHz, CDCl3, external stan-
dard C6F6 (δF -162.90 ppm), ppm) -175,36. MS (EI, 70 eV) m/z
(rel intensity, %) 203 (11), 156 (100), 128 (23), 104 (57), 85 (25).
HRMS (ESI) calcd for C10H18NO2F 203.13216, found
203.1342.
2
(d, JH-H = 14.9 Hz, 1H, H-1a); 3.45 (s, 2H, H-10); 3.78 (d,
2JH-H = 15.4 Hz, 1H, H-1b); 4.21 (q, 3JH-H = 7.1 Hz, 2H, H-
50); 5.79 (d, 2JH-H = 1.,3 Hz, 1H, H-30a); 6.33 (d, 2JH-H = 1.2
Hz, 1H, H-30b). 13C NMR (75 MHz, CDCl3, ppm) δ 14.5 (CH3,
C-60); 25.7 (d, 4JC-F = 6.7 Hz, CH3, C-11); 49.8 (CH2, C-1); 58.4
(CH2, C-10); 61.3 (CH2, C-50); 64.7 (CH2, C-3); 69.2 (C-4); 119.2
(m, C-9); 125.0 (m, C-10); 128.1 (CH2, C-30); 136.8 (C-20); 138.0,
141.7, 145.2, and 148.5 (C-5, C-6, C-7 and C-8); 166.8
(C-40). 19F{1H} NMR (282 MHz, CDCl3, external standard
C6F6 (δF -162.90 ppm), ppm) -140.91 (m, 1F, F-5); -145.51
(dd, 3JF-F = 22.6 Hz, 4JF-F = 14.1 Hz, 1F, F-8); -158.66 (t,
3JF-F = 20.8 Hz, 1F, F-6); -158.93 (t, 3JF-F = 20.3 Hz, 1F, F-
7). MS and HRMS analyses were not performed on this
compound due to its high instability.
Compound 4h00: 4,5,6,7,8-pentafluoro-1,2,3,4-tetrahydro-4-
methylisoquinoline: The optimized procedure (0 °C, 3 min reac-
tion time) was followed, starting from 250 mg of 3h0. Purifica-
tion by column chromatography (petroleum ether/ethyl acetate
70/30) afforded 111 mg of the title compound (44%). 1H NMR
Compound 4g: ethyl 2-((3,4-dihydro-4-methyl-6-nitroisoquino-
lin-2(1H)-yl)methyl)acrylate: The optimized procedure (0 °C, 3
min reaction time) was followed, starting from 300 mg of 3g.
Purification by column chromatography (dichloromethane)
afforded 139 mg of the title compound (46%). 1H NMR
(300 MHz, CDCl3, ppm) δ 1.29 (t, 3JH-H = 7.3 Hz, 3H, H-7);
1.33 (d, 3JH-H = 7.0 Hz, 3H, H-40); 2.49 (dd, 2JH-H = 11.5 Hz,
(300 MHz, CDCl3, ppm) δ 1.77 (dd, 3JH-F = 20.1 Hz, 5JH-F
1.6 Hz, 3H, H-11); 1.83 (br s, 1H, NH, H-2); 2.97 (dd, 3JH-F
=
=
23.0 Hz, 2JH-H = 14.1 Hz, 1H, H-3); 3.30 (t, 3JH-F = 14.8 Hz,
2JH-H = 14.8 Hz, 1H, H-3); 3.80 (dd, JH-H = 17.2 Hz,
2
4JH-F=4.2 Hz, 1H, H-1); 4.06 (d, 3JH-H=17.2 Hz, 1H, H-1).
3JH-H = 6.0 Hz, 1H, H-20); 2.81 (dd, JH-H = 11.5 Hz,
13C NMR (75 MHz, CDCl3, ppm) δ 24.3 (dd, JC-F=27 Hz,
2
2
3JH-H = 4.8 Hz, 1H, H-20); 3.07 (m, 1H, H-30); 3.37 (s, 2H,
4JC-F = 7 Hz, CH3, C-11); 42.3 (CH2, C-1); 55.7 (d, 2JH-F = 25
Hz, CH2, C-3); 87.1 (d, 1JC-F = 171 Hz, C-4); 120.5 (m, C-9);
121.6 (m, C-10); 141-149 (m, C-5, m, C-6, m, C-7 and m, C-8).
19F{1H} NMR (282 MHz, CDCl3, external standard C6F6 (δF -
162.90 ppm), ppm) -134.60 (br s, 1F, F-C4); -139.05 (m, 1F,
F-5); -145.70 (dd, 3JF-F = 22.0 Hz, 5JF-F = 13.0 Hz, 1F, F-8);
H-8); 3.66 (d, 2JH-H = 16.1 Hz, 1H, H-2); 3.75 (d, 2JH-H=16.1
3
Hz, 1H, H-2); 4.21 (q, JH-H = 7.1 Hz, 2H, H-6); 5.82 (d,
2JH-H = 0.8 Hz, 1H, H-4); 6.29 (d, 2JH-H = 0.7 Hz, 1H, H-4);
7.13 (d, 3JH-H = 8.5 Hz, 1H, H-200); 7.94 (dd, 3JH-H = 8.4 Hz,
4JH-H = 2.2 Hz, 1H, H-300); 8.06 (d, 4JH-H = 1.9 Hz, 1H, H-
500). 13C NMR (75 MHz, CDCl3, ppm) δ 14.5 (CH3, C-7); 21.5
(CH3, C-40); 33.7 (CH, C-30); 56.6 (CH2, C-8); 57.5 (CH2, C-20);
58.3 (CH2, C-2); 61.0 (CH2, C-6); 120.9 (CH, C-300); 123.2 (CH,
C-500); 126.7 (CH2, C-4); 127.6 (CH, C-200); 137.5, 141.9, 142.6,
and 146.9 (C-3, C-100, C-600, and C-400); 167.1 (C-5). MS and
HRMS analyses were not performed on this compound due to
its high instability.
-156.40 (tm, 3JF-F = 21.1 Hz, 1F, F-6); -158. 89 (t, 3JF-F
=
20.3 Hz, 1F, F-7). MS (EI, 70 eV) m/z (rel intensity, %) 237 (44),
216 (40), 208 (100), 187 (40), 169 (22). HRMS (ESI) calcd for
C10H8NF5 237.05769, found 237.0568.
Compound 4i: methyl 4-(3,4-dihydro-4-methyl-6-nitro-1-iso-
quinolin-2(1H)-yl)but-2-enoate: The optimized procedure
(0 °C, 3 min reaction time) was followed, starting from 200 mg
of 3i. Purification by column chromatography (petroleum ether/
ethyl acetate 90/10) afforded 102 mg of the title compound
Compounds 4h and 4h0. The optimized procedure (0 °C, 3 min
reaction time) was followed, starting from 100 mg of 3h.
Purification by column chromatography (petroleum ether/ethyl
acetate 98/2) afforded 37 mg of compound 4h (33%).
(51%). 1H NMR (300 MHz, CDCl3, ppm) δ 1.33 (d, 3JH-H
=
7.0 Hz, 3H, H-11); 2.42 (dd, 2JH-H = 11.5 Hz, 3JH-H = 6.5 Hz,
1H, H-3); 2.80 (dd, 2JH-H = 11.5 Hz, 3JH-H = 5.1 Hz, 1H, H-
3); 3.09 (qd, 3JH-H = 13.0 Hz, 3JH-H = 6.5 Hz, 1H, H-4); 3.29
(d, 3JH-H = 6.0 Hz, 2H, H-10); 3.67 (s, 2H, H-1); 3.72 (s, 3H, H-
50); 6.05 (dt, 3JH-H trans = 15.7 Hz, 4JH-H = 1.6 Hz, 1H, H-30);
Compound 4h: ethyl 2-((4,5,6,7,8-pentafluoro-3,4-dihydro-4-met-
hylisoquinolin-2(1H)-yl)methyl)acrylate: 1H NMR (300 MHz,
3
CDCl3, ppm) δ 1.29 (t, JH-H = 7.1 Hz, 3H, H-60); 1.78 (dd,
=
3JH-F = 20.6 Hz, 5JH-F = 1.1 Hz, 3H, H-11); 2.85 (d, 3JH-F
11.9 Hz, 2H, H-3); 3.44 (s, 2H, H-10); 3.54 (d, 2JH-H = 15.7 Hz,
1H, H-1); 3.73 (d, 2JH-H = 16.6 Hz, 1H, H-1); 4.21 (q, 3JH-H
6.97 (dt, JH-H trans = 15.7 Hz, JH-H = 6.0 Hz, 1H, H-20);
7.12 (d, 3JH-H = 8.5 Hz, 1H, H-8); 7,92 (dd, 3JH-H = 8.4 Hz,
4JH-H = 2.3 Hz, 1H, H-7); 8.06 (d, 4JH-H = 2.1 Hz, 1H, H-5).
13C NMR (75 MHz, CDCl3, ppm) δ 20.8 (CH3, C-11); 33.5
(CH, C-4); 51.9 (CH3, C-50); 56.6 (CH2, C-1); 57.8 (CH2, C-3);
58.9 (CH2, C-10); 121.0 (CH, C-7); 123.1 (CH, C-7); 123.4 (CH,
C-30); 127.6 (CH, C-8); 141.6 (C-9 or C-10); 142.1 (C-9 or C-10);
145.1 (CH, C-20); 147.0 (C-6); 166.8 (C-40). MS (EI, 70 eV) m/z
(rel intensity, %) 290 (16), 275 (26), 217 (28), 207 (32), 191 (53),
189 (28), 163 (38), 115 (100), 91 (37). HRMS (ESI) calcd for
C15H18N2O4 290.12666, found 290.1276.
3
4
=
7.1 Hz, 2H, H-50); 5.81 (s, 1H, H-30); 6.32 (s, 1H, H-30).
13C NMR (75 MHz, CDCl3, ppm) δ 14.5 (CH3, C-60); 25.7
(dd, 2JC-F = 27 Hz, 4JC-F = 4 Hz, CH3, C-11); 49.6 (CH2, C-1);
57.7 (CH2, C-10); 61.3 (CH2, C-50); 61.5 (d, 2JC-F = 27 Hz, CH2,
C-3); 90.5 (d, 1JC-F = 173 Hz, C-4); 119.9 (m, C-9); 121.2 (m, C-
10); 127.6 (CH2, C-30); 136.9 (C-20); 138.5, 141.9, 145.2, and
148.5 (C-5, C-6, C-7 and C-8); 166.9 (C-40). 19F{1H} NMR (282
MHz, CDCl3, external standard C6F6 (δF -162.90 ppm), ppm)
-139.94 (m, 1F, F-C4); -140.55 (m, 1F, F-5); -145.37
3
4
(dd, JF-F = 19.8 Hz, JF-F =11.3 Hz, 1F, F-8); -156.81
Compound 6e: (5S)-1-(4-nitrobenzyl)-3,3-difluoro-5-methylpi-
peridine: The optimized procedure (0 °C, 3 min reactiontime) was
followed, starting from 100 mg of 5e. Purification by column
chromatography (petroleum ether/ethyl acetate 95/5) afforded 58
mg of the title compound (57%). 1H NMR (500 MHz, CDCl3,
3
3
(t, JF-F = 19.8 Hz, 1F, F-6); -156.62 (t, JF-F = 18.3 Hz,
1F, F-7). MS and HRMS analyses were not performed on this
compound due to its high instability.
Then, petroleum ether/ethyl acetate 95/5 afforded 22 mg of
compound 4h0 (20%).
Compound 4h0: ethyl 2-((5,6,7,8-tetrafluoro-3,4-dihydro-4-hy-
droxy-4-methylisoquinolin-2(1H)-yl)methyl)acrylate: 1H NMR
ppm) δ 0.93 (d, 3JH-H = 6.7 Hz, 3H, CH3); 1.35 (dtd, 3JH-Fax
=
31.9 Hz, 3JH-H5ax and 2JH-H = 12.8 Hz, 3JH-Feq = 5.8 Hz, 1H,
H-4ax); 1.79 (t, 2JH-H and 3JH-H5ax = 10.9 Hz, 1H, H-6ax); 2.03
6032 J. Org. Chem. Vol. 74, No. 16, 2009

Vardelle et al.
JOCArticle
(m, 1H, H-5); 2.16 (m, 1H, H-4eq); 2.27 (ddd, 3JH-Fax = 27.7 Hz,
3JH-Feq = 9.5 Hz, 1H, H-4ax); 1.67 (dd, JH-H = 12.2 Hz,
3JH-H = 9.8 Hz, 1H, H-6ax); 2.10 (m, 1H, H-5); 2.27 (dd,
2JH-H = 11.6 Hz, 3JH-Feq = 5.3 Hz, 1H, H-2ax); 2.34 (m, 1H,
H-4eq); 2.35 (s, 3H, N-CH3); 2.82 (dm, 2JH-H = 11.4 Hz, 1H,
H-6eq); 3.16 (dm, 2JH-H = 11.6 Hz, 1H, H-2eq). 13C NMR (75
MHz, CDCl3, ppm) δ 18.3 (CH3); 28.9 (d, 3JC-F = 8.3 Hz, CH,
2
2JH-H = 11.8 Hz, JH-Feq = 2.2 Hz, 1H, H-2ax); 2.77 (d,
3
2JH-H=11.3 Hz, 1H, H-6eq); 2.99 (m, 1H, H-2eq); 3.64 (d,
2JH-H = 14.3 Hz, 1H, H-7); 3.70 (d, 2JH-H = 14.3 Hz, 1H, H-7);
7.52 (d, 3JH-H = 8.5 Hz, 2H, H-20); 8.19 (d, 3JH-H = 8.6 Hz, 2H,
H-30). 13C NMR (75 MHz, CDCl3, ppm) δ 18.8 (CH3); 28.5 (d,
3JC-F = 9.3 Hz, CH, C-5); 40.6 (dd, 2JC-F = 24.4 Hz, 2JC-F
=
C-5); 45.5 (N-CH3); 46.0 (d, JC-F = 17.7 Hz, CH2, C-4);
2
20.2 Hz, CH2, C-4); 58.3 (dd, 2JC-F = 31.2 Hz, 2JC-F = 25.0 Hz,
CH2, C-2); 60.2 (CH2, C-6); 61.3 (CH2, C-7); 120.8 (dd, 1JC-F
62.5 (CH2, C-6); 65.5 (d, 2JC-F = 27.3 Hz, CH2, C-2); 111.8 (d,
1JC-F = 241.5 Hz, C-3). 19F{1H} NMR (282 MHz, CDCl3,
external standard C6F6 (δF -162.90 ppm), ppm) -99.80. MS
and HRMS analyses were not performed on this compound due
to its high volatility.
=
243.7 Hz, 1JC-F = 239.5 Hz, C-3); 124.0 (CH, C-30); 129.6 (CH,
C-20); 146.0 (C-10); 147.6 (C-40). 19F{1H} NMR (282 MHz,
CDCl3, external standard C6F6 (δF -162.90 ppm), ppm)
-101.40 (d, 2JF-F = 241.3 Hz, Fax); -98.08 (d, 2JF-F = 241.3
Hz, Feq). MS (EI, 70 eV) m/z (rel intensity, %) 271 (94); 273 (18);
224 (28); 149 (100); 135 (98); 90 (38). HRMS (ESI) calcd for
C13H16N2O2F2 270.11798, found 270.1183. Mp 74 °C.
Then, dichloromethane afforded 26 mg of compound 7f
(26%).
Compound 7f: (3R,5S)-3-chloro-3-fluoro-1,5-dimethylpiperi-
1
3
dine: H NMR (300 MHz, CDCl3, ppm) δ 0.90 (d, JH-H
=
3
3
Compounds 7e and 7e0. The optimized procedure (-50 °C,
3 min reaction time) was followed, starting from 400 mg of 5e.
Purification by column chromatography (petroleum ether/ethyl
acetate 98/2) afforded 313 mg of the mixture 7e/7e0 (73%). A
second purification of the mixture by preparative chromato-
graphy afforded pure compound 7e.
6.7 Hz, 3H, CH3); 1.49 (ddd, JH-Fax = 36.4 Hz, JH-H or
2JH-2H = 13.8 Hz, 3JH-H or 2JH-H = 12.6 Hz, 1H, H-4ax); 1.61
(td, JH-H = 11.2 Hz3JH-H = 11.2 Hz and JH-H = 1.5 Hz,
4
1H, H-6ax); 2.05 (m, 1H, H-5); 2.30 (s, 3H, N-CH3); 2.30 (dd,
3JH-Fax = 30.0 Hz, 2JH-H = 12.4 Hz, 1H, H-2ax); 2.46 (m, 1H,
H-4eq); 2.81 (dm, JH-H = 11.4 Hz, 1H, H-6eq); 3.28 (tm,
2
Compound 7e: (3R,5S)-1-(4-nitrobenzyl)-3-chloro-3-fluoro-5-
methylpiperidine: 1H NMR (300 MHz, CDCl3, ppm) δ 0.91 (d,
3JH-H = 6.7 Hz, 3H, CH3); 1.60 (ddd, 3JH-Fax = 26.3 Hz, 2JH-H
3JH-Fax and 2JH-H = 10.5 Hz, 1H, H-2eq). 13C NMR (75 MHz,
CDCl3, ppm) δ 18.4 (CH3); 29.8 (CH, C-5); 45.3 (N-CH3); 46.5
2
(d, JC-F = 22.7 Hz, CH2, C-4); 61.8 (CH2, C-6); 65.3 (d,
3
2
3
or JH-H = 13.8 Hz and JH-H or JH-H = 12.5 Hz, 1H, H-
4ax); 1.85 (t, 2JH-H and 3JH-H = 11.2 Hz, 1H, H-6ax); 2.12 (m,
1H, H-5); 2.49 (dd, 3JH-Fax = 30.0 Hz, 2JH-H = 12.4 Hz, 1H, H-
2ax); 2.51 (m, 1H, H-4eq); 2.80 (dm, 2JH-H = 11.3 Hz, 1H, H-
2JC-F = 21.1 Hz, CH2, C-2); 110.0 (d, 1JC-F = 247.1 Hz, C-3).
19F{1H} NMR (282 MHz, CDCl3, external standard C6F6 (δF
-162.90 ppm), ppm) -108.80. MS and HRMS analyses were
not performed on this compound due to its high volatility.
Compound 6g: (5S)-3,3-difluoro-1-isopropyl-5-methylpiperi-
dine: The optimized procedure (0 °C, 3 min reaction time) was
followed, starting from 120 mg of 5g. Purification by column
chromatography (petroleum ether/ethyl acetate 95/5) afforded
40 mg of the title compound (33%). 1H NMR (300 MHz,
2
3
6eq); 3.28 (ddm, JH-H = 12.4 Hz, JH-Fax = 8.7 Hz, 1H, H-
2eq); 3.66 (d, JH-H = 14.2 Hz, 1H, H-7); 3.72 (d, JH-H =
3
3
3
14.3 Hz, 1H, H-7); 7.52 (d, JH-H = 8.8 Hz, 2H, H-20); 8.10
3
(d, JH-H = 8.7 Hz, 2H, H-30). 13C NMR (75 MHz, CDCl3,
ppm) δ 18.7 (CH3); 28.9 (CH, C-5); 47.3 (d, 2JC-F = 22.7 Hz,
=
CH2, C-4); 59.7 (CH2, C-6); 60.9 (CH2, C-7); 63.4 (d, 2JC-F
CDCl3, ppm) δ 0.93 (d, JH-H =6.4 Hz, 3H, H-9); 1.01 (d,
3
1
21.5 Hz, CH2, C-2); 110.4 (d, JC-F = 248.0 Hz, C-3); 124.0
(CH, C-20); 129.5 (CH, C-30); 146.0 (C-10); 147.6 (C-40). 19F{1H}
NMR (282 MHz, CDCl3, external standard C6F6 (δF -162.90
ppm), ppm) -109.06.MS (EI, 70 eV) m/z (rel intensity, %) 289
(37), 287 (100). HRMS (ESI) calcd for C13H16N2O2F35Cl
286.08843, found 286.0877. Mp 71 °C.
3JH-H = 6.6 Hz, 3H, H-8 or H-80); 1.03 (d, 3JH-H = 6.7 Hz, 3H,
=
H-8 or H-80); 1.28 (dtd, 3JH-Fax = 31.4 Hz, 3JH-H and 2JH-H
12.8 Hz, JH-Feq = 5.9 Hz, 1H, H-4ax); 1.81 (td, JH-H and
3
2
3JH-H = 10.7 Hz, 4JH-H = 1.3 Hz, 1H, H-6ax); 1.91 (m, 1H, H-
5); 2.11 (m, 1H, H-4eq); 2.28 (ddd, 3JH-Fax = 27.8 Hz, 2JH-H
=
11.6 Hz, 3JH-Feq = 2.9 Hz, 1H, H-2ax); 2.76 (d, 2JH-H = 10.0
Hz, 1H, H-6eq); 2.81 (m, 1H, H-7); 2.99 (m, 1H, H-2eq). 13C
NMR (75 MHz, CDCl3, ppm) δ 17.3 (CH3, C-9); 18.4 (CH3, C-8
or C-80); 18.7 (CH3, C-8 or C-80); 28.6 (d, 3JC-F = 9.6 Hz, CH,
C-5); 40.7 (dd, 2JC-F = 24.6 Hz, 2JC-F = 20.1 Hz, CH2, C-4);
Compound 6f: (5S)-3,3-difluoro-1,5-dimethylpiperidine: The
optimized procedure (0 °C, 3 min reaction time) was followed,
starting from 220 mg of 5f. Purification by column chromatog-
raphy (dichloromethane) afforded 57 mg of the title compound
(25%). 1H NMR (300 MHz, CDCl3, ppm) δ 0.95 (d, 3JH-H
=
53.5 (dd, JC-F = 24.6 Hz, JC-F = 20.1 Hz, CH2, C-2);
53.9 (CH, C-7); 56.0 (CH2, C-6); 121.1 (dd, 1JC-F = 243.4 Hz,
1JC-F = 238.6 Hz, C-3). 19F{1H} NMR (282 MHz, CDCl3,
external standard C6F6 (δF -162.90 ppm), ppm) -97.60 (d,
2JF-F = 238.1 Hz, Feq); -101.25 (d, 2JF-F = 238.1 Hz, Fax).
MS (EI, 70 eV) m/z (rel intensity, %) 162 (2) M-CH3; 128 (4); 99
(8); 28 (100). HRMS (ESI) calcd for C8H14NF2 162.10943,
found 162.1105.
Compounds 7g and 7g0. The optimized procedure (-50 °C, 3
min reaction time) was followed, starting from 175 mg of 5g.
Purification by column chromatography (petroleum ether/ethyl
acetate 99/1) afforded 15 mg of compound 7g0 (8%).
Compound 7g0: (3S,5S)-3-chloro-3-fluoro-1-isopropyl-5-
methylpiperidine: 1H NMR (300 MHz, CDCl3, ppm) δ 0.94 (d,
3JH-H = 6.5 Hz, 3H, CH3); 0.99 (d, 3JH-H = 6.5 Hz, 3H, H-8 or
H-80); 1.06 (d, 3JH-H = 6.6 Hz, 3H, H-8 or H-80); 1.52 (ddd, J =
13.0 Hz, J = 11.4 Hz, J = 9.9 Hz, 1H, H-4ax); 1.90 (t, 3JH-H
2
2
3
3
6.6 Hz, 3H, CH3); 1.28 (dtd, JH-Fax = 32.8 Hz, JH-H and
2JH-H = 12.9 Hz, 3JH-Feq = 6.2 Hz, 1H, H-4ax); 1.63 (t, 2JH-H
and 3JH-H = 11.0 Hz, 1H, H-6ax); 1.99 (m, 1H, H-5); 2.01 (m,
3
2
1H, H-4eq); 2.12 (ddd, JH-Fax = 27.8 Hz, JH-H = 11.8 Hz,
3JH-Feq = 3.1 Hz, 1H, H-2ax); 2.32 (s, 3H, N-CH3); 2.79 (dm,
=
2JH-H = 11.0 Hz, 1H, H-6eq); 3.01 (tm, 2JH-H and 3JH-Fax
11.4 Hz, 1H, H-2eq). 13C NMR (75 MHz, CDCl3, ppm) δ 18.9
3
2
(CH3); 28.7 (d, JC-F = 9.5 Hz, CH, C-5); 40.2 (dd, JC-F
=
24.6 Hz, 2JC-F = 20.1 Hz, CH2, C-4); 45.9 (N-CH3); 60.5 (dd,
2JC-F = 30.3 Hz, 2JC-F = 24.5 Hz, CH2, C-2); 62.5 (CH2, C-6);
120.9 (dd, 1JC-F = 242.9 Hz, 1JC-F = 239.3 Hz, C-3). 19F{1H}
NMR (282 MHz, CDCl3, external standard C6F6 (δF -162.90
2
ppm), ppm) -104.41 (d, JF-F = 242.0 Hz, Fax); -98.65 (d,
2JF-F = 242.1 Hz, Feq). MS and HRMS analyses were not
performed on this compound due to its high volatility.
Compounds 7f and 7f0. The optimized procedure (-50 °C,
3 min reaction time) was followed, starting from 200 mg of 5f.
Purification by column chromatography (dichloromethane)
afforded 13 mg of compound 7f0 (6%).
2
and JH-H = 10.6 Hz, 1H, H-6ax); 2.02 (m, 1H, H-5); 2.35
(dm, 2JH-H = 13.1 Hz, 1H, H-4eq); 2.43 (dd, 2JH-H = 11.5 Hz,
3JH-Feq = 5.2 Hz, 1H, H-2ax); 2.76 (dm, 2JH-H = 10.8 Hz, 1H,
H-6eq); 2.89 (m, 1H, H-7); 3.14 (dm, 2JH-H = 11.5 Hz, 1H, H-
2eq). 13C NMR (75 MHz, CDCl3, ppm) δ 17.1 (CH3, C-8 or
C-80); 18.8 (CH3, C-9); 19.5 (CH3, C-8 or C-80); 29.5 (d,
Compound 7f0: (3S,5S)-3-chloro-3-fluoro-1,5-dimethylpiperi-
1
3
dine: H NMR (300 MHz, CDCl3, ppm) δ 0.96 (d, JH-H
=
6.7 Hz, 3H, CH3); 1.50 (ddd, 2JH-H = 13.0 Hz, 3JH-H = 11.9 Hz,
J. Org. Chem. Vol. 74, No. 16, 2009 6033

Vardelle et al.
JOCArticle
3JC-F = 8.3 Hz, CH, C-5); 47.4 (d, 2JC-F = 17.9 Hz, CH2, C-4);
145.1 (C-10); 147.4 (C-40). 19F {1H} NMR (282 MHz, CDCl3,
external standard C6F6 (δF -162.90 ppm), ppm) -139.45. MS
(EI, 70 eV) m/z (rel intensity, %) 286 (13); 284 (25); 165 (22); 135
(33); 121 (42); 119 (100). HRMS (ESI)calcd for C13H14N2-
O2F35Cl 284.07278, found 284.0732.
Then, petroleum ether/ethyl acetate 90/10 afforded 57 mg of
compound 6h (28%).
Compound 6h: (3S,5S)-1-(4-nitrobenzyl)-3-chloro-3,5-di-
54.3 (CH, C-7); 57.2 (CH2, C-6); 58.7 (d, 2JC-F = 27.8 Hz, CH2,
C-2); 113.2 (d, JC-F = 241.1 Hz, C-3). 19F{1H} NMR (282
1
MHz, CDCl3, external standard C6F6 (δF -162.90 ppm), ppm)
-98.79. MS (EI, 70 eV) m/z (rel intensity, %) 180 (39); 178 (100);
158 (21); 69 (23). HRMS (ESI) calcd for C8H14NF35Cl
178.07988, found 178.0808.
Then, petroleum ether/ethyl acetate 98/2 afforded 57 mg of
compound 7g (29%).
1
fluoro-5-methylpiperidine: H NMR (300 MHz, CDCl3, ppm)
Compound
7g:
(3R,5S)-3-chloro-3-fluoro-1-isopropyl-5-
δ 1.35 (d, 3JH-Fax = 20.7 Hz, 3H, H-8); 2.10 (ddd, 3JH-Fax = 34.8
Hz, 3JH-Fax = 33.4 Hz, 2JH-H = 16.7 Hz, 1H, H-4ax); 2.37 (dd,
methylpiperidine: 1H NMR (300 MHz, CDCl3, ppm) δ 0.91 (d,
3JH-H = 6.6 Hz, 3H, CH3); 1.02 (d, 3JH-H = 6.6 Hz, 3H, H-8 or
3JH-Fax = 31.9 Hz, JH-H = 13.1 Hz, 1H, H-6ax); 2.72 (dd,
2
3
2
H-80); 1.05 (d, JH-H = 6.7 Hz, 3H, H-8 or H-80); 1.53 (ddd,
3JH-Fax = 28.9 Hz, JH-H = 13.0 Hz, 1H, H-2ax); 2.83 (qm,
3JH-Fax = 36.4 Hz, JH-H or JH-H = 13.7 Hz, JH-H or
2JH-H = 13.2 Hz, 3JH-Fax = 13.2 Hz and 3JH-Fax = 13.2 Hz, 1H,
H-4eq); 2.97 (bt, 2JH-H = 11.5 Hz, 3JH-Fax = 11.5 Hz, 1H, H-
6eq); 3.34 (bt, 2JH-H = 11.1 Hz, 3JH-Fax = 11.1 Hz, 1H, H-2eq);
3
2
3
2JH-H = 12.5 Hz, 1H, H-4ax); 1.83 (td, JH-H and JH-H
=
2
3
11.0 Hz, 4JH-H = 1.8 Hz, 1H, H-6ax); 2.01 (m, 1H, H-5); 2.48
(m, 1H, H-4eq); 2.51 (dd, 3JH-Fax = 29.4 Hz, 2JH-H = 12.2 Hz,
1H, H-2ax); 2.80 (m, 1H, H-6eq); 2.83 (m, 1H, H-7); 3.30 (m, 1H,
H-2eq). 13C NMR (75 MHz, CDCl3, ppm) δ 17.5 (CH3, C-9);
18.4 (CH3, C-8 or C-80); 18.6 (CH3, C-8 or C-80); 29.4 (CH, C-5);
47.7 (d, 2JC-F = 23.1 Hz, CH2, C-4); 54.0 (CH, C-7); 55.7 (CH2,
3
3.87 (s, 2H, H-7); 7.55 (d, JH-H = 8.5 Hz, H-20); 8.18 (d,
3JH-H = 8.6 Hz, 2H, H-30). 13C NMR (75 MHz, CDCl3, ppm) δ
25.0 (d, 2JC-F = 28.8 Hz, CH3, C-8); 48.0 (t, 2JC-F = 22.3 Hz,
CH2, C-4); 59.6 (d, 2JC-F = 21.0 Hz, CH2, C-6); 59.7 (CH2, C-
2
1
7); 62.1 (d, JC-F = 22.1 Hz, CH2, C-2); 91.8 (d, JC-F
=
2
1
C-6); 59.1 (d, JC-F = 20.9 Hz, CH2, C-2); 111.0 (d, JC-F
=
177.6 Hz, C-5); 108.6 (d, 1JC-F = 252.0 Hz, C-3); 123.6 (CH, C-
30); 129.2 (CH C-20); 145.2 (C-10); 147.3 (C-40). 19F {1H} NMR
(282 MHz, CDCl3, external standard C6F6 (δF -162.90 ppm),
ppm) -105.53 (F-CCl); -148.82 (F-CCH3). HRMS (ESI) calcd
for C13H15N2O2F235Cl 304.07901, found 304.0777. Mp 123 °C.
Then, petroleum ether/ethyl acetate 80/20 afforded 7 mg of
compound 7h (4%).
248.1 Hz, C-3). 19F{1H} NMR (282 MHz, CDCl3, external
standard C6F6 (δF -162.90 ppm), ppm) -108.60. MS (EI, 70
eV) m/z (rel intensity, %) 180 (39); 178 (100); 158 (21); 69 (23).
HRMS (ESI) calcd for C8H14NF35Cl 178.07988, found
178.0808.
Compounds 6h, 6h0, 7h, 7h0, and 8h. The optimized procedure
(-50 °C, 3 min reaction time) was followed, starting from 200
mg of 5h. Purification by column chromatography (petroleum
ether/ethyl acetate 98/2) afforded 41 mg of compound 6h0
(19%).
Compound 7h: (3R)-1-(4-nitrobenzyl)-5-chloro-1,2,3,6-tetra-
hydro-3-methylpyridin-3-ol: 1H NMR (300 MHz, CDCl3, ppm)
δ 1.24 (s, 3H, H-8); 2.31 (d, 2JH-H = 11.3 Hz, 1H, H-2ax); 2.61
(br s, 1H, OH); 2.69 (d, 2JH-H = 11.3 Hz, 1H, H-2eq); 2.92 (d,
2JH-H = 16.1 Hz, 1H, H-6ax); 3.24 (d, 2JH-H = 16.0 Hz, 1H, H-
6eq); 3.74 (s, 2H, H-7); 5.86 (s, 1H, H-4); 7.52 (d, 3JH-H = 8.4
Hz, 2H, H-20); 8.20 (d, 3JH-H = 8.4 Hz, 2H, H-30). 13C NMR (75
MHz, CDCl3, ppm) δ 24.7 (CH3, C-8); 57.6 (CH2, C-6); 60.7
(CH2, C-7); 62.3 (CH2, C-2); 68.6 (C-3); 123.8 (CH, C-30); 129.5
(CH, C-20); 130.0 (CH, C-4); 131.5 (C-5); 144.9 (C-10); 147.4 (C-
40). MS (EI, 70 eV) m/z (rel intensity, %) 282 (2); 161 (100); 133
(19); 118 (20); 116 (49); 103 (17); 101 (43). HRMS (ESI) calcd for
C13H15N2O335Cl 282.07712, found 282.0746.
Compound 6h0: (3S,5S)-1-(4-nitrobenzyl)-3,5-dichloro-3-
1
fluoro-5-methylpiperidine: H NMR (300 MHz, CDCl3, ppm)
δ 1.63 (s, 3H, H-8); 2.32 (dd, 3JH-Fax = 25.3 Hz, 2JH-H = 15.2
Hz, 1H, H-4ax); 2.46 (d, 2JH-H = 12.6 Hz, 1H, H-6ax); 2.78 (dd,
3JH-Fax = 28.5 Hz, JH-H = 13.8 Hz, 1H, H-2ax); 2.83 (t,
2
2JH-H = 12.5 Hz, JH-Fax = 12.5 Hz, 1H, H-4eq); 2.90 (d,
3
2JH-H = 12.2 Hz, 1H, H-6eq); 3.24 (t, JH-H = 11.0 Hz,
2
3JH-Fax=10.8 Hz, 1H, H-2eq); 3.76 (d, 2JH-H = 14.7 Hz, 1H,
H-7); 3.86 (d, JH-H = 14.6 Hz, 1H, H-7); 7.60 (d, JH-H =
2
3
8.6 Hz, 2H, H-20); 8.19 (d, 3JH-H = 8.7 Hz, 2H, H-30). 13C NMR
Then, petroleum ether/ethyl acetate 50/50 afforded 8 mg of
compound 8h (5%).
2
(75 MHz, CDCl3, ppm) δ 30.9 (CH3, C-8); 51.9 (d, JC-F
=
21.4 Hz, CH2, C-4); 59.9 (CH2, C-7); 63.2 (d, 2JC-F=23.6 Hz,
CH2, C-2); 64.2 (C-5); 64.5 (CH2, C-6); 108.2 (d, 1JC-F=251.7
Hz, C-3); 123.7 (CH, C-30); 129.1 (CH, C-20); 145.0 (C-10); 147.4
(C-40). 19F{1H} NMR (282 MHz, CDCl3, external standard
C6F6 (δF -162.90 ppm), ppm) -103,33. MS (ESI, 70 eV) m/z
(rel intensity, %) 343(14); 321 (52); 285 (100); 265 (19). HRMS
(ESI) calcd for C13H16N2O2F35Cl2 321.05729, found 321.0570.
Mp 125 °C.
Compound 8h: 1-(4-nitrobenzyl)-1,2-dihydro-5-methylpyridin-
3(6H)-one (20%): 1H NMR (300 MHz, CDCl3, ppm) δ 1.95 (s,
3H, H-8); 3.11 (s, 2H, H-2); 3.17 (s, 2H, H-6); 3.74 (s, 2H, H-7);
5.97 (q, 4JH-H = 1.4 Hz, 1H, H-4); 7.51 (d, 3JH-H = 8.8 Hz, 2H,
H-20); 8.18 (d, 3JH-H = 8.8 Hz, 2H, H-30). 13C NMR (75 MHz,
CDCl3, ppm) δ 21.7 (CH3, C-8); 56.3 (CH2, C-6); 60.2 (CH2, C-
2); 60.6 (CH2, C-7); 123.6 (CH, C-30); 125.0 (CH, C-4); 129.5
(CH, C-20); 144.6 (C-10); 147.4 (C-40); 160.2 (C-3); 195.1 (C-5).
MS (EI, 70 eV) m/z (rel intensity, %) 246 (10); 136 (11); 111 (19);
83 (89). HRMS (ESI) calcd for C13H14N2O3 246.10044, found
246.0983.
Then, petroleum ether/ethyl acetate 95/5 afforded 13 mg of
compound 7h0 (7%).
Compound 7h0: (3R)-1-(4-nitrobenzyl)-5-chloro-3-fluoro-
1,2,3,6-tetrahydro-3-methylpyridine. 1H NMR (300 MHz,
CDCl3, ppm): δ 1.42 (d, 3JH-F = 20.5 Hz, 3H, H-8); 2.48 (dd,
3JH-F = 23.3 Hz, 2JH-H = 12.5 Hz, 1H, H-2); 2.91 (t, 2JH-H
=
Acknowledgment. We thank the MENRT (grant to E.V.),
the CNRS, and the University of Poitiers for financial
support and Dr. T. Claridge for useful remarks concerning
NMR data.
12.5 Hz and 3JH-F = 12.5 Hz, H-2); 3.10 (dd, 2JH-H = 16.3 Hz,
=
4JH-H = 9.7 Hz, 1H, H-6); 3.26 (dd, 2JH-H = 16.3 Hz, 4JH-H
7.2 Hz, 1H, H-6): 3.75 (d, 2JH-H = 14.4 Hz, 1H, H-7); 3.83 (d,
2JH-H = 14.3 Hz, 1H, H-7); 5.93 (bs, 1H, H-4); 7.53 (d,
3
3JH-H = 8.4 Hz, 2H, H-2’); 8.18 (d, JH-H = 8.6 Hz, 2H, H-
30). 13C NMR (75 MHz, CDCl3, ppm): δ 24.9 (d, 2JC-F = 27.7
Hz, CH3, C-8); 57.0 (d, JC-F = 2.6 Hz, CH2, C-6); 58.9 (d,
=
Supporting Information Available: Experimental details,
spectral data, and copies of 1H and 13C NMR spectra for all new
compounds and X-ray structure and crystal data for compounds
2b, 6e, 7e, 6h and 6h0. This material is available free of charge via
the Internet at http://pubs.acs.org.
4
2JC-F = 23.9 Hz, CH2, C-2); 59.8 (CH2, C-7); 90.5 (d, 1JC-F
2
169.7 Hz, C-3); 123.7 (CH, C-30); 125.4 (d, JC-F = 22.0 Hz,
CH, C-4); 129.2 (CH, C-2’); 135.5 (d, JC-F = 12.6 Hz, C-5);
3
6034 J. Org. Chem. Vol. 74, No. 16, 2009