Diastereoselective synthesis of 2-phenyl-3-(trifluoromethyl)piperazines as building blocks for drug discovery

Article abstract of DOI:10.1021/jo500832j

The synthesis of enantiomerically pure cis- and trans-2-phenyl-3- (trifluoromethyl)piperazines is described. It involved, as the key step, a diastereoselective nucleophilic addition of the Ruppert-Prakash reagent (TMSCF₃) to α-amino sulfinylimines bearing Ellmans auxiliary. This methodology allows an entry into hitherto unknown trifluoromethylated and stereochemically defined piperazines, key scaffold components in medicinal chemistry.

Full text of DOI:10.1021/jo500832j

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Note
Diastereoselective Synthesis of 2-Phenyl-3-
(Trifluoromethyl)Piperazines as Building Blocks for Drug Discovery
Maria Sanchez-Rosello, Oscar Delgado, Natalia Mateu,
Andrés A. Trabanco, Michiel Van Gool, and Santos Fustero
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 23 May 2014
Downloaded from http://pubs.acs.org on May 25, 2014
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Diastereoselective Synthesis of 2-Phenyl-3-(Trifluoromethyl)Piperazines
as Building Blocks for Drug Discovery.
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María Sánchez-Roselló,*,† Oscar Delgado,*,§ Natalia Mateu,† Andrés A. Trabanco,§ Michiel
Van Gool§ and Santos Fustero.*,†,‡
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†
Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, E-46012
Valencia, Spain.
‡ Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot, Spain.
§ Janssen Research and Development, Neuroscience Medicinal Chemistry Department, E-
45007 Toledo, Spain.
santos.fustero@uv.es; odelgad1@its.jnj.com; maria.sanchez-rosello@uv.es
Abstract. The synthesis of enantiomerically pure cis- and trans- 2-phenyl-3-
(trifluoromethyl)piperazines is described. It involved, as the key step, a diastereoselective
nucleophilic addition of the Ruppert-Prakash reagent (TMSCF3) to -amino sulfinylimines
bearing Ellman´s auxiliary. This methodology allows an entry into hitherto unknown
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trifluoromethylated and stereochemically defined piperazines, key scaffold components in
medicinal chemistry.
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The piperazine ring is present in a great variety of molecules involved in the regulation of
many biological processes, therefore being classified as a privileged structural element for
the construction of drug-like molecules.1 Substituted piperazines are frequently embedded
in the molecular architecture of therapeutically valuable compounds,2 including antifungals,
antidepressants, antivirals and antibiotics, among others.3 Some examples of marketed
drugs that contain the piperazine motif are shown in Figure 1.
Figure 1. Marketed drugs containing the piperazine motif.
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Piperazines are small alicyclic platforms that allow for the differential derivatization of
their opposing nitrogens in a well-defined linear fashion. Additionally, the nitrogen atoms,
whose basicity can be modulated to a certain extent depending on the nature of the attached
substituents, can establish important hydrogen bond interactions with the target protein, and
often play a role in increasing the water solubility of lipophilic compounds.
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Although most pharmaceutically relevant compounds bearing the piperazine scaffold only
have substituents on the nitrogen atoms, carbon substituted piperazines have also been
reported and evaluated for their pharmacological properties.4 Several synthetic strategies
have been employed for the preparation of C-substituted piperazines, namely reductive
cyclocondensations,5 alkylation and reduction of 2-methylpyrazines,6 reduction of the
corresponding (di)ketopiperazines,7 -lithiation and alkylation of N-t-butyloxycarbonyl
(Boc) protected piperazines,8 and several intramolecular metal-mediated ring closure
strategies.9
The incorporation of fluorinated groups into the carbon skeleton of piperazines has not
been extensively explored to date.10 It is well known that selective introduction of fluorine
atoms into organic molecules has become a powerful strategy to modulate their biological
properties.11 Specifically, the replacement of one or more hydrogen atoms by fluorine in the
vicinity of an amine function often results in a lower basicity, a higher metabolic stability
and a decrease in acute toxicity.12 In the past decades, CF3 containing compounds have
attracted considerable synthetic interest13 mainly due to the effect that this particular
fluorinated group can have on the physicochemical and pharmacokinetic/pharmacodynamic
properties of organic molecules. For this reason, its introduction into potential drug
candidates is a commonly employed approach in drug discovery programs.
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Given the importance of piperazines in medicinal chemistry, 3-trifluoromethyl-2-
arylpiperazines (C) could constitute attractive building blocks for drug discovery.14 This
novel molecular template presents a pair of lipophilic functional groups (Ph and CF3) in a
well-defined spatial organization (cis or trans) enabling unprecedented hydrophobic
interactions with biological targets. Despite the relatively simple approach, and to the best
of our knowledge, the synthesis of C has not yet been described, triggering concerns about
the chemical and configurational stability of this type of diamines. Instead of commencing
the synthesis from a commercially available fluorinated building block, a potentially
stereoselective strategy that could use simple -amino acid derivatives as starting materials
was envisaged (Scheme 1). The nucleophilic addition of the Ruppert-Prakash reagent
(TMSCF3)15 to preformed -amino imines (A) represents a straightforward route to obtain
trifluoromethylated vicinal diamines (B).16 Ellman´s N-(tert-butanesulfinyl)imines have
been successfully employed in this context.17 Having access to an orthogonally protected
diamine building block (B) was deemed essential.
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Scheme 1. Synthetic strategy for the synthesis of fluorinated piperazines.
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As shown in Scheme 2, our synthesis began with the protection of (R)-phenylglycinol as
the corresponding bis- p-methoxybenzyl (PMB) derivative (R)-2 in good yield (73%).
Swern oxidation followed by condensation of the resulting -amino aldehyde with (S)-()-
2-methyl-2-propanesulfinamide, in the presence of titanium(IV) ethoxide as dehydrating
agent, yielded tert-butylsulfinimine (R, SS)-4 in enantiomerically pure form (60% yield).
With compound (R, SS)-4 in hand, we tested different conditions in order to carry out the
key diastereoselective nucleophilic trifluoromethylation.18 After a careful optimization, it
was found that the best conditions involved the dropwise addition of TMSCF3 to a solution
of the Ellman´s imine and finely ground tetramethylammonium fluoride (TMAF), as
activator of the Ruppert-Prakash reagent, at 35oC. Following this protocol, the protected
diamine (R, R, SS)-5 was obtained in 66% yield as a single diastereoisomer. According to
previous reports,17a imine 4 exists in the (E) configuration, and the diastereoselectivity
observed is due to the si face attack prompted by both chiral centers present in the
molecule. Then, the tert-butanesulfinyl group was removed upon exposure to hydrochloric
acid in refluxing methanol in a sealed tube, yielding the monoprotected diamine (R, R)-6.19
The use of a closed reaction vessel proved essential for the partial unmasking of the
benzylic amine, a prerequisite for the subsequent enclosure of both nitrogens into a
piperazine ring.
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Scheme 2. Synthesis of enantiomerically pure monoprotected diamine (R, R)-6.
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Cl
PMB
PMB
OH
N
NH2
N(PMB)2
H
OMe
(ClCO)2, DMSO, Et3N
CH2Cl2, 78 ºC
(>99%)
(2.1 equiv)
OH
O
K2CO3 (3 equiv)
CH3CN (0.2M) , 60oC, 60h
1
(R)-
2
3
(R)-
(R)-
(73%)
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O
S
t-Bu
NH2
THF, rt, 12h
(60%)
Ti(OEt)4
PMB
HN
N(PMB)2
CF3
N(PMB)2
H
TMSCF3 (1.5 equiv)
TMAF (1.2 equiv)
HCl/dioxane
(10 equiv)
CF3
NH2
(R, R)-6
HN
t-Bu
N
S
t-Bu
MeOH (0.1M)
70 ºC, 24h
S
THF (0.07M), 35 ºC, 1h
(66%)
O
O
(82%)
5
(R, R, SS)-
(R, SS)-4
We then decided to explore the formation of the required 6-membered heterocycles. Thus,
treatment of (R, R)-6 with 1,2-dibromoethane led to the formation of complex mixture of
products. In order to have a more predictable reactivity profile, 2-chloroacetyl chloride was
chosen as electrophile. This strategy divides the overall heterocycle formation process in
two trivial chemical reactions: a) an amide bond formation reaction; followed by b) a 6-exo
trig cyclization of the resulting chloroderivative (R, R)-7. As expected, the initial amide
coupling took place exclusively via the primary amine in compound 6, despite the strong
electron withdrawing effect of the contiguous trifluoromethyl group. -Chloroamide (R,
R)-7 was isolated in excellent yield (93%) after flash column chromatography. The
cyclization to the oxopiperazine (R, R)-8 proceeded in good yield (70%) upon treatment of
(R, R)-7 with sodium hydride (Scheme 3). Reduction of the keto group with lithium
aluminum hydride afforded the N-PMB protected piperazine (R, R)-9 in 76% yield. After
several unsuccessful attempts to remove the remaining PMB group under oxidative
conditions (DDQ, CAN), this was finally achieved by hydrogenolysis in the presence of
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catalytic amounts of Pd(OH)2. These optimized conditions could be also applied to
piperazinone (R, R)-8, obtaining the attractive fluorinated building block (R, R)-11 in
enantiopure form.
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Scheme 3. Synthesis of cis-2-phenyl-3-(trifluoromethyl) piperazine derivatives.
Access to the trans diastereoisomers was secured by a modified synthetic route that again
started from (R)-phenylglycinol but used the opposite enantiomer of Ellman´s auxiliary
(Scheme 4). Based on synthetic precedence, it was anticipated that the chiral auxiliary
would neglect any potential influence of the aminoalcohol chirality on the stereochemical
outcome of the 1,2-addition reaction. Thus, condensation of aldehyde (R)-3 with
commercially available (R)-N-tert-butanesulfinamide in the presence of Ti(OEt)4 yielded
sulfinylimine (R, RS)-4 (54% yield). Subsequent nucleophilic addition with the Ruppert-
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Prakash reagent gave the corresponding protected vicinal diamine in moderate yield (60%)
and complete diastereocontrol. The stereochemical outcome indicates that the chiral
auxiliary is able to overturn any intrinsic substrate selectivity. Unfortunately, attempts to
deprotect (R, S, RS)-5 under the conditions used for the cis diastereoisomer (HCl in MeOH,
70 ºC in a sealed tube) led to an unseparable mixture of mono and bis-PMB diamino
derivatives. Selective removal of the chiral auxiliary in compound (R, S, RS)-5 could be
achieved in 75% yield after treatment with hydrochloric acid in refluxing methanol for 1h.
Boc-protection of the free amine followed by hydrogenolysis with Pearlman’s catalyst
afforded amino carbamate (R, S)-14 in 57% yield (two steps). Monoprotected diamine (R,
S)-14 constitutes an interesting fluorinated scaffold for further derivatization.
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Scheme 4. Synthesis of enantiomerically pure Boc-protected diamine (R, S)-14.
O
S
N(PMB)2
H
N(PMB)2
H
N(PMB)2
CF3
t-Bu
NH2
TMSCF3 (1.5 equiv)
TMAF (1.2 equiv)
Ti(OEt)4
THF, rt, 12h
(54%)
O
N
S
t-Bu
HN
t-Bu
THF (0.07M), 35 ºC, 1h
(60%)
S
O
3
(R)-
O
(R, RS)-4
(R, S, RS)-5
HCl/dioxane
(10 equiv)
MeOH, reflux, 1h
(75%)
NH2
HN
N(PMB)2
CF3
N(PMB)2
CF3
(Boc)2O (3 equiv)
CF3
Boc
H2, Pd(OH)2
K2CO3 (4 equiv)
NH2
HN
1,4-dioxane, 50oC
(87%)
MeOH
(65%)
Boc
(R, S)-14
(R, S)-13
(R, S)-12
Following our cyclization strategy for the cis diastereoisomeric series, compound (R, S)-14
underwent smooth N-acylation to give the corresponding chloroacetamide (R, S)-15 in
quantitative yield. Attempts to cleave the Boc protecting group at this stage (TFA/CH2Cl2,
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rt, 20 h) resulted in the epimerization of the trifluoromethylated carbinamine as detected by
19F-NMR. This undesired event could be avoided when the ring closing alkylation was
carried out with N-Boc derivative (R, S)-15. Upon addition of NaH and
tetrabutylammonium iodide (TBAI) to a diluted solution of (R, S)-15 in a mixture of THF
and DMF, the corresponding Boc-protected piperazinone was obtained in high yield (90%)
as a single diastereoisomer. TFA mediated deprotection of (R, S)-16 could be carried out at
this stage avoiding the undesired acid-catalyzed epimerization observed in the acyclic
derivative. In this manner, ketopiperazine (R, S)-17 was obtained in very good yield (90%)
(Scheme 5).
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In order to complete the synthesis of the trans piperazine (R, S)-20, the amide group in (R,
S)-16 was efficiently converted into the corresponding thioamide (R, S)-18 in 72% yield.
Subsequent reduction with Ni-Raney under hydrogen atmosphere allowed the isolation of
the Boc protected piperazine (R, S)-19 in acceptable yield (69%). For the cleavage of the
Boc group, it was found that best results (90% yield) were obtained with solid phase
supported reagent amberlyst-15 (Scheme 5).
Scheme 5. Synthesis of trans-2-phenyl-3-(trifluoromethyl) piperazine derivatives.
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The relative stereochemistry for the compounds of each series (cis and trans) was proven
by analyzing the corresponding vicinal proton-proton coupling constants on the chair
conformations of compounds (R, R)-10 and (R, S)-20. According to the Karpluss equation,
3
value for JHH in the cis-disubstituted piperazine (R, R)-10 was 4.0 Hz, while in the trans-
3
substituted counterpart (R, S)-20 JHH was found to be 9.0 Hz. These values are consistent
with the axial-equatorial and the axial-axial relationship between vicinal protons Ha and Hb,
respectively (Figure 2). The same stereochemistry was assumed for previous compounds
within each series.
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Ph
HN
Ph
NH
CF3
NH
CF3
HN
Ha
Hb
3JH -Hb = 4.0 Hz
(R, R)-10
a
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Ha
HN
NH
NH
CF3
Ph
HN
Ph
Hb
CF3
3JH -Hb = 9.0 Hz
(R, S)-20
a
Figure 2. Relative stereochemistry for the cis- and trans- diastereoisomers
Summarizing, we have developed practical synthetic strategies to the cis and trans
diastereoisomers of 3-trifluoromethyl-2-arylpiperazines derivatives starting from
enantiomerically pure phenylglycinol. The introduction of the CF3 relies on the
nucleophilic 1,2-addition of TMSCF3 to t-butanesulfinyl imines. While this study focused
exclusively on the preparation of piperazines, the intermediate 1-trifluoromethyl-2-
phenyldiamines could serve as valid synthetic intermediates for other interesting scaffolds.
The presence of the CF3 at the piperazine core should have a noticeable effect on its
metabolic stability, basicity and lipophilicity.
Experimental Section
General Methods. All reactions involving moisture-sensitive chemicals were carried out in
flame-dried glassware with magnetic stirring under nitrogen atmosphere. The following
solvents were purified prior to use: THF was distilled from sodium/benzophenone, CH2Cl2
was distilled from calcium hydride. All other solvents and reagents were used as received.
The reactions were monitored with the aid of thin-layer chromatography (TLC) on 0.25 mm
precoated silica gel plates. Visualization was carried out with UV light and
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phosphomolybdic acid solution or potassium permanganate stains. Flash column
chromatography was performed with the indicated solvents on silica gel 60 (particle size
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0.040-0.063 mm). H and 13C NMR spectra were recorded on a 300 MHz spectrometer.
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Chemical shifts are given in ppm (δ), referenced to the residual proton resonances of the
solvents. Coupling constants (J) are given in Hertz (Hz). The letters m, s, d, t, and q stand
for multiplet, singlet, doublet, triplet and quartet, respectively. The letters br indicate that
the signal is broad. Melting points were determined in open capillary tubes with a
temperature gradient of 10 ºC/minute. They were read from a digital display and are
uncorrected. High resolution mass spectra were recorded on a QTof mass spectrometer
configured with an electrospray ionization source, maintained at 140 ºC, using nitrogen as
the nebulizer gas, argon as collision gas and Lockmass device for mass calibration using
Leucine-Enkephaline as standard substance. Spectra were acquired either in positive or in
negative ionization mode, by scanning from 50 to 1200 Da in 0.1 s. In positive mode the
capillary needle voltage was either 0.5 or 2.0 kV. In negative mode the capillary needle
voltage was 2.0 kV. Cone voltage was 25 V in both ionization modes.
Synthesis of (R)-2-[bis(4-methoxybenzyl)amino]-2-phenylethanol (2). A mixture of (R)-
phenylglycinol (1, 3 g, 21.87 mmol), 4-methoxybenzyl chloride (6.2 mL, 45.93 mmol) and
potassium carbonate (9 g, 65.61 mmol) in acetonitrile (109 mL) was stirred at 60 oC for 60
h. The resulting yellow suspension was filtered to separate solids and the filtrate was
concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel employing a mixture of hexane/ EtOAc (5:1) as eluent.
Compound (R)-2 was obtained as a thick colourless oil (6.03 g, 73% yield). []25 119.2
D
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 3.34 (d, J = 11.1 Hz, 2H), 3.77 (dd, J = 8.8,
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4.3 Hz, 1H), 3.94 (s, 6H), 3.99 (d, J = 11.1 Hz, 2H), 4.06 (dd, J = 8.8, 4.2 Hz, 1H), 4.22 (t,
5
6
13
J = 8.8 Hz, 1H), 6.50-6.54 (m, 4H), 6.81-6.84 (m, 6H), 6.92-6.97 (m, 3H). C NMR (75
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8
9
MHz, CDCl3) δ 52.6 (CH2), 55.2 (CH3), 60.3 (CH2), 62.6 (CH), 113.9 (CH), 127.9 (CH),
128.3 (CH), 129.2 (CH), 130.0 (CH), 131.1 (C), 135.2 (C), 158.8 (C). HRMS (EI) calcd for
C24H28NO3 [M + H]+: 378.2069; found: 378.2066.
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General procedure for the synthesis of sulfinylimines 4
To a stirred solution of oxalyl chloride (0.86 mL, 9.86 mmol) in dry CH2Cl2 (17 mL) at 78
oC under N2 atmosphere, dimethyl sulfoxide (1.47 mL, 20.67 mmol) was added. After 15
minutes, a solution of (R)-2 (3 g, 7.95 mmol) in CH2Cl2 (17 mL) was added dropwise.
After 30 minutes, NEt3 (3 mL, 21.47 mmol) was added and the resulting mixture was
stirred at 78 oC for 40 minutes, when the cooling bath was removed and, 10 minutes later,
TLC revealed the total disappearance of the starting material. The reaction mixture was
quenched with saturated aqueous NaHCO3 and the aqueous phase extracted with CH2Cl2 (3
x 20 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure to yield compound (R)-3 as a thick
colorless oil (quantitative yield) which was used without further purification in the next
step.
-Amino aldehyde (R)-3 (2.99 g, 7.95 mmol) and (S)- or (R)- 2-methyl-2-
propanesulfinamide (964 mg, 7.95 mmol) were dissolved in dry THF (40 mL) into a flame-
o
dried flask under N2 atmosphere. The reaction flask was cooled to 0 C and a solution of
titanium tetraethoxide (7.25 g, 31.80 mmol) in THF (20 mL) was slowly added from an
addition funnel. The reaction mixture was allowed to stir overnight and then it was
carefully poured into an ice-cooled solution of brine. The resulting suspension was filtered
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through a pad of Celite, rinsing it with EtOAc. The filtrate was taken to a separating funnel
and the aqueous layer was extracted with EtOAc (3 x 20 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel to yield imine 4.
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(S, E)-N-{(R)-2-[Bis(4-methoxybenzyl)amino]-2-phenylethylidene}-2-methylpropane-
2-sulfinamide [(R, SS)-4]. The title compound was obtained according to the general
procedure described above starting from aldehyde (R)-3 and (S)-()-2-methyl-2-
propanesulfinamide. Purification by flash chromatography (silica gel; hexane/ EtOAc,
gradient from 4:1 to 2:1) gave 2.28 g of imine (R, SS)-4 (60% yield) as a yellow oil. []25
D
1
+121.8 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) δ 1.08 (s, 9H), 3.47 (d, J = 13.8 Hz,
2H), 3.69 (d, J = 14.4 Hz, 2H), 3.72 (s, 6H), 4.64 (d, J = 5.9 Hz, 1H), 6.81-6.85 (m, 4H),
7.23-7.26 (m, 5H), 7.32-7.36 (m, 4H), 8.21 (d, J = 5.9 Hz, 1H). 13C NMR (75 MHz, CDCl3)
δ 22.2 (CH3), 53.2 (CH2), 54.9 (CH3), 57.1 (C), 68.1 (CH), 113.5 (CH), 127.8 (CH), 128.5
(CH), 128.6 (CH), 129.9 (CH), 130.3 (C), 137.1 (C), 158.6 (C), 169.3 (CH). HRMS (EI)
calcd for C28H35N2O3S [M+H]+: 479.2363; found: 479.2368.
(R, E)-N-{(R)-2-[Bis(4-methoxybenzyl)amino]-2-phenylethylidene}-2-methylpropane-
2-sulfinamide [(R, RS)-4]. The title compound was obtained according to the general
procedure described above starting from aldehyde (R)-3 and (R)-(+)-2-methyl-2-
propanesulfinamide. Purification by flash chromatography (silica gel; hexane/ EtOAc, 5:1)
gave 2.05 g of imine (R, RS)-4 (54% yield) as a yellow oil. []25D 81.2 (c 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3) δ 2.18 (s, 9H), 4.11 (d, J = 11.4 Hz, 2H), 4.21 (d, J = 11.4 Hz,
2H), 4.26 (s, 6H), 5.08 (d, J = 4.5 Hz, 1H), 6.84 (d, J = 7.2 Hz, 4H), 7.16-7.24 (m, 5H),
7.26-7.27 (m, 4H), 8.11 (d, J = 4.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 22.6 (CH3), 52.8
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(CH2), 55.1 (CH3), 56.7 (C), 66.3 (CH), 113.6 (CH), 127.8 (CH), 128.5 (CH), 128.95 (CH),
129.8 (CH), 130.6 (C), 136.8 (C), 158.6 (C), 169.3 (CH). HRMS (EI) calcd for
C28H35N2O3S [M+H]+: 479.2363; found: 479.2354.
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General procedure for the synthesis of protected diamines 5.
The corresponding N-sulfinyl imine 4 (500 mg, 1.04 mmol) was dissolved in dry THF (8
mL) into a flame-dried flask. To this solution tetramethylammonium fluoride (116 mg, 1.25
o
mmol) was added and the mixture was cooled to 35 C. A solution of Ruppert-Prakash
reagent, TMSCF3, (0.23 mL, 1.56 mmol) in THF (7 mL) was then added dropwise from an
addition funnel and the mixture was stirred at that temperature until TLC revealed the
disappearance of the starting material (1h). At that moment, the cooling bath was removed
and the reaction mixture was quenched with saturated aqueous NH4Cl, extracted with ethyl
acetate (3 x 15 mL), dried (Na2SO4), filtered and concentrated. The crude product was
purified by flash column chromatography on silica gel to afford diamine 5.
(S)-N-{(2R, 3R)-3-[Bis(4-methoxybenzyl)amino]-1,1,1-trifluoro-3-phenylpropan-2-yl)-
2-methylpropane-2-sulfinamide [(R, R, SS)-5]. The title compound was obtained
according to the general procedure described above starting from imine (R, SS)-4.
Purification by flash chromatography (silica gel; hexane/EtOAc, 4:1) gave 377 mg of (R, R,
SS)-5 (66% yield) as a white solid. Mp 108-109 ºC. []25 37.5 (c 1.0, CHCl3). H NMR
1
D
(300 MHz, CDCl3) δ 0.97 (s, 9H), 3.00-3.04 (m, 3H), 3.80 (s, 6H), 3.94 (d, J = 13.5 Hz,
2H), 4.15 (d, J = 8.8 Hz, 1H), 4.49-4.56 (m, 1H), 6.85-6.90 (m, 4H), 7.26-7.326 (m, 6H),
19
13
7.41-7.50 (m, 3H). F NMR (282 MHz, CDCl3) δ 71.05 (d, JHF = 6.7 Hz, 3F). C NMR
(75 MHz, CDCl3) δ 21.9 (CH3), 53.5 (CH2), 55.2 (CH3), 55.6 (q, 2JCF = 27.1 Hz, CH), 56.3
1
(C), 62.6 (CH), 113.7 (CH), 125.33 (q, JCF = 282.1 Hz, CF3), 128.5 (CH), 128.8 (CH),
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130.00 (CH), 130.4 (C), 130.5 (C), 130.8 (CH), 158.7 (C). HRMS (EI) calcd for
C29H36F3N2O3S [M + H]+: 549.2393; found: 549.2415.
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(R)-N-{(2S, 3R)-3-[Bis(4-methoxybenzyl)amino]-1,1,1-trifluoro-3-phenylpropan-2-yl)-
2-methylpropane-2-sulfinamide [(R, S, RS)-5]. The title compound was obtained
according to the general procedure described above starting from imine (R, RS)-4.
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Purification by flash chromatography (silica gel; hexane/EtOAc, 4:1) gave 342 mg of (R, S,
1
RS)-5 (60% yield) as a white solid. Mp 152-153 ºC. []25 86.9 (c 1.0, CHCl3). H NMR
D
(300 MHz, CDCl3) δ 1.32 (s, 9H), 2.89 (d, J = 12.9 Hz, 2H), 3.80 (s, 6H), 3.80-3.83 (m,
2H), 3.90 (d, J = 10.8 Hz, 1H), 4.45-4.54 (m, 1H), 5.27 (s, 1H), 6.84-6.89 (m, 4H), 7.26-
19
7.32 (m, 6H), 7.41-7.49 (m, 3H). F NMR (282 MHz, CDCl3) δ 71.09 (d, JHF = 5.9 Hz,
13
3F). C NMR (75 MHz, CDCl3) δ 22.5 (CH3), 51.0 (CH2), 55.01 (q, 2JCF = 26.6 Hz, CH),
55.2 (CH3), 56.4 (C), 59.7 (CH), 113.8 (CH), 125.1 (q, 1JCF = 282.2 Hz, CF3), 128.2 (CH),
128.3 (CH), 130.0 (CH), 130.1 (C), 130.8 (CH), 131.9 (C), 158.9 (C). HRMS (EI) calcd for
C29H36F3N2O3S [M + H] +: 549.2399; found: 549.2397.
Synthesis of (1R, 2R)-3,3,3-trifluoro N-(4-methoxybenzyl)- 1-phenylpropane-1,2-
diamine (6). HCl (4M solution in dioxane; 1.4 mL, 5.5 mmol) was dropwise added to a
solution of diamine (R, R, SS)-5 (300 mg, 0.55 mmol) in MeOH (5.5 mL) and the mixture
was stirred at 70 oC in a sealed tube overnight. Then, solvents were removed under reduced
pressure and the residue was quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (3 x 15 mL). Organic layers were dried over anhydrous Na2SO4, filtered and
evaporated in vacuum. Crude product was purified by flash column chromatography on
silica gel (hexane/EtOAc, gradient from 4:1 to 2:1) to yield compound (R, R)-6 as a light
yellow oil (146 mg, 82% yield). []25D 33.8 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ
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1.64 (br s, 2H), 3.47 (d, J = 12.9 Hz, 1H), 3.53-3.62 (m, 1H), 3.62 (d, J = 12.9 Hz, 1H),
3.80 (s, 3H), 4.00 (d, J = 4.6 Hz, 1H), 6.83-6.88 (m, 2H), 7.15-7.20 (m, 2H), 7.32-7.41 (m,
5H). 19F NMR (282 MHz, CDCl3) δ 73.49 (d, JHF = 7.6 Hz, 3F). 13C NMR (75 MHz,
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CDCl3) δ 50.3 (CH2), 55.2 (CH3), 57.9 (q, JCF = 27.0 Hz, CH), 60.6 (q, JCF = 1.5 Hz,
1
CH), 113.78 (CH), 125.97 (q, JCF = 282.4 Hz, CF3), 127.96 (CH), 128.34 (CH), 128.47
(CH), 129.31 (CH), 131.9 (C), 137.9 (C), 158.7 (C). HRMS (EI) calcd for C17H20F3N2O [M
+ H]+: 325.1522; found: 325.1524.
Synthesis of 2-chloro-N-[(2R, 3R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)amino]-3-
phenylpropan-2-yl] acetamide (7). To a suspension of PMB-protected diamine (R, R)-6
(400 mg, 1.23 mmol) in a mixture of EtOAc and saturated aqueous NaHCO3 (1:1, 24 mL)
at 0 oC, 2-chloroacetyl chloride was added (0.3 mL, 3.69 mmol) and the mixture was stirred
for 1.5 h, when TLC revealed the disappearance of the starting material. Layers were
separated and the aqueous phase was extracted twice with CH2Cl2. The combined organic
extracts were washed with brine, dried (Na2SO4) and filtered. After evaporation of solvents,
the crude product was purified by column chromatography on silica gel (hexane/EtOAc,
5:1) to yield compound (R, R)-7 as a white solid (458 mg, 93% yield). Mp 84-85 ºC. []25
D
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63.1 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) δ 1.98 (br s, 1H), 3.53 (d, J = 12.9 Hz,
1H), 3.74 (d, J = 12.8 Hz, 1H), 3.81 (s, 3H), 4.06 (dd, J = 7.2, 15.3 Hz, 2H), 4.10 (d, J = 4.5
Hz, 1H), 4.87-4.97 (m, 1H), 6.83-6.86 (m, 2H), 7.08 (d, J = 9.8 Hz, 1H), 7.17-7.20 (m, 2H),
7.31-7.441 (m, 5H). 19F NMR (282 MHz, CDCl3) δ 70.00 (d, JHF = 7.8 Hz, 3F). 13C NMR
2
(75 MHz, CDCl3) δ 42.4 (CH2), 50.4 (CH2), 54.03 (q, JCF = 28.4 Hz, CH), 55.24 (CH3),
1
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(CH), 129.5 (CH), 131.1 (C), 136.6 (C), 158.9 (C), 166.0 (C). HRMS (EI) calcd for
C19H21ClF3N2O2 [M + H]+: 401.1238; found: 401.1250.
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Synthesis of (5R, 6R)- 4-(4-methoxybenzyl)- 5-phenyl- 6-(trifluoromethyl) piperazin-2-
one (8). To a solution of (R, R)-7 (300 mg, 0.75 mmol) in dry THF, NaH (60% in mineral
oil; 45 mg, 1.13 mmol) was added portionwise at 0 oC. The resulting suspension was stirred
overnight and then, the reaction mixture was quenched with saturated aqueous NH4Cl. The
aqueous phase was extracted with EtOAc (3 x 15 mL) and the combined organic layers
were dried (Na2SO4), filtered and concentrated in vacuum. The crude product was purified
by flash column chromatography on silica gel (hexane/EtOAc, gradient from 5:1 to 2:1) to
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yield 191 mg of keto piperazine (R, R)-8 as a white solid (70% yield). Mp 91-92 ºC. []25
D
34.4 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 3.29 (d, J = 13.4 Hz, 1H), 3.33 (dd, J
= 4.0, 17.8 Hz, 2H), 3.39 (d, J = 13.2 Hz, 1H), 3.81 (s, 3H), 4.16 (d, J = 4.6 Hz, 1H), 4.46-
4.55 (m, 1H), 6.85-6.90 (m, 2H), 6.96 (br s, 1H), 7.16-7.21 (m, 2H), 7.25-7.28 (m, 2H),
7.35-7.38 (m, 3H). 19F NMR (282 MHz, CDCl3) δ 71.40 (d, JHF = 7.4 Hz, 3F). 13C NMR
(75 MHz, CDCl3) δ 52.5 (CH2), 55.3 (CH3), 57.2 (CH2), 58.3 (q, 2JCF = 29.7 Hz, CH), 59.2
1
(CH), 114.02 (CH), 123.31 (d, JCF = 281.9 Hz, CF3), 128.3 (CH), 128.6 (CH), 128.7 (C),
129.8 (CH), 130.0 (CH), 131.4 (C), 159.1 (C), 170.0 (C). HRMS (EI) calcd for
C19H19F3N2O2Na [M + Na]+: 387.1291; found: 387.1291.
Synthesis of (2R, 3R)- 1-(4-methoxybenzyl)- 2-phenyl- 3-(trifluoromethyl) piperazine
(9). LiAlH4 (63 mg, 1.65 mmol) was added portionwise to a solution of keto piperazine 8
(200 mg, 0.55 mmol) in dry THF (5.5 mL) at 0 oC. The resulting suspension was heated at
reflux for 1h, when TLC revealed the disappearance of the starting material. The reaction
o
mixture was quenched at 0 C with Na2SO4·10H2O, stirring until aluminum salts turned
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white (1 h approx.). Then, it was filtered through a pad of Celite and washed with CH2Cl2.
The filtrate was dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash column chromatography (silica;
hexane/EtOAc, 5:1) to give PMB-protected piperazine (R, R)-9 as a colourless oil (147 mg,
76% yield). []25D 8.1 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 3.21 (dt, J = 9.6, 3.3
Hz, 1H), 3.61-3.75 (m, 2H), 3.90-3.99 (m, 3H), 4.31-4.38 (m, 1H), 4.38 (s, 3H), 4.47 (d, J
= 3.2 Hz, 1H), 6.92 (d, J = 7.2 Hz, 2H), 7.20 (d, J = 7.2 Hz, 2H), 7.31-7.34 (m, 3H), 7.49-
7.51 (m, 2H). 19F NMR (282 MHz, CDCl3) δ 69.58 (s, 3F). 13C NMR (75 MHz, CDCl3) δ
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44.8 (CH2), 46.9 (CH2), 55.2 (CH3), 58.4 (CH2), 61.6 (d, JCF = 26.9 Hz, CH), 61.9 (CH,
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113.66 (CH), 125.2 (d, JCF = 282.6 Hz, CF3), 127.7 (2CH), 129.7 (CH), 130.5 (C), 130.7
(CH), 135.9 (C), 158.7 (C). HRMS (EI) calcd for C19H22F3N2O [M + H]+: 351.1679; found:
351.1685.
Synthesis of (2R, 3R)- 2-phenyl- 3-(trifluoromethyl) piperazine (10). To a solution of
piperazine (R, R)-9 (70 mg, 0.20 mmol) in MeOH (2 mL), Pd(OH)2 on carbon (20% in Pd;
140 mg, 0.20 mmol) was added portionwise. A balloon filled with hydrogen was then
connected and the resulting black suspension was stirred overnight. The reaction mixture
was filtered through a pad of Celite, rinsing it with EtOAc and the filtrate was concentrated
under reduced pressure. Purification by flash column chromatography (silica;
hexane/EtOAc, gradient from 1:1 to 1:2) yielded unprotected piperazine (R, R)-10 as a
1
colourless oil (21 mg, 45% yield). []25 45.7 (c 0.4, CHCl3). H NMR (300 MHz,
D
CDCl3) δ 2.02 (br s, 2H), 2.81-2.86 (m, 1H), 3.00-3.16 (m, 2H), 3.20-3.27 (m, 1H), 3.54
(qd, J = 9.3, 4.0 Hz, 1H), 4.36 (dq, J = 4.0, 2.0 Hz, 1H), 7.26-7.43 (m, 5H). 19F NMR (282
13
MHz, CDCl3) δ 64.15 (d, JHF = 8.4 Hz, 3F). C NMR (75 MHz, CDCl3) δ 41.6 (CH2),
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5
6
5
(q, JCF = 0.9 Hz, CH), 127.5 (CH), 128.2 (CH), 139.4 (C). HRMS (EI) calcd for
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C11H14F3N2 [M + H]+: 231.1109; found: 231.1117.
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Synthesis of (5R, 6R)- 5-phenyl- 6-(trifluoromethyl) piperazin-2-one (11). Pd(OH)2 on
carbon (20% in Pd; 190 mg, 0.27 mmol) was added portionwise to a solution of (R, R)-8
(100 mg, 0.27 mmol) in MeOH (3 mL), A balloon filled with hydrogen was then connected
and the resulting black suspension was stirred overnight. The reaction mixture was filtered
through a pad of Celite, rinsing it with EtOAc and the filtrate was concentrated under
reduced pressure. Purification by flash column chromatography (silica; hexane/EtOAc,
gradient from 1:1 to 1:2) yielded unprotected keto piperazine (R, R)-11 as a white solid (40
1
mg, 60% yield). Mp 95-97 ºC. []25D 154.4 (c 1.0, MeOH). H NMR (300 MHz, MeOD)
δ 3.54-3.68 (m, 2H), 4.20 (qd, J = 7.6, 4.3 Hz, 1H), 4.52-4.54 (m, 1H), 7.23-7.39 (m, 5H).
13
19F NMR (282 MHz, MeOD) δ 70.63 (dd, JHF = 7.6, 2.2 Hz, 3F). C NMR (75 MHz,
2
1
MeOD) δ 48.5 (CH2), 55.7 (CH), 56.4 (q, JCF = 26.5 Hz, CH), 124.6 (q, JCF = 284.3 Hz,
CF3), 126.4 (CH), 127.5 (CH), 127.9 (CH), 136.8 (C), 171.2 (C). HRMS (EI) calcd for
C11H12F3N2O [M + H]+: 245.0896; found: 245.0900.
Synthesis of (1R, 2S)- 3,3,3-trifluoro-N, N-bis(4-methoxybenzyl)-1-phenylpropane-1,2-
diamine (12). HCl (4M solution in dioxane; 3.7 mL, 14.6 mmol) was dropwise added to a
solution of diamine (R, S, RS)-5 (800 mg, 1.46 mmol) in MeOH (15 mL) and the mixture
was heated at reflux for 1 h. Then, solvents were removed under reduced pressure and the
residue was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3 x 15
mL). Organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo.
Crude product was purified by flash column chromatography on silica gel (hexane/EtOAc,
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gradient from 8:1 to 5:1) to yield 486 mg of compound (R, S)-12 as a white solid (75%
yield). Mp 51-52 ºC. []25D 74.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 2.15 (br s,
2H), 3.01 (d, J = 13.4 Hz, 2H), 3.78-3.84 (m, 1H), 3.81 (s, 6H), 3.85 (d, J = 13.8 Hz, 2H),
4.00-4.11 (m, 1H), 6.88-6.93 (m, 4H), 7.20-7.28 (m, 6H), 7.38-7.44 (m, 3H). 19F NMR
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(282 MHz, CDCl3) δ 73.03 (d, JHF = 6.1 Hz, 3F). 13C NMR (75 MHz, CDCl3) δ 52.8
2
(CH2), 53.5 (q, JCF = 26.6 Hz, CH), 55.2 (CH3), 61.5 (CH), 114.0 (CH), 126.07 (q, 1JCF
=
280.2 Hz, CF3), 127.9 (CH), 127.9 (CH), 129.7 (CH), 129.9 (CH), 130.6 (C), 133.2 (C),
158.8 (C). HRMS (EI) calcd for C25H28F3N2O2 [M + H]+: 445.2103; found: 445.2103.
Synthesis of tert-butyl {[(2S, 3R)- 3-bis(4-methoxybenzyl)amino]- 1,1,1-trifluoro- 3-
phenylpropan-2-yl} carbamate (13). A solution of di-tert-butyl dicarbonate (661 mg, 3.03
mmol) in 1,4-dioxane (4 mL) was added to a solution of (R, S)-12 (450 mg, 1.01 mmol) and
K2CO3 (558 mg, 4.04 mmol) in 1,4-dioxane (4 mL). The resulting colorless solution was
stirred at 50 ºC in a sealed tube for 15 h. After cooling, the reaction mixture was quenched
with sat. aq. NH4Cl and the aqueous layer extracted with EtOAc. The combined organic
layers were dried over Na2SO4, filtered and concentrated at reduced pressure. The crude
product was purified by flash chromatography on silica gel (hexane/EtOAc, 10:1) to afford
479 mg of (R, S)-13 as a white solid (87% yield). Mp 70-72 ºC. []25 +12.4 (c 1.0,
D
CHCl3). 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 2.91 (d, J = 13.3 Hz, 2H), 3.70 (d, J =
13.3 Hz, 2H), 3.81 (s, 6H), 3.91 (d, J = 11.8 Hz, 1H), 4.86 (br s, 1H), 5.24 (br s, 1H), 6.87-
6.90 (m, 4H), 7.23-7.27 (m, 6H), 7.39-7.45 (m, 3H). 19F NMR (282 MHz, CDCl3) δ 72.65
(s, 3F). 13C NMR (75 MHz, CDCl3) δ 28.2 (CH3), 52.5 (CH2), 52.8 (q, 2JCF = 26.0 Hz, CH),
55.0 (CH3), 59.2 (CH), 80.6 (C), 113.9 (CH), 125.2 (q, 1JCF = 282.9 Hz, CF3), 128.1 (CH),
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128.1 (CH), 129.4 (CH), 129.8 (CH), 130.5 (C), 132.9 (C), 155.6 (C), 158.8 (C). HRMS
(EI) calcd for C30H36F3N2O4 [M + H]+: 545.2627; found: 545.2642.
7
8
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Synthesis of tert-butyl [(2S, 3R)- 3-amino- 1,1,1-trifluoro- 3-phenylpropan-2-yl]
carbamate (14). Pd(OH)2 on carbon (20% in Pd; 583 mg, 0.83 mmol) was added
portionwise to a solution of (R, S)-13 (450 mg, 0.83 mmol) in MeOH (8 mL), A balloon
filled with hydrogen was then connected and the resulting black suspension was stirred
overnight. The reaction mixture was filtered through a pad of Celite, rinsing it with EtOAc
and the filtrate was concentrated under reduced pressure. Purification by flash column
chromatography (silica; hexane/EtOAc, 4:1) yielded Boc-protected diamine (R, S)-14 as a
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16
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white solid (164 mg, 65% yield). Mp 69-70 ºC. []25 13.5 (c 1.0, CHCl3). This
D
1
compound was obtained as a mixture of rotamers. H NMR (300 MHz, CDCl3) δ 1.19 (s,
2H), 1.35 (s, 7H), 1.53 (s, 2H), 4.17-4.28 (m, 1H), 4.58 (s, 1H), 5.89 (d, J = 8.8 Hz, 1H),
7.28-7.38 (m, 5H). 19F NMR (282 MHz, CDCl3) δ 73.91 (d, JHF = 8.5 Hz, 3F). 13C NMR
2
(75 MHz, CDCl3) δ 28.2 (CH3), 52.5 (CH), 56.5 (q, JCF = 28.8 Hz, CH), 80.2 (C), 125.3
1
(q, JCF = 283.5 Hz, CF3), 126.3 (CH), 128.1 (CH), 128.7 (CH), 141.0 (C), 155.3 (C).
HRMS (EI) calcd for C10H12F3N2O2 [M + H (t-Bu)]+: 249.0851; found: 249.0861.
Synthesis of (2S, 3R)- tert-butyl 5-oxo-3-phenyl 2-(trifluoromethyl)piperazine-1-
carboxylate (16). To a suspension of (R, S)-14 (100 mg, 0.33 mmol) in a mixture of EtOAc
o
and saturated aqueous NaHCO3 (1:1, 6 mL) at 0 C, 2-chloroacetyl chloride was added
(0.08 mL, 0.99 mmol) and the mixture was stirred for 1.5 h, when TLC revealed the
disappearance of the starting material. Layers were separated and the aqueous phase was
extracted twice with CH2Cl2. The combined organic extracts were washed with brine, dried
(Na2SO4), filtered and concentrated under reduced pressure to yield compound (R, S)-15 as
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a white solid (quantitative yield), which was used without further purification in the next
step.
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Crude chloroacetamide (R, S)-15 (126 mg, 0.33 mmol) was dissolved in a 10:1 mixture of
THF/DMF (0.2M) unser N2 atmosphere. To this solution NaH (60% in mineral oil; 26 mg,
0.66 mmol) and TBAI (122 mg, 0.33 mmol) were successively added and the resulting
yellow suspension was stirred at room temperature overnight. Then, H2O was added and
the aqueous layer was extracted with EtOAc, dried (Na2SO4), filtered and concentrated at
reduced pressure. The crude product was purified by flash chromatography on silica gel
(hexane/EtOAc, gradient from 4:1 to 2:1) to give (R, S)-16 as a white solid (102 mg, 90%
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yield). Mp 141-142 ºC. []25 38.9 (c 1.0, CHCl3). This compound was obtained as a
D
mixture of rotamers. 1H NMR (300 MHz, CDCl3) δ 1.15 (s, 5H), 1.36 (s, 4H), 3.84 (d, J =
28.2, 0.5H), 3.92 (d, J = 27.9, 0.5H), 4.47 (d, J = 18.9 Hz, 0.5H), 4.65 (d, J = 19.2 Hz,
0.5H), 4.73 (dd, J = 17.4, 9.3 Hz, 0.5H), 4.92 (d, J = 4.65 Hz, 1H), 4.97 (dd, J = 17.1, 8.7
Hz, 0.5H), 7.20-7.22 (m, 2H), 7.33-7.42 (m, 3H), 7.48 (br s, 1H). 19F NMR (282 MHz,
CDCl3) δ 72.15 (t, J = 8.0 Hz, 3F). 13C NMR (75 MHz, CDCl3) δ 27.7 (CH3), 27.9 (CH3),
44.4 (CH2), 45.5 (CH2), 53.2 (CH), 53.4 (CH), 54.4 (q, 2JCF = 31.2 Hz, CH), 56.6 (q, 2JCF
=
1
1
30.7 Hz, CH), 82.1 (C), 82.4 (C), 124.2 (q, JCF = 283.8 Hz, CF3), 124.30 (q, JCF = 284.2
Hz, CF3), 125.7 (CH), 125.6 (CH), 128.7 (CH), 128.7 (CH), 129.1 (CH), 129.1 (CH), 138.6
(C), 138.9 (C), 152.9 (C), 153.5 (C), 167.0 (C), 167.3 (C). HRMS (EI) calcd for
C16H18F3N2O3 [M H]-: 343.1269; found: 343.1269.
Synthesis of (5S, 6R)- 6-phenyl- 5-(trifluoromethyl)piperazin-2-one (17). TFA (1 mL)
was added to a stirred solution of (R, S)-16 (75 mg, 0.22 mmol) in CH2Cl2 (1 mL) at 0 ºC
and the mixture was stirred for 2 h at that temperature, when TLC revealed the
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disappearance of the starting material. Then, it was quenched with sat. aq. Na2CO3 and the
aqueous layer was extracted with CH2Cl2. The organic phase was then dried (Na2SO4),
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filtered and concentrated at reduced pressure to yield 48 mg of (R, S)-17 as a colourless oil
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(90% yield). []25 12.1 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) δ 2.08 (br s, 1H),
D
3.39-3.49 (m, 1H), 3.61 (q, J = 18.4 Hz, 2H), 4.73 (dd, J = 4.7, 2.0 Hz, 1H), 6.92 (s, 1H),
7.29-7.41 (m, 5H). 19F NMR (282 MHz, CDCl3) δ 72.39 (d, JHF = 7.9 Hz, 3F). 13C NMR
2
1
(75 MHz, CDCl3) δ 46.2 (CH2), 55.5 (CH), 58.9 (q, JCF = 28.0 Hz, CH), 125.0 (q, JCF
=
284.6 Hz, CF3), 126.7 (CH), 128.8 (CH), 128.9 (CH), 139.1 (C), 168.9 (C). HRMS (EI)
calcd for C11H12F3N2O [M + H]+: 245.0902; found: 245.0904.
Synthesis of (2S, 3R)- tert-butyl -3-phenyl- 5-thioxo- 2-(trifluoromethyl)piperazine-1-
carboxylate (18). P2S5 (51 mg, 0.23 mmol) was added to a solution of (R, S)-16 (100 mg,
0.29 mmol) in THF (3 mL) under N2 atmosphere and the resulting yellow suspension was
heated at 50 ºC for 30 min, when TLC revealed the disappearance of the starting material.
The reaction mixture was filtered and solvents were removed in vacuum. The crude product
was purified by flash chromatography on silica gel (hexane/EtOAc, 4:1) to give (R, S)-18 as
a light yellow solid (75 mg, 72% yield). Mp 137-138 ºC. []25D 14.5 (c 1.0, CHCl3). This
1
compound was obtained as a mixture of rotamers. H NMR (300 MHz, CDCl3) δ 1.16 (s,
4H), 1.39 (s, 5H), 4.24 (d, J = 20.6 Hz, 0.5H), 4.35 (d, J = 20.4 Hz, 0.5H), 4.78 (dd, J =
15.8, 7.7 Hz, 0.5H), 4.90-5.09 (m, 2H), 5.21 (d, J = 20.8 Hz, 0.5H), 7.17-7.19 (m, 2H),
7.37-7.39 (m, 3H), 8.81 (s, 0.5H), 8.91 (s, 0.5H). 19F NMR (282 MHz, CDCl3) δ -72.46 (d,
JHF = 8.1 Hz, 3F). 13C NMR (75 MHz, CDCl3) δ 27.7 (CH3), 28.0 (CH3), 50.1 (CH2), 51.4
(CH2), 53.8 (q, 2JCF = 31.6 Hz, CH), 55.4 (CH), 55.5 (CH), 82.3 (C), 82.8 (C), 125.8 (CH),
125.9 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH), 136.9 (C), 137.4 (C), 152.3 (C), 153.2
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(C), 196.0 (C), 196.6 (C). HRMS (EI) calcd for C16H18F3N2O2S [M  H]-: 359.1041; found:
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359.1041.
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Synthesis of (2S, 3R)- tert-butyl -3-phenyl- 2-(trifluoromethyl)piperazine-1-
carboxylate (19). To a solution of thioamide (R, S)-18 (75 mg, 0.21 mmol) in EtOH (2
mL) Raney Ni was added and the mixture was stirred under H2 atmosphere (balloon) at
room temperature for 30 min. The reaction mixture was filtered through a pad of Celite,
rinsing it with EtOAc and the filtrate was concentrated under reduced pressure. Purification
by flash column chromatography (silica; hexane/EtOAc, 4:1) yielded Boc-protected
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piperazine (R, S)-19 as a colourless oil (48 mg, 69% yield). []25 74.8 (c 1.0, CHCl3).
D
This compound was obtained as a mixture of rotamers. 1H NMR (300 MHz, CDCl3) δ 1.50
(s, 9H), 1.98 (s, 1H), 2.73 (br s, 2H), 3.10 (br s, 1H), 3.87-4.00 (m, 1H), 4.37 (s, 1H), 5.02
(br s, 0.5H), 5.22 (br s, 0.5H), 7.29-7.45 (m, 5H). 19F NMR (282 MHz, CDCl3) δ 70.18 (s,
13
1.5F), -70.38 (s, 1.5F). C NMR (75 MHz, CDCl3) δ 28.2 (CH3), 30.9 (CH3), 38.4 (CH2),
1
39.6 (CH2), 41.1 (CH2), 51.9 (CH), 53.2 (q, J = 26.4 Hz, CH), 81.3 (C), 125.9 (q, JCF
=
287.0 Hz, CF3), 127.4 (CH), 127.5 (CH), 128.6 (CH), 139.8 (C), 154.4 (C), 155.0 (C).
HRMS (EI) calcd for C12H14F3N2O2 [M + H (t-Bu)]+: 275.1007; found: 275.1009.
Synthesis of (2S, 3R)- 2-phenyl- 3-(trifluoromethyl)piperazine (20). Amberlyst-15 (310
mg, 4.1 mmol/g, 1.27 mmol) was added to a solution of Boc-protected piperazine (R, S)-19
(42 mg, 0.13 mmol) in MeOH (2 mL) in a solid phase reactor. The resulting mixture was
shaken at room temperature for 18 h. The resin was then filtered and washed with MeOH.
Then 7N NH3 in MeOH (5 mL) was added to the solid phase reactor and the resulting
mixture was shaken at room temperature for 5 h. The resin was filtered and washed with
7N NH3 in MeOH. The combined organic extracts were concentrated in vacuum yielding
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piperazine (R, S)-20 as a colourless oil (26 mg, 90% yield). []25D 64.9 (c 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3) δ 2.18 (s, 2H), 2.04-3.14 (m, 4H), 3.41 (dq, J = 9.0, 6.8 Hz, 1H),
3.77 (d, J = 9.0 Hz, 1H), 7.30-7.42 (m, 5H). 19F NMR (282 MHz, CDCl3) δ 72.18 (d, JHF
= 6.9 Hz, 3F). 13C NMR (75 MHz, CDCl3) δ 45.2 (CH2), 46.3 (CH2), 61.7 (q, 3JCF = 1.3 Hz,
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CH), 62.6 (q, JCF = 25.4 Hz, CH), 124.7 (d, JCF = 281.1 Hz, CF3), 128.1 (CH), 128.3
(CH), 128.4 (CH), 139.6 (C). HRMS (EI) calcd for C11H14F3N2 [M + H]+: 231.1109; found:
231.1109.
Acknowledgments. This research was partially supported by a Grant for Scientific
Research from the Spanish Ministerio de Ciencia e Innovación (CTQ2010-19774-C02-01)
and the Generalitat Valenciana (PROMETEO/2010/061). We would also like to thank
Alberto Fontana for HRMS analysis.
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19
Supporting Information. Copies of H, C and F NMR spectra for all new compounds
are provided. This material is available free of charge via the Internet at http://pubs.acs.org.
(1) (a) The term “privileged structure” was introduced in 1988 as a molecular scaffold that is highly
represented in biologically active compounds (capable of binding to multiple receptors with high affinity).
Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.;
Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235-2246. (b) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893-930. (c) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr.
Opin. Chem. Biol. 2010, 14, 347-361.
(2) (a) Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.; Durst, G. L.;
Hipskind, P. A. J. Med. Chem. 2004, 47, 224-232. (b) Wishart, D. S.; Knox, C.; Guo, A. C.; Cheng, D.;
Shrivastava, S.; Tzur, D.; Gautam, B.; Hassanali, M. Nucleic Acids Res. 2008, 36, D901. (c) Dömling, A.;
Huang, Y. Synthesis 2010, 2859–2883.
(3) See, for example: (a) Fisher, M. J.; Backer, R. T.; Collado, I.; de Frutos, O.; Husain, S.; Hsiung, H. M.;
Kuklish, S. L.; Mateo, A. I.; Mullaney, J. T.; Ornstein, P. L.; García Paredes, C.; O´Brian, T. P.; Richardson,
T. I.; Shah, J.; Zgombick, J. M.; Briner, K. Bioorg. Med. Chem. Lett. 2005, 15, 4973-4978. (b) Stewart, A. O.;
Cowart, M. D.; Moreland, R. B.; Latshaw, S. P.; Matulenko, M. A.; Bhatia, P. A.; Wang, X.; Daanen, J. F.;
Nelson, S. L.; Terranova, M. A.; Namovic, M. T.; Donnelly-Roberts, D. L.; Miller, N. L.; Nakane, M.;
Sullivan, J. P.; Brioni, J. D. J. Med. Chem. 2004, 47, 2348-2355.
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7
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(4) See, for example: (a) Clark, R. B.; Elbaum, D. Tetrahedron 2007, 63, 3057-3065. (b) Revesz, L.; Blum,
E.; Wicki, R. Tetrahedron Lett. 2005, 46, 5577-5580. (c) Anstiss, M.; Nelson, A. Org. Biomol. Chem. 2006,
4, 4135-4143. (d) Opatz, T. Eur. J. Org. Chem. 2004, 4113-4118.
(5) (a) Nordstrom, U. L.; Madsen, R. Chem. Commun. 2007, 5034-5036. (b) Giardinà, D.; Gulini, U.; Massi,
M.; Piloni, M. G.; Pompei, P.; Rafaiani, G.; Melchiorre, C. J. Med. Chem. 1993, 36, 690-698.
10
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(6) (a) Binisti, C.; Assogba, L.; Touboul, E.; Mounier, C.; Huet, J.; Ombetta, J.-E.; Dong, C. Z.;Redeuilh, C.;
Heymans, F.; Godfroid, J.-J. Eur. J. Med. Chem. 2001, 36, 809-828. (b) Scapecchi, S.; Martini, E.; Manetti,
D.; Ghelardini, C.; Martelli, C.; Dei, S.; Galeotti, N.; Guandalini, L.; Novella, R. M.; Teodori, E. Bioorg.
Med. Chem. 2004, 12, 71-85.
(7) (a) For a review, see: Dinsmore, C. J.; Beshore, D. C. Org. Prep. Proced. Int. 2002, 34, 367-404. (b) Jung,
M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909-4913. (c) Aicher, T. D.; Anderson, R. C.; Gao, J.; Shetty,
S. S.; Coppola, G. M.; Stanton, J. L.; Knorr, D. C.; Sperbeck, D. M.; Brand, L. J.; Vinluan, C. C.; Kaplan, E.
L.; Dragland, C. J.; Tomaselli, H. C.; Islam, A.; Lozito, R. J.; Liu, X.; Maniara, W. M.; Fillers, W. S.;
DelGrande, D.; Walter, R. E.; Mann, W. R. J. Med. Chem. 2000, 43, 236-249.
(8) Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer, D. J.; Terpstra, J. W.; Himestra, H.; Iwema Bakker,
W. I.; van den Hoogenband, A.; van Maarseveen, J. H. Tetrahedron Lett. 2005, 46, 2369-2371.
(9) (a) Vairaprakash, P.; Periasamy, M. J. Org. Chem. 2006, 71, 3636-3638. (b) Cochran, B. M.; Michael, F.
E. Org. Lett. 2008, 10, 329-332. (c) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257-
260. (d) Lu, Z.; Stalh, S, S. Org. Lett. 2012, 14, 1234-1237. (e) Zhai, H.; Borzenko, A.; Lau, Y. Y.; Ahn, S.
H.; Schafer, L. L. Angew. Chem. Int. Ed. 2012, 51, 12219-12223. (f) Ruider, S. A.; Müller, S.; Carreira, E. M.
Angew. Chem. Int. Ed. 2013, 52, 11908-11911. (g) Luescher, M. U.; Vo, C-V. T.; Bode, J. W. Org. Lett.
2014, 16, 1236-1239.
(10) (a) Napolitano, C.; Borriello, M.; Cardullo, F.; Donati, D.; Paio, A.; Manfredini, F. Synth. Commun.
2011, 41, 2031-2035. (b) Bourbeau, M. P.; Siegmund, A.; Allen, J. G.; Shu, H.; Fotsch, C.; Bartberger, M. D.;
Kim,K.-W.; Komorowski, R.; Graham, M.; Busby, J.; Wang, M.; Meyer, J.; Xu, Y.; Salyers, K.; Fielden, M.;
Véniant, M. M.; Gu, W. J. Med. Chem. 2013, 56, 10132-10141. (c) The preparation of N-(2-amino-3,3,3-
trifluoro-1-phenylpropyl)carboxamides has been reported in the patent: Katz, J.; Knowles, S. L.; Jewell, J. P.;
Sloman, D. L.; Stanton, M. G.; Noucti, N. WO 2010/017046 A1.
(11) (a) Bègué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; Wiley: Hoboken,
NJ, 2008. For selected reviews, see: (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881-1886. (c)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320-330. (d) Wang, J.;
Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.
Chem. Rev. 2014, 114, 2432-2506. (e) For a recent analysis regarding the presence of sulfur and fluorine
within several marketed drugs, see: Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem. 2014, 57, 2832-
2842.
(12) Morgenthaler, M.; Schweizer, E.; Hoffman-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner,
B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K.
ChemMedChem 2007, 2, 1100-1115.
(13) For reviews on trifluoromethylation of organic compounds see, for example: (a) Liang, T.; Neumann, C.
N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214-8264. (b) Liu, H.; Gu, Z.; Jiang, X. Adv. Synth. Catal.
2013, 355, 617-626. (c) Studer, A. Angew. Chem. Int. Ed. 2012, 51, 8950-8958. (d) Furuya, T.; Kamlet, A. S.;
Ritter, T. Nature 2011, 473, 470-477. (e) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111,
455-529. (f) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475-4521.
(14) The synthesis of enantiomerically pure 2-phenyl piperazines (non-fluorinated) is reported in the
following patent: Demong, D. E.; Miller, M. W.; Gilbert, E. J.; Scott, J. D.; Stamford. A.; Greenlee, W. J. WO
2009/005645 A1.
(15) (a) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195-2198. (b) Prakash, G. K. S.;
Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393-395.
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(16) The use of 3, 3, 3-trifluoro-1-phenyl-propane-1,2-diamine is described in the following patent. However,
no details on its synthesis and isolation are provided. Stanton, M. G.; Noucti, N.; Sloman, D. J.; Munoz, B.;
Lim, J. WO 2009/014620 A1.
(17) (a) Prakash, G. K. S.; Mandel, M. J. Am. Chem. Soc. 2002, 124, 6538. (b) For an exhaustive review on
tert-butanesulfinamide and its use in synthesis, see: Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600-3740. For recent examples of diastereoselective addition of fluorinated nucleophiles to
Ellman’s N-(tert-butanesulfinyl)imines, see: (c) Fustero, S; Moscardó, J.; Sánchez-Roselló, M.; Rodríguez, E.;
Barrio, P. Org. Lett. 2010, 12, 5494-5497. (d) Fustero, S; Ibáñez, I.; Barrio, P.; Maestro, M. A.; Catalán, S.
Org. Lett. 2013, 15, 832-835.
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(18) Several activators of the Ruppert-Prakash reagent such as TMAF, TBAT, TBAF and AcONBu4 were
tested, as well as different reaction temperatures and times.
(19) (a) Related enantiomerically pure -amino -trifluoromethyl alcohols have been reported: Fustero, S.;
Albert, L.; Aceña, J. L.; Sanz-Cervera, J. F.; Asensio, A. Org. Lett. 2008, 10, 605-608. (b) For the synthesis of
enantiomerically pure -aryl--alkyl aminoalcohols and derivatives, see: Delgado, O.; Monteagudo, A.; Van
Gool, M.; Trabanco, A. A.; Fustero, S. Org. Biomol. Chem. 2012, 10, 6758-6766.
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