A simple stereoselective route to α-trifluoromethyl analogues of piperidine alkaloids

Article abstract of DOI:10.1002/ejoc.200600157

The highly diastereoselective synthesis of five trifluoro-substituted analogues of mono-, di-, and trisubstituted piperidine alkaloids was accomplished in two to four steps from 2-trifluoromethyl keto-protected 4-piperidones, prepared by an intramolecular

Full text of DOI:10.1002/ejoc.200600157

FULL PAPER
DOI: 10.1002/ejoc.200600157
A Simple Stereoselective Route to α-Trifluoromethyl Analogues of Piperidine
Alkaloids
Annabelle Bariau,[a] Wahid Bux Jatoi,[a] Pierre Calinaud,[a] Yves Troin,*[a] and
Jean-Louis Canet*[a]
Keywords: Fluorine / Piperidine alkaloids / Intramolecular Mannich reaction / Diastereoselectivity
The highly diastereoselective synthesis of five trifluoro-sub-
stituted analogues of mono-, di-, and trisubstituted piperi-
dine alkaloids was accomplished in two to four steps from 2-
trifluoromethyl keto-protected 4-piperidones, prepared by an
intramolecular Mannich-type reaction methodology. A sim-
ple stereoselective elaboration of new 2-(trifluoromethyl)-4-
piperidinols and 4-amino-2-(trifluoromethyl)piperidines is
also described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Part of our research activity is devoted to the asymmetric
synthesis of saturated N-heterocycles. In this context, we
have studied a simple and efficient Mannich-type cycliza-
tion permitting rapid and highly stereoselective access to
polysubstituted piperidine systems,[11] which we were able
to validate through the enantioselective synthesis of various
alkaloids.[12,13] In order to extend the field of applications
of this approach to more challenging synthetic questions,
we decided to evaluate its potential in the field of organo-
fluorine chemistry. Effectively, we reasoned that intra-
molecular Mannich reactions of 1,3-aminoketals, offering
a double opportunity for the selective incorporation of a
trifluoromethyl group as summarized in Scheme 1, seemed
particularly suitable for the elaboration of piperidines tri-
fluoromethylated in the key α position.
Accordingly, we have recently been able to demon-
strate[14] that α-trifluoromethylated piperidines 1 are access-
ible, diastereoselectively, either from aminoketals 2, through
the use of a stable fluoral equivalent as fluorine source
(route A), or from a preformed α-(trifluoromethyl)amine 3
(route B). If the first pathway, presumably involving the
N,O-hemiacetal 4 and then the (trifluoromethyl)iminium
ion 5 as intermediates,[15] may appear quite limited, since it
requires the systematic preparation of amines 2, the alterna-
tive route B has a more general character, potentially per-
mitting the preparation of a range of targets 1 from the
single precursor 3. These promising preliminary results
prompted us to consider direct applications of this strategy,
and we naturally focused our attention on piperidine-based
natural products. The synthesis of fluorinated analogues of
representative mono-, di- and trisubstituted piperidine alka-
loids was thus entered into.
Endowed with diverse and notable bioactivities, piperi-
dine alkaloids, together with their nonnatural analogues,
are the objects of continuous and intensive synthetic ef-
forts.[1] From a different viewpoint, it is generally acknowl-
edged that incorporation of one or more fluorine atom(s)
into an active molecule may profoundly modify its physico-
chemical and biological properties.[2] Indeed, because of the
unique specificities of the fluorine atom, substitution of an
hydrogen by a fluorine or introduction of a trifluoromethyl
group in place of a methyl may significantly improve the
pharmacodynamic and pharmacokinetic profiles of a drug
through simultaneous alteration of its electronic, lipophilic,
and steric characteristics, as well as its metabolic sta-
bility.[2,3] As a consequence, selectively (poly)fluorinated an-
alogues of biologically active compounds are regarded as
tools of relevant interest for pharmaceutical research,[3,4] in
part explaining the considerable progress of fluoroorganic
chemistry.[5] If some domains of organofluorine chemistry
are well documented, however, others still need to be devel-
oped. This applies, for instance, to the selective preparation
of α-trifluoromethyl-substituted saturated N-heterocycles,
including piperidines, an area weakly explored to date.[6–10]
Actually, and even though trifluoromethylated analogues of
aliphatic N-heterocyclic alkaloids constitute attractive tar-
gets for reasons evoked above,[9] stereoselective elaboration
of this kind of compound has rarely been described.
[a] Laboratoire de Chimie des Hétérocycles et des Glucides, EA
987, Ecole Nationale Supérieure de Chimie de Clermont-Fer-
rand, Université Blaise Pascal,
63174 Aubière cedex, France
E-mail: canet@chimie.univ-bpclermont.fr
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Scheme 1. Diastereoselective synthesis of α-(trifluoromethyl)piperidines through intramolecular Mannich-type reactions.
acetaldehyde under our standard acidic cyclization condi-
Results and Discussion
tions[11] thus cleanly afforded the expected (trifluoro-
As far as we know, the simplest monosubstituted piperi-
dine alkaloid, pipecoline (6), is also the only one for which
methyl)piperidine 9 in 71% yield (Scheme 2).
Piperidine 9 was then treated with an excess of ethanedi-
thiol in the presence of excess boron trifluoride etherate in
the preparation of a trifluoro analogue 7 has been re-
ported.[16]
dichloromethane at room temperature to give the dithioke-
tal derivative 10 (88% yield). Finally, hydrogenolysis of 10
(W2 Raney nickel[19]) in ethanol at reflux furnished the vol-
atile trifluoropipecoline 7, which was isolated (90%) as its
hydrochloride salt, presenting physical and spectroscopic
data consistent with those already reported.[10b] As the in-
volved intramolecular Mannich-type process affords hetero-
cycles possessing masked keto functions, it provides the op-
portunity to apply further selective transformations of
these. We then decided to regenerate the carbonyl group in
order to examine its stereoreactivity under some reductive
and amino-reductive conditions (Scheme 3).
The first synthesis of 7 (free base) was achieved by
Raasch,[17] through conversion of the pipecolic acid car-
boxyl group into a trifluoromethyl group by treatment with
sulfur tetrafluoride in hydrogen fluoride. Recently, Billard,
Langlois et al.[10b] prepared the same compound (HCl salt)
through an efficient ring-closure metathesis as the key het-
erocycle formation step. In our case, we thought that tri-
As attempts to deprotect the keto function in free amine
fluoropipecoline 7 should be easily accessible by route A 9 directly under standard acidic conditions did not gave sat-
(Scheme 1) and therefore decided to embark upon its syn- isfactory results, this compound was at first transformed
thesis. Treatment of the aminoketal 8[18] with trifluoro- into the parent benzyl carbamate derivative 11. Regenera-
Scheme 2.
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Scheme 3. a) de determined from GC/MS analysis of the crude reaction mixture; yield refers to the pure isolated diastereomer.
tion of the carbonyl group of 11 was then quantitatively borohydride in methanol at –10 °C, which gave the axial 4-
achieved after a three-day exposure period to 50% aqueous piperidinol 13 almost exclusively (88% yield, de = 96%[21]).
trifluoroacetic acid in dichloromethane at room tempera- The relative cis configuration of 13 was unambiguously
ture. We also noticed that the same transformation could be confirmed after catalytic hydrogenolysis into 14, the 1H
accomplished (80% yield) within a few minutes by Markò’s NMR spectroscopic data for which clearly indicated a 2,4-
procedure,[20] with ceric ammonium nitrate at 70 °C in diequatorial disubstitution pattern in a chair conformation.
water/acetonitrile.
Similarly, treatment of piperidone 12 with p-methoxyani-
To anticipate the stereochemical behavior of the N-pro- line at room temperature in dichloromethane in the pres-
tected-4-piperidone 12 under reductive conditions, it has to ence of sodium acetoxyborohydride and acetic acid[22] gave
be considered that its conformational equilibrium, unlike the desired cis-4-aza-2-(trifluoromethyl)piperidine 15 in
that of the free cyclic amine, should be displaced in favor 85% yield and with an interesting 94:6 diastereomeric ra-
of a pseudoaxial position of the trifluoromethyl group in tio.[21] Such discrimination confirmed the involvement of
order to minimize A(1,3) strain[1a] (Scheme 4). Accordingly, imine conformer 19 as the probable intermediate
a predominantly equatorial hydride attack was expected. (Scheme 4). The cis relationship of the heterocycle substitu-
This could be verified by treatment of 12 with sodium ents in 15 was clearly established through 1H NMR analysis
Scheme 4.
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of diamine 16, easily obtained by selective removal of the oxolanes,[26] and this may constitute a nonnegligible advan-
piperidine N-protective group. Employment of other tage for the further transformations. Finally, hydrazinolysis
amines (4-chloroaniline, benzylamine) for the reductive am- of the phthalimide moiety furnished the trifluoro-substi-
ination of 12 permitted the corresponding 4-aminopiperi- tuted 1,3-aminoketals 3 in 65–85% overall yield from 24
dines 17 and 18 to be isolated with comparable stereoselec- (Scheme 5).
tivities (Scheme 3). In the process, we were able to demon-
Amine 3b was next engaged in the key cyclization step,
strate that the readily available piperidone 12 constitutes a at first with n-butanal. While piperidine 27 could be isolated
valuable source of new functionalized α-trifluoromethylated from a complex reaction mixture, it has to be noted that
piperidine scaffolds, compounds of interest for pharma- disappointing results in terms of efficiency (32% isolated
ceutical research.[1a] It is noteworthy that a generalizable yield) and selectivity (de = 50%) were obtained, due to par-
stereoselective reductive amination of 12 should give access tial butanal aldol condensation prior to ring formation.
to a broad library of original 2-(trifluoromethyl)-4-azapip- Consequently, non-enolizable aldehydes were considered,
eridines and this question is currently under investigation and treatment of amines 3 with crotonaldehyde, trans,trans-
in our laboratory.
2,4-decadienal, and even with benzaldehyde and 4-fluoro-
Next was the evaluation of our intramolecular Mannich benzaldehyde under our standard reaction conditions[11]
reaction strategy towards the elaboration of α-trifluoro- yielded (66–78%) the corresponding cis-2,6-disubstituted
methyl analogues of polysubstituted piperidine alkaloids. piperidines 28–31 (Scheme 5). Consistently with results pre-
Route B, (Scheme 1), permitting the substitution of the 6- viously observed for a parent nonfluorinated series,[11c] the
position of the heterocycle, seemed particularly appropriate expected cis 2,6-diastereomer was formed highly predomi-
for this purpose and so was investigated. Compounds 20– nantly (de up to 95%, GC/MS of the crude product). The
22 – trifluoro analogues of the representative di- and trisub- relative configurations of 28–31 were unambiguously de-
1
stituted piperidine alkaloids dihydropinidine, isosolenopsin, duced from their H NMR spectroscopic data, particularly
and alkaloid 241D – were selected as targets, as was 23, an from the signals corresponding to axial H-3 and axial H-
analogue of the less well known[23] naturally occurring 5, which exhibited typical J values for a 2,6-diequatorial
cis,cis-2-methyl-6-propylpiperidin-4-ol.
disubstitution arrangement in a chair conformation.
The synthesis of trifluorodihydropinidine 20 (which may
also be regarded as the αЈ-trifluoromethylated analogue of
the well known alkaloid coniine) and trifluoroisosolenopsin
21 could then be easily achieved in two or three steps from
28 and 29, respectively, by simple deoxygenation and hydro-
genation methods as summarized in Scheme 6. Both prod-
ucts were isolated and characterized as their hydrochloride
salts.
Although not necessary, the reduction of crude 29 into
33 was performed here, if only in order to confirm the de-
gree of diastereoselection (90% de) of its formation. Effec-
tively, the commercial trans,trans-2,4-decadienal used for
the elaboration of 29 revealed (GC/MS) contamination with
isomers (a few %), perturbing any accurate valuation of its
diastereomeric excess, a problem that could be solved after
saturation of the nonadienyl side chain.
We next turned our attention to the preparation of the
trifluoro analogues of the cis,cis-2,4,6-trisubstituted piperi-
dine alkaloids alkaloid 241D (22) and 23. Once again (vide
supra), direct attempts to regenerate the keto function of
the free piperidine 28 under acidic conditions (HCl, TFA)
The N-hetero-Michael acceptor[24] 5,5,5-trifluoropent-3- failed to give the corresponding 4-piperidone in a reason-
en-2-one (24),[25] conveniently obtained as described by able time, necessitating the protection of the amino func-
Dmowski et al.,[25b] was considered a suitable precursor for tion. Surprisingly, it remained impossible to protect it either
the preparation of the α-(trifluoromethyl)amine 3, the key as a benzyl or as a tert-butyl carbamate by classical pro-
synthon of route B (Scheme 5). The enone 24 was treated cedures. We thus decided to protect piperidine 28 as an
with phthalimide in ethyl acetate at reflux, in the presence amide, even though those functional groups are reputed to
of Triton B, to afford the phthalimido derivative 25, which be resistant to hydrolysis, and selected the trifluoroacetam-
was transformed into the parent ketals 26 with ethylene ide, one of the more easily cleaved amides.[27] Treatment of
glycol or propane-1,3-diol under Dean–Stark conditions. 28 with trifluoroacetic anhydride at 0 °C in dichlorometh-
Protection of the keto function of 25 as a 1,3-dioxane 26b, ane, in the presence of triethylamine and N,N-dimethylami-
as well as the 1,3-dioxolane 26a, is justified by the fact that nopyridine gave trifluorocetamide 35 in 93% yield
dioxanes are much more easily cleaved than the parent di- (Scheme 7).
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Scheme 5. (a) de determined from GC/MS analysis of the crude reaction mixture; yield refers to the pure isolated diastereomer.
Scheme 6.
Keto-deprotection of 35 was then cleanly and rapidly cleave some trifluoroacetamides,[27] making these transfor-
carried out by treatment with ceric ammonium nitrate[19] at mations simultaneously possible. Meanwhile, as an all-cis
70 °C in acetonitrile/water to give the 4-piperidone 36 (75% stereochemistry is required for the target, the inevitable
yield). The last problems to solve were the stereoselective question of the effect of the reaction sequence (reduction/
reduction of the keto function of 36, together with the N- deprotection v/s deprotection/reduction) on the reduction
deprotection. Interestingly, whilst sodium borohydride may stereoselectivity arose. As shown in Scheme 7, and for
be used for the keto reduction, this reagent is also prone to reasons identical to those seen above, we thought that the
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A. Bariau, W. B. Jatoi, P. Calinaud, Y. Troin, J.-L. Canet
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Scheme 7. [a] de determined from GC/MS analysis of the crude reaction mixture; yield refers to the pure isolated diastereomer.
conformational equilibrium of 36 should be strongly dis-
placed in favor of 2,6-diaxal disubstitution. If deprotection
Conclusions
From the results detailed here we assume that intramo-
lecular Mannich reactions of 1,3-aminoketals, and notably
those involving α-(trifluoromethyl)amines 3, constitute a
were to occur first, the diequatorial conformer 38, liberated
from A(1,3) strain, would be expected as the stable interme-
diate. In this case, and as already observed with similar non-
fluorinated systems,[12b,22] an axial hydride attack should
predominate, mostly giving the cis,cis-piperidinol 37. The
inversion of the sequence should entail an equatorial hy-
dride attack on ketone 36, due to significant steric hin-
drance, but still leading after deprotection of the intermedi-
ate 39 to the same all-cis reaction product 37. We thus rea-
soned that, whatever the pathway involved, there was no
concern since they are stereoconvergent and should both
selectively give the desired epimer. This proved to be justi-
fied, since treatment of piperidone 36 with an excess of so-
dium borohydride in methanol at –30 °C gave the predicted
cis,cis-2,4,6-trisubstituted piperidine 37 as almost the sole
epimer (de = 96%, GC/MS of the crude product), and this
was easily hydrogenated to afford the trifluoro analogue of
the trisubstituted piperidine alkaloid 23. Finally, the same
synthetic scheme was applied to piperidine 29 to afford, in
four steps (40% overall yield) and in a highly stereoselective
manner, the 4-piperidinol 22, the trifluoro analogue of alka-
loid 241D (Scheme 7).
valuable stereoselective source of a broad range of new α-
(trifluoromethyl)piperidines, compounds of undeniable bio-
logical interest. The validity of this method was illustrated
through the simple and highly diastereoselective synthesis
of five trifluoro analogues of mono-, di-, and trisubstituted
piperidine alkaloids. The crucial question of the extension
of this strategy to the field of enantioselective synthesis is
of course in our minds. For this purpose, several concise
routes to homochiral amines 3 are currently being devel-
oped in our laboratory and will be reported in due course.
Experimental Section
General Remarks: Solvents were distilled prior to use. Other rea-
gents were used as received. Product organic solutions were dried
with sodium sulfate prior to removal of the solvents under reduced
pressure on a rotary evaporator. Thin layer chromatography was
performed on precoated aluminium-backed silica TLC plates and
spots were visualized under UV light (254 nm) before treatment
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with ethanolic phosphomolybdic acid solution (heating). Column
The combined organic extracts were dried, filtered, and concen-
trated before purification of the product by column chromatog-
raphy (ethyl acetate/cyclohexane).
chromatography was carried out on silica gel (70–230 mesh). Melt-
1
ing points are uncorrected. H NMR and 13C NMR spectra were
recorded at 400.13 and 100.61 MHz, respectively. Chemical shifts
are reported in ppm relative to SiMe4. Signals are quoted as s (sing-
let), d (doublet), t (triplet), q (quartet), Q (quintet), m (multiplet),
br (broad), and coupling constant (J) values are given in Hertz.
Infrared spectra were recorded on a FTIR spectrophotometer.
Electron Impact Mass Spectra (EI-MS) were obtained at 70 eV.
High Resolution Electro-Spray Ionization Mass Spectra (HR-ESI-
MS) were obtained from the Centre Régional de Mesures Phys-
iques de l’Université Blaise Pascal (Clermont II), France. GC/MS
analysis conditions used for determination of diastereomeric excess
were as follows; column: UB 1701 (14% cyanopropylphenyl-meth-
ylpolysiloxane); injector temperature: 250 °C; oven temperature:
50 °C for 2 min then heating 50 °Cmin–1 until 290 °C. Amine 8
was prepared according to ref.[18], with propane-1,3-diol in place of
ethane-1,2-diol. Enone 24 was prepared by the procedure described
in ref.[25b] and was used either purified by distillation or without
purification.
( )-8-(Trifluoromethyl)-1,5-dioxa-9-azaspiro[5.5]undecane (9): Tri-
fluoroacetaldehyde methyl hemiacetal (3.36 g, 27.9 mmol) in
CH2Cl2 (3 mL), MgSO4 (ca. 1 g), and a catalytic amount of p-tolu-
enesulfonic acid were added to a stirred solution of amine 8 (2.5 g,
17.2 mmol) in dichloromethane (25 mL). The resulting mixture was
heated at gentle reflux for 4 hours, allowed to cool to room tem-
perature, and then transferred into a solution of pTsOH (4.5 g,
23.7 mmol; previously dried under Dean–Stark conditions) in tolu-
ene (250 mL). The resulting mixture was heated at 80 °C for
1.5 hours, and was then allowed to cool to room temperature and
diluted with ethyl acetate (100 mL) before addition of saturated
NaHCO3 (35 mL). After separation, the aqueous layer was ex-
tracted with ethyl acetate (3×100 mL) and the combined organic
extracts were dried, filtered, and concentrated under reduced pres-
sure to afford clean piperidine 9 as a pale brown oil (2.75 g, 71%),
which solidified upon standing in freezer and could be engaged in
the next step without purification. Silica gel column chromatog-
raphy (ethyl acetate/cyclohexane, 1:1) gave pure piperidine 9
(1.90 g, 49%) as a pale yellow solid. M.p. 44–45 °C. 1H NMR
(CDCl3): δ = 3.94 (t, J = 5 Hz, 2 H), 3.88 (t, J = 5 Hz, 2 H), 3.37
(m, 1 H), 3.12 (m, 1 H), 2.85 (t, J = 12 Hz, 1 H), 2.44 (d, J = 12
Hz, 1 H), 2.30 (br. s, 1 H), 2.28 (d, J = 12 Hz, 1 H), 1.75 (m, 2 H),
General Procedures
Intramolecular Mannich-Type Cyclization with Amines 3: MgSO4
(ca. 1 g) was added to a stirred solution of amine 3a or 3b (1 mmol)
in dichloromethane (10 mL), followed by the aldehyde (1.1 mmol)
and then a catalytic amount of pTsOH. The resulting mixture was
heated at gentle reflux until complete disappearance (TLC moni-
toring) of the amine (1–4 h) and was then allowed to cool to room
temperature and transferred to a solution of dry pTsOH (2 mmol)
in toluene (40 mL). The resulting mixture was heated (70–110 °C)
for 3–12 h. After the system had cooled to room temperature, satu-
rated aqueous NaHCO3 (10 mL) was added and the keto-protected
piperidone was extracted with ethyl acetate (4×30 mL). The com-
bined organic extracts were dried, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy with ethyl acetate/cyclohexane as eluent.
1.50 (m, 2 H) ppm. 13C NMR (CDCl3): δ = 125.5 (q, JC–F
=
265 Hz), 95.7, 59.1, 55.0 (q, JC–F = 29 Hz), 41.7, 32.5, 25.2 ppm.
IR (neat): νmax = 3300, 1283, 1173, 1095 cm–1. EI-MS (70 eV): m/z
˜
= 225 [M]+ (10), 224 (12), 166 (90), 156 (100), 124 (60), 113 (55),
101 (80), 100 (80), 98 (90), 56 (70), 43 (60) cm–1. HR-ESI-MS calcu-
lated for C9H15F3NO2 [M+H]+: 226.1055; found 226.1060.
( )-7-(Trifluoromethyl)-1,4-dithia-8-azaspiro[5.4]decane (10): Treat-
ment of piperidine 9 (225 mg, 1 mmol) as described in the dithioke-
talization General Procedure furnished dithioketal 10 (214 mg,
88%) as a colorless oil after silica gel column chromatography
1
(ethyl acetate/cyclohexane, 1:6). H NMR (CDCl3): δ = 3.36 (m, 5
Dithioketalization: Ethane-1,2-dithiol (5 mmol) and then BF3·Et2O
(5 mmol) were added dropwise at room temperature to a stirred
solution of keto-protected piperidone (1 mmol) in dichloromethane
(10 mL). The resulting solution was heated at reflux until complete
disappearance (TLC monitoring) of the starting material and was
then allowed to cool to room temperature and treated with an ex-
cess of aqueous NaOH (2 ). The layers were separated, and the
aqueous phase was extracted (3×30 mL) with dichloromethane.
The combined organic extracts were washed with brine, dried, and
filtered. After evaporation of the solvent, the residue was purified
by column chromatography with ethyl acetate/cyclohexane as elu-
ent.
H), 3.20 (dt, J = 12 and 3 Hz, 1 H), 2.87 (m, 1 H), 2.24 (dt, J =
12 and 1.5 Hz, 1 H), 2.09 (m, 2 H), 2.00 (dd, J = 11.5 and 11 Hz,
1 H), 1.67 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 125.3 (q,
JC–F = 279 Hz), 65.0, 57.4 (q, JC–F = 29 Hz), 45.2, 41.5, 41.45, 39.0,
38.0 ppm. IR (neat): νmax = 3308, 1277, 1162, 1133, 1097 cm–1. EI-
˜
MS (70 eV): m/z = 243 [M]+ (15), 182 (20), 150 (100), 124 (10), 110
(12). HR-ESI-MS calculated for C8H13F3NS2 [M+H]+: 244.0442;
found 244. 0450.
HCl Salt of ( )-2-(Trifluoromethyl)piperidine (Trifluoropipecoline,
7): Treatment of dithioketal 10 (100 mg, 0.41 mmol) as described
in the reduction with Raney nickel General Procedure afforded the
hydrochloride salt of trifluoropipecoline 7 (70 mg, 90%). M.p.
218 °C (dec.), lit.[10b] 220 °C (dec.). EI-MS (70 eV) (free base): m/z
= 153 [M]+ (8), 152 (7), 84 (100), 56 (20). Other spectroscopic data
were identical with those already reported.[10b]
Reduction with W2 Raney Nickel: Freshly prepared W2 Raney
nickel[19] (ca. 1.0 g) was added to a stirred solution of dithioketal
(100 mg) in absolute ethanol (5 mL). The resulting suspension was
heated at reflux for 30 min and then allowed to cool to room tem-
perature. The solution was filtered through Celite® and washed
with ethanol and H2O. Concentrated HCl (1 mL) was then added
to the filtrate. Evaporation of the solvent afforded the attempted
piperidine hydrochloride salt.
( )-N-(Benzyloxycarbonyl)-8-(trifluoromethyl)-1,5-dioxa-9-azaspiro-
[5.5]undecane (11): Aqueous sodium carbonate solution (0.44 ,
20 mL) and then, at 0 °C, benzyl chloroformate (1.27 mL,
8.8 mmol) were added to a stirred solution of piperidine derivative
9 (1 g, 4.4 mmol) in dichloromethane (20 mL). The resulting mix-
ture was stirred overnight at room temperature before addition of
dichloromethane (50 mL). The aqueous layer was extracted with
CH2Cl2 (2×50 mL), the combined organic extracts were dried and
filtered, and the solvent was eliminated under reduced pressure.
Purification by column chromatography (ethyl acetate/cyclohexane,
1:5) gave carbamate 11 (1.51 g, 95%) as a white solid. M.p. 97–
Reductive Amination of Piperidone 12: Sodium triacetoxyborohyd-
ride (300 mg, 1.4 mmol) and then AcOH (60 µL, 1 mmol) were
added to a stirred solution of piperidone 12 (301 mg, 1 mmol) and
amine (1 mmol) in CH2Cl2 (4 mL). The resulting solution was
stirred at room temperature until completion of the reaction (TLC
or GC analysis). The reaction was quenched by addition of NaOH
(1 ) and the product was extracted with diethyl ether (3×20 mL).
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1
98 °C. H NMR (CDCl3): δ = 7.36 (m, 5 H), 5.19 (d, J = 12 Hz, 1 2.65 (dt, J = 12 and 1.5 Hz, 1 H), 2.17 (m, 1 H), 1.98 (m, 1 H),
H), 5.16 (d, J = 12 Hz, 1 H), 4.83 (br. s, 1 H), 4.15 (m, 1 H), 3.88
(m, 4 H), 3.25 (dt, J = 12 and 3 Hz, 1 H), 2.48 (dd, J = 12 and
1.70 (br. s, 2 H), 1.42 (qd, J = 12 and 3 Hz, 1 H), 1.38 (q, J =
12 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 124.8 (q, JC–F = 279 Hz),
3 Hz, 1 H), 2.00 (m, 2 H), 1.80 (m, 2 H), 1.66 (m, 1 H) ppm. 13C 67.6, 56.9 (q, JC–F = 29 Hz), 43.8, 34.7, 34.1 ppm. IR (neat) ν
˜
max
NMR (CDCl3): δ = 155.5, 136.1, 128.5, 128.1, 127.8, 125.4 (q, JC–
= 3279, 1273, 1182, 1070 cm–1. EI-MS (70 eV): m/z = 169 [M]+ (5),
= 285 Hz), 95.2, 67.8, 59.5, 51.6 (q, JC–F = 32 Hz), 38.2,
150 (15), 124 (20), 110 (30), 100 (100), 82 (50), 56 (50). HR-ESI-
F
25.1 ppm. IR (neat): νmax = 1698, 1429, 1362, 1142, 1109 cm–1. EI-
MS calculated for C6H11F3NO [M+H]+: 170.093; found 170.091.
˜
MS (70 eV): m/z = 359 [M]+ (5), 268 (30), 248 (32), 224 (30), 166
(20), 91 (100). HR-ESI-MS calculated for C17H20F3NNaO4
[M+Na]+: 382.1242; found 382.1247.
(
)-(2R*,4S*)-N-Benzyloxycarbonyl-4-[N-(4-methoxyphenyl)-
amino]-2-(trifluoromethyl)piperidine (15): Treatment of piperidone
12 (1 g, 3.3 mmol) and 4-methoxyaniline as described in the re-
ductive amination General Procedure afforded 4-aminopiperidine
15 (1.17 g, 85%) as a brown oil after column chromatography (ethyl
acetate/cyclohexane, 1:3). 1H NMR (CDCl3, low-resolution spec-
trum due to the coexistence of carbamate rotamers): δ = 7.37 (m,
5 H), 6.80 (dd, J = 9 and 1.5 Hz, 2 H), 6.57 (dd, J = 9 and 1.5 Hz,
2 H), 5.21 (d, J = 14 Hz, 2 H), 5.17 (d, J = 14 Hz, 2 H), 4.70 (m,
1 H), 4.14 (m, 1 H), 3.75 (s, 3 H), 3.54 (m, 1 H), 3.40 (br. s, 1 H),
3.27 (m, 1 H), 2.25 (m, 1 H), 2.14 (m, 1 H), 1.86 (m, 1 H), 1.58
(m, 1 H) ppm. 13C NMR (CDCl3): δ = 155.7, 152.5, 135.9, 128.5,
128.2, 127.9, 125.5 (q, JC–F = 281 Hz), 115.0, 114.9, 67.9, 55.6, 51.6
( )-N-(Benzyloxycarbonyl)-2-(trifluoromethyl)piperidin-4-one (12):
Aqueous trifluoroacetic acid solution (50%, 6 mL) was added to a
stirred solution of piperidine 11 (1 g, 2.8 mmol) in dichloromethane
(10 mL). The resulting mixture was vigorously stirred for 3 days
and was then neutralized by addition of NaOH (4 ). The depro-
tected product was extracted with dichloromethane (3×50 mL),
and the combined organic extracts were dried, filtered, and then
concentrated in vacuo. Purification by silica gel column chromatog-
raphy (ethyl acetate/cyclohexane, 1:5) furnished piperidone 12
1
(796 mg, 95%) as a white solid. M.p. 67–68 °C. H NMR (CDCl3,
(q, JC–F = 31 Hz), 45.2, 37.2, 29.1, 26.1 ppm. IR (neat) νmax = 3379,
˜
low-resolution spectrum due to the coexistence of carbamate rota-
mers): δ = 7.36 (m, 5 H), 5.40–5.05 (m, 3 H), 4.60–4.35 (m, 1 H),
3.45 (m, 1 H), 2.69 (m, 2 H), 2.50, (m, 2 H) ppm. 13C NMR
(CDCl3): δ = 203.5, 155.4, 135.4, 128.6, 128.5, 128.1, 125.0 (q,
JC–F = 267 Hz), 68.2, 53.3 (q, JC–F = 32 Hz), 40.1, 39.3, 37.7 ppm.
1706, 1513, 1422, 1270, 1234, 1150, 1036 cm–1. EI-MS (70 eV): m/z
= 408 [M]+ (60), 273 (15), 134 (25), 91 (100), 65 (10). HR-ESI-MS
calculated for C21H24F3N2O3 [M+H]+: 409.1739; found 409.1728.
( )-(2R*,4S*)-4-[N-(4-Methoxyphenyl)amino]-2-(trifluoromethyl)-
piperidine (16): Pd(OH)2/C (20%, 100 mg) and ammonium formate
(386 mg, 6.1 mmol) were added to a stirred solution of compound
15 (500 mg, 1.2 mmol) in methanol (20 mL). The mixture was
heated at 60 °C for 2 h. After the system had cooled to room tem-
perature, the solution was filtered through celite®, and the filtrate
was concentrated under reduced pressure to give a residue, which
was diluted with saturated aqueous NaHCO3 (8 mL) before extrac-
tion with dichloromethane (5×40 mL). The combined organic ex-
tracts were dried and filtered. Evaporation of the solvent followed
by column chromatography (ethyl acetate/cyclohexane, 1:1 to ethyl
IR (neat) νmax = 1713, 1423, 1271, 1169, 1135 cm–1. EI-MS (70 eV):
˜
m/z = 301 [M]+ (15), 210 (15), 166 (10), 91 (100) 65 (17). HR-ESI-
MS calculated for C14H14F3NNaO3 [M+Na]+: 324.0823; found
324.0828.
( )-(2R*,4S*)-N-(Benzyloxycarbonyl)-2-(trifluoromethyl)piperidin-
4-ol (13): Sodium borohydride (76 mg, 2 mmol) was added at
–10 °C to a stirred solution of piperidone 12 (301 mg, 1 mmol) in
methanol (8 mL). The resulting mixture was stirred for 1 hour be-
fore addition of saturated NH4Cl (3 mL) and subsequent heating
to room temperature. The methanol was eliminated under reduced
pressure and the piperidinol was extracted with dichloromethane
(4 × 20 mL). The combined organic extracts were washed with
brine, dried, and filtered. Evaporation of the solvent followed by
column chromatography (ethyl acetate/cyclohexane, 1:3) gave pip-
eridinol 13 (267 mg, 88%) as a colorless oil. 1H NMR (CDCl3, low-
resolution spectrum due to the coexistence of carbamate rotamers):
δ = 7.35 (m, 5 H), 5.19 (d, J = 12 Hz, 1 H), 5.15 (d, J = 12 Hz, 1
H), 4.82 (m, 1 H), 4.11 (m, 2 H), 3.40 (m, 1 H), 2.06 (m, 2 H), 1.77
(m, 2 H), 1.6 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 155.5, 135.9,
128.5, 128.2, 127.9, 125.5 (q, JC–F = 285 Hz), 68.0, 62.0, 50.4 (q,
1
acetate) gave 4-aminopiperidine 16 (235 mg, 70%) as a red oil. H
NMR (CDCl3): δ = 6.79 (m, 2 H), 6.59 (m, 2 H), 3.75 (s, 3 H),
3.25 (m, 3 H), 2.76 (td, J = 13 and 2.5 Hz, 1 H), 2.40 (br. s, 2 H),
2.30 (m, 1 H), 2.09 (m, 1 H), 1.29 (qd, J = 12.5 and 4 Hz, 1 H),
1.21 (q, J = 11.5 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 152.4,
140.6, 125.3 (q, JC–F = 280 Hz), 115.2, 114.9, 57.5 (q, JC–F
=
29 Hz), 55.6, 50.8, 44.8, 33.1, 32.2 ppm. IR (neat) ν = 3333,
˜
max
2953, 1518, 1228, 1138, 1036, 821 cm–1. EI-MS (70 eV): m/z = 274
[M]+ (100), 229 (10), 205 (10), 160 (15), 149 (30), 134 (40), 123 (50),
108 (25), 82 (30), 56 (15). HR-ESI-MS calculated for C13H17F3N2O
[M+H]+: 275.1371; found 275.1382.
JC–F = 31 Hz), 35.7, 31.2, 29.1 ppm. IR (neat) ν
= 3457, 1710,
˜
max
( )-(2R*,4S*)-N-Benzyloxycarbonyl-4-[N-(4-chlorophenyl)amino]-
2-(trifluoromethyl)piperidine (17): Treatment of piperidone 12
(301 mg, 1 mmol) and 4-chloroaniline as described in the General
Procedure for reductive amination afforded 4-aminopiperidine 17
(235 mg, 60%) as a brown oil after column chromatography (ethyl
acetate/cyclohexane, 1:5). 1H NMR (CDCl3, low-resolution spec-
trum due to the coexistence of carbamate rotamers): δ = 7.38 (m,
5 H), 7.12 (m, 2 H), 6.50 (m, 2 H), 5.21 (d, J = 12.5 Hz, 1 H), 5.18
(d, J = 12.5 Hz, 1 H), 4.82 (m, 1 H), 4.15 (m, 1 H), 3.60 (m, 1 H),
3.26 (m, 1 H), 2.23 (m, 1 H), 2.11 (m, 1 H), 1.91 (m, 1 H), 1.62
1424, 1283, 1141, 1051 cm–1. EI-MS (70 eV): m/z = 303 [M]+ (5),
212 (10), 190 (15), 91 (100), 65 (10). HR-ESI-MS calculated for
C14H16F3NNaO3 [M+Na]+: 326.0980; found 326.0996.
( )-(2R*,4S*)-2-(Trifluoromethyl)piperidin-4-ol (14): Pd(OH)2/C
(20%, 50 mg) and ammonium formate (208 mg, 3.3 mmol) were
added to a stirred solution of compound 13 (200 mg, 0.66 mmol)
in methanol (10 mL). The mixture was heated at 60 °C for 2 h.
After the system had cooled to room temperature, the solution was
filtered through celite®, and the filtrate was concentrated under
reduced pressure to give a residue that was diluted with saturated
aqueous NaHCO3 (5 mL) before extraction with dichloromethane
(5×20 mL). The combined organic extracts were dried and filtered.
Evaporation of the solvent followed by column chromatography
(ethyl acetate/cyclohexane, 1:1 to pure ethyl acetate) gave piperidi-
(m, 1 H) ppm. IR (neat) νmax = 3383, 1704, 1599, 1499, 1422, 1276,
˜
1150, 1118, 817, 698 cm–1. EI-MS (70 eV): m/z = 414 [M]+ 37Cl (5),
412 [M]+ 35Cl (15), 277 (10), 140 (10), 91 (100), 65 (10). HR-ESI-
MS calculated for C20H21ClF3N2O2 [M+ H]+: 413.1244; found
413.1259.
nol 14 (102 mg, 92%) as a colorless oil. 1H NMR (CDCl3): δ = ( )-(2R*,4S*)-N-Benzyloxycarbonyl-4-(N-benzylamino)-2-(tri-
3.70 (m, 1 H), 3.22 (dd, J = 12.5 and 1.5 Hz, 1 H), 3.14 (m, 1 H), fluoromethyl)piperidine (18): Treatment of piperidone 12 (301 mg,
3428
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3421–3433

α-Trifluoromethyl Analogues of Piperidine Alkaloids
FULL PAPER
1 mmol) and benzylamine as described in General Procedure for
the reductive amination afforded 4-aminopiperidine 18 (251 mg,
64%) as a pale yellow oil after column chromatography (ethyl ace-
tate/cyclohexane, 1:3). 1H NMR (CDCl3): δ = 7.32 (m, 10 H), 5.18
H), 7.76–7.71 (m, 2 H), 5.40–4.30 (m, 1 H), 3.91 (dt, J = 12 and
3 Hz, 1 H), 3.86–3.81 (m, 1 H), 3.76 (dt, J = 12 and 3 Hz, 1 H),
3.30–3.25 (m, 1 H), 3.08 (dd, J = 15.0 and 11.0 Hz, 1 H), 2.01 (dd,
J = 15.0 and 1.5 Hz, 1 H), 1.83–1.71 (m, 1 H), 1.42 (s, 3 H), 1.22–
(d, J = 12 Hz, 1 H), 5.14 (d, J = 12 Hz, 1 H), 4.61 (m, 1 H), 4.06 1.16 (m, 1 H) ppm. 13C NMR (CDCl3): δ = 167.5, 134.2, 134.0,
(m, 1 H), 3.82 (d, J = 12 Hz, 1 H), 3.75 (d, J = 12 Hz, 1 H), 3.27 132.2, 131.3, 124.7 (q, JC–F = 282 Hz), 123.5, 123.4, 97.6, 60.0,
(m, 1 H), 2.83 (m, 1 H), 2.08 (m, 2 H), 1.81 (m, 1 H), 1.47 (m, 1
H), 1.33 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 155.8, 139.9, 2959, 2888, 1778, 1725, 1383, 1290, 1247, 1186, 1118, 1086, 1068,
136.0, 128.5, 128.4, 128.1, 127.9, 127.8, 127.0, 125.5 (q, JC–F
889, 729 cm–1. EI-MS (70 eV): m/z = 328 [M–Me]+ (85), 181 (95),
59.9, 47.7 (q, JC–F = 33 Hz), 34.6, 24.8 ppm. IR (KBr): ν
=
˜
max
=
284 Hz), 115.2, 114.9, 52.0 (q, JC–F = 31 Hz), 67.9, 51.1, 48.6, 37.3, 123 (45), 101 (100), 43 (60). HR-ESI-MS calculated for
29.3, 26.5 ppm. IR (neat): νmax = 3314, 1713, 1422, 1274, 1151, 698
C16H16F3NNaO4 [M+Na]+: 366.0929; found 366.0947.
˜
cm–1. EI-MS (70 eV): m/z = 392 [M]+ (1), 301 (20), 257 (15), 106
(15), 91 (100).
( )-2-(2-Amino-3,3,3-trifluoropropyl)-2-methyl-1,3-dioxolane (3a):
Hydrazine monohydrate (4.6 mL, 95 mmol) was added to a solu-
5,5,5-Trifluoro-4-N-phthalimidopentan-2-one (25): Phthalimide tion of 26a (6.24 g, 19 mmol) in methanol (100 mL). The resulting
(8.53 g, 58 mmol) and a solution of Triton B® in methanol (40%,
1 mL) were added to a stirred solution of enone 24 (8.0 g, 58 mmol)
in ethyl acetate (230 mL). The resulting solution was heated at re-
flux for 5 h, and was then allowed to cool to room temperature
and treated with NaOH solution (1 , 50 mL). The two layers were
separated, and the aqueous phase was extracted with ethyl acetate
(3×100 mL). The combined organic extracts were dried, filtered,
and concentrated to afford 25 (15.94 g, 96%) very cleanly as a pale
yellow solid that could be engaged directly in the following step.
Recrystallization (EtOH) afforded pure phthalimido compound 25
mixture was heated at reflux until complete disappearance (TLC
monitoring) of the compound 26a. The mixture was then allowed
to cool to room temperature and cautiously concentrated under
reduced pressure. The residue, diluted with dichloromethane
(100 mL), was then treated with KOH solution (2 , 76 mL,
152 mmol; vigorous stirring for 30 min.). The two layers were sepa-
rated, and the aqueous phase was extracted with dichloromethane
(3×100 mL). The combined organic extracts were dried and fil-
tered, and the solvents were evaporated. Amine 3a (3.21 g, 85%)
was obtained as a pale yellow liquid and was pure enough to be
(10.74 g, 65 %) as a white solid. M.p. 100–101 °C. 1H NMR used without further purification. Silica gel column chromatog-
(CDCl3): δ = 7.85 (m, 2 H), 7.74 (m, 2 H), 5.27 (m, 1 H), 4.03 (dd,
J = 19.0 and 11.0 Hz, 1 H), 3.08 (dd, J = 19.0 and 4.0 Hz, 1 H),
2.18 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 202.8, 167.1, 134.5,
raphy (ethyl acetate/cyclohexane, 1:3) afforded pure amine 3a as a
colorless liquid. H NMR (CDCl3): δ = 4.02–3.94 (m, 4 H), 3.54–
3.46 (m, 1 H), 2.05 (br. d, J = 14.5 Hz, 1 H), 1.63 (dd, J = 14.5
and 10 Hz, 1 H), 1.65 (br. s, 2 H), 1.38 (s, 3 H) ppm. 13C NMR
(CDCl3): δ = 126.3 (q, JC–F = 280 Hz), 108.7, 64.6, 64.2, 50.3 (q,
1
134.2, 127.0 (q, JC–F = 282 Hz), 123.7, 123.5, 47.8 (q, JC–F
=
33 Hz), 37.6, 29.8 ppm. IR (KBr) ν
= 2966, 1775, 1722, 1386,
˜
max
1284, 1174, 1105, 729 cm–1. EI-MS (70 eV): m/z = 285 [M]+ (5),
265 (80), 222 (50), 174 (90), 76 (50), 43 (100). HR-ESI-MS calcu-
lated for C13H10F3NNaO3 [M+Na]+: 308.0510; found 308.0516.
JC–F = 29 Hz), 38.1, 24.0 ppm. IR (neat) ν
= 3405, 3340, 2988,
˜
max
2892, 1618, 1381, 1307, 1249, 1219, 1148, 1112, 1045, 949, 813
cm–1. EI-MS (70 eV): m/z = 184 [M–Me]+ (20), 98 (25), 87 (100),
43 (70). HR-ESI-MS calculated for C7H13F3NO2 [M + H]+:
200.0898; found 200.0903.
( )-2-Methyl-2-(3,3,3-trifluoro-2-N-phthalimidopropyl)-1,3-di-
oxolane (26a): Ethane-1,2-diol (4.1 mL, 73 mmol) and pTsOH
(200 mg) were added to a solution of 25 (10.4 g, 36.5 mmol) in
toluene (140 mL) in a flask fitted with a Dean–Stark apparatus.
The resulting mixture was heated at reflux until complete disap-
pearance (TLC monitoring) of the compound 25. The mixture was
then allowed to cool to room temperature and concentrated in
vacuo. The residue, diluted with ethyl acetate (100 mL), was then
treated with a saturated NaHCO3 solution. The two layers were
separated, and the aqueous phase was extracted with ethyl acetate
(2×100 mL). The combined organic extracts were dried, filtered,
and concentrated. Simple washing of the solid residue with cold
cyclohexane afforded pure phthalimido compound 26a (9.60 g,
( )-2-(2-Amino-3,3,3-trifluoropropyl)-2-methyl-1,3-dioxane (3b): By
starting from 26b (5.3 g, 15.5 mmol) in methanol (200 mL) and hy-
drazine monohydrate (3.7 mL, 77 mmol) as described in the pro-
cedure above, amine 3b (2.99 g, 91%) was obtained as a pale yellow
liquid, which could be used without purification. Silica gel column
chromatography (ethyl acetate/cyclohexane, 1:3) afforded pure
amine 3b as a colorless liquid. 1H NMR (CDCl3): δ = 4.04–3.96
(m, 2 H), 3.91–3.80 (m, 2 H), 3.80–3.71 (m, 1 H), 2.11 (br. s, 2 H),
1.98 (dd, J = 14.5 and 1.5 Hz, 1 H), 1.97–1.87 (m, 1 H), 1.79 (dd,
J = 14.5 and 10.0 Hz, 1 H), 1.49 (s, 3 H), 1.49–1.12 (m, 1 H) ppm.
13C NMR (CDCl3): δ = 126.5 (q, JC–F = 280 Hz), 98.2, 59.7, 59.6,
80%) as a white solid. M.p. 94–95 °C. 1H NMR (CDCl3): δ = 7.87– 49.6 (q, JC–F = 29 Hz), 40.3, 25.2, 19.5 ppm. IR (neat) νmax = 3402,
˜
7.85 (m, 2 H), 7.75–7.73 (m, 2 H), 5.08–4.99 (m, 1 H), 3.92–3.85
3338, 2973, 2877, 1617, 1376, 1246, 1152, 1108, 1081, 966, 804
(m, 2 H), 3.79–3.73 (m, 1 H), 3.67–3.62 (m, 1 H), 3.20 (dd, J = 15 cm–1. EI-MS (70 eV): m/z = 213 [M]+ (1), 198 (40), 101 (100), 73
and 11.5 Hz, 1 H), 2.14 (dd, J = 15 and 1.5 Hz, 1 H), 1.28 (s, 3
H) ppm. 13C NMR (CDCl3): δ = 167.1, 134.5, 134.1, 124.4 (q, JC–
F = 232 Hz), 123.5, 123.4, 108.1, 64.6, 64.3, 48.2 (q, JC–F = 33 Hz),
(40), 43 (90). HR-ESI-MS calculated for C8H15F3NO2 [M+H]+:
214.1055; found 214.1050.
( )-(8R*,10R*)-10-Propyl-8-(trifluoromethyl)-1,5-dioxa-9-azaspiro-
[5.5]undecane (27): Amine 3b (400 mg, 1.9 mmol), butanal (186 µL,
2.1 mmol), and pTsOH (711 mg, 3.7 mmol), treated as described in
the General Procedure for the intramolecular Mannich-type reac-
tion (reaction temperature = 72 °C), gave cis-piperidine 27 (161 mg,
32%, yellow oil) after chromatography (ethyl acetate/cyclohexane,
31.4, 23.8 ppm. IR (KBr) ν
= 2980, 2894, 1774, 1727, 1382,
˜
max
1289, 1186, 1119, 1079, 1067, 1036, 909, 890, 735, 720 cm–1. EI-
MS (70 eV): m/z = 314 [M–Me]+ (25), 269 (15), 167 (75), 123 (15),
87 (100), 43 (25). HR-ESI-MS calculated for C15H14F3NNaO4
[M+Na]+: 352.0773; found 352.0785.
( )-2-Methyl-2-(3,3,3-trifluoropropyl-2-N-phthalimido)-1,3-dioxane 1:6). The trans isomer could not be separated from undesired side
(26b): By starting from 25 (9.24 g, 32.4 mmol), propane-1,3-diol products (see “Results and Discussion”). 1H NMR (CDCl3): δ =
(4.7 mL, 64.8 mmol), and pTsOH (200 mg) as described in the 3.94 (t, J = 5.5 Hz, 2 H), 3.88 (t, J = 5.5 Hz, 2 H), 3.42–3.33 (m,
above procedure, compound 26b (10.78 g, 97%) was obtained as a
white solid. M.p. 124 °C. H NMR (CDCl3): δ = 7.89–7.85 (m, 2
1 H), 2.86–2.77 (m, 1 H), 2.47 (br. d, J = 13 Hz, 1 H), 2.26 (br. d,
J = 13 Hz, 1 H), 1.81–1.67 (m, 3 H), 1.52–1.31 (m, 5 H), 1.28–1.11
1
Eur. J. Org. Chem. 2006, 3421–3433
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3429

A. Bariau, W. B. Jatoi, P. Calinaud, Y. Troin, J.-L. Canet
(m, 1 H), 0.92 (t, 3 H, J = 6.5 Hz) ppm. 13C NMR (CDCl3): δ = ( )-(7R*,9S*)-9-(4-Fluorophenyl)-7-(trifluoromethyl)-1,4-dioxa-8-
FULL PAPER
125.6 (q, JC–F = 279 Hz), 96.4, 59.3, 59.2, 55.0 (q, JC–F = 29 Hz),
51.9, 39.2, 38.4, 32.0, 25.3, 18.9, 14.1 ppm. IR (neat): ν = 3316,
2961, 2933, 2873, 1337, 1268, 1180, 1142, 1092, 1023, 934, 793
cm–1. EI-MS (70 eV): m/z = 267 [M]+ (1), 224 (60), 208 (25), 181
(100), 166 (30), 124 (25), 101 (40), 43 (25). HR-ESI-MS calculated
for C12H21F3NO2 [M+H]+: 268.1524; found 268.1534.
azaspiro[5.4]decane (31): Amine 3a (200 mg, 1 mmol), 4-fluoro-
benzaldehyde (117 µL, 1.1 mmol), and pTsOH (382 mg, 2 mmol),
treated as described in the General Procedure for the intramolecu-
lar Mannich-type reaction (reaction temperature = 70 °C), gave pi-
peridine 31 (215 mg, 70 %) as a white solid after column
chromatography (ethyl acetate/cyclohexane, 1:6). M.p. 85–89 °C.
1H NMR (CDCl3): δ = 7.38 (m, 2 H), 7.02 (m, 2 H), 6.04–3.93 (m,
5 H), 3.55 (m, 1 H), 1.92 (br. s, 1 H), 1.92 (dt, J = 12.5 and 3 Hz,
1 H), 1.82 (dt, J = 13 and 3 Hz, 1 H), 1.76 (t, J = 12.5 Hz, 1 H),
1.73 (t, J = 13 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 163.4 (d,
JC–F = 245.5 Hz), 138.6, 128.4, 128.3, 125.5 (q, JC–F = 279 Hz),
115.5, 115.2, 106.8, 64.6, 64.5, 57.4, 56.3 (q, JC–F = 30 Hz), 43.4,
˜
max
( )-(8R*,10S*)-10-(Prop-1-enyl)-8-(trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undecane (28): Amine 3b (2.0 g, 9.4 mmol), crotonalde-
hyde (842 µL, 10.4 mmol), and pTsOH (3.58 g, 18.8 mmol), treated
as described in the General Procedure for the intramolecular Man-
nich-type reaction (reaction temperature = 76 °C), gave piperidine
28 (1.94 g, 78%) as a pale yellow oil after chromatography (ethyl
33.8 ppm. IR (KBr) ν
= 3305, 1605, 1509, 1276, 1180, 1135,
˜
max
1
1013, 840 cm–1. EI-MS (70 eV): m/z = 305 [M]+ (10), 260 (100), 150
(40), 122 (60), 86 (50). HR-ESI-MS calculated for C14H16F4NO2
[M+H]+: 306.1117; found 306.1117.
acetate/cyclohexane, 1:9). H NMR (CDCl3): δ = 5.67 (dq, J = 15
and 6.5 Hz, 1 H), 5.45 (dd, J = 15 and 7 Hz, 1 H), 3.94 (br. t, J =
5.5 Hz, 2 H), 3.89 (t, J = 5.5 Hz, 2 H), 3.45–3.38 (m, 1 H), 3.35–
3.30 (m, 1 H), 2.40 (dt, J = 13 and 3 Hz, 1 H), 2.26 (dd, J = 13.5
and 3 Hz, 1 H), 1.78–1.70 (m, 2 H), 1.68 (d, J = 6.5 Hz, 3 H), 1.45
(t, J = 12.5 Hz, 1 H), 1.3 (t, J = 13 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 132.6, 127.0, 125.6 (q, JC–F = 279 Hz), 96.2, 59.3,
59.2, 54.6 (q, JC–F = 29 Hz), 54.3, 38.7, 32.0, 25.3, 17.7 ppm. IR
( )-(7R*,9S*)-9-(Prop-1-enyl)-7-(trifluoromethyl)-1,4-dithia-8-aza-
spiro[5.4]decane (32): Protected piperidone 28 (200 mg, 0.75 mmol)
in dichloromethane (10 mL), ethanedithiol (320 µL, 3.8 mmol), and
BF3·Et2O (481 µL, 3.8 mmol), treated as described in the General
Procedure for dithioaketalization, gave dithiolane 32 (164 mg,
77%) as a pale yellow oil after purification by column chromatog-
raphy (ethyl acetate/cyclohexane, 1:19). 1H NMR (CDCl3): δ = 5.70
(dq, J = 15 and 6.5 Hz, 1 H), 5.44 (dd, J = 15 and 7.0 Hz, 1 H),
3.51–3.41 (m, 1 H), 3.36–3.29 (m, 5 H), 2.22 (ddd, J = 13, 4.5 and
2.5 Hz, 1 H), 2.10 (ddd, J = 13.5, 5 and 2.5 Hz, 1 H), 1.98 (m, 1 H),
1.85 (m, 1 H), 1.68 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3): δ
= 132.2, 127.4, 125.3 (q, JC–F = 279 Hz), 64.8, 57.7, 57.3 (q, JC–F
(neat) νmax = 3310, 2969, 2868, 1336, 1279, 1267, 1176, 1137, 1020,
˜
971 cm–1. EI-MS (70 eV): m/z = 265 [M]+ (5), 206 (100), 181 (30),
101 (25). HR-ESI-MS calculated for C12H19F3NO2 [M + H]+:
266.1368; found 266.1362.
( )-(8R*,10S*)-10-((E,E)-Nona-1,3-dienyl)-8-(trifluoromethyl)-1,5-
dioxa-9-azaspiro[5.5]undecane (29): Amine 3b (2.88 g, 13.5 mmol),
trans,trans-2,4-decadienal (2.60 mL, 14.9 mmol), and pTsOH
(5.15 g, 27.1 mmol), treated as described in the General Procedure
for the intramolecular Mannich-type reaction (reaction tempera-
ture = 70 °C), gave piperidine 29 (3.33 g, 71%) as a yellow oil after
column chromatography (ethyl acetate/cyclohexane, 1:19). 1H
NMR (CDCl3): δ = 6.18 (dd, J = 15 and 10.5 Hz, 1 H), 5.99 (dd,
J = 15 and 10.5 Hz, 1 H), 5.72–5.65 (m, 1 H), 5.53 (dd, J = 15 and
7.5 Hz, 1 H), 3.90 (m, 4 H), 3.47–3.35 (m, 2 H), 2.38 (dt, J = 13.0
and 3 Hz, 1 H), 2.29 (dt, J = 13 and 3 Hz, 1 H), 2.06 (q, J = 7 Hz,
2 H), 1.81–1.66 (m, 2 H), 1.48–1.21 (m, 8 H), 0.88 (m, 4 H) ppm.
13C NMR (CDCl3): δ = 135.7, 131.7, 131.5, 129.3, 125.6 (q, JC–F
= 279 Hz), 96.1, 59.3, 59.2, 54.7 (q, JC–F = 29 Hz), 54.3, 38.6, 32.5,
= 29 Hz), 47.4, 40.7, 39.3, 38.0, 17.7 ppm. IR (neat) ν
= 3308,
˜
max
2957, 2926, 2837, 1275, 1173, 1139, 1125, 1060, 968, 815, 786 cm–1.
HR-ESI-MS calculated for C11H17F3NS2 [M + H]+: 284.0755;
found 284.0750.
( )-(2R*,6R*)-6-Propyl-2-(trifluoromethyl)piperidine Hydrochloride
(Trifluorodihydropinidine Hydrochloride) (20·HCl): Dithioketal 32
(70 mg, 0.24 mmol) in solution in absolute ethanol (7 mL) and
treated with W2 Raney nickel (ca. 700 mg), as described in the
General Procedure for hydrogenolysis, gave pure compound 20·HCl
(51 mg, 90 %) as a white solid. M.p. 201 °C (dec.). 1H NMR
(CD3OD): δ = 5.15–5.06 (m, 1 H), 4.39–4.31 (m, 1 H), 3.29–3.16
(m, 2 H), 3.13–3.06 (m, 1 H), 2.83–2.37 (m, 7 H), 1.98 (t, J =
33.1, 31.3, 28.8, 25.4, 22.5, 13.9 ppm. IR (neat): νmax = 3321, 2958,
˜
2930, 2861, 1728, 1459, 1429, 1400, 1379, 1337, 1280, 1175, 1135,
1018, 990 cm–1. EI-MS (70 eV): m/z = 347 [M]+ (20), 290 (20), 276
(20), 181 (100), 150 (25), 123 (20), 101 (20): HR-ESI-MS calculated
for C18H29F3NO2 [M+H]+: 348.2150; found 348.2157.
7.5 Hz, 3 H) ppm. 13C NMR (CD3OD): δ = 124.6 (q, JC–F
280 Hz), 60.3, 58.6 (q, JC–F = 32 Hz), 36.0, 28.4, 23.1, 22.0, 19.6,
=
14.0 ppm. IR (KBr) ν
= 2935, 1271, 1192, 1119 cm–1. EI-MS
˜
max
(70 eV, free base): m/z = 195 [M]+ (1), 194 (3), 152 (100), 55 (10).
HR-ESI-MS calculated for C9H17ClF3N [M–Cl]+: 196.1313; found
196.1317.
( )-(7R*,9S*)-9-Phenyl-7-(trifluoromethyl)-1,4-dioxa-8-azaspiro-
[5.4]decane (30): Amine 3a (200 mg, 1 mmol), benzaldehyde
(112 µL, 1.1 mmol), and pTsOH (382 mg, 2 mmol), treated as de-
scribed in the General Procedure for the intramolecular Mannich-
type reaction (reaction temperature = 110 °C), gave piperidine 30
( )-(8R*,10R*)-10-Nonyl-8-(trifluoromethyl)-1,5-dioxa-9-azaspiro-
[5.5]undecane (33): Pd(OH)2/C (20%, 50 mg) and ammonium for-
mate (182 mg, 2.9 mmol) were added to a stirred solution of com-
(191 mg, 66%) as a pale yellow oil after chromatography (ethyl pound 29 (200 mg, 0.6 mmol) in methanol (10 mL). The mixture
1
acetate/cyclohexane, 1:6). H NMR (CDCl3): δ = 7.43–7.27 (m, 5
was heated at reflux for 2 h. After the system had cooled to room
H), 4.05–3.98 (m, 4 H), 3.95 (dd, J = 12 and 3 Hz, 1 H), 3.56 (m, temperature, the solution was filtered through celite®, and the fil-
1 H), 1.93 (dt, J = 12.5 and 3 Hz, 1 H), 1.85 (dt, J = 13 and 3 Hz, trate was concentrated under reduced pressure to give a residue
1 H), 1.77 (t, J = 12 Hz, 1 H), 1.75 (t, J = 12 Hz, 1 H), 1.60 (br. s,
1 H) ppm. 13C NMR (CDCl3): δ = 142.9, 128.6, 127.7, 126.8, 125.6
(q, JC–F = 278 Hz),107.0, 64.6, 64.5, 58.1, 56.4 (q, JC–F = 29.0 Hz),
that was diluted with saturated aqueous NaHCO3 (5 mL) before
extraction with dichloromethane (3×20 mL). The combined or-
ganic extracts were dried, filtered, and evaporated, to afford satu-
1
43.3, 34.0 ppm. IR (neat): ν
= 3313, 3032, 2977, 2887, 1455,
rated piperidine 33 (186 mg, 92%) as a pale yellow oil. H NMR
˜
max
1401, 1337, 1280, 1247, 1174, 1124, 1077, 1058, 1015, 948, 761, 701
cm–1. EI-MS (70 eV): m/z = 287 [M]+ (10), 242 (100), 266 (20), 132
(20), 104 (40), 86 (35). HR-ESI-MS calculated for C14H17F3NO2
[M+H]+: 288.1211; found 288.1207.
(CDCl3): δ = 3.93 (t, J = 5.5 Hz, 2 H), 3.87 (t, J = 5.5 Hz, 2 H),
3.39–3.30 (m, 1 H), 2.79–2.72 (m, 1 H), 2.45 (dt, J = 13 and 2.5 Hz,
1 H), 2.24, (dt, J = 13 and 2.5 Hz, 1 H), 2.12–1.93 (m, 1 H), 1.79–
1.66 (m, 2 H), 1.40 (t, J = 12.5 Hz, 1 H), 1.34–1.18 (m, 16 H), 1.12
3430
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3421–3433

α-Trifluoromethyl Analogues of Piperidine Alkaloids
(t, J = 13 Hz, 1 H), 0.89–0.87 (m, 4 H) ppm. 13C NMR (100 MHz, was then allowed to cool to room temperature and poured into
FULL PAPER
CDCl3): δ = 125.7 (q, JC–F = 279 Hz), 96.4, 66.8, 59.2, 59.1, 54.9
(q, JC–F = 29 Hz), 52.0, 39.2, 36.4, 32.0, 31.8, 29.6, 29.4, 29.2, 25.7,
H2O (75 mL) before extraction with dichloromethane (3×75 mL).
The combined organic extracts were dried and filtered, and the
solvents were evaporated. The residue was purified by column
chromatography (ethyl acetate/cyclohexane, 1:3) to afford com-
pound 36 (513 mg, 75%) as a pale yellow oil. 1H NMR (CDCl3,
very complex spectrum due to the coexistence of amide rotamers):
δ = 8.80–5.07 (m, 4 H), 2.96–2.71 (m, 4 H), 1.72 (d, J = 6.5 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 201.0, 158.0, 131.0,
128.2, 124.0 (q, JC–F = 284 Hz), 116.1 (q, JC–F = 287 Hz), 54.3 (m),
25.3, 22.6, 14.0 ppm. IR (neat) νmax = 3338, 2956, 2927, 2856, 1671,
˜
1467, 1338, 1279, 1172, 1137, 1091, 1018. HR-ESI-MS calculated
for C18H33F3NO2 [M+H]+: 352.2463; found 352.2461.
( )-(7R*,9R*)-9-Nonyl-7-(trifluoromethyl)-1,4-dithia-8-azaspiro-
[5.4]decane (34): By starting from ketal 33 (378 mg, 1.1 mmol) in
dichloromethane (12 mL), ethanedithiol (450 µL, 5.4 mmol), and
BF3·Et2O (700 µL, 5.4 mmol), as described in the General Pro-
cedure for dithioketalization, dithiolane 34 (238 mg, 60%) was ob-
tained as a yellow oil after purification by column chromatography
(ethyl acetate/cyclohexane, 1:19). 1H NMR (CDCl3): δ = 3.48–3.31
(m, 1 H), 3.33 (br. s, 4 H), 2.79–2.73 (m, 1 H), 2.25 (dt, J = 13 and
2.5 Hz, 1 H), 2.13 (dt, J = 13 and 2.5 Hz, 1 H), 1.96 (t, J = 12 Hz,
1 H), 1.72 (t, J = 12 Hz, 1 H), 1.48–1.23 (m, 17 H), 0.90 (t, J =
7 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 125.4 (q, JC–F = 279 Hz),
65.2, 57.5 (q, JC–F = 29 Hz), 55.7, 47.4, 41.5, 39.2, 38.0, 36.5, 31.8,
42.5, 36.4, 17.6 ppm. IR (neat): ν
= 3042, 2977, 2926, 2862,
˜
max
1732, 1708, 1433, 1384, 1346, 1297, 1275, 1210, 1182, 1148, 1128,
1006, 972, 941, 760, 694 cm–1. HR-ESI-MS calculated for
C11H14F6NNaO2 [M+Na]+: 326.0592; found 326.0596.
( )-(2R*,4S*,6S*)-6-(Prop-1-enyl)-2-(trifluoromethyl)piperidin-4-ol
(37): Sodium borohydride (74 mg, 1.97 mmol) was added to a co-
oled (–30 °C), stirred solution of piperidone 37 (298 mg,
0.98 mmol) in methanol (20 mL). The resulting mixture was stirred
for 1 h before addition of saturated aqueous NH4Cl (8 mL). After
the mixture had been heated to room temperature, the methanol
was removed in vacuo and the residue was then extracted with
dichloromethane (5×20 mL). The combined organic extracts were
dried and filtered. Evaporation of the solvent, followed by column
chromatography (ethyl acetate/cyclohexane, 1:3) afforded piperid-
29.6, 29.5, 29.3, 25.6, 22.6, 14.1 ppm. IR (neat) ν
= 3339, 2926,
˜
max
2854, 1466, 1397, 1277, 1172, 1142 cm–1. EI-MS (70 eV): m/z = 369
[M]+ (2), 308 (30), 276 (70), 242 (100), 199 (25), 182 (15), 138 (15),
119 (20). HR-ESI-MS calculated for C17H31F3NS2 [M + H]+:
370.1850; found 370.1840.
( )-(2R*,6R*)-7-Nonyl-2-(trifluoromethyl)piperidine·HCl (Trifluo-
roisosolenopsin) (21·HCl): By starting from thioketal 34 (200 mg,
0.5 mmol) in absolute ethanol (20 mL), and W2 Raney nickel (ca.
2.0 g), as described in the General Procedure, trifluoroisosolenop-
sine HCl salt 21·HCl (157 mg, 92%) was obtained without purifica-
1
inol 37 (132 mg, 64%) as a white solid. M.p. 77–80 °C. H NMR
(CDCl3): δ = 5.66 (dq, J = 15 and 6.5 Hz, 1 H), 5.77 (ddq, J = 15,
7 and 1.5 Hz, 1 H), 3.75 (m, 1 H), 3.23 (m, 1 H), 3.14 (m, 1 H),
2.14 (m, 1 H), 1.99 (m, 1 H), 1.69 (d, J = 6.5 Hz, 3 H), 1.58, (br.
s, 2 H), 1.37 (q, J = 11.5 Hz, 1 H), 1.24 (q, J = 11.5 Hz, 1 H) ppm.
13C NMR (CDCl3): δ = 132.3, 127.1, 125.2 (q, JC–F = 279 Hz),
67.7, 56.5, 56.4 (q, JC–F = 29 Hz), 41.0, 38.4, 17.6 ppm. IR (KBr)
1
tion as a white solid. M.p. 165–166 °C (dec.); H NMR (CD3OD):
δ = 5.19–5.10 (m, 1 H), 4.27–4.20 (m, 1 H), 3.18–3.07 (m, 2 H),
3.04–2.98 (m, 1 H), 2.87–2.78 (m, 1 H), 2.74–2.54 (m, 3 H), 2.49–
2.22 (m, 16 H), 1.87 (t, 3 H, J = 7 Hz) ppm. 13C NMR (CD3OD):
δ = 124.6 (q, JC–F = 280 Hz), 60.5, 58.6 (q, JC–F = 32 Hz), 34.0,
33.0, 30.6, 30, 30.4, 28.4, 26.3, 23.7, 23.2, 23.1, 22.6, 14.5 ppm. IR
ν
= 3296, 1677, 1268, 1185, 1153, 1089, 1046, 879 cm–1. EI-MS
˜
max
(70 eV): m/z = 209 [M]+ (25), 194 (100), 176 (50), 164 (40), 150 (60),
96 (570), 68 (80), 41 (50). HR-ESI-MS calculated for C9H15F3NO
[M+H]+: 210.1106; found 210.1112.
(KBr) ν
= 3420, 2023, 1468, 1270, 1190, 1135 cm–1. EI-MS
˜
max
(70 eV, free base): m/z = 279 [M]+ (1), 278 (3), 152 (100), 55 (10).
HR-ESI-MS calculated for C15H29F3N [M+H]+: 280.2252; found
280.2260.
( )-(2R*,4S*,6R*)-6-Propyl-2-(trifluoromethyl)piperidin-4-ol (23):
By starting from compound 37 (82 mg, 0.39 mmol) in anhydrous
methanol (10 mL), ammonium formate (123 mg, 1.95 mmol), and
Pd(OH)2/C (20%, 30 mg), as described in the procedure employed
for the synthesis of compound 33, piperidinol 23 (70 mg, 85%) was
obtained as a white solid without need for purification. M.p. 47–
49 °C. 1H NMR (CDCl3): δ = 3.70 (tt, J = 11 and 4.5 Hz, 1 H),
3.18 (qdd, J = 10, 7 and 2.5 Hz, 1 H), 2.60 (m, 1 H), 2.14 (dQ, J
= 12 and 2 Hz, 1 H), 2.00 (dQ, J = 12 and 2 Hz, 1 H), 1.66 (br. s,
2 H), 1.50–1.31 (m, 5 H), 1.06 (q, J = 11.5 Hz, 1 H), 0.92 (t, J =
7 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 125.3 (q, JC–F = 278 Hz),
68.0, 56.7 (q, JC–F = 29 Hz), 54.1, 41.1, 38.6, 34.1, 18.9, 14.0 ppm.
( )-(8R*,10S*)-10-(Prop-1-enyl)-8-(trifluoromethyl)-9-(trifluoro-
methylcarbonyl)-1,5-dioxa-9-azaspiro[5.5]undecane (35): Triethyl-
amine (4.2 mL, 30.1 mmol) and DMAP (139 mg, 1.1 mmol) were
added to a stirred solution of compound 28 (1.0 g, 3.8 mmol) in
dichloromethane (30 mL), and trifluoroacetic anhydride (2.1 mL,
15.2 mmol) was added at 0 °C to the resulting solution. The re-
sulting mixture was stirred at room temperature for 30 min, and
then concentrated in vacuo. The residue was separated by column
chromatography (ethyl acetate/cyclohexane, 1:3) to afford com-
pound 36 (1.27 g, 93%) as a pale yellow oil. 1H NMR (CDCl3,
very complex spectrum due to the coexistence of amide rotamers):
δ = 5.90–5.36 (m, 2 H), 5.15–5.04 (m, 1 H), 4.82–4.55 (m, 1 H),
4.02–3.81 (m, 4 H), 2.71–2.42 (m, 2 H), 2.19–1.53 (m, 7 H) ppm.
IR (KBr) νmax = 3264, 2956, 1267, 1150, 1111, 1086 1046, 884 cm–1.
˜
EI-MS (70 eV): m/z = 211 [M]+ (1), 168 (100), 150 (50), 124 (40), 98
(10): HR-ESI-MS calculated for C9H17F3NO [M+H]+: 212.1262;
found 212.1279.
13C NMR (CDCl3): δ = 158.0, 129.9, 128.7, 124.5 (q, JC–F
282 Hz), 116.3 (q, JC–F = 287 Hz), 94.9, 60.0, 59.8, 52.9, 51.0 (q,
JC–F = 34 Hz), 36.1, 27.5, 24.9, 17.5 ppm. IR (neat) ν = 2974,
=
( )-(8R*,10S*)-10-(Nona-1,3-dienyl)-8-(trifluoromethyl)-9-(tri-
fluoromethylcarbonyl)-1,5-dioxa-9-azaspiro[5.5]undecane (40): By
starting from ketal 29 (500 mg, 1.44 mmol) in dichloromethane
(12 mL), triethylamine (1.6 mL, 11.5 mmol), DMAP (53 mg,
0.43 mmol), and trifluoroacetic anhydride (0.8 mL, 5.8 mmol), as
described in the procedure employed for the synthesis of compound
35, compound 40 (447 mg, 70%) was obtained after purification
by column chromatography (ethyl acetate/cyclohexane, 1:19) as a
˜
max
2872, 1705, 1433, 1360, 1287, 1254, 1212, 1182, 1150, 1119, 1016,
964, 958 cm–1. HR-ESI-MS calculated for C14H17F6NNaO3
[M+Na]+: 384.1010; found 384.1017.
( )-(2R*,6S*)-6-(Prop-1-enyl)-2-(trifluoromethyl)-1-(trifluorometh-
ylcarbonyl)piperidin-4-one (36): A solution of CAN (3.08 g,
5.6 mmol) in H2O (10 mL) was added, at 70 °C, in one portion, to
a stirred solution of ketal 36 (815 mg, 2.2 mmol) in CH3CN (5 mL).
The resulting mixture was stirred for 30 min. The reaction mixture
1
dark yellow oil. H NMR (CDCl3, very complex spectrum due to
the coexistence of amide rotamers): δ = 6.38–4.51 (m, 6 H), 3.99–
3.83 (m, 4 H), 2.72–2.45 (m, 2 H), 2.20–1.57 (m, 6 H), 1.42–1.24
Eur. J. Org. Chem. 2006, 3421–3433
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3431

A. Bariau, W. B. Jatoi, P. Calinaud, Y. Troin, J.-L. Canet
FULL PAPER
(m, 6 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3): δ =
158.0, 136.3, 133.6, 131.8, 127.7, 123.5 (q, JC–F = 286 Hz), 115.3
(q, JC–F = 286 Hz), 93.9, 59.1, 58.9, 52.0, 50.5 (q, JC–F = 34.0 Hz),
Acknowledgments
We thank the Ministère de la Jeunesse, de l’Education Nationale et
de la Recherche for financial support. We thank Bertrand Legeret,
Centre Régional de Mesures Physiques, Université Blaise Pascal,
for high-resolution mass spectra measurements and analysis. We
thank Eric Busseron, Agnès Corbères, Anne-Laure Dorange, Nic-
olas Guilloteau, Anne-Laure Texier, and Sophie Vuong (under-
graduate students of the ENSCCF) who checked some experiments
during their “Projet Technologique” at the ENSCCF.
35.4, 31.6, 30.4, 27.8, 26.5, 24.0, 21.5, 13.0 ppm. IR (neat) ν
=
˜
max
2960, 2930, 2861, 1706, 1431, 1213, 1183, 1148, 990 cm–1. EI-MS
(70 eV): m/z = 443 [M]+ (15), 181 (100), 166 (25), 123 (100), 79
(50), 55 (25), 41 (65): HR-ESI-MS calculated for C20H28F6NO3
[M+H]+: 444.1973; found 444.1968.
( )-(2R*,6S*)-6-(Nona-1,3-dienyl)-2-(trifluoromethyl)-1-(trifluoro-
methylcarbonyl)piperidin-4-one (41): HCl (4 , 6 mL) was added to
a stirred solution of ketal 40 (593 mg, 1.3 mmol) in acetone
(20 mL). The resulting mixture was stirred at room temperature for
4 days, and was then quenched with an excess of NaOH (4 ).
Acetone was eliminated under reduced pressure and the residue
was diluted with diethyl ether (50 mL). The two layers were sepa-
rated, and the aqueous phase was extracted with Et2O (3×30 mL).
The combined organic extracts were dried, filtered, and concen-
trated. The residue, after purification by column chromatography
(ethyl acetate/cyclohexane, 1:9), afforded compound 41 (335 mg,
[1] a) P. S. Watson, B. Jiang, B. Scott, Org. Lett. 2000, 2, 3679–
3681; b) For a recent review concerning piperidine synthesis
strategies, see: P. M. Weintraub, J. S. Sabol, J. M. Kane, D. R.
Borcherding, Tetrahedron 2003, 59, 2953–2989.
[2] B. E. Smart, J. Fluorine Chem. 2001, 109, 3–11.
[3] a) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637–
643; b) F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27–33 and
references cited therein.
[4] a) J.-P. Bégué, D. Bonnet-Delpon, in Chimie bioorganique et
médicinale du fluor, EDP Sciences/CNRS Ed., 2005; b) Fluo-
roorganic Chemistry: Synthetic Challenge and Biomedical Re-
wards (Eds.: G. Resnati, V. A. Soloshonok), Tetrahedron Sym-
posia-in-Print, No 58; Tetrahedron 1996, 52, 1–330.
[5] a) W. R. Dolbier Jr, J. Fluorine Chem. 2005, 126, 157–163; b)
H. Schofield, J. Fluorine Chem. 1999, 100, 7–11.
[6] For a review concerning monotrifluoromethylated saturated
cycles see:P. Lin, J. Jiang, Tetrahedron 2000, 56, 3635–3671.
[7] J. Jiang, H. Shah, R. J. DeVita, Org. Lett. 2003, 5, 4101–4103.
[8] J. Jiang, R. J. DeVita, G. A. Doss, M. T. Goulet, M. J. Wyvratt,
J. Am. Chem. Soc. 1999, 121, 593–594.
1
65%) as a yellow oil. H NMR (CDCl3, complex spectrum due to
the coexistence of amide rotamers): δ = 6.29–5.06 (m, 4 H), 2.88–
2.72 (m, 4 H), 2.18–2.05 (m, 2 H), 1.59 (br. s, 1 H), 1.42–1.23 (m,
7 H), 0.88 (t, J = 8 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 157.7,
138.6, 134.7, 128.4, 125.5, 122.7 (q, JC–F = 215.5 Hz), 115.2 (q,
JC–F = 287 Hz), 54.4, 54.1, 42.5, 32.5, 31.3, 28.6, 22.4, 13.9 ppm.
IR (neat) ν
= 3026, 2960, 2931, 2861, 1732, 1709, 1430, 1274,
˜
max
1227, 1178, 1149, 993 cm–1. EI-MS (70 eV): m/z = 385 [M]+ (30),
215 (30), 202 (30), 175 (30), 123 (100), 91 (70), 79 (70), 55 (30), 41
(40).
( )-(2R*,4S*,6S*)-6-(Nona-1,3-dienyl)-2-(trifluoromethyl)piperidin-
4-ol (42): By starting from compound 41 (150 mg, 0.39 mmol) in
anhydrous methanol (10 mL) and sodium borohydride (29 mg,
0.78 mmol), as described in the procedure employed for the synthe-
sis of compound 37, compound 42 (84 mg, 74%) was obtained after
purification by column chromatography (ethyl acetate/cyclohexane,
[9] T. Okano, M. Fumoto, T. Kusukawa, M. Fujita, Org. Lett.
2002, 4, 1571–1573.
[10] For representative examples of preparations of α-(trifluorome-
thyl)piperidines and -piperideines see: a) Ref.[8]; b) S. Gille, A.
Ferry, T. Billard, B. R. Langlois, J. Org. Chem. 2003, 68, 8932–
8935; c) M. V. Spanedda, M. Ourévitch, B. Crousse, J.-P.
Bégué, D. Bonnet-Delpon, Tetrahedron Lett. 2004, 45, 5023–
5025; d) G. Margueur, J. Legros, F. Meyer, M. Ourévitch, B.
Crousse, D. Bonnet-Delpon, Eur. J. Org. Chem. 2005, 1258–
1265.
[11] a) S. Rougnon Glasson, C. Tratrat, J.-L. Canet, P. Chalard, Y.
Troin, Tetrahedron: Asymmetry 2004, 15, 1561–1567; b) S.
Rougnon Glasson, J.-L. Canet, Y. Troin, Tetrahedron Lett.
2000, 41, 9797–9802; c) S. Ciblat, P. Besse, J.-L. Canet, Y. Troin,
H. Veschambre, J. Gelas, Tetrahedron: Asymmetry 1999, 10,
2225–2235.
1
1:4) as a white solid. M.p. 93–95 °C. H NMR (CDCl3): δ = 6.17
(dd, J = 15 and 10 Hz, 1 H), 6.00 (dd, J = 15 and 10 Hz, 1 H),
5.68 (m, 1 H), 5.55 (dd, J = 15 and 7 Hz, 1 H), 3.74 (m, 1 H), 3.23
(m, 2 H), 1.95–2.20 (m, 4 H), 1.60 (br. s, 3 H), 1.43–1.21 (m, 8 H),
0.88 (t, J = 7 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 135.9, 131.5,
131.4, 129.2, 125.2 (q, JC–F = 279 Hz), 67.9, 56.4 (q, JC–F = 29 Hz),
56.3, 41.1, 33.6, 32.6, 31.4, 28.9, 22.5, 14.0 ppm. IR (KBr) ν
=
˜
max
3263, 1658, 1266, 1190, 1157, 1086, 988, 886 cm–1. EI-MS (70 eV):
m/z = 291 [M]+ (35), 234 (75), 220 (85), 181 (100), 112 (40). HR-
ESI-MS calculated for C15H23F3N [M – H2O + H]+: 274.1783;
found 274.1771.
[12] a) S. Ciblat, P. Besse, V. Papastergiou, H. Veschambre, J.-L.
Canet, Y. Troin, Tetrahedron: Asymmetry 2000, 11, 2221–2229;
b) S. Ciblat, P. Calinaud, J.-L. Canet, Y. Troin, J. Chem. Soc.,
Perkin Trans. 1 2000, 353–357.
( )-(2R*,4S*,6R*)-6-Nonyl-2-(trifluoromethyl)piperidin-4-ol (Tri-
fluoro-241 D) (22): By starting from compound 42 (65 mg,
0.22 mmol) in anhydrous methanol (10 mL), ammonium formate
(70 mg, 1.1 mmol), and Pd(OH)2/C (20%, 20 mg), as described in
the procedure employed for the synthesis of compound 23, com-
pound 22 (61 mg, 93%) was obtained as a white solid without need
for purification. M.p. 78.4–80.9 °C. 1H NMR (CDCl3): δ = 3.71
(m, 1 H), 3.18 (m, 1 H), 2.58 (m, 1 H), 2.14 (dQ, J = 12 and 2.5 Hz,
1 H), 2.0 (dQ, J = 12.5 and 2 Hz, 1 H), 1.56 (br. s, 2 H), 1.49–1.26
(m, 17 H), 1.07 (q, J = 11.5 Hz, 1 H), 0.88 (t, J = 7 Hz, 3 H) ppm.
13C NMR (CDCl3): δ = 125.3 (q, JC–F = 279 Hz), 68.2, 56.7 (q,
JC–F = 29 Hz), 54.4, 41.2, 36.5, 34.2, 31.9, 29.6, 29.5, 29.3, 25.8,
[13] For successful application of our methodology in enantioselec-
tive synthesis of indolizidine alkaloids see: F. A. Davis, B.
Yang, Org. Lett. 2003, 5, 5011–5014.
[14] A. Bariau, J.-Ph. Roblin, Y. Troin, J.-L. Canet, Synlett 2005,
1731–1733.
[15] For recent reviews concerning the chemistry of fluoral-derived
imines, iminiums, and hemiaminals see: a) J.-P. Bégué, D. Bon-
net-Delpon, B. Crousse, J. Legros, Chem. Soc. Rev. 2005, 34,
562–572; b) T. Billard, S. Gille, A. Ferry, A. Barthélémy, C.
Christophe, B. R. Langlois, J. Fluorine Chem. 2005, 126, 189–
196.
[16] For an example of a stereoselective synthesis of a trifluoro ana-
logue of an indolizidine alkaloid containing an α-(trifluoro-
methyl)piperidine moiety, see: G. Kim, N. Kim, Tetrahedron
Lett. 2005, 46, 423–425.
22.7, 14.1 ppm. IR (KBr) ν
= 3269, 2964, 1264, 1191, 1146,
˜
max
1089, 1043 cm–1. EI-MS (70 eV): m/z = 295 [M]+ (1), 168 (100),
150 (25), 124(20). HR-ESI-MS calculated for C15H29F3NO [M+H]+
296.2201; found 296.2195.
[17] M. S. Raasch, J. Org. Chem. 1962, 27, 1406–1409.
[18] A. M. Islam, R. A. Raphael, J. Chem. Soc. 1955, 3151–3154.
3432
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3421–3433

α-Trifluoromethyl Analogues of Piperidine Alkaloids
FULL PAPER
[19] R. L. Augustine, in: Catalytic Hydrogenation (Ed.: M. Dekker
Inc.): New York, 1965, p. 23.
[25] a) H. Molines, C. Wakselman, J. Fluorine Chem. 1980, 16, 97–
101; b) H. Plenkiewicz, W. Dmowski, M. Lipinski, J. Fluorine
Chem. 2001, 111, 227–232.
[26] T. W. Greene, P. G. Wuts, in: Protective groups in organic syn-
thesis, 3rd ed., John Wiley & Sons, New York, 1999, p. 307.
[27] T. W. Greene, P. G. Wuts, in: Protective groups in organic syn-
thesis, 3rd ed., John Wiley & Sons, New York, 1999, p. 557.
Received: February 23, 2006
[20] A. Ates, A. Gautier, B. Leroy, J.-M. Plancher, Y. Quesnel, I. E.
Markò, Tetrahedron Lett. 1999, 40, 1799–1802.
[21] GC/MS analysis of the crude reaction product.
[22] A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryan-
off, R. D. Shah, J. Org. Chem. 1996, 61, 3849–3862.
[23] For characterization and unique synthesis (racemic) see: J. N.
Tawara, P. Lorenz, F. R. Stermitz, J. Nat. Prod. 1999, 62, 321–
323.
Published Online: June 7, 2006
[24] H. Ogoshi, H. Mizushima, H. Toi, Y. Aoyama, J. Org. Chem.
1986, 51, 2366–2368.
Eur. J. Org. Chem. 2006, 3421–3433
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www.eurjoc.org
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