Synthesis and evaluation of fluorinated analogues of monoamine reuptake inhibitors

Article abstract of DOI:10.1016/j.jfluchem.2011.02.018

The synthesis of two series of fluorinated analogues of monoamines reuptake inhibitors based on tertiary alcohols 2-substituted morpholines scaffold has been achieved through the incorporation of fluorinated substituent into 2-substituted morpholino ketones. Their binding affinities have been measured on different monoamine transporters.

Full text of DOI:10.1016/j.jfluchem.2011.02.018

Journal of Fluorine Chemistry 134 (2012) 136–145
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and evaluation of fluorinated analogues of monoamine reuptake
inhibitors
*
`
Christine Philippe, Julia Kaffy, Thierry Milcent , Daniele Bonnet-Delpon
ˆ
Laboratoire BioCIS-CNRS, Faculte´ de Pharmacie, Univ Paris-Sud, Rue J. B. Cle´ment, F-92296 Chatenay-Malabry, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of two series of fluorinated analogues of monoamines reuptake inhibitors based on tertiary
alcohols 2-substituted morpholines scaffold has been achieved through the incorporation of fluorinated
substituent into 2-substituted morpholino ketones. Their binding affinities have been measured on
different monoamine transporters.
Received 18 January 2011
Received in revised form 9 February 2011
Accepted 27 February 2011
Available online 15 March 2011
ß 2011 Elsevier B.V. All rights reserved.
Key words:
Monoamine reuptake inhibition
Fluoroalkyl
Trifluoromethyl
Fluorine
1. Introduction
In the central nervous system (CNS), monoamine neurotrans-
mitters such as serotonin (SER), norepinephrine (NE), and
dopamine (DA), are involved in many physiological and pathologi-
cal processes. Their regulations are ensured by transporters,
The research pursued in our group focuses on new synthetic
methodologies, involving organofluorine and peptide chemis-
try, devoted to medicinal chemistry and effort towards new
processes respectful of environment. Due to the increasing
importance of fluorinated compounds in a large number of
domains (drugs, materials, surfactants, contrasting agents, etc.)
the search for new fluorinated molecules is a permanent quest.
The group has a long lasting experience in biologically active
molecules where the introduction of fluoroalkyl substituents
can improve the pharmacological profile of drugs. Typical
examples are fluorinated analogues of natural products: arte-
misinin derivatives (anti-malaria and anti-cancer) and styryl
lactone analogues (anti-tumor), and new fluorinated peptido-
mimetic units as inhibitors of protein-protein interactions (anti-
infectious, anti-tumor drugs and inhibition of amyloide aggre-
gation).
respectively SERT, NET, and DAT which are integral membrane
proteins that uptake the monoamine neurotransmitter from the
extracellular space into neurons [1,2]. The development of
monoamines reuptake inhibitors has shown a significant thera-
peutic advance in many CNS diseases [3,4]. For example, selective
serotonin reuptake inhibitors, such as fluoxetine (Prozac1), have
been considered as a breakthrough in the antidepressant therapy
[5–7]. Among these inhibitors, the 3-aryloxypropylamine scaffold
has been shown to be a privileged motif in the selective (SER) or
dual (SER/NE) monoamine transporter inhibition as exemplified by
the marketed drugs: fluoxetine, reboxetine and duloxetine (Fig. 1)
[8–15].
Although numerous monoamine transporter inhibitors are
clinically available, little is known regarding the structural basis of
inhibitor function [16]. Thus, there is still continuous interest in
developing novel selective or mixed inhibitors with improved
pharmacological and metabolic properties. Indeed, recently novel
series of ketones or tertiary alcohols with expanded sets of aryl and
heteroaryl moieties have been reported [17–19]. Among them,
tertiary alcohol containing 2-substituted morpholines 1 has been
discovered as potent and selective inhibitors of norepinephrine
transporters with Ki values up to 4 nM [8]. These inhibitors are
characterized by a high hydrophobicity due to the presence of
aromatic rings, but the role of the hydroxyl function still remain
* Corresponding author. Fax: +33 1 46 83 57 40.
E-mail address: thierry.milcent@u-psud.fr (T. Milcent).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.02.018

C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
137
O
HO R
CF3
O
O
O
O
CN
Rf
R
R
O
O
O
HO
N
O
N
N
O
Bn
2-3
Bn
Bn
6-7
5
N
H
N
H
S
N
H
N
H
1
Scheme 2.
Fluoxetine
Duloxetine
Reboxetine
Fig. 1. Selective or dual monoamine reuptake inhibitors.
would further react with an appropriate organometallic reagent in
a diastereoselective manner to give alcohols 2 or 3 (Scheme 1).
Unfortunately, whatever the reaction conditions (trifluoro-
methylation of the ester analogue of 5 using the trifluoromethyl
trimethysilane (CF3TMS) reagent or addition of fluoroalkyl
organometallic reagents to the nitrile 5), fluorinated ketones were
obtained under highly stable hydrated forms which could not be
dehydrated and neither further reacted to lead to the correspond-
ing alcohols even with a large excess of organometallic reagent. We
thus turned to an alternative strategy in which the different steps
were inverted: a previous generation of a non-fluorinated ketone
followed by the addition of a fluoroalkylation reagent (Scheme 2).
The reaction of the morpholinonitrile 5 with ortho-substituted
benzyl Grignard reagents afforded the corresponding ketones 6a–c
in good yields (Scheme 3). The synthesis of trifluoromethyl alcohol
containing 2-substituted morpholines 7a–c was achieved by the
addition of the CF3TMS reagent to ketones 6a–c, which afforded a
1/1 mixture of 2 diastereoisomers in moderate yields (40–52%). In
the case of compounds 7c each diastereoisomer 7c1 and 7c2 could
be isolated separately by silica gel purification.
The N-debenzylation of compounds 7a–c could not be achieved
by standard hydrogenolysis. A two-step procedure has been
applied: carbamate exchange with benzylchloroformate (com-
pounds 8a–c) [31] followed by hydrogenolysis using Pd/C 10%.
Morpholino derivatives 2a–c have been isolated in good yields as
chloride salts. On the other hand, the pentafluoroethyl derivative 9
has been prepared only from 6a (R55H) by addition of the
pentafluoroethyllithium reagent (Scheme 4) and was obtained in a
moderate yield (52%). The N-debenzylated compound 3 was
obtained in good yield following the previously two-step proce-
dure.
Rf
HO
O
R
R
HO
HO
O
O
N
Rf
H
4
N
H
N
H
Rf= -CF2CF3, -CH2CF3
1
2-3
Rf= -CF3, -C2F5
F
F
R= -H, -Ph, -OMe
F
Fig. 2. Fluorinated analogues of monoamine reuptake inhibitors.
unclear (hydrogen bond acceptor or donor). The introduction of
fluorinated tertiary alcohols into this series of molecules could
provide a better understanding of the interaction with the
receptor. The incorporation of fluorine into molecules has become
a useful tool in medicinal chemistry for improving the pharmaco-
logical profile of bioactive compounds [20–27]. Indeed, the high
electrowithdrawing effect of fluoroalkyl groups can modify the pKa
of neighboring functions and their ability to form hydrogen bonds
[28,29]. Furthermore, fluoroalkyl groups, at the same time highly
hydrophobic, and sterically demanding, are able to mimic phenyl
or benzyl groups with beneficial effects. In addition, a fluoroalkyl
tertiary alcohol is expected to be more stable towards solvolysis or
dehydration process. In order to explore the potential replacement
of aromatic rings and study the effect of fluorinated groups in these
series of compounds, we have synthesized two types of fluorinated
analogues. In the first one the phenyl substituent is replaced by a
trifluoromethyl or pentafluoroethyl group (molecules 2–3). In the
second one, the ortho-substituted benzyl group is replaced by a
fluorinated substituent bearing a CH2 or CF2 spacer (–C2F5, –
CH2CF3, pentafluorobenzyl and 1,1-difluoro-4-methylcyclohexyl),
molecules 4 (Fig. 2).
In this case, the reaction is highly diastereoselective leading to
only one diastereoisomer like the closely related previously
reported system by Cases-Thomas [8], and thus, the present
isomer was strongly assumed to have a cis relative configuration
due to the chelation-controlled attack of the organometallic
reagent.
Herein we report the synthesis and binding affinities of these
two series of fluorinated tertiary alcohols containing the 2-
substituted morpholine scaffold.
The same procedure was applied for the synthesis of fluorinated
analogues 4a–d (Scheme 5). The addition of phenylmagnesium
bromide to the N-benzyl-2-cyanomorpholine
5 afforded the
2. Chemistry
corresponding phenyl ketone 11 in good yield (79%). This latter
was then submitted to various fluorinated organometallic
reagents: lithium or magnesium reagents were prepared from
commercially available halides (CF3CH2CH2I, C2F5I, and C6F5CH2Br)
and from the iodomethyl-difluorocyclohexane prepared according
to the literature [32]. The addition of these organometallic reagents
to 11 was in all cases diastereoselective. Removal of the benzyl
group as previously described, afforded compounds 4a–d as single
cis diastereoisomers in good yields (Scheme 5).
The first approach developed to synthesize molecules 2 and 3
was based on the previously reported synthesis of 2-substituted
morpholines [8] starting from the 4-benzylmorpholine-2-carbo-
nitrile 5, prepared itself by the addition of the N-benzyl
ethanolamine to the 2-chloroacrylonitrile (Scheme 1) [30].
Reaction of the nitrile 5 or the corresponding ester with a
fluoroakylation reagent would provide fluoroalkyl ketones which
O
HO R1
O
OH
Cl
CN
O
O
CN
Rf
Rf
+
N
H
NHBn
N
N
Bn
Bn
2-3
5
Scheme 1.

138
C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
HO CF3
HO CF3
O
O
R
R
ii
HCl
N
H
N
O
Bn
2a-c (83-98%)
7a-c (40-52%)
O
CN
O
i
HO CF3
R
N
N
iv
iii
O
Bn
Bn
6a R = H (87%)
6b R = OMe (90%)
6c R = Ph (48%)
5
R
N
Cbz
8a-c (83-93%)
Scheme 3. Reagents and conditions: (i) ortho-substituted benzyl bromide, Mg, Et2O 0 8C to rt, then HCl aq. 1 M 48–90%. (ii) CF3TMS, CsF, toluene 0 8C to rt, then TBAFÁ3H2O,
THF 0 8C to rt, 40–52%. (iii) PhCH2OCOCl 5 equiv., THF 0 8C to rt, 1 day 83–93%. (iv) H2, Pd/C 10%, MeOH at rt, then HCl/EtOH 6 M, EtOH 0 8C 30 min 83–98%.
O
HO C2F5
HO C2F5
HO C2F5
HCl
O
O
N
O
N
i
ii
iii
O
N
N
H
Bn
6a
9 (52%)
Cbz 10 (90%)
3 (90%)
Bn
Scheme 4. Reagents and conditions: (i) IC2F5, MeLi, Et2O À78 8C, 45 min, then H2O, 52%. (ii) PhCH2OCOCl 5 equiv., THF 0 8C to rt, 1 day 90%. (iii) H2, Pd/C 10%, MeOH at rt, then
HCl/EtOH 6 M, EtOH 0 8C 30 min 90%.
O
Rf
Ph
Rf
Rf
HO
HO
HO
O
CN
O
O
O
O
i
Ph
iv
ii
iii
N
N
N
N
N
H
HCl
Bn
Bn
Bn
Cbz
11 (79%)
5
12a-d (64-91%)
13a-d (86-95%)
4a-d (78-97%)
4b Rf: -(CH2)2CF3
4c Rf: -C2F5
F
F
F
4a Rf:
4d Rf:
Scheme 5. Reagents and conditions: (i) phenyl bromide, Mg, Et2O 0 8C to rt, then HCl aq. 1 M, 79%. (ii) RfLi or RfMgBr, Et2O À78 8C or 0 8C to rt, 64–91%. (iii) PhCH2OCOCl
5 equiv., THF 0 8C to rt, 1 day 86–95%. (iv) H2, Pd/C 10%, MeOH at rt, then HCl/EtOH 6 M, EtOH 0 8C 30 min 78–97%.
The in vitro binding affinities of fluorinated analogues 2–4 were
measured on 5-HT, NE and DA transporters by competition assays
using specific radioligands. Compounds 4a–d in which the benzyl
group have been replaced by a fluorinated substituent did not
show any binding affinity to the transporters. In the same line the
replacement of the phenyl group by a pentafluoroethyl substituent
(compound 3) did not afford any binding to the transporters. This
loss of binding activity cannot be ascribed to the configuration of
compounds 2–4 since, for the reference non fluorinated com-
pounds (with benzyl and phenyl substituents) all 4 stereoisomers
are active towards NE transporters with Ki values ranging from 3.2
to 160 nM [8]. These data seem to show that the benzyl substituent
does not bring only hydrophobic interactions but more likely
activity of the compound 4d. Indeed the substitution of the
aromatic protons by fluorine atoms modifies the electron density
of the aromatic ring which could lead to a disruption of the
p–
stacking interactions. In contrast, the replacement of the phenyl
substituent by a trifluoromethyl one resulted in a quite good
binding activity to the norepinephrine transporter, with
Ki = 240 nM for 2b and 95 nM for the stereoisomer 2c2 (Table 1).
Considering they are mixture of diastereoisomers, it can be
assumed that CF3 well mimics the phenyl substituent.
This suggests that in this site: (i)
p–p interactions are of less
importance and (ii) both H-bond donor and acceptor ability of the
alcohol function is not the main factor for binding affinity. Indeed a
trifluoromethyl ethanol structure is more acidic than a benzyl one
interactions through the aromatic group, such as
interactions. These assumptions could be supported by the loss of
p
–stacking
(pKa ꢀ 12 vs 14–15) and conversely
b-values are respectively 0
and 0.5 for CF3CH2OH and benzylic alcohol [33,34].
Table 1
NET, SERT and DAT binding affinities of fluorinated analogues.
Entry
Compound
n
R1
R2
Ki (mM)
SERT
NET
DAT
1
2a
2b
2c1
2c2
3
1
1
1
1
1
0
0
0
0
0
1
CF3
H
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
> 3
> 10
> 10
> 32
12
2
CF3
OMe
0.24
1.7
3
CF3
Ph isomer 1
4
CF3
Ph isomer 2
0.095
>10
>10
>10
>10
>10
>10
0.0037
5
C2F5
H
H
H
H
H
H
Ph
>10
>10
>10
>10
>10
>10
0.0029
6
4a
4b
4c
4d
4a
–
CH2(C6H9F2)
(CH2)2CF3
C2F5
7
8
9
CH2C6F5
CH2(C6H9F2)
Ph
10
11a
0.003
a
Binding affinities of non-fluorinated reference compound [8].

C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
139
3. Conclusions
cooled to 0 8C for the addition of a 1 M HCl aqueous solution. After
5 min of stirring, a 10 M NaOH aqueous solution was added and the
product was extracted with Et2O. The organic layer was dried over
magnesium sulphate, filtrated and concentrated under reduced
pressure. The resulting oil was then purified by chromatography on
silica gel to afford products as a racemic mixture.
In summary, we have designed and synthesized new fluorinat-
ed analogues of monoamines transporters inhibitors. Most of the
fluorinated compounds exhibit low activity, only one exhibits a
binding affinity to the transporters in the nanomolar range.
Moreover, the half-life of non-fluorinated tertiary alcohols is
usually very short and a possible advantage of replacing the phenyl
group by a CF3 could be the increase of the tertiary alcohol
metabolic stability.
4.3.1. 1-(4-Benzylmorpholin-2-yl)-2-phenylethanone 6a
Magnesium (972 mg, 40.0 mmol, I2 (several crystals), benzyl
chloride (5.06 g, 40.0 mmol in 20 mL of anhydrous Et2O) and
compound 5 (2.32 g, 11.5 mmol in 19 mL of anhydrous Et2O) gave
after purification (cyclohexane/AcOEt: 17/3) product 6a (2.94 g,
4. Experimental
87%) as a colourless oil. 1H NMR (CDCl3)
d ppm: 7.05–7.24 (m, 10H,
4.1. General experimental procedures
HAr), 3.98 (dd, 1H, J = 10.1, 2.7 Hz, OCH), 3.86 (ddd, 1H, J = 11.1, 3.3,
2.1 Hz, OCH2), 3.80 (d, 1H, J = 15.9 Hz, NCH2Ph), 3.71 (d, 1H,
J = 15.9 Hz, NCH2Ph), 3.58 (td, 1H, J = 11.1, 2.1 Hz, OCH2), 3.42 (d,
1H, J = 13.1 Hz, COCH2), 3.35 (d, 1H, J = 13.1 Hz, COCH2), 2.88 (ddd,
1H, J = 11.1, 2.7, 2.1 Hz, NCH2CH), 2.53 (dq, 1H, J = 11.1, 2.1 Hz,
NCH2CH2), 2.09 (td, 1H, J = 11.1, 3.3 Hz, NCH2CH2), 1.94 (dd, 1H,
Melting points were measured on a Stuart1 SMP10 apparatus.
1H, 13C and 19F NMR spectra were recorded on a Bruker1 ARX 200
apparatus at respectively 300, 75 and 188 MHz (unless precised) in
deutered solvent (CDCl3, MeOD or DMSO) with TMS as internal
standard for 1H and 13C and CFCl3 for 19F NMR. Mass spectra were
performed on a Bruker1 Esquire-LC apparatus. IR spectra were
recorded on a Bruker1 Vector 22 apparatus. Elemental analyses
were carried out on an Ankersmit CAHN1 25 apparatus. TLC
monitoring was performed with Merk1 silica gel aluminium
sheets (type 60 F254). Visualization were performed under a SVL
Bioblock Scientific lamp at 254 nm and/or by developing the plates
with KMnO4 solution followed by heating. Purifications were done
by column chromatography at atmospheric pressure with Merk1
J = 11.1, 10.1 Hz, NCH2CH). 13C NMR (CDCl3)
d ppm: 206.7 (CO),
137.4(Cq), 133.7 (Cq), 129.8, 129.2, 128.6, 128.4, 127.4, 126.9, 80.3
(OCH), 66.8 (CH2), 63.2 (CH2), 54.4 (CH2), 52.6(CH2), 45.3 (CH2). IR
(cmÀ1): 2810, 1720, 1494, 1453, 1122, 1028, 738, 697. MS (APCI)
m/z: 296 (MH)+. Anal. Calcd for C19H21NO2 (%): C, 77.26; H, 7.17; N,
4.74. Found: C, 76.90; H, 6.98; N, 4.50.
4.3.2. 1-(4-Benzylmorpholin-2-yl)-2-(2-methoxyphenyl)-ethanone
6b
silica gel (60
m
m).
Magnesium (2.64 g, 108.6 mmol), 1,2-dibromoethane (three
drops), 2-methoxybenzyl chloride (5.00 g, 32.0 mmol in solution in
15 mL of anhydrous Et2O) and compound 5 (1.74 g, 8.6 mmol in
14 mL of anhydrous Et2O) gave, after purification (cyclohexane/
AcOEt: 8/2), product 6b (2.50 g, 90%) as a colourless oil. 1H NMR
4.2. 4-Benzylmorpholine-2-carbonitrile 5
2-Chloroacrylonitrile (2.1 mL, 26.4 mmol) was added dropwise
at 0 8C to a cooled solution of N-benzylethanolamine (3.8 mL) to
0 8C. The mixture was allowed to warm to room temperature and
after 20 h of stirring, it was dissolved in 13 mL of anhydrous THF.
The resulting solution was cooled to 0 8C for the addition of several
portions of t-BuOK (4.40 g, 39.6 mmol). After 1 h of stirring, an
aqueous solution of NaHCO3 was added. The product was extracted
several times with Et2O and the organic layer was dried over
magnesium sulphate, filtrated and concentrated under reduced
pressure. Purification of the resulting oil by chromatography on
silica gel (cyclohexane/AcOEt: 9/1) provided 3.58 g (74%) of a
(CDCl3) d ppm: 7.13–7.25 (m, 6H, HAr), 6.98 (dd, 1H, J = 7.5, 1.8 Hz,
HAr), 6.82 (td, 1H, J = 7.5, 0.9 Hz, HAr), 6.76 (d, 1H, J = 8.4 Hz, HAr),
4.08 (dd, 1H, J = 10.0, 2.7 Hz, OCH), 3.90 (ddd, 1H, J = 11.1, 3.3,
2.1 Hz, OCH2), 3.65 (s, 3H, OCH3), 3.74 (s, 2H, COCH2), 3.62 (td, 1H,
J = 11.1, 2.1 Hz, OCH2), 3.48 (d, 1H, J = 12.9 Hz, NCH2Ph), 3.42 (d,
1H, J = 12.9 Hz, NCH2Ph), 2.95 (ddd, 1H, J = 11.1, 2.7, 2.1 Hz,
NCH2CH), 2.57 (dq, 1H, J = 11.1, 2.1 Hz, NCH2CH2), 2.17 (td, 1H,
J = 11.1, 3.3 Hz, NCH2CH2), 2.07 (dd, 1H, J = 11.1, 10.0 Hz, NCH2CH).
13C NMR (CDCl3)
d ppm: 206.1 (CO), 157.2 (Cq), 137.2 (Cq), 131.3,
129.1, 128.3, 128.2, 127.2, 122.9 (Cq), 120.5, 110.3, 80.5 (OCH),
66.5 (CH2), 63.1 (CH2), 55.2(CH3), 54.2 (CH2), 52.5 (CH2), 40.4
(CH2). IR (cmÀ1): 2811, 1723, 1495, 1456, 1246, 1115, 1029. MS
(ESI) m/z: 348.2 (MNa)+. Anal. Calcd for C20H23NO3 (%): C, 73.82; H,
7.12; N, 4.30. Found: C, 74.31; H, 7.05; N, 4.14.
yellow light oil, 5 as a racemic mixture. 1H NMR (CDCl3)
d ppm:
7.26–7.38 (m, 5H), 4.59 (t, 1H, J = 3.9 Hz), 4.02 (ddd, 1H, J = 11.7,
8.7, 2.7 Hz), 3.77 (dt, 1H, J = 11.7, 3.9 Hz), 3.61 (d, 1H, J = 13.2 Hz),
3.54 (d, 1H, J = 13.2 Hz), 2.76 (ddd, 1H, J = 12.0, 3.9, 1.2 Hz), 2.64
(dddd, 1H, J = 12.0, 3.9, 2.7, 1.2 Hz), 2.56 (dd, 1H, J = 12.0, 3.3 Hz),
2.42 (ddd, 1H, J = 12.0, 8.7, 3.3 Hz). 13C NMR (CDCl3)
d
ppm: 136.7,
4.3.3. 1-(4-Benzylmorpholin-2-yl)-2-(2-phenylphenyl)-ethanone 6c
Magnesium (2.64 g, 108.6 mmol, 7.3 equiv.), 1,2-dibro-
moethane (three drops), 2-phenylbenzyl bromide (5.00 g,
20.2 mmol in solution in 15 mL of anhydrous Et2O) and compound
5 (2.99 g, 14.8 mmol, 1 equiv. in 15 mL of anhydrous Et2O) gave,
after purification (cyclohexane/AcOEt: 9/1) product 6c (2.64 g,
128.7, 128.3, 127.3, 117.0, 65.0, 64.3, 62.2, 54.4, 52.1. IR (cmÀ1):
2817, 1454, 1114, 1094, 1022, 862, 742, 699. MS (APCI) m/z: 203
(MH)+. Anal. Calcd for C12H14N2O (%): C, 71.26; H, 6.98; N, 13.85.
Found: C, 71.78; H, 7.05; N, 14.06.
4.3. General procedure and characterization for ketones 6a–c
48%) as a colourless oil. 1H NMR (CDCl3)
d ppm: 7.16–7.40 (m, 14H,
HAr), 3.90 (dd, 1H, J = 10.1, 2.7 Hz, OCH), 3.89 (d, 1H, J = 18.3 Hz,
COCH2), 3.80–3.86 (m, 1H, OCH2), 3.81 (d, 1H, J = 18.3 Hz, COCH2),
3.57 (td, 1H, J = 11.1, 2.1 Hz, OCH2), 3.47 (d, 1H, J = 13.1 Hz,
NCH2Ph), 3.40 (d, 1H, J = 13.1 Hz, NCH2Ph), 2.78 (ddd, 1H, J = 11.1,
2.7, 2.1 Hz, NCH2CH), 2.48 (dq, 1H, J = 11.1, 2.1 Hz, NCH2CH2), 2.09
(td, 1H, J = 11.1, 3.3 Hz, NCH2CH2), 1.78 (dd, 1H, J = 11.1, 10.1 Hz,
I2 or 1,2-dibromoethane was added to an anhydrous etheral
solution (few mL) of magnesium in a three-neck round bottom
flask fitted with a refluxing condenser. The flask was placed in an
ice bath and an ethereal solution of the halogenated compound
was introduced dropwise with a dropping funnel. After total
addition of the halogenated compound solution, the mixture was
allowed to warm to room temperature and was stirred for 30 min.
The flask was cooled to 0 8C and an ethereal solution of compound
5 was added dropwise. The mixture was then allowed to warm to
room temperature and was stirred for 2 h. Then, the mixture was
NCH2CH). 13C NMR (CDCl3)
d ppm: 206.9(CO), 142.6 (Cq), 141.4
(Cq), 137.2 (Cq), 131.6 (Cq), 130.8, 130.0, 129.1, 129.1, 128.3, 128.1,
127.4, 127.3, 127.0, 127.0, 80.6 (OCH), 66.4 (CH2), 63.1 (CH2), 54.1
(CH2), 52.4 (CH2), 43.3 (CH2). IR (cmÀ1): 2923, 1721, 1126, 748,
703. MS (ESI) m/z: 372.2 (MH)+, 394.1 (MNa)+, 765.4 (2MNa)+. Anal.

140
C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
Calcd for C25H25NO2 (%): C, 80.83; H, 6.78; N, 3.77. Found: C, 80.74;
H, 6.64; N, 3.47.
tedious chromatography (cyclohexane/AcOEt: 9/1) to give 7c1
(16 mg, 13%) and 7c2 (20 mg, 17%).
Characterization of 7c1: 1H NMR (CDCl3)
d ppm: 7.13–7.48 (m,
4.4. General procedure and characterization for fluorinated alcohols
14H), 3.77 (dt, 1H, J = 11.4, 4.5 Hz), 3.35–3.46 (m, 3H), 3.11–3.25
(m, 3H), 2.56 (d, 1H, J = 11.9 Hz), 2.41 (d, 1H, J = 11.9 Hz), 2.03 (td,
7a, 7b, 7c1 and 7c2
1H, J = 10.5, 3.3 Hz), 1.92 (t, 1H, J = 10.5 Hz). 13C NMR (CDCl3)
d
Dry TMSCF3 and CsF were successively added to a 0 8C solution
of carbonylated product 6 in anhydrous toluene under inert
atmosphere. The mixture was allowed to warm to room
temperature and stirred for 2 days. After removal of toluene
under reduced pressure, the crude product was dissolved in Et2O
and the organic layer was washed with an aqueous solution of
NaHCO3. The organic layer was dried over magnesium sulphate,
filtrated and concentrated under reduced pressure. The resulting
oil was dissolved in THF, cooled to 0 8C, a 1 M solution of
TBAFÁ3H2O in THF was added and the mixture was stirred for 1 h at
room temperature. The solution was then washed with an aqueous
solution of NaHCO3 and with brine. The organic layer was dried
over magnesium sulphate, filtrated and concentrated under
reduced pressure. The resulting oil was then purified by
chromatography on silica gel to afford products as 2 racemic
mixtures (1/1) of diastereoisomers.
ppm: 143.4, 141.7, 138.1, 132.1, 131.8, 130.6, 130.1, 129.7, 129.3,
129.2, 128.6, 128.4, 128.3, 127.8, 127.4, 127.3, 127.3, 127.2, 125.5
(q, J = 286.9 Hz), 76.5 (q, J = 26.2 Hz), 75.6, 66.6, 63.2, 53.2, 52.3,
33.1. 19F NMR (CDCl3)
d
ppm: À75.81. IR (cmÀ1): 3493, 2963, 1252,
1163, 1096, 1043, 800, 755, 741, 698. MS (ESI) m/z: 442.4 (MH)+,
464.3 (MNa)+. Anal. Calcd for C26H26F3NO2 + 0.25H2O (%): C, 69.32;
H, 6.04; N, 3.11. Found: C, 69.24; H, 5.82; N, 2.49.
Characterization of 7c2: 1H NMR (CDCl3)
d ppm: 7.52–7.57 (m,
1H), 7.15–7.32 (m, 13H), 3.67 (ddd, 1H, J = 1.1, 2.0, 11.1 Hz), 3.00–
3.38 (m, 6H), 2.34 (d, 1H, J = 11.4 Hz), 1.97 (d, 1H, J = 11.4 Hz), 1.84
(td, 2H, J = 11.1 3.0 Hz), 13C NMR (CDCl3)
d ppm: 143.4, 141.6,
137.7, 132.6, 131.4, 130.4, 129.7, 128.7, 128.3, 128.2, 127.2, 127.0,
127.0, 127.0, 125.6 (q, J = 286.9 Hz), 75.9 (q, J = 26.2 Hz), 75.6, 67.3,
62.6, 53.4, 51.7, 31.8. 19F NMR (CDCl3)
3495, 2961, 1255, 1160, 1098, 1043, 801, 757, 740, 699. MS (ESI) m/
z: 442.4 (MH)+, 464.4 (MNa)+. Anal. Calcd for C26H26F3NO2 + 1H2O
(%): C, 67.96; H, 6.14; N, 3.05. Found: C, 67.55; H, 5.81; N, 2.52.
d
ppm: À76.42. IR (cmÀ1):
4.4.1. 2-(4-Benzyl-morpholin-2-yl)-1,1,1-trifluoro-3-phenylpropan-
2-ol 7a
4.5. General procedure and characterization for compounds 8a, 8b,
8c1 and 8c2
Product 6a (0.50 g, 1.7 mmol), TMSCF3 (1.3 mL, 8.5 mmol), CsF
(approximately 0.5 equiv.) and TBAFÁ3H2O (2.0 mL) gave after
purification (cyclohexane/AcOEt: 9/1), product 7a (322 mg, 52%) as
Benzyl chloroformate was added dropwise to a 0 8C solution of
product 7 in anhydrous THF under inert atmosphere. The resulting
mixture was allowed to warm to room temperature and was
stirred for one day. An aqueous solution of NaHCO3 was added and
product 8 was extracted with Et2O. The organic layer was dried
over magnesium sulphate, filtrated and concentrated under
reduced pressure. The resulting oil was then purified by
chromatography on silica gel.
a colourless oil. 1H NMR (CDCl3)
d ppm: 7.38–7.53 (m, 20H, HAr),
4.08–4.14 (m, 2H, OCH), 3.60–3.84 (m, 8H), 3.34–3.41 (m, 2H),),
3.00–3.11 (m, 4H), 2.71–2.78 (m, 2H), 2.32–2.55 (m, 4H). 13C NMR
(CDCl3)
d ppm: 137.1, 137.1, 134.1, 134.0, 130.8, 130.7, 129.0,
128.9, 128.2, 128.2, 128.1, 128.0, 127.3, 127.2, 126.9, 126.9, 125.5
(q, J = 286.5 Hz), 125.5 (q, J = 285.9 Hz), 77.2 (q, J = 31.5 Hz), 76.4
(q, J = 26.2 Hz), 75.9, 66.7, 66.5, 63.1, 62.8, 52.9, 52.9, 52.7, 52.5,
37.4, 37.3. 19F NMR (CDCl3)
d
ppm: À74.64, À74.84. IR (cmÀ1):
2817, 1454, 1165, 1112, 741, 698. MS (ESI) m/z: 366 (MH)+, 388
(MNa)+. Anal. Calcd for C20H22F3NO2 + 0.33 H2O (%): C, 64.68; H,
6.15; N, 3.77. Found: C, 64.46; H, 5.93; N, 3.52.
4.5.1. Benzyl 2-(1-benzyl-2,2,2-trifluoro-1-
hydroxyethyl)morpholine-4-carboxylate 8a
Product 7a (1.50 g, 4.1 mmol) and benzyl chloroformate
(2.9 mL, 20.6 mmol) gave, after purification eluting with cyclohex-
ane/AcOEt: 9/1, 1.39 g (83%) of product 8a (colourless oil) as 2
racemic mixtures (1/1) of diastereoisomers. 1H NMR (CDCl3)
d
4.4.2. 2-(4-Benzyl-morpholin-2-yl)-1,1,1-trifluoro-3-(2-methoxy-
phenyl)-propan-2-ol 7b
Product 6b (100 mg, 0.31 mmol), TMSCF3 (230
CsF (approximately 0.5 equiv.) and 370
L of TBAFÁ3H2O gave,
after purification (cyclohexane/AcOEt: 9/1) 49 mg of product 7b
(40%) as a colourless oil. 1H NMR (CDCl3)
ppm: 7.25–7.35 (m,
m
L, 1.5 mmol),
ppm: 7.17–7.28 (m, 20H), 5.07 (s, 2H), 5.03 (s, 2H), 4.13–4.24 (br s,
2H), 3.81–3.91 (m, 4H), 3.26–3.41 (m, 4H), 3.16 (d, 1H, J = 14.4 Hz),
3.11 (d, 1H, J = 14.4 Hz), 2.86–3.00 (m, 6H). 13C NMR (CDCl3)
dppm:
m
d
155.1, 140.8, 136.3, 130.8, 129.7, 128.5, 128.4, 128.3, 128.2, 128.1,
14H, HAr), 6.88–7.03 (m, 4H, HAr), 3.89–3.97 (m, 2H, OCH), 3.85 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 3.03–3.63 (m, 14H), 2.60–2.64 (m,
127.9, 127.6, 127.3, 127.2, 126.9, 126.0 (q, J = 285.0 Hz), 76.3, 75.9,
75.9 (q, J = 26.2 Hz), 67.5, 67.4, 43.8, 37.0, 36.9. 19F NMR (CDCl3)
d
2H), 2.25–2.32 (m, 1H), 2.10–2.19 (m, 3H). 13C NMR (CDCl3)
d
ppm:
ppm: À74.87, À75.66. IR (cmÀ1): 3317, 2861, 1674, 1437, 1239,
157.2, 157.1, 137.6, 137.4, 133.5, 133.1, 129.1, 129.0, 128.7, 128.4,
128.2, 128.1, 127.1, 127.0, 125.9 (q, J = 286.0 Hz), 125.7 (q,
J = 286.5 Hz), 123.4, 122.9, 121.5, 120.9, 110.6, 110.3, 77.2, 76.7
(q, J = 26.5 Hz), 76.6 (q, J = 25.8 Hz), 76.5, 67.2, 67.1, 63.3, 63.3,
1170, 1105, 732, 695. MS (ESI) m/z: 432.5 (MNa)+. Anal. Calcd for
C21H22F3NO4 (%): C, 62.61; H, 5.42; N, 3.42. Found: C, 62.74; H,
5.30; N, 3.21.
55.5, 55.3, 53.3, 53.1, 52.6, 52.5, 32.6, 31.4. 19F NMR (CDCl3)
d
ppm:
4.5.2. (2-Methoxyphenyl)methyl 2-(1-benzyl-2,2,2-trifluoro-1-
hydroxyethyl)morpholine-4-carboxylate 8b
Product 7b (450 mg, 1.2 mmol) and benzyl chloroformate
(0.82 mL, 5.7 mmol) gave, after purification eluting with cyclohex-
ane/AcOEt: 9/1, 0.47 g (93%) of product 8b (colourless oil) as 2
racemic mixtures (1/1) of diastereoisomers. 1H NMR (400 MHz,
À75.62, À76.89. IR (cmÀ1): 2927, 1493, 1455, 1241, 1172, 1117,
1027, 751, 699. MS (ESI) m/z: 395.8 (MH)+, 417.6 (MNa)+. Anal.
Calcd for C21H24F3NO4 + 0.33H2O (%): C, 61.91; H, 6.27; N, 3.44.
Found: C, 61.83; H, 6.08; N, 3.18.
4.4.3. 2-(4-Benzyl-morpholin-2-yl)-3-biphenyl-2-yl-1,1,1-
CDCl3, 323 K) d ppm: 7.20–7.37 (m, 14H), 6.88–7.00 (m, 4H), 5.06–
trifluoropropan-2-ol 7c1 and 7c2
5.19 (m, 4H), 4.53–4.70 (m, 2H), 4.22–4.25 (m, 2H), 3.93–3.39 (m,
Product 6c (100 mg, 0.270 mmol), TMSCF3 (200
1.54 mmol), CsF (approximately 0.5 equiv.) and 320
m
of
L,
3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.62 (dd, 1H, J = 10.9, 1.9 Hz), 3.49 (td,
1H, J = 11.6, 1.8 Hz), 2.92–3.39 (m, 8H), 2.82 (t, 1H, J = 12.1 Hz). 13
C
m
L
TBAFÁ3H2O gave after purification eluting with cyclohexane/
AcOEt: 9/1, product 7c (50 mg, 42%) as a colourless oil containing
a mixture of 2 diastereoisomers. They could be separated after a
NMR (CDCl3) d ppm: 157.1, 157.0, 155.1, 155.0, 136.4, 136.4, 133.4,
132.8, 128.9, 128.6, 128.4, 128.3, 128.3, 128.0, 127.8, 127.7, 125.7
(q, J = 285.8 Hz), 125.5 (q, J = 286.3 Hz), 123.0, 122.5, 121.5, 121.1,

C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
141
110.7, 110.4, 77.1, 76.4 (q, J = 26.7 Hz), 67.2, 67.0, 66.9, 66.8, 55.5,
4.6.2. 1,1,1-Trifluoro-3-(2-methoxyphenyl)-2-(morpholin-2-yl)-
propan-2-ol hydrochloride 2b
Product 8b (200 mg, 0.46 mmol) and Pd/C (60 mg) gave
product 2b (129 mg, 83%) as a yellow sticky oil containing 2
racemic mixtures (1/1) of diastereoisomers. 1H NMR (MeOD)
55.4, 44.0, 43.7, 43.3, 43.3, 32.5, 31.3. 19F NMR (376 MHz, CDCl3,
323 K)
d
ppm: À75.48, À77.58. MS (ESI) m/z: 462.0 (MNa)+. Anal.
Calcd for C22H24F3NO5 (%): C, 60.13; H, 5.51; N, 3.19. Found: C,
60.31; H, 5.62; N, 2.95.
d
ppm: 7.27–7.37 (m, 4H), 6.93–7.08 (m, 4H), 4.14–4.26 (m, 2H),
4.5.3. Benzyl 2-[2,2,2-trifluoro-1-hydroxy-1-[(2-
4.04 (d, 1H, J = 10.8 Hz), 3.91 (s, 3H), 3.90 (s, 3H), 3.65–3.75 (m,
phenylphenyl)methyl]ethyl]morpholine-4-carboxylate 8c1, 8c2
8c1: Product 7c1 (510 mg, 1.2 mmol) and benzyl chloroformate
(0.83 mL, 5.8 mmol) gave, after purification (cyclohexane/AcOEt:
9/1) product 8c1 (470 mg, 84%) as a yellow oil as one racemic
2H), 2.89–3.47 (m, 13H). 13C NMR (75 MHz, MeOD)
d ppm: 159.3,
159.2, 134.2, 134.1, 130.3, 130.0, 127.3 (q, J = 286.0 Hz), 126.9 (q,
J = 285.5 Hz), 124.1, 123.3, 122.1, 121.9, 112.2, 112.1, 77.7 (q,
J = 26.8 Hz), 77.4 (q, J = 26.3 Hz), 75.9, 75.2, 65.7, 65.2, 56.4, 56.3,
44.7 (q, J = 3.1 Hz), 44.2 (q, J = 2.5 Hz), 44.1, 43.9, 32.6, 31.6. 19F
mixture. 1H NMR (CDCl3)
3.90–4.23 (m, 3H), 3.45–3.50 (m, 3H), 2.88–3.03 (m, 2H), 2.45–2.58
(m, 1H). 13C NMR (CDCl3)
ppm: 155.0, 143.4, 141.4, 136.3, 131.7,
d ppm: 7.30–7.54 (m, 14H), 5.20 (s, 2H),
NMR (188 MHz, MeOD)
d
ppm: À78.58, À76.74. MS (ESI) m/z:
d
306.3 (M)+. IR (cmÀ1): 3355, 2263, 2454, 1587, 1492, 1441, 1271,
1235, 1216, 1172, 1144, 1125, 1094, 1013, 761. Anal. Calcd for
131.1, 130.6, 129.8, 129.5, 128.9, 128.5, 128.4, 128.4, 128.1, 128.1,
127.9, 127.2, 127.2, 127.0, 125.4 (q, J = 292.2 Hz), 76.2, 76.1 (q,
C22H24F3NO5 + 0.75H2O (%): C, 47.33; H, 5.83; N, 3.94. Found: C,
47.45; H, 5.61; N, 3.72.
J = 26.7 Hz), 67.3, 67.2, 43.4, 43.4, 32.5. 19F NMR (CDCl3)
d
ppm:
À75.70. MS (ESI) m/z: 508.4 (MNa)+. IR (cmÀ1): 2923, 1700, 1432,
1235, 1169, 1109, 748, 699. Anal. Calcd for C27H26F3NO4 + 0.25H2O
(%): C, 66.18; H, 5.45; N, 2.86. Found: C, 66.13; H, 5.12; N, 2.66.
8c2: Product 7c2 (358 mg, 0.8 mmol) and benzyl chloroformate
(0.58 mL, 4.1 mmol) gave, after purification eluting with cyclohex-
ane/AcOEt: 9/1, product 8c2 (335 mg, 85%) as a yellow oil as one
4.6.3. 1,1,1-Trifluoro-2-(morpholin-2-yl)-3-(2-phenylphenyl)-
propan-2-ol hydrochloride 2c1, 2c2
2c1: Product 8c1 (135 mg, 0.28 mmol) and Pd/C (41 mg) gave
product 2c1 (100 mg, 93%) as a yellow sticky oil as one racemic
mixture. 1H NMR (MeOD)
d
ppm: 7.56–7.62 (m, 1H), 7.07–7.35
(m, 8H), 3.66 (dd, 1H, J = 12.8, 3.5 Hz), 3.36–3.44 (m, 2H), 3.13–
3.23 (m, 2H), 2.85–3.03 (m, 4H). 13C NMR (MeOD)
ppm: 145.1,
racemic mixture. 1H NMR (CDCl3)
d ppm: 7.39–7.42 (m, 1H), 7.11–
7.30 (m, 13H), 5.07 (d, 1H, J = 12.3 Hz), 4.99 (d, 1H, J = 12.3 Hz),
d
3.70–3.82 (m, 3H), 3.15–3.33 (m, 3H), 2.68–2.96 (m, 2H), 2.47 (t,
143.0, 132.7, 132.6, 131.8, 130.8, 129.3, 128.2, 128.2, 128.2,
1H, J = 12.2 Hz). 13C NMR (CDCl3)
d
ppm: 155.1, 143.7, 141.4, 136.4,
127.2 (q, J = 286.4 Hz), 77.4 (q, J = 26.2 Hz), 75.3, 65.6, 44.6 (q,
132.0, 131.2, 130.6, 129.5, 128.5, 128.3, 128.1, 127.9, 127.2, 127.1,
126.9, 125.2 (q, J = 287.4 Hz), 76.0, 75.6 (q, J = 26.8 Hz), 67.3, 66.9,
J = 3.8 Hz), 43.9, 33,9 (q, J = 2.3 Hz). 19F NMR (MeOD)
d ppm:
À76.90. MS (ESI) m/z: 352.3 (M)+. IR (cmÀ1): 3365, 2930, 1650,
43.4, 43.3, 32.5. 19F NMR (CDCl3)
1700, 1431, 1236, 1173, 1106, 750, 699. MS (ESI) m/z: 508.4
(MNa)+. Anal. Calcd for C27H26F3NO4 + 0.5H2O (%): C, 65.58; H,
5.50; N, 2.83. Found: C, 65.40; H, 5.50; N, 2.65.
d
ppm: À76.68. IR (cmÀ1): 2929,
1480, 1453, 1255, 1171, 1126, 1104, 752, 705. Anal. Calcd for
C19H21ClF3NO2 (%): C, 58.84; H, 5.46; N, 3.61. Found: C, 59.03; H,
5.59; N, 3.73.
2c2: Product 8c2 (194 mg, 0.40 mmol) and Pd/C (58 mg) gave
product 2c2 (152 mg, 98%) as a yellow sticky oil as one racemic
mixture. 1H NMR (MeOD)
d ppm: 7.52–7.55 (m, 1H), 7.12–7.36 (m,
4.6. General procedure and characterization for hydrochloride
compounds 2a, 2b, 2c1 and 2c2
8H), 3.72–3.85 (m, 2H), 3.55 (t, 1H, J = 13.6 Hz), 3.30 (d, 1H,
J = 14.4 Hz), 3.09 (d, 1H, J = 14.4 Hz), 3.03–3.12 (m, 1H), 2.91 (d, 1H,
J = 13.6 Hz), 2.81 (td, 1H, J = 12.0, 3.6 Hz), 2.38 (t, 1H, J = 12.0 Hz).
d ppm: 145.0, 143.3, 133.1, 133.0, 131.7, 130.9,
129.3, 128.2, 128.1, 128.1, 126.9 (q, J = 286.4 Hz), 77.4 (q,
J = 26.2 Hz), 75.1, 64.9, 44.1 (q, J = 2.5 Hz), 43.7, 32.7. 19F NMR
Pd/C (30% in mass) was added to a solution of carbamate 9 in
MeOH. The mixture was vigorously stirred for one night under H2
atmosphere and after four filtrations on celite and concentration
under reduced pressure; the crude product was dissolved in
absolute ethanol. The resulting solution was cooled to 0 8C and a
few drops of a 7 M ethanolic solution of HCl were added. After
30 min of stirring, EtOH and HCl were removed under reduced
pressure. Few drops of CDCl3 were added to the crude product and
addition of cyclohexane provided precipitation of the product. The
solid was then washed several times with distilled cyclohexane
and distilled Et2O.
13C NMR (MeOD)
(MeOD)
d
ppm: À78.91. MS (ESI) m/z: 352.4 (M) +. IR (cmÀ1): 3387,
2925, 1655, 1453, 1176, 1102, 750, 704. Anal. Calcd for
C19H21ClF3NO2 + 0.4H2O (%): C, 57.77; H, 5.57; N, 3.55. Found: C,
57.71; H, 5.59; N, 3.17.
4.7. 2-(4-Benzyl-morpholin-2-yl)-3,3,4,4,4-pentafluoro-1-
phenylbutan-2-ol 9
4.6.1. 1,1,1-Trifluoro-2-morpholin-2-yl-3-phenylpropan-2-ol
hydrochloride 2a
Product 8a (139 mg, 0.34 mmol) and Pd/C (42 mg) gave product
2a (100 mg, 95%) as a yellow light solid containing 2 racemic
mixtures (1/1) of diastereoisomers. M.p. = 178–182 8C; 1H NMR
An anhydrous ethereal solution (20 mL) of 6a (917 mg,
3.1 mmol) was cooled to À78 8C. Under anhydrous conditions,
CF3CF2I (2.5 g, 10.1 mmol) was bubbling into the mixture and a
1.6 M ethereal solution of methyl lithium was added (4.8 mL,
7.7 mmol). After 45 min of stirring at À78 8C, an aqueous
solution of HCl 1 M was added. The mixture was basified with a
10 M aqueous solution of NaOH and the product was extracted
with Et2O. The organic layer was dried over magnesium
sulphate, filtrated and concentrated under reduced pressure.
The resulting oil was then purified by chromatography on silica
(cyclohexane/AcOEt: 8/2) to afford product 9 (664 mg, 1 racemic
mixture) as a colourless oil with the yield of 52%. 1H NMR
(MeOD)
d ppm: 7.29–7.40 (m, 10H), 4.27 (dd, 1H, J = 13.4, 4.1 Hz),
4.19 (dd, 1H, J = 11.7, 3.5 Hz), 3.97 (dd, 1H, J = 11.7, 2.1 Hz), 3.85
(td, 1H, J = 12.6, 2.1 Hz), 3.39–3.60 (m, 4H), 3.12–3.27 (m, 8H),
3.01–3.09 (m, 2H). 13C NMR (75 MHz, MeOD)
d ppm: 135.9, 135.4,
132.3, 132.2, 129.4, 129.3, 128.4, 125.6 (q, J = 285.0 Hz), 125.5 (q,
J = 285.9 Hz), 76.7 (q, J = 26.3 Hz), 76.1 (q, J = 26.1 Hz), 75.5, 74.1,
65.6, 65.1, 44.7 (q, J = 4.0 Hz), 44.1, 43.9 (q, J = 2.3 Hz), 43.7, 38.4 (q,
J = 2.1 Hz), 37.9 (q, J = 1.0 Hz). 19F NMR (188 MHz, CDCl3)
d
ppm:
(400 MHz, CDCl3, 323 K) d ppm: 7.26–7.38 (m, 10H, HAr), 3.92
À74.74, À76.31. MS (ESI) m/z: 276.3 (M)+. IR (cmÀ1): 3123, 2262,
(dd, 1H, J = 11.1, 1.8 Hz), 3.70 (d, 1H, J = 10.0 Hz), 3.62 (td, 1H,
J = 11.3, 2.3 Hz), 3.44–3.55 (m, 2H), 3.17 (d, 1H, J = 14.8 Hz), 3.04
(d, 1H, J = 14.8 Hz), 2.89 (d, 1H, J = 11.3 Hz), 2.64 (d, 1H,
J = 11.1 Hz), 2.16–2.22 (m, 2H). 13C NMR (100 MHz, CDCl3,
2480, 1603, 1456, 1183, 1154, 1132, 1080, 755, 700. Anal. Calcd for
C13H17F3ClNO2 + 0.6H2O (%): C, 48.41; H, 5.69; N, 4.34. Found: C,
48.32; H, 5.23; N, 3.96.

142
C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
323 K)
d
ppm: 137.5, 134.7, 131.2, 129.2, 128.4, 128.2, 127.4,
eluting with cyclohexane/AcOEt: 8/2 to give product 11 (7.79 g,
127.0, 111.8–121.0 (m, CF2, CF3), 76.9, 76.7, 67.2, 63.4, 53.2,
52.7, 36.9. 19F NMR (376 MHz, CDCl3, 300 K):
79% mmol, 1 racemic mixture) as a yellow oil. 1H NMR (300 MHz,
d
ppm: À78.66 (s,
CDCl3) d ppm: 7.86–7.89 (m, 2H), 7.43–7.49 (m, 1H), 7.32–7.38 (m,
3F, CF3), À118.49 (d, 1F, J = 285.8 Hz, CF2), À119.41 (d, 1F,
J = 285.8 Hz, CF2). IR (cmÀ1): 3529, 3477, 3032, 1496, 1455,
1331, 1214, 1177, 1108, 1027, 744, 698. MS (APCI) m/z: 416.3
(MH)+. Anal. Calcd for C21H22F5NO2 (%): C, 60.72; H, 5.34; N,
3.37. Found: C, 61.01; H, 5.42; N, 3.16.
2H), 7.14–7.26 (m, 5H), 4.83 (dd, 1H, J = 9.9, 2.7, Hz), 3.94 (ddd, 1H,
J = 11.1, 3.3, 2.1 Hz), 3.74 (td, 1H, J = 11.1, 2.7 Hz), 3.51 (d, 1H,
J = 13.2 Hz), 3.41 (d, 1H, J = 13.2 Hz), 2.98 (dt, 1H, J = 11.4, 2.1 Hz),
2.61 (dq, 1H, J = 11.4, 2.1 Hz), 2.16–2.28 (m, 2H).13C NMR (CDCl3)
d
ppm: 196.7, 137.3, 135.0, 133.3, 129.0, 128.8, 128.4, 128.2, 127.2,
78.0, 67.0, 63.1, 55.0, 52.5. MS (APCI) m/z: 282 (MH)+. IR (cmÀ1):
2806, 1689, 1449, 1204, 1119, 1027, 739, 693. Anal. Calcd for
4.8. [2-(1-Benzyl-2,2,3,3,3-pentafluoro-1-hydroxy-
propyl)morpholin-4-yl] 2-phenylacetate 10
C18H19NO2 (%): C, 76.84; H, 6.81; N, 4.98. Found: C, 76.54; H, 6.68;
N, 4.99.
See protocol used for synthesis of products 9a–c. Product 8
(580 mg, 1.4 mmol) and benzyl chloroformate (0.99 mL,
6.9 mmol) gave, after purification eluting with cyclohexane/
AcOEt: 9/1, product 10 (570 mg, 90%, 1 racemic mixture) as a
4.11. General procedure and characterization for compounds 12a and
12b
colourless oil. 1H NMR (400 MHz, DMSO, 333 K)
d
ppm: 7.27–7.35
Under inert atmosphere, a solution of tert-butyl lithium (1.6 M
in pentane) was added to an anhydrous ethereal solution of iodide
compound cooled to À85 8C. After 5 min of stirring, an ethereal
solution of methanone 11 was added and the resulting mixture
was stirred at À85 8C for 2 h. The mixture was allowed to warm to
room temperature after addition of an aqueous solution of
NaHCO3. The product was extracted with Et2O; the organic layer
was dried over magnesium sulphate, filtrated and concentrated
under reduced pressure. The resulting oil was purified by
chromatography on silica gel. Products were obtained in the form
of 1 racemic mixture.
(m, 10H), 5.06 (d, 1H, J = 12.0 Hz), 5.02 (d, 1H, J = 12.0 Hz), 4.09 (d,
1H, J = 12.0 Hz), 3.92 (dd, 1H, J = 12.0, 4.0 Hz), 3.77 (d, 1H,
J = 12.0 Hz), 2.87–3.19 (m, 6H). 13C NMR (100 MHz, DMSO, 333 K)
d
ppm: 154.2, 136.6, 134.3, 130.9, 128.2, 127.6, 127.2, 126.5,
112.9–121.7 (m, CF2, CF3), 76.7, 76.7 (t, J = 19.0 Hz), 66.3, 66.2,
43.3, 43.1, 37.3. 19F NMR (376 MHz, DMSO, 353 K)
d
ppm: À77.04
(s, 3F, CF3), À116.38 (d, 1F, J = 282.0 Hz, CF2), À117.86 (d, 1F,
J = 282.0 Hz, CF2). IR (cmÀ1): 3380, 1681, 1435, 1213, 1177, 1106,
1004, 988, 753, 697. MS (APCI) m/z: 460.2 (MH)+. Anal. Calcd for
C
22H22F5NO4 + H2O (%): C, 57.07; H, 4.88; N, 3.03. Found: C, 56.71;
H, 5.29; N, 2.87.
4.11.1. 1-(4-Benzyl-morpholin-2-yl)-2-(4,4-difluoro-cyclohexyl)-1-
phenylethanol 12a
4.9. 3,3,4,4,4-Pentafluoro-2-morpholin-2-yl-1-phenylbutan-2-ol
hydrochloride 3
1,1-Difluoro-4-iodomethyl-cyclohexane (613 mg, 2.4 mmol,
in 15 mL of anhydrous ether), tert-butyl lithium (1.5 mL,
2.4 mmol), product 11 (335 mg, 1.2 mmol) in 15 mL of anhy-
drous Et2O, gave, after purification eluting with cyclohexane/
AcOEt: 8/2, product 12a (311 mg, 64%) as a yellow solid.
See protocol used for synthesis of products 2a–c. Product 10
(230 mg, 0.5 mmol) and Pd/C (66 mg) gave 156 mg of product 3
(90%, 1 racemic mixture) as a yellow oil. 1H NMR (300 MHz, MeOD)
d
ppm: 7.28–7.38 (m, 5H, HAr),), 4.15 (dd, 1H, J = 12.9, 3.6 Hz,
OCH2), 3.37–3.52 (m, 3H), 3.03–3.31 (m, 5H). 13C NMR (75 MHz,
MeOD) ppm: 135.4 (CqAr), 132.3 (CHAr), 129.3 (CHAr), 128.4
M.p. = 106–108 8C. 1H NMR (CDCl3)
d ppm: 7.09–7.27 (m, 10H),
3.97 (dt, 1H, J = 11.1, 3.6 Hz), 3.56–3.66 (m, 2H), 3.37 (d, 1H,
J = 12.6 Hz), 3.08 (d, 1H, J = 12.6), 2.42 (dt, 1H, J = 3.3, 11.4 Hz),
2.01–2.11 (m, 4H), 0.96–1.92 (m, 10H). 13C NMR (CDCl3)
d ppm:
142.5, 137.2, 129.2, 128.2, 128.1, 127.2, 126.7, 125.5, 123.6 (dd,
J = 237.8, 240.7 Hz), 80.4, 78.4, 66.2, 63.2, 53.1, 52.3, 44.7, 33.4
(dd, J = 22.3, 23.4 Hz), 31.2, 30.3 (d, J = 9.9 Hz). 19F NMR (CDCl3)
d
ppm: À91.19 to À92.68 (m, 1F), À101.25 to À103.09 (m, 1F). IR
(cmÀ1): 3554, 2937, 2874, 1447, 1359, 1111, 1030, 963, 939,
914, 859, 743, 699. MS (APCI) m/z: 416 (MH)+. Anal. Calcd for
d
(CHAr), 114.8–133.1 (m, CF2, CF3), 78.3 (t, J = 20.6 Hz, COHCF2),
76.2 (OCH), 65.5 (OCH2), 44.5 (t, J = 5.3 Hz, NCH2CH), 44.0
(NCH2CH2), 38.8 (CH2Ph). 19F NMR (188 MHz, MeOD)
À79.85 (s, 3F, CF3), À119.34 (d, 1F, J = 283.0 Hz, CF2), À121.59 (d,
1F, J = 283.0 Hz, CF2). MS (APCI) m/z: 326.2 (M)+. IR (cmÀ1): 3254,
2741, 2431, 2116, 1449, 1335, 1212, 1181, 1141, 1094, 1004, 715.
Anal. Calcd for C14H17ClF5NO2 + 0.5H2O (%): C, 45.35; H, 4.89; N,
3.78. Found: C, 45.16; H, 4.94; N, 4.03.
d
ppm:
C
25H31F2NO2 + 0.33H2O (%): C, 71.23; H, 7.57; N, 3.32. Found: C,
71.16; H, 7.21; N, 3.36.
4.10. (4-Benzyl-morpholin-2-yl)-phenylmethanone 11
4.11.2. 1-(4-Benzyl-morpholin-2-yl)-4,4,4-trifluoro-1-phenylbutan-
1-ol 12b
Several crystals of I2 and 1 mL of phenyl bromide were added to
an anhydrous etheral solution (few mL) of magnesium (8.56 g,
352 mmol) in a three-neck round bottom flask fitted with a
refluxing condenser. The flask was placed in an ice bath and a
solution of phenyl bromide (14.8 mL, 140.8 mmol in 75 mL of
anhydrous Et2O) was introduced dropwise. After total addition of
the halogenated compound solution, the mixture was allowed to
warm to room temperature and was stirred for 15 min. The flask
was cooled to 0 8C and the solution of product 5 (7.09 g, 35.2 mmol,
in solution in 75 mL of anhydrous Et2O) was added dropwise. The
mixture was allowed to warm to room temperature and was
stirred for 1.5 h. The mixture was cooled to 0 8C for the addition of a
1 M HCl aqueous solution. After 5 min of stirring, a 10 M NaOH
aqueous solution was added and product 11 was extracted with
Et2O and CH2Cl2. The organic layer was dried over magnesium
sulphate, filtrated and concentrated under reduced pressure. The
resulting oil was then purified by chromatography on silica gel
1,1,1-Trifluoro-3-iodopropane (2.87 g, 12.8 mmol, in 22 mL of
anhydrous Et2O), tert-butyl lithium (8 mL, 12.8 mmol), product 11
(1.2 g, 4.3 mmol, in 22 mL of anhydrous Et2O), gave, after
purification (cyclohexane/AcOEt: 8.5/1.5), product 12b (1.38 g,
85%) as a yellow light solid. M.p. = 71–72 8C. 1H NMR (CDCl3)
d
ppm: 7.09–7.23 (m, 10H), 3.97 (dt, 1H, J = 11.4, 3.6 Hz), 3.60–3.67
(m, 2H), 3.38 (d, 1H, J = 12.9 Hz), 3.08 (d, 1H, J = 12.9 Hz), 2.43 (dt,
1H, J = 12.3, 3.6 Hz), 2.34 (dd, 1H, J = 13.2, 3.6 Hz), 2.04–2.09 (m,
4H), 1.90–1.95 (m, 1H), 1.39–1.60 (m, 1H). 13C NMR (CDCl3)
d ppm:
141.1, 137.2, 129.2, 128.4, 128.3, 127.8 (q, J = 274.4 Hz), 127.2,
127.1, 125.3, 79.7, 77.2, 66.2, 63.2, 53.1, 52.3, 31.9 (q, J = 2.3 Hz),
28.3 (q, J = 28.35 Hz). 19F NMR (CDCl3)
d
ppm: À66.55 (t,
J = 11.1 Hz). IR (cmÀ1): 3541, 3029, 2949, 2862, 1451, 1385,
1316, 1254, 1231, 1129, 1069, 1042, 993, 913, 872, 739, 700. MS
(APCI) m/z: 380 (MH)+. Anal. Calcd for C21H24F3NO2 (%): C, 66.48; H,
6.38; N, 3.69. Found: C, 66.34; H, 6.11; N, 3.63.

C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
143
4.12. 1-(4-Benzylmorpholin-2-yl)-3,3,3,3,3-pentafluoro-1-
resulting mixture was allowed to warm to room temperature
and was stirred for one day. An aqueous solution of NaHCO3 was
added and product 13 was extracted with Et2O. The organic layer
was dried over magnesium sulphate, filtrated and concentrated
under reduced pressure. The resulting oil was then purified by
chromatography on silica gel to obtain products as a racemic
mixture.
phenylprop-2-yn-1-ol 12c
Under inert atmosphere, CF3CF2I (4.0 g, 16.3 mmol) was added
to an anhydrous etheral solution (20 mL) of 11 (1.50 g, 5.3 mmol)
cooled to À78 8C. A solution of methyl lithium (1.6 M in Et2O,
4.7 mL, 7.5 mmol) was added and after 45 min of stirring at À78 8C,
the reaction mixture was treated with an aqueous solution of HCl,
basified with a 10 M aqueous solution of NaOH and the product
was extracted with Et2O. The organic layer was dried over
magnesium sulphate, filtrated and concentrated under reduced
pressure. The resulting oil was then purified by chromatography on
silica gel (cyclohexane/AcOEt: 8/2). Product 12c (1.94 g, 91%, 1
racemic mixture) was obtained as a white pinkish solid. M.p. = 59–
4.14.1. Benzyl-2-[2-(4,4-difluorocyclohexyl)-1-hydroxy-1-phenyl-
ethyl]morpholine-4-carboxylate 13a
Product 12a (239 mg, 0.58 mmol), THF (4.5 mL) and benzyl
chloroformate (0.4 mL, 2.9 mmol) gave, after purification (cyclo-
hexane/AcOEt: 8/2), product 13a (228 mg, 86%) as a colourless oil.
1H NMR (400 MHz, 328 K, CDCl3)
d ppm: 7.18–7.39 (m, 10H), 5.09
60 8C. 1H NMR (CDCl3)
d
ppm: 7.59–7.61 (m, 2H), 7.25–7.40 (m,
(d, 1H, J = 12.6 Hz), 4.99 (d, 1H, J = 12.6 Hz), 3.92–4.00 (m, 2H), 3.62
(td, 1H, J = 11.6, 2.5 Hz), 3.48 (dd, 1H, J = 10.7, 1.7 Hz), 3.38 (d, 1H,
J = 13.2 Hz), 2.92 (td, 1H, J = 12.8, 3.4, Hz), 2.75 (dd, 1H, J = 13.2,
11.6 Hz), 2.12 (dd, 1H, J = 14.8, 6.0 Hz), 1.77 (dd, 1H, J = 14.8,
8H), 5.14–5.20 (br s, 1H, OH), 4.50–4.53 (m, 1H), 4.19 (dt, 1H,
J = 11.7, 3.6 Hz), 3.89 (ddd, 1H, J = 11.7, 9.3, 3.0 Hz), 3.50 (d, 1H,
J = 13.1 Hz), 3.27 (d, 1H, J = 13.1 Hz), 2.62 (dt, 1H, J = 3.0, 11.7),
2.24–2.33 (m, 2H), 2.11 (dd, 1H, J = 8.3, 11.7 Hz). 13C NMR (CDCl3)
d
4.0 Hz), 1.08–2.04 (m, 9H). 13C NMR (100 MHz, 323 K, CDCl3)
d
ppm: 136.7, 134.7, 129.1, 128.5, 128.2, 128.1, 127.2, 126.1, 110.3–
121.5 (m, CF2, CF3), 77.9 (t, J = 21.9 Hz), 75.1, 66.0, 62.9, 52.5, 51.9.
ppm: 155.3, 141.2, 136.7, 128.5, 128.0, 127.6, 127.3, 125.5, 123.5
(dd, J = 239.0, 240.0 Hz), 81.4, 77.2, 67.2, 67.0, 45.0, 43.9, 43.8, 33.6
(t, J = 24.0 Hz), 31.3, 30.4 (dd, J = 9.0, 2.0 Hz). 19F NMR (376 MHz,
19F NMR (CDCl3)
d
ppm: À78.79 (s, 3F, CF3), À119.44 (d, 1F,
J = 277.3 Hz, CF2), À122.03 (d, 1F, J = 277.3 Hz, CF2). IR (cmÀ1):
2817, 1453, 1221, 1175, 1136, 1111, 1069, 1029, 870, 745, 716,
699. MS (APCI) m/z: 402 (MH)+. Anal. Calcd for C20H20F5NO2 (%): C,
59.85; H, 5.02; N, 3.49. Found: C, 59.65; H, 4.96; N, 3.55.
300 K, CDCl3)
d
ppm: À91.65 (d, 1F, J = 235.7 Hz), À101.81 (d, 1F,
J = 235.7 Hz). IR (cmÀ1): 3526, 2933, 2862, 1699, 1429, 1359, 1272,
1233, 1106, 1029, 964, 941, 868, 760, 735, 700. MS (ESI) m/z: 483
(MNa)+.
4.13. (4-Benzylmorpholin-2-yl)-2-(2,3,4,5,6-pentafluorophenyl)-1-
4.14.2. Benzyl-2-(4,4,4-trifluoro-1-hydroxy-1-phenyl-
phenylethanol 12d
butyl)morpholine-4-carboxylate 13b
Product 12b (1.11 g, 2.9 mmol), THF (22 mL) and benzyl
chloroformate (2.1 mL, 14.7 mmol) gave, after purification on
silica gel eluting with cyclohexane/AcOEt: 8/2, product 13b (1.16 g,
94%) as a white solid. M.p. = 118 8C. 1H NMR (400 MHz, 328 K,
Anhydrous Et2O (2 mL), several crystals of I2 and a piece of
2,3,4,5,6-pentafluorobenzyl bromide were introduced under
inert atmosphere, in a three-neck round bottom flask fitted
with
a
refluxing condenser, containing Magnesium (1.04 g,
CDCl3) d ppm: 7.20–7.39 (m, 10H), 5.12 (d, 1H, J = 12.5 Hz), 5.02 (d,
42.7 mmol). The flask was immediately placed in an ice bath, an
ethereal solution of 2,3,4,5,6-pentafluorobenzyl bromide (4.40 g,
17.0 mmol, in 22 mL of anhydrous Et2O) was introduced
dropwise at 0 8C and the mixture was stirred for 15 min. An
ethereal solution of product 11 (1.2 g, 4.3 mmol, in 11 mL of
anhydrous Et2O) was then added dropwise at 0 8C. The mixture
was allowed to warm to room temperature, was stirred for 1.5 h
and was cooled to 0 8C for the addition of an aqueous solution of
NaHCO3. Product 12d was extracted with Et2O. The organic layer
was dried over magnesium sulphate, filtrated and concentrated
under reduced pressure. The resulting oil was purified by
chromatography on silica gel (cyclohexane/AcOEt: 8/2) to give
product 12d (1.47 g, 74%, racemic mixture) as a yellow light
1H, J = 12.5 Hz), 3.95–4.02 (m, 2H), 3.65 (td, 1H, J = 11.8, 2.8 Hz),
3.59 (dd, 1H, J = 10.8, 2.1 Hz), 3.45 (d, 1H, J = 13.2 Hz), 2.94 (td, 1H,
J = 13.2, 3.6 Hz), 2.80 (dd, 1H, J = 13.2, 11.2 Hz), 2.46 (td, 1H,
J = 13.2, 3.6 Hz), 2.13–2.30 (m, 1H), 2.02 (td, 1H, J = 13.2, 4.4 Hz),
1.63–1.75 (m, 1H). 13C NMR (75 MHz, 300 K, CDCl3)
d ppm: 154.9,
139.5, 136.2, 128.4, 128.2, 127.7, 127.5 (q, J = 274.5 Hz), 127.3,
126.6, 124.9, 80.3, 75.5, 66.8, 66.5, 43.6, 31.6, 28.6 (q, J = 28.6 Hz).
19F NMR (188 MHz, 300 K, CDCl3)
d
ppm: À66.34 (t, J = 10.7 Hz). IR
(cmÀ1): 3495, 1683, 1434, 1370, 1294, 1253, 1232, 1117, 1069,
983, 875, 764, 738, 709, 698, 654. MS (ESI) m/z: 446 (MNa)+. Anal.
Calcd for C22H24F3NO4 (%): C, 62.40; H, 5.71; N, 3.31. Found: C,
62.25; H, 5.69; N, 3.24.
solid. M.p. = 91–92 8C. 1H NMR (CDCl3)
d
ppm: 7.05–7.17
4.14.3. Benzyl-2-(-3,3,3,3,3-pentafluoro-1-hydroxy-1-phenyl-prop-
2-ynyl)morpholine-4-carboxylate 13c
Product 12c (1.62 g, 4.0 mmol), THF (20 mL) and benzyl
chloroformate (2.8 mL, 20.2 mmol) gave, after purification on
silica gel (cyclohexane/AcOEt: 8/2), product 13c (1.71 g, 95%) as a
white solid. M.p. = 92 8C. 1H NMR (400 MHz, CDCl3, 328 K)
d ppm:
(m, 10H), 3.90–3.95 (m, 2H), 3.66 (td, 1H, J = 10.5, 2.4 Hz),
3.54 (d, 1H, J = 13.6), 3.33 (d, 1H, J = 12.9 Hz), 3.03 (d, 1H,
J = 12.9 Hz), 2.96 (d, 1H, J = 13.6 Hz), 2.42 (d, 1H, J = 11.4 Hz),
2.17 (d, 1H, J = 11.4 Hz), 1.94–2.03 (m, 2H). 13C NMR (CDCl3)
d
ppm: 140.4, 137.2, 129.0, 128.1, 127.8, 127.2, 127.0, 125.2,
110.7–147.4 (m, CF), 79.1, 77.5, 66.5, 63.0, 53.1, 52.0, 33.6. 19F
7.59–7.60 (m, 2H), 7.26–7.40 (m, 8H), 5.19 (d, 1H, J = 12.4 Hz), 5.06
(d, 1H, J = 12.4 Hz), 4.29 (d, 1H, J = 10.3 Hz), 3.97–4.02 (m, 1H), 3.99
(dd, 1H, J = 11.5, 3.2 Hz), 3.71 (td, 1H, J = 11.5, 2.6 Hz), 3.53 (d, 1H,
J = 13.2 Hz), 2.94 (td, 1H, J = 13.2, 3.2 Hz), 2.69 (dd, 1H, J = 13.2,
NMR (CDCl3)
d
ppm: À140.5 (d, J = 7.7 Hz, 1F), À140.6
(d, J = 7.7 Hz, 1F), À157.8 (t, J = 20.9 Hz, 1F), À164.1 to À164.4
(m, 2F). IR (cmÀ1): 3585, 2881, 1522, 1498, 1449, 1172, 1126,
1070, 1008, 955, 867, 747, 702. MS (APCI) m/z: 464 (MH)+. Anal.
Calcd for C25H22F5NO2 (%): C, 64.79; H, 4.78; N, 3.02. Found: C,
64.63; H, 4.70; N, 2.97.
11.5 Hz). 13C NMR (100 MHz, CDCl3, 300 K)
d ppm: 155.0, 136.2,
133.1, 128.9, 128.4, 128.0, 127.3, 126.8, 126.0, 119.0 (qt, J = 287.0,
36.0 Hz, CF3), 114.4 (qt, J = 265.0, 34.0 Hz, CF2), 76.5 (t, J = 21.5 Hz),
75.6, 67.2, 66.5, 43.5, 43.2. 19F NMR (188 MHz, CDCl3, 300 K)
d
4.14. General procedure and characterization for benzylcarboxylate
ppm: À78.84 (s, 3F, CF3), À119.28 (d, 1F, J = 277.6 Hz, CF2), À121.70
(d, 1F, J = 277.6 Hz, CF2). IR (cmÀ1): 3507, 1704, 1429, 1219, 1176,
1136, 1070, 866, 717. MS (ESI) m/z: 468.0 (MNa)+. Anal. Calcd for
compounds 13a–d
Benzyl chloroformate was added dropwise to a 0 8C solution of
product 12 in anhydrous THF under inert atmosphere. The
C
21H20F5NO4 (%): C, 56.63; H, 4.53; N, 3.14. Found: C, 56.65; H,
4.45; N, 3.10.

144
C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
4.14.4. Benzyl-2-[1-hydroxy-2-(2,3,4,5,6-pentafluorophenyl)-1-
phenyl-ethyl]morpholine-4-carboxylate 13d
Product 12d (899 mg, 1.9 mmol), THF (14 mL) and benzyl
chloroformate (1.4 mL, 9.7 mmol) gave, after purification on silica
gel (cyclohexane/AcOEt: 8/2), product 13d (920 mg, 93%) as a
translucent solid. M.p. = 112–115 8C. 1H NMR (400 MHz, 328 K,
1315, 1257, 1134, 1095, 1075, 1000, 762, 700. MS (APCI) m/z: 290
(M)+. Anal. Calcd for C14H19ClF3NO2 + 0.75H2O (%): C, 49.56; H,
6.09; N, 4.13. Found: C, 49.46; H, 5.91; N, 4.05.
4.15.3. 3,3,3,3,3-Pentafluoro-1-(morpholin-2-yl)-1-phenylprop-2-
yn-1-ol hydrochloride 4c
CDCl3)
d
ppm: 7.20–7.34 (m, 10H), 5.12 (d, 1H, J = 12.5 Hz), 5.00 (d,
Product 13c (300 mg, 0.67 mmol) and Pd/C (90 mg) gave
product 4c (190 mg, 81%) as a white solid. M.p. = 240–248 8C 1H
NMR (MeOD) d ppm: 7.63–7.65 (m, 2H), 7.41–7.48 (m, 3H), 4.76 (d,
1H, J = 12.6 Hz), 4.25 (dd, 1H, J = 12.6, 3.6 Hz), 4.04 (t, 1H,
J = 12.6 Hz), 3.30 (d, 1H, J = 12.6 Hz), 3.16 (td, 1H, J = 12.6,
3.6 Hz), 2.95 (t, 1H, J = 12.6 Hz), 2.52 (d, 1H, J = 12.6 Hz). 13C
1H, J = 12.5 Hz), 3.96–4.04 (m, 2H), 3.84 (dd, 1H, J = 10.8, 1.8 Hz),
3.71 (td, 1H, J = 11.8, 2.7 Hz), 3.53–3.60 (m, 2H), 3.10 (d, 1H,
J = 13.6 Hz), 2.95 (td, 1H, J = 13.1, 3.4, Hz), 2.75 (dd, 1H, J = 13.6,
10.8, Hz). 13C NMR (75 MHz, 300 K, CDCl3)
136.3, 128.2, 128.0, 127.7, 127.5, 126.7, 125.0, 110.2–147.3 (m, CF),
79.3, 76.5, 66.9, 66.7, 43.6, 43.3, 33.6. 19F NMR (188 MHz, 300 K,
CDCl3)
1F), À157.34 (t, J = 19.7 Hz, 1F), À164.00 (d, J = 19.7 Hz, 1F),
À164.11 (d, J = 19.7 Hz, 1F). IR (cmÀ1): 3513, 2930, 1698, 1520,
1500, 1428, 1272, 1235, 1177, 1124, 1013, 957, 910, 887, 733, 701.
MS (ESI) m/z: 530 (MNa)+. Anal. Calcd for C26H22F5NO4 (%): C,
61.54; H, 4.37; N, 2.76. Found: C, 61.33; H, 4.33; N, 2.68.
d ppm: 155.0, 139.0,
NMR (MeOD)
d ppm: 135.0, 130.4, 129.8, 127.4, 112.3–122.2 (m,
d
ppm: À140.77 (d, J = 7.7 Hz, 1F), À140.89 (d, J = 7.7 Hz,
CF2, CF3), 77.7 (t, J = 21.6 Hz), 76.4, 64.7, 43.6, 43.2. 19F NMR
(MeOD)
d
ppm: À80.26 (s, 3F, CF3), À119.05 (d, 1F, J = 277.7 Hz,
CF2), À123.01 (d, 1F, J = 277.7 Hz, CF2). IR (cmÀ1): 3324, 1213,
1182, 1142, 835, 716, 648. MS (ESI) m/z: 312 (M)+. Anal. Calcd for
C13H15ClF5NO2 + 2/3H2O (%): C, 44.06; H, 4.65; N, 3.95. Found: C,
44.13; H, 4.31; N, 3.80.
4.15. General procedure and characterization for hydrochloride
4.15.4. 1-(Morpholin-2-yl)-2-(2,3,4,5,6-pentafluorophenyl)-1-
phenylethanol hydrochloride 4d
compounds 4a–d
Product 13d (300 mg, 0.59 mmol) and Pd/C (90 mg) gave
product 4d (189 mg, 78%) as a white solid. M.p. = 242–244 8C 1H
Pd/C (30% in mass) was added to a solution of carboxylate 13 in
MeOH. The mixture was vigorously stirred for one night under H2
atmosphere and after four filtrations on celite and concentration
under reduced pressure; the crude product was dissolved in
absolute ethanol. The resulting solution was cooled to 0 8C and a
few drops of a 7 M ethanolic solution of HCl were added. After
30 min of stirring, EtOH and HCl were removed under reduced
pressure. Few drops of CDCl3 were added to the crude product and
addition of cyclohexane provided precipitation of the compound 4.
The solid was then washed several times with distilled cyclohex-
ane and distilled Et2O. Products 4 were obtained as a racemic
mixture.
NMR (MeOD)
d ppm: 7.39–7.42 (m, 2H), 7.25–7.35 (m, 3H), 4.45
(dd, 1H, J = 11.1, 2.1 Hz), 4.30 (dd, 1H, J = 12.6, 3.9 Hz), 4.11 (td, 1H,
J = 12.6, 2.1 Hz), 3.61 (d, 1H, J = 14.1 Hz), 3.31–3.36 (m, 2H), 3.19
(td, 1H, J = 12.6, 3.9 Hz), 3.02 (t, 1H, J = 12.6 Hz), 2.70 (d, 1H,
J = 12.6 Hz). 13C NMR (MeOD)
d
ppm: 141.0, 129.3, 128.9, 126.7,
112.2–148.9 (m, CF), 79.0, 77.8, 65.0, 43.9, 43.8, 33.9. 19F NMR
(MeOD)
d
ppm: À141.39 (d, J = 7.7 Hz, 1F), À141.50 (d, J = 7.7 Hz,
1F), À160.80 (t, J = 19.9 Hz, 1F), À167.26 to À167.56 (m, 2F). IR
(cmÀ1): 3570, 2779, 1525, 1502, 1446, 1178, 1126, 1098, 1014,
963, 950, 872, 748, 704, 621, 581. MS (APCI) m/z: 374 (M)+. Anal.
Calcd for C18H17ClF5NO2 + 0.5H2O (%): C, 51.62; H, 4.33; N, 3.34.
Found: C, 51.78; H, 4.16; N, 3.37.
4.15.1. 2-(4,4-Difluorocyclohexyl)-1-(morpholin-2-yl)-1-
phenylethanol hydrochloride 4a
4.16. Monoamine transporter binding assays
Product 13a (172 mg, 0.38 mmol) and Pd/C (52 mg) gave
product 4a (131 mg, 97%) as a white solid. M.p. = 170–176 8C 1H
4.16.1. Binding at hSERT, hNET and hDAT
NMR (MeOD)
d
ppm: 7.51 (d, 2H, J = 7.2 Hz), 7.40 (t, 2H, J = 7.2 Hz),
Binding affinity was determined by competition using [3H]cita-
lopram (2 nM, PerkinElmer Life Sciences), [3H]nisoxetine (2 nM,
Amersham) and [3H]GBR12909 (1 nM, PerkinElmer Life Sciences)
as radioligands for hSERT, hNET and hDAT, respectively. Mem-
branes prepared from HEK293 cells, Madin–Darby canine kidney
cells and CHO cells stably expressing hSERT, hNET and hDAT,
respectively, and purchased from PerkinElmer Life Sciences
(Beltsville, MD) were incubated in a buffer containing HEPES
(20 mM), NaCl (120 mM) and KCl (5 mM) with the radioligand and
7.30 (t, 1H, J = 7.2 Hz), 4.21 (d, 1H, J = 13.2 Hz), 3.91–4.00 (m, 2H),
3.24 (d, 1H, J = 12.6 Hz), 2.96–3.14 (m, 2H), 2.54 (d, 1H, J = 12.6 Hz),
2.18–2.23 (m, 1H), 0.98–1.95 (m, 10H). 13C NMR (MeOD)
d ppm:
142.9, 129.5, 128.4, 126.8, 124.5 (dd, J = 236.9, 239.9 Hz, CF2), 80.8,
77.8, 64.8, 44.5, 44.0, 43.8, 34.4 (dd, J = 24.0, 26.3 Hz, CH2CF2), 32.3,
31.3 (dd, J = 14.3, 9.3 Hz, CH2CH2CF2). 19F NMR (MeOD)
d ppm:
À93.26 (d, 1F, J = 234.8 Hz), À103.59 (br d, 1F, J = 234.8 Hz). IR
(cmÀ1): 3563, 3334, 2938, 1448, 1360, 1212, 1099, 963, 941, 915,
+
865, 701. MS (APCI) m/z: 326 (M)
.
Anal. Calcd for
competing ligand in a final volume of 250
specific binding was defined with paroxetine (1
desipramine (10 M) for hNET and GBR12909 (10
m
L for 2 h at 22 8C. Non-
M) for hSERT,
Mp) for hDAT.
C
18H26ClF2NO2 + 2H2O (%): C, 54.34; H, 7.60; N, 3.52. Found: C,
m
m
54.35; H, 6.83; N, 3.08.
m
4.15.2. 4,4,4-Trifluoro-1-(morpholin-2-yl)-1-phenylbutan-1-ol
hydrochloride 4b
Product 13b (300 mg, 0.70 mmol) and Pd/C (90 mg) gave
product 4b (216 mg, 94%) as a white solid. M.p. = 206–208 8C 1H
4.16.2. Data analysis for binding studies
At the end of the incubation period, membranes were filtered
through Whatman (Packard, Meriden, CT) GF/B filters pretreated
with 0.1% polyethylenimine. Radioactivity retained on the filters
was determined by scintillation counting. Binding isotherms were
analyzed by nonlinear regression using Prism software (GraphPad
Software Inc., San Diego, CA) to determine IC50 values. These were
converted to inhibition constants (Ki) by use of the Cheng–Prusoff
equation: Ki = IC50/{(L/KD) À 1}, where L is the concentration of 3H-
labeled ligand and KD is its dissociation constant determined in
saturation binding experiments. The KD values were as follows:
2 nM for [3H]citalopram at hSERTs; 2.2 nM for [3H]nisoxetine at
hNETs and 1 nM for [3H]GBR12909 at hDATs.
NMR (MeOD) d ppm: 7.51 (d, 2H, J = 7.2 Hz), 7.43 (t, 2H, J = 7.2 Hz),
7.33 (t, 1H, J = 7.2 Hz), 4.23 (d, 1H, J = 12.6 Hz), 4.08 (d, 1H,
J = 11.4 Hz), 4.00 (t, 1H, J = 12.6 Hz), 3.27 (d, 1H, J = 12.6 Hz), 3.10–
3.17 (m, 1H), 3.06 (t, 1H, J = 11.4 Hz), 2.60 (d, 1H, J = 12.6 Hz), 2.51
(t, 1H, J = 12.6 Hz), 2.04–2.29 (m, 2H), 1.55 (q, 1H, J = 12.6 Hz). 13
C
NMR (MeOD)
d ppm: 141.6, 129.9, 129.1 (q, J = 273.3 Hz, CF3),
128.8, 126.6, 80.1, 76.6, 64.9, 44.0, 43.9, 31.7 (q, J = 2.7 Hz,
CH2CH2CF3), 29.2 (q, J = 28.4 Hz, CH2CF3). 19F NMR (MeOD)
d
ppm: À68.22 (t, J = 11.1 Hz). IR (cmÀ1): 3390, 2957, 1449, 1391,

C. Philippe et al. / Journal of Fluorine Chemistry 134 (2012) 136–145
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