Asymmetric synthesis of trifluoromethyl-piperidine based γ-amino acids and of trifluoromethyl-indolizidines

Article abstract of DOI:10.1016/j.jfluchem.2012.11.006

The asymmetric synthesis of trifluoromethyl-piperidine-based γ-aminoacids and of indolizidines bearing a trifluoromethyl group is reported. These rarely described compounds are prepared in a highly enantio-enriched form employing as key step an intramolecular Mannich type process, involving an enantiopure Tfm-aminoketal and ethyl oxobutenoate as aldehyde partner. Used strategy together with obtained compounds allows the access to a wide range of Tfm-N-(poly)heterocycles, structures of obvious interest for the research of new bioactive drugs.

Full text of DOI:10.1016/j.jfluchem.2012.11.006

Journal of Fluorine Chemistry 145 (2013) 8–17
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Asymmetric synthesis of trifluoromethyl-piperidine based
g-amino acids and of
trifluoromethyl-indolizidines
Wahid Bux Jatoi a,b, Agnes Desiront , Aurelie Job a,d, Yves Troin c,d, Jean-Louis Canet c,d,
a,d
*
`
´
a Clermont Universite´, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France
b Department of Chemistry, Shah Abdul Latif University, Khairpur, 66020 Sindh, Pakistan
c Clermont Universite´, ENSCCF, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France
d CNRS, UMR 6296, ICCF, F-63171 Aubie`re, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The asymmetric synthesis of trifluoromethyl-piperidine-based
g-aminoacids and of indolizidines
Received 5 October 2012
bearing a trifluoromethyl group is reported. These rarely described compounds are prepared in a highly
enantio-enriched form employing as key step an intramolecular Mannich type process, involving an
enantiopure Tfm-aminoketal and ethyl oxobutenoate as aldehyde partner. Used strategy together with
obtained compounds allows the access to a wide range of Tfm-N-(poly)heterocycles, structures of
obvious interest for the research of new bioactive drugs.
Received in revised form 15 November 2012
Accepted 17 November 2012
Available online 29 November 2012
Keywords:
ß 2012 Elsevier B.V. All rights reserved.
Intramolecular Mannich reaction
Asymmetric synthesis
Trifluoromethyl-piperidines
Trifluoromethyl-indolizidines
1. Introduction
niable interest for the research of new bioactive structures, CF3-
piperidine-based
targeted (Fig. 1).
g-amino acids 1 and indolizidines 2 were
Due to the therapeutic benefits issued from the incorporation of
fluorine atom(s) into the skeleton of bioactive molecules, fluoro-
organic chemistry became a major research field for pharmaceuti-
cal industry [1]. As a consequence, organo-fluorine chemistry
makes the object of continuous and intensive research efforts [2].
Meanwhile, some areas remain poorly explored, as the stereo-
selective synthesis of saturated N-heterocycles bearing a trifluor-
omethyl (CF3) group, and, among these challenging targets [3], the
case of CF3-piperidines. Effectively, despite the high potential of
the piperidine ring system for drug discovery [4], enantio-enriched
trifluoromethylated analogues have been very rarely described
[5,6].
2. Results and discussion
The asymmetric synthesis of the trifluoromethylated analogue
1 of g-aminobutyric acid (GABA) was considered at first. GABA is
the main inhibitory neurotransmitter in the central nervous
system and several important neurological or psychiatric disorders
are associated with its deficiency. Unfortunately, inability of GABA
to cross the blood-brain barrier makes its general administration
(oral or intravenous) vain for the treatment of such illness. As a
consequence, research toward more lipophilic and active analo-
gues received considerable attention. Nevertheless, among the
multiple studies engaged to solve this problem [9], a very few
described the enantioselective synthesis of structures possessing a
piperidine backbone. Furthermore and as far as we know, only one
In this context, we have communicated [7] a highly stereo-
selective access to enantiopure
a-CF3-piperidines relying on an
intramolecular Mannich strategy [8] for the key cyclization step
(Scheme 1).
In order to explore the synthetic potential of this approach, we
decided to apply it to the elaboration of original fluorinated
(poly)heterocyclic frameworks. Because they represent an unde-
[10] CF3-piperidine bearing also a
compound) has been described [11].
Because the intramolecular Mannich route seemed appropriate
for the stereoselective construction of piperidine-based -amino
acids bearing a lipophilic CF3 group, their synthesis was engaged.
As already reported [7] enantiopure [12] antipodes of
aminoketal key synthon 3 were easily prepared in a conventional
three steps sequence from fluorinated enone 4 [13] via inter-
mediates 5–6, but also in a highly diastereoselective manner [14]
g-amino acid function (achiral
g
b
-
´
* Corresponding author at: Clermont Universite, ENSCCF, Institut de Chimie de
Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
Tel.: +33 (0)4 73 40 70 32.
E-mail address: j-louis.canet@ensccf.fr (J.-L. Canet).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.11.006

W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
9
H
F3C
N
R
CF3
O
O
+
RCHO
NH2
O
O
Scheme 1. A stereoselective access to Tfm-piperidines.
H
F3C
N
F3C
N
CO2H
*
*
*
*
2
1
Fig. 1. Targeted Tfm-N-heterocycles.
using a ‘‘Fox’’ (chiral fluorinated oxazolidine) methodology [15]
involving oxazolidine 7 [16] and enoxysilane 8 (Scheme 2).
Next was the key cyclization step. Thus, reaction of aminoketal
(+)-3 with ethyl (E)-oxobutenoate was conducted under our
classical acidic intramolecular Mannich process conditions [8]. An
interesting diastereoselectivity was achieved (de = 85% from GC/
MS of the crude). The expected [8] cis-2,6-disubstituted CF3-
piperidine (+)-11 was isolated in 68% yield (Scheme 3) with an high
enantiopurity (ee = 96% from chiral HPLC, in comparison with the
racemic material). Our first free azacyclic
g
-amino acid (ꢀ)-12 was
then easily obtained from racemic 11. A simple palladium hydroxide
catalyzed saturation of the double bond was followed by saponifica-
tion of the resulting ester (ꢀ)-13. Acidic work-up then migration of
the formed hydrochloride through an ion-exchange resin furnished
(ꢀ)-12 (87% overall yield).
Scheme 2. Asymmetric synthesis of keto-protected Tfm-aminobutanone.
With enantio-enriched piperidine (+)-11 in hands, we had the
opportunity to propose – to our knowledge – the first asymmetric
synthesis of a CF3-piperidine-based GABA analogue (Scheme 3).
As summarized in Scheme 3, this was efficiently achieved in
three steps from piperidine (+)-11. The dioxane moiety of (+)-11
was transformed into dithiolane (+)-14 which, upon hydrogena-
tion/hydrogenolysis using excess of Raney nickel in ethanol at
reflux furnished the cyclic
g-aminoester (+)-15. Finally, saponifi-
cation of the latter followed by purification on a Dowex1 resin
Scheme 3. Stereoselective preparation of Tfm-piperidine-based g-amino acids.

10
W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
O
liberated the targeted heterocycle (ꢁ)-16 in a 71% total isolated
yield. As observed – and as already proven [7,17] with other related
series – that these reaction conditions did not provoke any
H
N
F3C
CO2H
F3C
N
, NEt3
Cl
N
I
epimerization so no racemization, we assume that CF3-azacyclic g-
amino acid (ꢁ)-16 such synthetized presents an excellent
enantiomeric purity (ee = 96%). Moreover, we assume also that,
with poly-functionalized intermediates such as piperidine 11, the
results described herein open a stereoselective entry to a wide
range of new lipophilic and constrained GABA analogues.
O
O
O
O
CH2Cl2, r. t.
67%
( )-12
Scheme 4. Synthesis of a Tfm-indolizidinone.
( )-17
Next was the valuation of this intramolecular Mannich
methodology toward the construction of trifluoromethylated
indolizidine-type systems. Indeed, although this bicyclic frame-
work is commonly encountered in Nature and even if it has been
outlined [18] that the incorporation of a CF3 group in an alkaloid
skeleton may serve the development of new bio-active com-
pounds, the selective synthesis of mono CF3 indolizidines remains
a quasi virginal research domain. Effectively, we were able to find
in the literature only two CF3-indolizidines [5d,19] and only five
CF3-indolizidinones [18,19]. It has to be noticed that among these
scarce compounds, only one indolizidine has been obtained in a
non-racemic form (trifluoromethylated analogue of the well
known alkaloid monomorine [5d]). For our own, we thought that
enantiopure indolizin(on)es would be quite rapidly attainable
Scheme 4). The corresponding indolizidine would be at this stage
easily obtained from 17 by lithium aluminum hydride or borane
mediated deoxygenation of the amido group. Anyway, as we wished
to develop a more concise and in particular a more general pathway
to this molecular scaffold, allowing the selective introduction of a
supplementary stereogenic center, an alternative route was foreseen
(Scheme 5).
We reasoned that trifluoromethyl indolizidines 18 would
directly arise from simple hydrogenation of enone 19 through
an double bond saturation – intramolecular reductive amination
cascade [21]. Access to key unsaturated ketones 19 appeared
conceivable by the use of Grignard reagents addition onto Weinreb
amide 20, intramolecular Mannich reaction adduct of amine 3 and
functionalized aldehyde 21.
Synthesis of enal 21 was envisaged by oxidation of allylic
alcohol 22, available in two steps from maleimide, according to
Jacobi’s procedure [22] (Scheme 6).
Treatment of alcohol 22 with manganese dioxide at 60 8C in
toluene furnished in 94% yield aldehyde 21. Next was its
employment in our Mannich-type process. Unexpectedly, all
cyclization trials conducted either with amines 3 or 23, failed to
give piperidine 20 (<10%, GC/MS) efficiently, but yielded in a
reproducible manner the transacetalization products 24. This very
from our piperidine-based
(Scheme 4).
g-aminoesters or derived amino acids
First direct cyclization attempts concerned product 13, but
gave disappointing results. Whatever the reaction conditions
involved – use of an organic base or of a Lewis acid – the formation
of the expected heterobicycle 17 could not be observed, starting
material remaining intact. To circumvent this difficulty, the
lactamization of amino acid 12 was taken into account. Thus,
treatment of (ꢀ)-12 with Mukaiyama’s reagent [20], at room
temperature in dichloromethane in the presence of triethylamine,
resulted this time in the clean formation of indolizidinone (ꢀ)-17,
the first trifluoromethyl aza-bicyclic g-lactam (67% isolated yield,
R
R
*
R
H
F C
3
N
F C
N
F C
3
N
3
O
O
O
O
O
R
O
O
18
O
O
H
N
H
N
F C
3
F C
OMe
3
N
Me
O
O
O
O
19
20
O
OMe
OHC
N
3
+
Me
21
Scheme 5. Retrosynthetic pathway to Tfm-indolizidines.

W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
11
O
O
O
H
N
MnO2
11
F3C
OMe
HO
OMe
OMe
N
N
OHC
N
tol., 60°C
94%
Me
Me
Me
21
22
X
X
( )-14
( ) n
( ) n
O
O
20 X = O, n = 2
25 X = S, n = 1
CF3
O
OMe
O
0.3M NaOH, MeOH,
21
N
+
then HCl
NH2
70-80%
O
M
( ) n
24
23, n = 1
3, n = 2
O
N
Cl
H
H
H
MeO
Me
F3C
N
OMe
F3C
N
CO2H
NH.HCl, NEt3
, CH2Cl2, r.t.
< 10%
Me
S
S
O
S
S
H
N
79%
F3C
OMe
N
Cl
( )-27
RMgCl
N
( )-26
I
Me
O
O
20
( ) n
degradation
Scheme 6.
Scheme 7.
disappointing result forced us to revisit our synthetic scheme. For
this reason, piperidines 11 and 14 were submitted to Weinreb’s
procedure [23] in order to prepare the corresponding amides 20
and 25, but with no more success, due to their degradation during
the reaction (Scheme 7).
then furnished expediently the wished CF3-indolizidine (ꢁ)-30 in a
40% overall yield from (ꢁ)-11.
In order to prepare related trifluoromethylated polycyclic
systems but incorporating a supplementary asymmetric center,
a similar pathway was considered (Scheme 8).
Finally, saponification of ester 14 followed by treatment of the
resulting acid 26 with N,O-dimethylhydroxylamine hydrochloride,
in the presence of triethylamine and of Mukaiyama’s coupling
reagent, allowed us to get the Weinreb amide 27. Unluckily, using
various Grignard reagents under different reaction conditions, it
has never been possible to obtain cleanly the desired dithio
analogues of ketones 19, due to extensive degradation. In our
minds, these last and surprising failures condemned the ‘‘Weinreb
route’’ to sink into oblivion.
Addition of methyl magnesium bromide on aldehyde (ꢁ)-28,
carried out at -78 8C in tetrahydrofuran, led in a 71% yield to an
inseparable mixture of epimers 31, that was oxidized with MnO2 to
give the corresponding enone (ꢁ)-32. Palladium hydroxide
catalyzed hydrogenation of (ꢁ)-32 then afforded, highly stereo-
selectively, (only one stereoisomer from GC/MS and 1H NMR data of
the crude reaction mixture) the three stereogenic centers-contain-
ing CF3-indolizidine (ꢁ)-33 (24% overall yield from piperidine 28).
Applying the same reaction sequence, using butyl magnesium
chloride instead of methyl magnesium bromide, a new CF3-
indolizidine (+)-34 – a trifluoro-analogue enantiomer of alkaloid
monomorine [24] – was formed as the sole detectable stereoiso-
mer, in three steps and in 29% overall yield from enal (ꢁ)-28.
Relative all-cis and therefore absolute configuration of the newly
created stereogenic carbons, represented in Scheme 8, were
assigned in total respect with unambiguous literature data
[5d,21]. As it was established that in these series experimental
conditions entailed no epimerization and in consequence no
racemization (see above), we can consider that CF3-indolizidines
described here possess an identical enantio-purity to those of
starting piperidine 11 (ee = 96%).
Anyway, because transformation of an
a,b-unsaturated ester
into the corresponding enal or alkyl enone doesn’t constitute a
major problem, we redefined a synthetic scheme starting from CF3
piperidine (ꢁ)-11, as shown in Scheme 8. Reduction of (ꢁ)-11
using strictly one equivalent of diisobutyl aluminum hydride at
low temperature (ꢁ78 8C) led to a statistical mixture of unreacted
ester, parent aldehyde (ꢁ)-28 and alcohol (ꢁ)-29. It appeared so
preferable to completely reduce the ester function with an excess
of reducing agent. Allylic alcohol (ꢁ)-29 thus conveniently
prepared (90% yield) was subsequently converted into aldehyde
(ꢁ)-28 by MnO2 mediated oxidation. Catalytic hydrogenation of
(ꢁ)-28 using Pearlman’s reagent at room temperature in ethanol
Scheme 8. Preparation of highly enantio-enriched Tfm-indolizidines.

12
W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
3. Conclusion
Saturated NaHCO3 (25 mL) was added before extraction with
ethyl acetate (3ꢂ 150 mL) and the combined organic extracts were
dried over Na2SO4, filtered then concentrated under reduced
pressure. Silica gel column chromatography (ethyl acetate/
cyclohexane = 1/3) gave title compound 5 (1/1 inseparable mixture
of diastereoisomers, 13.8 g, yield: 92%) as a pale yellow oil. Rf: 0.65
(ethyl acetate/cyclohexane = 1/3). dH (400 MHz, CDCl3) 7.30 (m,
5H, H-Ar); 4.08 (q, J = 6.5 Hz, 0.5H, 1st dia); 4.00 (q, J = 6.5 Hz, 0.5H,
2nd dia), 3.68 (m, 0.5H, 1st dia), 3.42 (m, 0.5H, 2nd dia), 2.76–2.44
(m, 2H), 2.16 (s, 1.5H, 1st dia), 2.02 (s, 1.5H, 2nd dia), 1.60 (br s, 1H,
NH), 1.34 (d, J = 6.5 Hz, 1.5H, 1st dia), 1.32 (d, J = 6.5 Hz, 1.5H, 2nd
dia). dC (100 MHz, CDCl3) 205.7, 140.3, 128.6, 128.2, 127.4, 126.3
(q, JC–F = 283 Hz, CF3), 67.2, 62.2, 53.5 (q, JC–F = 29 Hz), 43.0, 30.6. dF
(376 MHz, CDCl3) ꢁ77.9 (1st dia), ꢁ77.0 (2nd dia). EI-MS (70 eV)
m/z 259 (M+, 1), 244 (100), 200 (25), 186 (30), 159 (40), 120 (50),
105 (90), 77 (40), 43 (50). HR-ESI-MS calculated for C13H17NOF3
(M+H)+: 260.1262, found 260.1258.
We have reported herein the highly stereoselective syntheses of
original trifluoromethylated saturated N-(poly)heterocycles. These
recognized challenging – and in consequence very scarcely
described compounds – were prepared in a straightforward
fashion. A maximum of six steps starting from a readily available
enantiopure a-CF3-aminoketal chiron was necessary. An intramo-
lecular Mannich-type process constituted the key cyclization step.
Simple synthetic methods, associated with polyfunctional CF3-
structures isolated – possessing notably a latent keto function
susceptible to endure multiple transformations – make, we think,
this work of great interest for research of new fluorinated bioactive
products.
4. Experimental
4.1. General
4.1.2. (2S)-(ꢁ)-1,1,1-Trifluoro-3-(2-methyl-1,3-dioxan-2-yl)-N-
[(R)-1-phenylethyl]propan-2-amine (6a)
Solvents were distilled prior to use. Other reagents were used as
received. Product organic solutions were dried over sodium sulfate
prior to evaporation of the solvents under reduced pressure on a
rotatory evaporator. Thin layer chromatography was performed on
TLC pre-coated aluminum backed silica plates Kieselgel 60 F254
(Merck) or glass backed silica Duracil 25 UV254 (Macherey Nagel).
Spots were visualized using UV light (254 nm) before using an
ethanolic solution of phosphomolybdic acid (heating). Enantio-
meric excess determination of compound 11 was carried out by
HPLC using a Chiralcel OB column (hexane/isopranol, 90/10, v/v,
350 psi). Purifications by column chromatography were carried
out on silica gel (70–230 mesh). Purifications on resin were carried
out on an ion-exchange resin Dowex1 50WX8-100, regenerated
with a solution of 1 N HCl and washed with distilled water. Melting
points were measured by a Reichert plate-heating microscope.
Optical rotations were measured on a Jasco DIP-370 polarimeter at
In a flask fitted with a Dean–Stark apparatus, was added to a
solution of ketone 5 (12 g, 46.3 mmol) in toluene (200 mL),
propane-1,3-diol (8.3 mL, 109 mmol) and p-TsOH (3.5 g,
18.4 mmol). The resulting mixture was heated at reflux for 5 h,
then cooled to room temperature and was treated with 50 mL of a
saturated NaHCO3 solution. The two layers were separated and the
aqueous phase was extracted with ethyl acetate (3ꢂ 100 mL). The
combined organic extracts were dried over Na2SO4, filtered and
concentrated under reduced pressure. The 2 diastereoisomers
were separated by silica gel column chromatography (ethyl
acetate/cyclohexane = 1/19) to afford 5.03 g (34%, pale yellow
liquid) of (2R)-(ꢁ)-6a, and 4.60 g (31%, pale yellow liquid) of
another diastereomer (2S)-(+)-6b.
Analytical data for 6a: Rf: 0.55 (ethyl acetate/cyclohexane = 1/
3). ½a 2D5
ꢃ
¼ ꢁ1:5 (c 1.06, CHCl3).
nmax (liquid film) 3357, 2967, 2874,
1245, 115, 1107, 701. dH (400 MHz, CDCl3) 7.40–7.20 (m, 5H), 4.05
the wavelength of sodium D ray (
l
= 589 nm). The Infra-Red
spectra were recorded on a Perkin Elmer Paragon 500 FTIR
spectrophotometer in the form of film between NaCl plates
(liquids), or in the form of pellets of KBr (solids). The characteristic
(m, 3H,), 3.89 (m, 2H), 3.56 (Qd, 1H, J = 8 and 1.5 Hz), 2.05 (dd, 1H,
J = 15 and 1.5 Hz), 1.95 (m, 2H), 1.82 (dd, 1H, J = 15 and 8 Hz), 1.52
(s, 3H,), 1.46 (m, 1H), 1.40 (d, 3H, J = 6.5 Hz). dC (100 MHz, CDCl3)
145.7, 128.2, 126.8, 127.3 (q, JC–F = 280 Hz, CF3), 98.2, 59.8 (2C),
56.6, 53.7 (q, JC–F = 28 Hz), 40.7, 25.3, 23.1, 19.7. dF (376 MHz,
CDCl3) ꢁ78.0. EI-MS (70 eV) m/z 317 (M+, 2), 302 (60), 258 (45),
244 (65), 200 (30), 186 (35), 120 (35), 105 (100), 101 (80), 77 (20),
43 (40). HR-ESI-MS calculated for C16H23F3NO2 (M+H)+: 318.1681,
found 318.1669.
band positions
19F NMR spectra were recorded on a Bruker Avance spectrometer
at 400.13, 100.61 and 376.50 MHz respectively. Chemical shifts
are reported in ppm relative to solvent residual signals (1H and 13C)
or to hexafluorobenzene (19F,
n
max are expressed in cmꢁ1. 1H NMR, 13C NMR and
d
d
= ꢁ164.9 ppm). The coupling
constants J are given in Hertz (Hz). Electron Impact Mass Spectra
(EI-MS) were obtained on a spectrometer Hewlett Packard 5989B
at 70 eV. High Resolution Electro-Spray Ionization Mass Spectra
4.1.3. (2R)-(+)-1,1,1-Trifluoro-3-(2-methyl-1,3-dioxan-2-yl)-N-[(R)-
1-phenylethyl]propan-2-amine (6b)
´
(HR-ESI-MS) were obtained from the ‘‘Centre Regional de Mesures
´
Physiques de l’Universite Blaise Pascal’’. GC/MS analysis conditions
For preparation of the title compound, see Section 4.1.2.
used for diastereomeric excess determination were as follows:
column: UB 1701 (14% cyanopropylphenyl)-methylpolysiloxane;
injector temperature: 250 8C; oven temperature: 50 8C for 2 min
then heating 50 8C/min until 290 8C.
The abbreviations used for signal descriptions are as:
s: singlet, br s: broad singlet, d: doublet, dd: doublet of doublets,
ddd: doublet of doublet of doublets, dt: doublet of triplets, dq:
doublet of quartets, t: triplet, tt: triplet of triplets, q: quartet, Q:
quintet, m: multiplet, ax: axial, eq: equatorial.
Rf: 0.51 (ethyl acetate/cyclohexane = 1/3). ½a D25
¼ þ27:5 (c 1.06,
ꢃ
CHCl3). nmax (liquid film) 3350, 2973, 2873, 1247, 1150, 1107, 701.
d
H (400 MHz, CDCl3) 7.30 (m, 5H), 3.99 (q, 1H, J = 6.5 Hz), 3.87 (m,
2H), 3.71 (m, 2H), 3.28 (m, 1H), 2.40 (br s, 1H, NH), 1.83 (m, 2H),
1.62 (m, 1H), 1.39 (d, 3H, J = 6.5 Hz), 1.29 (m, 1H), 1.20 (s, 3H). dC
(100 MHz, CDCl3) 144.3, 128.3, 127.2, 127.1, 127.1 (q, JC–F = 282 Hz,
CF3), 98.3, 59.6 (2C), 56.6, 53.0 (q, JC–F = 27 Hz,), 40.0, 24.8, 24.1,
18.8.
d
F (376 MHz, CDCl3) ꢁ77.6. EI-MS (70 eV) m/z 317 (M+, 1), 302
(60), 258 (45), 244 (65), 200 (30), 186 (35), 120 (70), 105 (100), 101
(80), 77 (20), 43 (40). HR-ESI-MS calculated for C16H23F3NO2
(M+H)+: 318.1681, found 318.1669.
4.1.1. (+)-5,5,5-Trifluoro-4-[(R)-1-phenylethylamino] pentan-2-one
(5)
To
(11.07 mL, 91 mmol) and trifluoromethane sulfonic acid
(514 L, 3.4 mmol) in acetonitrile (150 mL) was added, trans-
5,5,5-trifluoropent-3-en-2-one [13] (8.00 g, 58 mmol) and the
reaction mixture was stirred at room temperature for 1 h.
a
stirred solution of (R)-(+)-
a
-methylbenzylamine
4.1.4. (4R)-(ꢁ)-5,5,5-Trifluoro-4-[(1R)-2-hydroxy-1-
phenylethylamino]pentan-2-one (9)
m
To a stirred solution of oxazolidine 7 [16] (1.00 g, 4.6 mmol)
in dichloromethane (30 mL) was added isopropenyloxytri-
methylsilane (1.15 mL, 10 mmol) and the reaction mixture

W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
13
was cooled to ꢁ15 8C before addition of borontrifluoride diethyl
4.1.7. (R)-(+)-1,1,1-Trifluoro-3-(2-methyl-1,3-dioxan-2-yl)propan-
2-amine (3)
Method A: In an hydrogenation vessel (Parr apparatus) was
placed solution of diastereoisomer (2R)-(+)-6b (2.20 g,
etherate (1.41 mL, 10 mmol). The resulting mixture was stirred
at ꢁ15 8C for 1 h before addition of 10 mL of saturated NaHCO3.
After separation, the aqueous layer was extracted with
dichloromethane (3ꢂ 30 mL) and the combined organic extracts
were dried over sodium sulfate, filtered then concentrated under
reduced pressure. Silica gel column chromatography (ethyl
acetate/cyclohexane = 1/3) gave ketone 9 (1.12 g, yield: 89%) as
a colorless liquid. Rf: 0.15 (ethyl acetate/cyclohexane = 1/3).
a
6.94 mmol) in methanol (80 mL), then was added 20% Pd (OH)2/
C (500 mg). The mixture was stirred at room temperature under
hydrogen pressure (50 Psi) for 3 h, then was filtered through
Celite1. The filtrate was concentrated under reduced pressure to
afford very clean amine (S)-(+) 3 (1.39 g, yield: 95%) as a pale
½
a 2D5
ꢃ
¼ ꢁ24:1 (c 0.90, CHCl3). nmax (liquid film): 3421, 3346,
yellow liquid. ½a D25
¼ þ16:0 (c 1.30, CHCl3). Other analytical data
ꢃ
2934, 1719, 1362, 1266, 1165, 1130. dH (400 MHz, CDCl3) 7.32
(m, 5H), 4.03 (dd, 1H, J = 8 and 4 Hz), 3.81 (m, 1H), 3.75 (dd, 1H,
J = 11 and 4 Hz), 3.58 (dd, 1H, J = 11.5 and 8 Hz), 2.94 (br s, 1H,
OH), 2.80 (dd, 1H, J = 17.5 and 4 Hz,), 2.70 (dd, 1H, J = 17.5 and
8.5 Hz), 2.18 (s, 3H), 1.90 (br s, 1H, NH). dC (100 MHz, CDCl3)
205.7, 140.3, 128.6, 128.2, 127.4, 126.3 (q, JC–F = 283 Hz, CF3),
67.2, 62.2, 53.5 (q, JC–F = 29 Hz), 43.0, 30.6. dF (376 MHz, CDCl3)
ꢁ78.1. EI-MS (70 eV) m/z: 244 ((M–CH2OH)+; 100), 186, 159, 104
(10) 77 (20), 43 (15). HR-ESI-MS calculated for C13H16F3NNaO2
(M+Na)+: 298.1013, found 298.1018.
are identical to those given for its enantiomer (ꢁ)-3 (vide supra).
Method B: Following the same procedure but starting from
amino-alcohol (2R)-10, trifluoromethyl amine (R)-(+)-3 was
obtained in 80% yield, after silica-gel column chromatography
(ethyl acetate/cyclohexane = 1/3). ½a D25
¼ þ16:1 (c 1.22, CHCl3).
ꢃ
Other analytical data are identical to those given for its enantiomer
(ꢁ)-3 (vide supra).
4.1.8. (2E)-(+)-Ethyl 3-[(8S, 10R)-10-(trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undec-8-yl]prop-2-enoate (11)
To a stirred solution of amine (R)-(+)-3 (1.00 g, 4.7 mmol) in
toluene (25 mL) was added ethyl trans-4-oxo-2-butenoate 96%
4.1.5. (2R)-2-Phenyl-2-[(2R)-1,1,1-trifluoro-3-(2-methyl-1,3-
dioxan-2-yl)propan-2-ylamino]ethanol (10)
(625
mL, 4.9 mmol) and 500 mg of MgSO4. The mixture was stirred
In a flask fitted with a Dean–Stark apparatus, was added to a
solution of (ꢁ)-9 (915 mg, 3.3 mmol) in benzene (40 mL),
at room temperature for 30 min. Intermediate imine solution thus
formed was filtered in order to remove the magnesium sulfate. A
solution of dry para-toluenesulfonic acid (864 mg, 4.5 mmol,
previously dried for 3 h under Dean–Stark conditions in 70 mL
of toluene) was transferred into the stirred solution of imine at
70 8C and stirred at same temperature for 1 h. The reaction mixture
was cooled to room temperature and treated with a saturated
NaHCO3 solution (15 mL). The two layers were separated and
aqueous layer was extracted with ethyl acetate (3ꢂ 80 mL). The
combined organic extracts were dried over Na2SO4, filtered then
concentrated in vacuo. Purification by silica gel column chroma-
tography (ethyl acetate/cyclohexane = 1/7) afforded piperidine
(+)-11 (1.03 g, yield: 68%) as a yellow oil. Rf: 0.55 (ethyl acetate/
propane-1,3-diol (640
mL, 8.25 mmol) and p-TsOH (316 mg,
1.6 mmol). The resulting mixture was heated at reflux for 2 h
then allowed to cool to room temperature and was treated with a
saturated NaHCO3 solution (10 mL). The two layers were
separated and the aqueous phase was extracted with dichlor-
omethane (3ꢂ 50 mL). The combined organic extracts were dried
over Na2SO4, filtered and concentrated under reduced pressure.
Silica gel column chromatography (ethyl acetate/cyclohex-
ane = 1/3) gave compound 10 (831 mg, yield: 75%), accompanied
with a minor unseparable and unidentified impurity (presence
certainly of a ketals equilibrium, second ketal formed with the
hydroxyl group of the phenylglycinol moiety). Rf: 0.32 (ethyl
acetate/cyclohexane = 1/2). dH (400 MHz, CDCl3) 7.34 (m, 5H),
4.10–3.46 (m, 8H,), 3.40 (br s, 1H, OH), 2.03 (dd, 1H, J = 15 and
2 Hz), 1.99 (m, 1H), 1.87 (dd, 1H, J = 15 and 8 Hz), 1.87 (br s, 1H,
cyclohexane = 1/3). ½a D25
ꢃ
¼ þ18:5 (c 1.02, CHCl3).
nmax (liquid film)
H (400 MHz, CDCl3) 6.81 (dd,
3315, 1715, 1659, 1273, 1173, 1131.
d
1H, J = 16 and 6 Hz), 5.95 (dd, 1H, J = 16 and 0.5 Hz), 4.10 (q, 2H,
J = 7 Hz), 3.85 (t, 2H, J = 5.5 Hz), 3.80 (t, 2H, J = 5.5 Hz), 3.49 (m, 1H),
3.35 (m, 1H), 2.38 (dt, 1H, J = 13 and 2.5 Hz, H-7eq), 2.26 (dt, 1H,
J = 13 and 2.5 Hz, H-11eq), 1.67 (m, 3H), 1.38 (t, 1H, J = 13 Hz, H-
7ax), 1.23 (t, 1H, J = 13 Hz, H-11ax), 1.22 (t, 3H, J = 7 Hz). dC
(100 MHz, CDCl3) 166.2, 148.1, 125.5 (q, JC–F = 277 Hz, CF3), 121.3,
95.8, 60.5, 59.4, 59.3, 54.7 (q JC–F = 30 Hz), 52.9, 38.1, 31.8, 25.3,
NH), 1.80 (s, 3H), 1.46 (m, 1H). dC (100 MHz, CDCl3) 141.2, 128.6,
128.2, 127.3, 126.8 (q, JC–F = 280 Hz, CF3), 98.5, 66.7, 63.2, 60.0
(2C), 54.3 (q, JC–F = 28 Hz), 41.7, 25.1, 19.5. dF (376 MHz, CDCl3)
ꢁ79.0. EI-MS (70 eV) m/z: 318 ((M-Me)+, 5), 302 (100), 244 (90),
186 (50), 159 (25), 106 (25), 43 (40). HR-ESI-MS calculated for
C
16H23F3NO3 (M+H)+: 334.1630, found 334.1615.
14.2.
d
F (376 MHz, CDCl3) ꢁ80.5. EI-MS (70 eV) m/z: 323 (M+, 10),
294 (100), 264 (40), 236 (40), 181 (60), 150 (20), 101 (60), 43 (40).
HR-ESI-MS calculated for C14H21F3NO4 (M+H)+: 324.1423, found
324.1437.
4.1.6. (S)-(ꢁ)-1,1,1-Trifluoro-3-(2-methyl-1,3-dioxan-2-yl)propan-
2-amine (3)
In an hydrogenation vessel (Parr apparatus) was placed a
solution of diastereoisomer 6a (2.20 g, 6.94 mmol) in methanol
(80 mL), then was added 20% Pd(OH)2/C (500 mg). The mixture
was stirred at room temperature under hydrogen pressure (50 Psi)
for 3 h, then was filtered through Celite1. The filtrate was
concentrated under reduced pressure to afford very clean amine
4.1.9. (2E)-(ꢁ)-Ethyl 3-[(8R, 10S)-10-(trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undec-8-yl]prop-2-enoate (11)
Following the preceding procedure, amine (S)-(ꢁ)-3 (1.00 g,
4.7 mmol) and ethyl trans-4-oxo-2-butenoate (680
mL, 5.3 mmol),
afforded piperidine (ꢁ)-11 (1.00 g, yield: 66%) as a yellow oil.
(S)-(ꢁ)-3 (1.40 g, yield: 95%) as a pale yellow liquid. ½a D25
ꢃ
¼ ꢁ16:5
½
a 2D5
ꢃ
¼ ꢁ18:5 (c 1.10, CHCl3). Other analytical data are identical to
(c 1.15, CHCl3). Rf: 0.15 (ethyl acetate/cyclohexane = 1/2). nmax
those given for the compound (+)-11.
(liquid film) 3402, 3338, 2973, 2877, 1617, 1376, 1246, 1152, 1108,
1081, 966, 804.
d
H (400 MHz, CDCl3) 4.00 (m, 2H, H); 3.85 (m, 2H);
4.1.10. (ꢀ)-Ethyl 3[(8S*, 10S*)-10-(trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undecan-8-yl]propanoate (13)
3.76 (m, 1H); 2.11 (br s, 2H, NH2); 1.98 (dd, 1H, J = 14.5 and 1.5 Hz);
1.92 (m, 1H); 1.79 (dd, 1H, J = 14.5 and 10 Hz); 1.49 (s, 3H, Me);
1.30 (m, 1H). dC (100 MHz, CDCl3) 126.5 (q, JC–F = 280 Hz, CF3), 98.2,
59.7, 59.6, 49.6 (q, JC–F = 29 Hz), 40.3, 25.2, 19.5. dF (376 MHz,
CDCl3) ꢁ81.9. EI-MS (70 eV) m/z: 213 (M+, 1), 198 (40), 101 (100),
73 (40), 43 (90). HR-ESI-MS calculated for C8H15F3NO2 (M+H)+:
214.1055, found 214.1050.
To a stirred solution of compound (ꢀ)-11 (500 mg, 1.5 mmol) in
methanol (20 mL) was added Pd(OH)2/C 20% (200 mg). The mixture
was stirred at room temperature under hydrogen atmosphere for 1 h
then filtered through Celite1. The filtrate was concentrated under
reduced pressure then purified by column chromatography on silica
gel (ethyl actetate/cyclohexane = 1/3), to afford saturated piperidine

14
W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
13 (477 mg, yield: 95%) as a colorless liquid. Rf: 0.40 (ethyl acetate/
cyclohexane = 1/3). nmax (liquid film) 3321, 2976, 1731, 1266, 1171,
1133, 1088, 1016. dH (400 MHz, CDCl3) 3.89 (q, 2H, J = 7 Hz), 3.70 (t,
2H, J = 5.5 Hz), 3.63 (t, 2H, J = 5.5 Hz), 3.12 (m, 1H), 2.60 (m, 1H), 2.22
(dt, 1H, J = 13 and 2.5 Hz, H-7eq), 2.17 (t, 2H, J = 7 Hz), 2.02 (dt, 1H,
J = 13 and 2.5 Hz, H-11eq), 1.51 (m, 4H), 1.38 (t, 1H, J = 12.5 Hz, H-
7ax), 1.38 (br s, 1H, NH), 1.25 (t, 3H, J = 7 Hz), 1.15 (t, 1H, J = 12 Hz, H-
11ax). dC (100 MHz, CDCl3) 173.4, 125.5 (q, JC–F = 277 Hz, CF3), 96.3,
60.5, 59.3, 59.2, 55.0 (q, JC–F = 29 Hz), 51.5, 39.0, 32.1, 31.1, 30.6, 25.3,
14.1. dF (376 MHz, CDCl3) ꢁ80.4. EI-MS (70 eV) m/z 325 (M+, 5), 280
(20), 266 (50), 224 (50), 181 (100), 166 (20), 124 (20), 101 (30), 43
(25). HR-ESI-MS calculated for C14H23F3NO4 (M+H)+: 326.1579, found
326.1569.
through Celite1 and the filtrate evaporated under reduced
pressure. The residue was dissolved in dichloromethane (20 mL)
and this organic phase was washed with 1 M NaOH, dried on
Na2SO4 before evaporation of the solvent in vacuo. Silica gel
column chromatography (ethyl acetate/cyclohexane = 1/5)
afforded title compound 15 (83 mg, yield: 80%) as a colorless
liquid. Rf: 0.45 (ethyl acetate/cyclohexane = 1/3). ½a D25
¼ þ12:1 (c
ꢃ
0.96, CHCl3). nmax (liquid film) 3323, 2940, 1732, 1277, 1175, 1116.
dH (400 MHz, CDCl3) 4.12 (q, 2H, J = 7 Hz), 3.12 (m, 1H), 2.56 (m,
1H), 2.37 (t, 2H, J = 7.5 Hz), 1.90–1.64 (m, 5H), 1.46 (br s, 1H, NH),
1.28 (m, 2H), 1.22 (t, 3H, J = 7 Hz), 1.07 (m, 1H). dC (100 MHz,
CDCl3) 173.5, 125.7 (q, JC–F = 277 Hz, CF3), 60.4, 58.4 (q, JC–
F = 29 Hz), 55.5, 31.8, 31.2, 30.5, 24.7, 23.2, 14.1. dF (376 MHz,
CDCl3) ꢁ80.0. EI-MS (70 eV) m/z: 253 (M+, 1), 208 (30), 152 (100),
96 (10), 55 (10). HR-ESI-MS calculated for C11H19F3NO2 (M+H)+:
254.1368, found 254.1359.
4.1.11. (ꢀ)-3-[(8S*, 10S*)-10-(Trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undecan-8-yl]propanoic acid (12)
To a stirred solution of ester 13 (56 mg, 0.17 mmol) in methanol
(5 mL) was added a 0.3 M NaOH solution (1.8 mL, 0.54 mmol). The
mixture was heated at reflux for 1 h then cooled to room
temperature before addition of 1 M HCl (2.5 mL). After evaporation
of the solvents, the residue was dissolved in the minimum quantity
of water and the solution was applied to a column of Dowex1 50
WX 8-100 ion-exchange resin. After elution of water until the
eluent was neutral, elution with 1 M NH4OH followed by
concentration to dryness afforded pure amino acid 12 (47 mg,
yield: 92%) as a white solid. M.p.: 149 8C. Rf: 0.10 (ethyl acetate).
nmax (KBr) 3434, 3240, 2962, 1704, 1276, 1117, 1026, 929. dH
(400 MHz, D2O) 4.08–3.92 (m, 5H, H-10), 3.26 (m, 1H), 2.77 (dt, 1H,
J = 13 and 2.5 Hz, H-7eq), 2.59 (dt, 1H, J = 13 and 2.5 Hz, H-11eq),
2.49–2.32 (m, 2H), 1.97 (m, 1H), 1.85–1.75 (m, 3H), 1.75 (t, 1H,
J = 14 Hz, H-7 ax), 1.52 (dd, 1H, J = 13 and 12.5 Hz, H-11ax). dC
(100 MHz, D2O) 180.1, 123.6 (q, JC–F = 277 Hz, CF3), 95.4, 60.0, 59.9,
54.3 (q, JC–F = 31 Hz), 54.1, 35.5, 32.5, 29.6, 28.6, 24.4.
4.1.14. (ꢁ)-3-[(2S, 6R)-6-(Trifluoromethyl)piperidin-2-yl]propanoic
acid (16)
To a stirred solution of ester (+)-15 (75 mg, 0.29 mmol) in
methanol (5 mL) was added a 0.3 M NaOH solution (1.2 mL,
0.36 mmol). The mixture was heated at reflux for 1 h then cooled to
room temperature before addition of 1 M HCl (2 mL). After
evaporation of the solvents, the residue was dissolved in the
minimum quantity of water and the solution was applied to a
column of Dowex1 50 WX 8-100 ion-exchange resin. After elution
of water until the eluent was neutral, elution with 1 M NH4OH
followed by concentration to dryness afforded pure amino acid 16
as a white solid. M.p.: 160 8C. ½a D25
¼ ꢁ14:6 (c 0.65, MeOH). Rf: 0.10
ꢃ
(ethyl acetate/cyclohexane = 1/1). nmax (KBr) 2500–3500; 1735,
1404, 1263, 1200, 1120. dH (400 MHz, D2O) 3.98 (m, 1H), 3.27 (m,
1H), 2.46 (m, 2H), 2.02 (m, 4H), 1.79 (m, 1H), 1.62 (qd, 1H, J = 13
and 3.5 Hz, H-50ax), 1.51 (qt, 1H, J = 13 and 3.5 Hz, H-40ax), 1.35
(qd, 1H, J = 12.5 and 3.5 Hz, H-30ax).
dC (100 MHz, D2O) 176.8, 122.9
4.1.12. (2E)-(+)-Ethyl 3-[(7S, 9R)-9-(trifluoromethyl)-1,4-dithia-8-
azaspiro[4.5]dec-7-yl]prop-2-enoate (14).
(q, JC–F = 278 Hz, CF3), 58.1, 57.2 (q, JC–F = 32 Hz), 29.4, 27.5, 26.6,
21.3, 20.3. dF (376 MHz, D2O) ꢁ75.5. HR-ESI-MS calculated for
C9H15F3NO2 (M+H)+: 226.1055, found 226.1045.
To
dichloromethane (10 mL), was added dropwise ethanedithiol
(260 L, 2.7 mmol). The resulting
L, 2.7 mmol) and BF3ꢄEt2O (382
a stirred solution of (+)-11 (200 mg, 0.62 mmol) in
m
m
4.1.15. (ꢀ)-(50S*, 8a0S*)-50-(Trifluoromethyl)tetrahydro-10H-spiro[1,3-
dioxane-2,70-indolizin]-30(30H)-one (17)
mixture was refluxed until disappearance (TLC monitoring) of the
starting material, then cooled to room temperature before addition
of an excess of 2 M NaOH. The layers were separated and the
aqueous phase was extracted with dichoromethane (3ꢂ 30 mL).
Combined organic extracts were washed with brine, dried over
Na2SO4, filtered then concentrated in vacuo to give, after
purification by column chromatography on silica gel (ethyl
acetate/cyclohexane = 1/5), title compound 14 (192 mg, yield:
91%) as a yellow oil. Rf: 0.50 (ethyl acetate/cyclohexane = 1/3). nmax
(liquid film) 3310, 2923, 1713, 1658, 1397, 1270, 1172, 1040, 978.
dH (400 MHz, CDCl3) 6.88 (dd, 1H, J = 16 and 6 Hz), 6.03 (d, 1H,
J = 16 Hz), 4.19 (q, 2H, J = 7 Hz), 3.58 (m, 1H), 3.47 (m, 1H), 3.34 (s,
4H), 2.25 (dt, 1H, J = 13 and 2.5 Hz, H-6eq), 2.17 (dt, 1H, J = 13 and
2.5 Hz, H-10eq), 2.0 (dd, 1H, J = 13 and 11.5 Hz, H-6ax), 1.84 (dd,
1H, J = 13 and 11.5 Hz, H-10ax), 1.82 (br s, 1H, NH), 1.30 (t, 3H,
To a stirred solution of 2-chloro-1-methylpyridinium iodide
(19.7 mg, 0.84 mmol) and triethylamine (21
mL, 0.21 mmol) in
anhydrous CH2Cl2 (5 mL) was added compound 12 (20 mg,
0.06 mmol). The resulting mixture was stirred for 2 h at room
temperature before evaporation of solvent under reduced pres-
sure. The residue was purified by column chromatography (ethyl
acetate/cyclohexane = 1/3) to afford title compound 17 (12 mg,
yield: 67%) as a white solid. M.p.: 112 8C. Rf: 0.40 (ethyl acetate/
cyclohexane = 1/3).
nmax (KBr) 2971, 1714, 1407, 1277, 1242, 1135,
1012. H (400 MHz, CDCl3) 4.08 (m, 1H), 3.91 (m, 4H), 3.65 (m, 1H),
d
2.48–2.14 (m, 6H), 1.80–1.63 (m, 3H), 1.59 (t, 1H, J = 13.5 Hz). dC
(100 MHz, CDCl3) 173.5, 125.5 (q, JC–F = 280 Hz, CF3), 96.6, 59.7,
59.6, 54.7, 52.1 (q, JC–F = 33 Hz), 39.3, 32.2, 30.1, 25.1 (2C). dF
(376 MHz, CDCl3) ꢁ72.1. EI-MS (70 eV) m/z: 279 (M+, 10), 259 (15),
220 (100), 210 (25), 181 (40), 152 (50), 123 (40), 110 (60), 83 (30),
55 (30), 42 (25). HR-ESI-MS calculated for C12H17F3NO3 (M+H)+:
280.1161, found 280.1169.
J = 7 Hz). dC (100 MHz, CDCl3) 166.0, 147.8, 128.0 (q, JC–F = 278 Hz,
CF3); 121.5, 64.4, 60.5, 57.1 (q, JC–F = 29 Hz), 56.0, 46.6, 40.5, 39.4,
38.2, 14.2. EI-MS (70 eV) m/z: 341 (M+, 20), 312 (20), 280 (30), 248
(100), 199 (25), 163 (20), 112 (15). HR-ESI-MS calculated for
C
13H19F3NO2S2 (M+H)+: 342.0809, found 342.0792.
4.1.16. (2E)-N-methoxy-N-methyl-4-oxobut-2-enamide (21)
To a stirred solution of alcohol 22 [22] (318 mg, 2.19 mmol) in
toluene (40 mL) was added MnO2 (428 mg, 5 mmol). The mixture
was heated at 60 8C for 4 h, cooled to room temperature then
filtrated through Celite1. The filtrate was concentrated under
reduced pressure and the crude product was purified by
chromatography on silica gel (acetone/dichloromethane = 1/3).
Title compound 21 (295 mg, yield: 94%) was obtained as a yellow
4.1.13. (+)-Ethyl 3-[(2S, 6R)-6-(trifluoromethyl)piperidin-2-
yl]propanoate (15)
To a stirred solution of dithioketal (+)-14 (140 mg, 0.41 mmol)
in absolute ethanol (7 mL) was added W2 Raney nickel (ca.
500 mg). The resulting suspension was heated at refux for 30 min
then cooled to room temperature. The suspension was filtered

W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
15
oil. Rf: 0.55 (ethyl acetate/cyclohexane = 1/1). nmax (liquid film)
2941, 2830, 2735, 1693, 1652, 1423, 1380, 1180, 1118, 997. dH
(400 MHz, CDCl3) 9.80 (d, 1H, J = 7 Hz), 7.38 (d, 1H, J = 16 Hz), 7.05
(dd, 1H, J = 16 and 7 Hz), 3.80 (s, 3H), 3.31 (s, 3H). dC (100 MHz,
CDCl3) 193.6, 164.3, 139.5, 137.7, 62.2, 32.4. EI-MS (70 eV) m/z:
143 (M+, 5), 114 (70), 83 (70), 61 (10), 55 (100).
Title compound (ꢁ)-28 (210 mg, yield: 53%) was obtained as a
colorless oil. Rf: 0.25 (ethyl acetate/cyclohexane = 1/3). ½a D25
¼
ꢃ
ꢁ30:1 (c 1.08, CHCl3). nmax (liquid film) 3306, 2953, 1694, 1275,
1171, 1124, 1088, 974. dH (400 MHz, CDCl3) 9.55 (dd, 1H, J = 7.5 and
1.5 Hz), 6.75 (dd, 1H, J = 16 and 6 Hz), 5.95 (m, 1H), 3.93 (m, 4H),
3.72 (m, 1H), 3.45 (m, 1H), 2.52 (dt, 1H, J = 13 and 2.5 Hz, H-7eq),
2.32 (dt, 1H, J = 13 and 2.5 Hz, H-11eq), 1.76 (m, 2H), 1.65 (br s, 1H),
1.45 (t, 1H, J = 13 Hz, H-7ax), 1.35 (t, 1H, J = 13 Hz, H-11ax). dC
(100 MHz, CDCl3) 193.4, 156.6, 131.7, 125.4 (q, JC–F = 278 Hz, CF3),
95.7, 59.4 (2C), 54.6 (q, JC–F = 30 Hz), 53.1, 38.3, 31.4, 25.2. dF
(376 MHz, CDCl3) ꢁ80.5. EI-MS (70 eV) m/z: 279 (M, 100), 220 (35),
192 (60), 150 (40), 101 (90), 43 (55). HR-ESI-MS calculated for
4.1.17. (ꢀ)-(2E)-N-Methoxy-N-methyl-3-[(7R*,9S*)-9-
(trifluoromethyl)-1,4-dithia-8-azaspiro[4.5]dec-7-yl]prop-2-enamide
(27)
To a stirred solution of triethylamine (112
mL, 1.5 mmol) and 2-
chloro-1-methyl pyridinium iodide (112 mg, 0.44 mmol) in
dichloromethane (3 mL) was added, in one portion, a solution of
C
12H17F3NO3 (M+H)+: 280.1166, found 280.1163.
N,O-dimethylhydroxylamine
0.71 mmol), triethylamine (112
hydrochloride
salt
(70 mg,
m
L, 1.5 mmol) and crude hydro-
4.1.20. (50S, 8a0S)-(ꢁ)-50-(Trifluoromethyl)hexahydro-10H-spiro[1,3-
dioxane-2,70-indolizine] (30)
chloride salt of amino acid 26 (125 mg, 0.35 mmol, prepared by
quantitative saponification of ester 14 according to Section 4.1.11,
in CH2Cl2 (3 mL). The resulting mixture was stirred at room
temperature for 2 h. Evaporation of the solvent, followed by
column chromatography (ethyl acetate/cyclohexane 1/1) afforded
title compound 27 (100 mg, yield: 79% from 14) as a yellow oil. Rf:
0.75 (ethyl acetate). nmax (liquid film) 3301, 2929, 1732, 1633,
1424, 1375, 1274, 1244, 1172, 1134, 1046. dH (400 MHz, CDCl3)
6.90 (dd, 1H, J = 15.5 and 6 Hz), 6.58 (d, 1H, J = 16 Hz), 3.71 (s, 3H),
3.62 (m, 1H), 3.56 (m, 1H), 3.35 (m, 4H), 3.24 (s, 3H), 2.25 (dt, 1H,
J = 13 and 2.5 Hz, H-6eq), 2.17 (dt, 1H, J = 13 and 2.5 Hz, H-10eq),
2.01 (br s, 1H), 2.00 (dd, 1H, J = 13 and 12.5 Hz, H-6ax), 1.91 (dd,
1H, J = 13 and 12.5 Hz, H-10ax). EI-MS (70 eV) m/z: 356 (M+, 25);
325 (55); 242 (25); 199 (50); 84 (100); 42 (55).
To a stirred solution of aldehyde (ꢁ)-28 (72 mg, 0.26 mmol) in
absolute ethanol (5 mL) was added Pd(OH)2/C 20% (100 mg). The
mixture was stirred at room temperature under a hydrogen
atmosphere for 1 h then filtered through Celite1. The filtrate was
concentrated under reduced pressure. Purification on silica gel
column (ethyl acetate/cyclohexane = 1/5) afforded title compound
(ꢁ)-30 (63 mg, yield: 93%) as a colorless oil. Rf: 0.50 (ethyl acetate/
cyclohexane = 1/3). ½a D25
¼ ꢁ31:6 (c 1.0, CHCl3). nmax (liquid film)
ꢃ
2966, 2869, 1341, 1272, 1175, 1126, 1017, 927. dH (400 MHz,
CDCl3) 3.93 (m, 2H), 3.88 (t, 2H, J = 5.5, Hz), 3.23 (m, 1H), 2.83 (m,
1H), 2.44 (br d, 2H, J = 13 Hz, H-6eq and H-7eq), 2.33 (m, 1H), 2.25
(q, 1H, J = 9 Hz), 1.91–1.65 (m, 5H), 1.61 (t, 1H, J = 12.5 Hz, H-6ax),
1.45 (m, 1H), 1.31 (t, 1H, J = 12.5 Hz, H-7ax). dC (100 MHz, CDCl3)
125.6 (q, JC–F = 279 Hz, CF3), 98.8, 60.6, 60.0 (q, JC–F = 29 Hz, C-5),
59.6, 59.2, 51.1, 37.0, 32.8, 29.0, 25.4, 21.5. dF (376 MHz, CDCl3)
ꢁ75.3. EI-MS (70 eV) m/z: 265 (M+, 10), 206 (80), 196 (50), 164
(20), 96 (100), 41 (15). HR-ESI-MS calculated for C12H19F3NO2
(M+H)+: 266.1378, found 266.1378.
4.1.18. (2E)-(ꢁ)-3-[(8R, 10S)-10-(Trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undecan-8-yl]prop-2-en-1-ol (29)
To a cooled (ꢁ10 8C) stirred solution of piperidine (ꢁ)-11
(323 mg, 1 mmol) in toluene (10 mL) was added dropwise a 20%
solution of diisobutyl aluminum hydride in toluene (1.64 mL,
2.2 mmol). The resulting mixture was stirred at ꢁ10 8C for 20 min
before addition of methanol (1 mL). After heating to room
temperature, the resulting mixture was poured into a mixture
of ethyl acetate/saturated sodium chloride (6/1, 70 mL) before
extraction with dichloromethane (4ꢂ 50 mL). The combined
organic extracts were dried over Na2SO4 and filtered. Evaporation
of the solvents, followed by column chromatography on silica gel
(ethyl acetate/cyclohexane = 1/1) afforded alcohol (ꢁ)-29 (253 mg,
yield: 90%) as a colorless liquid. Rf: 0.20 (ethyl acetate/cyclohex-
4.1.21. (3E)-4-[(8R, 10S)-10-(Trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undecan-8-yl]but-3-en-2-ol (31)
To a cooled (ꢁ78 8C) stirred solution of aldehyde (ꢁ)-28
(100 mg, 0.36 mmol) in anhydrous THF (5 mL), under argon, was
added a 3 M solution of methyl magnesium bromide in diethyl
ether (36
mL, 1.1 mmol). The resulting mixture was stirred at
ꢁ78 8C for 15 min then at 0 8C for 1 h. After warming to room
temperature, the reaction mixture was diluted with diethyl ether
(5 mL) and a saturated solution of NH4Cl (3 mL) was added before
extraction with diethyl ether (3ꢂ 10 mL). The combined organic
extracts were dried over Na2SO4, filtered and concentrated under
reduced pressure. Purification by column chromatography on silica
gel (ethyl acetate/cyclohexane 1/1) title compound 31 (inseparable
1/1 epimeric mixture, 75 mg, yield: 71%) as a pale yellow oil. Rf:
0.15 (ethyl acetate/cyclohexane = 1/2). dH (400 MHz, CDCl3) 5.75
(dd, 1H, J = 15.5 and 6 Hz), 5.65 (dd, 1H, J = 15.5 and 6.5 Hz), 4.30
(Q, 1H, J = 6 Hz), 3.93 (t, 2H, J = 5.5 Hz), 3.89 (t, 2H, J = 5.5 Hz), 3.39
(m, 2H), 2.42 (m, 1H), 2.29 (dt, 0.5H, J = 13 and 2.5 Hz, H-11eq, 1st
dia), 2.26 (dt, 0.5H, J = 13 and 2.5 Hz, H-11eq, 2nd dia), 1.74 (Q, 2H,
J = 5 Hz), 1.58 (br s, 2H), 1.44 (t, 1H, J = 13 Hz, H-7ax), 1.29 (t, 1H,
J = 13 Hz, H-11ax), 1.27 (d, 3H, J = 6.5 Hz). EI-MS (70 eV) m/z: 295
(M+, 1), 277 (50), 250 (25), 236 (100), 198 (30), 181 (80), 150 (25),
101 (50), 43 (60).
ane = 1/1). ½a 2D5
ꢃ
¼ ꢁ11:58 (c 1.07, CHCl3). nmax (liquid film) 3407,
H (400 MHz, CDCl3) 5.86
3302, 2962, 1266, 1134, 1020, 974, 862.
d
(dtd, 1H, J = 15.5, 5.5 and 1 Hz), 5.71 (ddt, 1H, J = 15.5, 7 and
1.5 Hz), 4.14 (dd, 2H, J = 5.5 and 1.5 Hz), 3.91 (t, 2H, J = 5.5 Hz), 3.80
(t, 2H, J = 5.5 Hz), 3.42 (m, 2H), 2.43 (dt, 1H, J = 13 and 2.5 Hz, H-
7eq), 2.28 (dt, 1H, J = 13 and 2.5 Hz, H-11eq), 1.74 (Q, 2H,
J = 5.5 Hz), 1.57 (br s, 2H), 1.38 (t, 1H, J = 12.5 Hz, H-7ax), 1.23
(dd, 1H, J = 13 and 12 Hz, H-11ax). dC (100 MHz, CDCl3) 132.5,
130.7, 125.5 (q, JC–F = 277 Hz, CF3), 96.1, 62.7, 59.3, 59.2, 54.6 (q JC–
F = 29 Hz), 53.7, 38.6, 32.0, 25.3.
(70 eV) m/z: 281 (M+, 5), 263 (40), 250 (30), 222 (100), 181 (95),
d
F (376 MHz, CDCl3) ꢁ80.5. EI-MS
150 (40), 101 (80), 69 (50), 43 (60). HR-ESI-MS calculated for
C
12H19F3NO3 (M+H)+: 282.1317, found 282.1325.
4.1.19. (2E)-(ꢁ)3-[(8R, 10S) -10-(Trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undecan-8-yl]prop-2-enal (28)
4.1.22. (3E)-(ꢁ)-4-[(8R, 10S)-10-(Trifluoromethyl)-1,5-dioxa-9-
azaspiro[5.5]undecan-8-yl]but-3-en-2-one (32)
To a stirred solution of alcohol 31 (100 mg, 0.34 mmol) in
toluene (5 mL) was added MnO2 (88 mg, 1.02 mmol). The resulting
suspension was heated at gentle reflux for 5 h, then was cooled to
room temperature and filtered through Celite1. The filtrate was
To a stirred solution of alcohol (ꢁ)-29 (400 mg, 1.4 mmol) in
toluene (15 mL) was added MnO2 (371 mg, 4.27 mmol). The
mixture was heated at 60 8C for 3 h, cooled to room temperature,
then filtrated through Celite1. The filtrate was concentrated under
reduced pressure and the crude product was purified by
chomatography on silica gel (ethyl acetate/cyclohexane = 1/5).
concentrated under reduced pressure. Following,
a silica

16
W.B. Jatoi et al. / Journal of Fluorine Chemistry 145 (2013) 8–17
gel-column chromatography (ethyl acetate/cyclohexane = 1/3)
J = 5.5 Hz), 3.90 (t, 2H, J = 5.5 Hz), 3.58 (m, 1H), 3.44 (m, 1H), 2.55 (t,
2H, J = 7 Hz), 2.46 (dt, 1H, J = 13 and 3 Hz, H-7eq), 2.32 (dt, 1H,
J = 13 and 3 Hz, H-11eq), 1.75 (Q, 2H, J = 5.5 Hz), 1.62 (br s, 1H),
1.58 (Q, 2H, J = 7 Hz), 1.42 (t, 1H, J = 12 Hz, H-7ax), 1.38–1.25 (m,
afforded title compound 32 (50 mg, yield: 50%) as yellow oil. Rf:
0.44 (ethyl acetate/cyclohexane = 1/1). ½a D25
¼ ꢁ28:6 (c 1.4, CHCl3).
ꢃ
n
max (liquid film) 3309, 2971, 1680, 1632, 1265, 1173, 1130, 1021,
979. dH (400 MHz, CDCl3) 6.70 (dd, 1H, J = 16 and 6 Hz), 6.50 (dd,
1H, J = 16 and 1.5 Hz), 3.95 (t, 2H, J = 5.5 Hz), 3.90 (t, 2H, J = 5.5 Hz),
3.60 (m, 1H), 3.45 (m, 1H), 2.47 (dt, 1H, J = 13 and 2.5 Hz, H-7eq),
2.32 (dt, 1H, J = 13 and 2.5 Hz), 2.28 (s, 3H), 1.75 (m, 2H), 1.65 (br s,
1H), 1.45 (t, 1H, J = 12 Hz, H-7ax), 1.32 (t, 1H, J = 12 Hz, H-11ax). dC
(100 MHz, CDCl3) 198.3, 146.8, 130.3, 125.4 (q, JC–F = 277 Hz, CF3),
95.8, 59.4, 59.3, 54.1 (q, JC–F = 29 Hz), 53.2, 38.3, 31.7, 27.2, 25.2. dF
(376 MHz, CDCl3) ꢁ80.5. EI-MS (70 eV) m/z: 293 (M+, 90), 250 (65),
234 (50), 192 (100), 181 (60), 150 (50), 101 (65), 82 (50), 43 (90).
HR-ESI-MS calculated for C13H19F3NO3 (M+H)+: 294.1317, found
294.1318.
3H), 0.90 (t, 3H, J = 7 Hz). dC (100 MHz, CDCl3) 200.5, 145.7, 129.2,
125.4 (q, JC–F = 277 Hz, CF3), 95.8, 59.7, 59.4, 54.6 (q, JC–F = 29 Hz),
53.2, 40.2, 38.3, 31.8, 26.1, 25.2, 22.3, 13.8. dF (376 MHz, CDCl3)
ꢁ80.5. EI-MS (70 eV) m/z: 335 (M+, 85), 276 (35), 250 (100), 192
(70), 181 (95), 150 (35), 123 (65), 101 (70), 41 (35). HR-ESI-MS
calculated for C16H25F3NO3 (M+H)+: 336.1787, found 336.1769.
4.1.26. (30S, 50S, 8a0S)-(+)-30-Butyl-50-(trifluoromethyl)hexahydro-
10H-spiro[1,3-dioxane-2,70-indolizine] (34)
Compound 34 was prepared from piperidine (ꢁ)-36 (100 mg,
0.29 mmol) following the procedure described above for the
synthesis of (ꢁ)-33. The product was purified on silica gel column
(ethyl acetate/cyclohexane = 1/2) to afford title compound (+)-34
(75 mg, yield: 79%) as a yellow oil. Rf: 0.78 (ethyl acetate/
4.1.23. (ꢁ)-(30S, 50S, 8a0S)-30-Methyl-50-(trifluoromethyl)hexahydro-
10H-spiro[1,3-dioxane-2,70-indolizine] (33)
To a stirred solution of enone (ꢁ)-32 (62 mg, 0.21 mmol) in
absolute ethanol (5 mL) was added Pd(OH)2/C 20% (100 mg). The
mixture was stirred under an hydrogen atmosphere for 1 h then
filtered through Celite1. The filtrate was concentrated under
reduced pressure. Following, a purification on silica gel column
(ethyl acetate/cyclohexane = 1/2) afforded indolizidine (ꢁ)-33
(40 mg, yield: 68%) as a yellow oil. Rf: 0.60 (ethyl acetate/
cyclohexane = 1/2). ½a D25
¼ þ1:8 (c 1.0, CHCl3). nmax (liquid film)
ꢃ
2960, 1468, 1340, 1272, 1165, 1116 (C–O), 1090 (C–O), 1000, 928.
d
H (400 MHz, CDCl3) 3.89 (m, 4H), 3.95 (m, 1H), 2.81 (m, 1H), 2.47
(m, 1H), 2.42 (m, 2H, H-6eq and H-7eq), 1.85–1.10 (m, 14H), 0.87 (t,
3H, J = 7 Hz). C (100 MHz, CDCl3) 125.5 (q, JC–F = 279 Hz, CF3), 96.7,
d
62.4, 60.7, 60.1 (q, JC–F = 27 Hz), 59.6, 59.1, 37.6, 37.3, 34.5, 30.6,
29.1, 29.0, 25.4, 22.7, 14.1. dF (376 MHz, CDCl3) ꢁ73.8. EI-MS
(70 eV) m/z: 321 (M–C4H9)+, 264 (100), 206 (20), 188 (90), 41 (20).
HR-ESI-MS calculated for C16H27F3NO2 (M+H)+: 322.1994, found
322.1984.
cyclohexane = 1/3). ½a D25
ꢃ
¼ ꢁ25:6 (c 0.92, CHCl3).
nmax (liquid film)
2960, 1593, 1340, 1272, 1114, 1086, 1039, 997. dH (400 MHz,
CDCl3) 3.92 (m, 2H), 3.88 (t, 2H, J = 5.5 Hz), 2.95 (m, 2H, H-5), 2.58
(m, 1H), 2.45 (dt, 1H, J = 13 and 2.5 Hz, H-6eq), 2.40 (dt, 1H, J = 13
and 2.5 Hz, H-7eq), 2.06–1.96 (m, 1H), 1.79–1.68 (m, 2H), 1.66–
1.58 (m, 2H), 1.55–1.40 (m, 2H), 1.35 (t, 1H, J = 12.5 Hz, H-6ax),
1.11 (d, 3H, J = 6 Hz). dC (100 MHz, CDCl3) 125.5 (q, JC–F = 279 Hz,
CF3), 96.7, 60.0, 60.2 (q, JC–F = 27 Hz), 59.6, 59.1, 55.8, 37.4, 34.4,
Acknowledgments
We thank the Ministe`re de l’Enseignement Supe´rieur et de la
Recherche for financial support. W.B. Jatoi is grateful to Higher
Education Commission of Pakistan for research fellowship.
33.2, 28.9, 25.4, 24.3.
d
F (376 MHz, CDCl3) ꢁ73.6. EI-MS (70 eV) m/
z: 279 (M+, 5), 264 (100), 206 (20), 188 (85), 164 (15), 110 (60), 41
(20). HR-ESI-MS calculated for C13H21F3NO2 (M+H)+: 280.1524,
found 280.1524.
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ꢃ
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d
C (400 MHz, CDCl3) 6.73 (dd,
1H, J = 16 and 6 Hz), 6.26 (dd, 1H, J = 16 and 1.5 Hz), 3.95 (t, 2H,

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