Enantiodivergent approach to trifluoromethylated amines: A concise route to both enantiomeric analogues of calcimimetic NPS R-568

Article abstract of DOI:10.1002/ejoc.200901158

Reported herein is a straightforward and enantiodivergent synthesis of both enantiomers of trifluoromethylated analogues of calcimimetic NPS R-569 in a highly estereoselective manner. The synthesis features a diastereoselective synthesis of the N-(isopropylsulfinyl)imine unit by the "DAG methodology" and a diastereoselective addition of Ruppert Prakash's reagent to the imine as the key steps. No protecting groups were necessary, permitting an atom economic synthesis in only six steps. Further addition reactions of the CF³ anion to different N-(isopropylsulfinyl)imines were performed to demonstrate the suitability of the sulfinyl substituent to balance perfectly reactivity and diastereoselectivity.

Full text of DOI:10.1002/ejoc.200901158

FULL PAPER
DOI: 10.1002/ejoc.200901158
Enantiodivergent Approach to Trifluoromethylated Amines: A Concise Route to
Both Enantiomeric Analogues of Calcimimetic NPS R-568
Inmaculada Fernández,*[a] Victoria Valdivia,[b] Ana Alcudia,[a] Ahmed Chelouan,[a] and
Noureddine Khiar*[b]
Keywords: Amines / Diastereoselectivity / Enantioselectivity / Sulfinylimines / Sulfinamides
Reported herein is a straightforward and enantiodivergent
synthesis of both enantiomers of trifluoromethylated ana-
logues of calcimimetic NPS R-569 in a highly estereoselective
manner. The synthesis features a diastereoselective synthesis
of the N-(isopropylsulfinyl)imine unit by the “DAG meth-
odology” and a diastereoselective addition of Ruppert–
Prakash’s reagent to the imine as the key steps. No protect-
ing groups were necessary, permitting an atom economic
synthesis in only six steps. Further addition reactions of the
CF3 anion to different N-(isopropylsulfinyl)imines were per-
formed to demonstrate the suitability of the sulfinyl substitu-
ent to balance perfectly reactivity and diastereoselectivity.
The gold standard of this approach is that reported by
Prakash et al. using N-(tert-butylsulfinyl)imine,[7] developed
by Ellman et al.,[8] as the activated imine and Ruppert–
Prakash’s reagent (CF3SiMe3) as the trifluoromethylating
agent. The exceptional behaviour of the chiral sulfinyl
group in N-sulfinylimines as activator, chiral controller and
finally as a useful protecting group makes the sulfinamides
of type I an extremely versatile chiral intermediate in the
construction of chiral trifluoromethylated amines (Fig-
ure 1).[9] Although the addition of Ruppert–Prakash’s rea-
gent to N-(p-tolylsulfinyl)imines, pioneered by Davis,[10] has
been reported to add only with moderate selectivity,[11] re-
cently Kawano and Mukayama reported that the use of am-
monium salts nBu4NOAc or nBu4NOPh as catalyst allows
the formation of trifluoromethylated amine II with high
diastereoselectivity.[12] On the other hand, as the addition of
the methyl Grignard reagent to N-(tert-butylsulfinyl)imine
takes place through a coordinated Zimmerman–Traxler-like
transition state, the major isomer is the syn-sulfinamide.[13]
In contrast, it has been shown that the addition of the tri-
fluoromethyl group takes place through the Cram open
transition state, affording the anti-sulfinamide as the main
isomer.[7] Consequently, the methyl- and trifluoromethyl-
amine obtained using either tert-butyl- or p-tolylsulfinyl-
imines as chiral intermediate have the opposite configura-
tion. Taking into account that in a medicinal chemistry pro-
gram, the desired trifluoromethylated analogue of a chiral
drug should have the same absolute configuration as the
corresponding biologically active amine, both enantiomers
of the sulfinylimine intermediate should be accessible, pref-
erably at no additional cost. In this regard it is worth men-
tioning that none of the methods described for the synthesis
of the tert-butyl- or p-tolylsulfinylimines is able to give both
enantiomers in an enantiodivergent way. In this paper we
Introduction
In the last decade fluorinated drugs have gained increas-
ing significance in medical applications, including finding
use in central nervous system, anticancer, antibacterial, car-
diovascular, and antiviral therapies as well as in in vivo nu-
clear medical tomography (PET).[1] Since the first fluor-
inated drug, 5-fluorouracil, was synthesized in 1957 as a po-
tent antineoplasic agent inhibiting the enzyme thymidylate
synthetase, several key drugs with great structural diversity
have been launched on the market and account currently
for almost 25% of drugs in the pharmaceutical develop-
ment.[2] It has become evident that fluorinated compounds
have a critical role and impact in drug potency, construc-
tively altering pharmacological properties.[3] Accordingly,
amides derived from trifluoromethylamines are generally
more resistant to enzymatic hydrolysis, have different solu-
bilities and present different desolvation capacities.[4] Be-
cause of their importance, the preparation of chiral tri-
fluoromethylated amines is a current area of interest.[5]
Even though the enantioselective trifluoromethylation of
carbonyl compounds has recently been studied in some
depth, there is no enantioselective approach as yet to the
enantioselective trifluoromethylation of imines.[6] The best
way to synthesise chiral trifluoromethylated amines is by
the addition of a trifluoromethyl anion to an imine bearing
a chiral auxiliary.
[a] Departamento de Química Orgánica y Farmacéutica, Facultad
de Farmacia, Universidad de Sevilla,
c/. Profesor García González, 2, 41012 Sevilla, Spain
[b] Instituto de Investigaciones Químicas, C.S.I.C. – Universidad
de Sevilla,
c/. Américo Vespucio, 49, Isla de la Cartuja, 41092 Sevilla,
Spain
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Enantiodivergent Approach to Trifluoromethylated Amines
report the use of a single chiral auxiliary in a highly dia-
stereoselective approach to the synthesis of sulfinamides
III, important intermediates in the synthesis of both
enantiomers of trifluoromethylated amines.
Figure 2. Chemical structure of (R)-(+)-NPS R-568 (1) and its tri-
fluoromethylated analogue S-2.
The spatially related trifluoromethylated analogue S-2
should be accessible using the same route but by the ad-
dition of a trifluoromethyl group instead of a methyl Grig-
nard as long as the stereochemical outcome of the reaction
is the desired one. To determine the degree and sense of the
stereocontrol exerted by the isopropylsulfinyl group, we
have synthesized a number of N-(isopropylsulfinyl)imines
and studied their reaction with Ruppert–Prakash’s reagent.
The asymmetric synthesis of both enantiomers of N,N-bis-
(trimethylsilyl)-2-propanesulfinamide (5) (see Scheme 2) has
been achieved in an enantiodivergent manner using sugar-
based sufinates R-4 and S-4 as sulfinylating agents, pre-
pared by our DAG methodology (Scheme 1).[18]
Figure 1. Trifluoromethylated sulfinamides I–III.
Within our research program directed towards the devel-
opment of new asymmetric methodologies promoted by
sulfur-based auxiliaries or ligands,[14] we have recently in-
troduced N-(isopropylsulfinyl)imine as an alternative inter-
mediate to the widely used (tert-butylsulfinyl)imine and (p-
tolylsulfinyl)imine.[15a]
Besides the advantage of a lower molecular weight, in
previous investigations we have highlighted the role of the
isopropylsulfinyl group in conferring better enantiomeric
discrimination than the p-tolylsulfinyl group and higher
chemical reactivity with equal or even better enantiomeric
discrimination than the most popular tert-butylsulfinyl
group in the Corey–Chaykovsky reaction of chiral sulfin-
ylimine,[15a] in the organocatalytic allylation of acyl hydraz-
ones with ferrocenylsulfinyl derivatives[15b] and in the syn-
thesis of enantiopure α-arylamines.[15c] In this paper we re-
port a highly diastereoselective addition of Ruppert–Prak-
ash’s reagent to N-(isopropylsulfinyl)imines for the synthe-
sis of various enantiomerically pure trifluoromethylated
amines. The synthetic value of this approach is further dem-
onstrated by the enantiodivergent synthesis of both
enantiomers of trifluoromethylated analogues of a potent
calcimimetic drug employing a single chiral auxiliary (dicy-
clohexylidene--glucose, DCGOH).
Results and Discussion
Scheme 1. Enantiodivergent approach to the synthesis of SS-4 and
RS-4 DCG 2-propanesulfinates.
NPS R-568 (1; Figure 2) is a member of a new family
of drugs named calcimimetics, recently launched onto the
market for the treatment of hyperparathyroidism in patients
The condensation of 1 mol-equiv. of the secondary carb-
with chronic kidney disease who are on dialysis and for the inol 3 with 1.8 mol-equiv. of racemic iPrSOCl in THF using
treatment of hypercalcemia in patients with parathyroid pyridine as base afforded the 2-propanesulfinate RS-4 in
carcinoma.[16] Clinical studies with the calcimimetic NPS 97% chemical yield and 76% de (Scheme 1). As expected,
R-568 (1) have shown that its biological activity is closely by employing toluene as the solvent and by using exactly
related to the configuration of the chiral centre.[17] Accord- the same conditions as before but changing the base from
ingly, (R)-(+)-NPS R-568, the eutomer, is 10–100 times pyridine to iPr2NEt, 2-propanesulfinate SS-4 was obtained
more potent than the (S)-(–) enantiomer, the distomer. We diastereoselectively in quantitative yield and 96% de
have recently disclosed an enantioselective synthesis of (Scheme 1). In addition, the DCG 2-propanesulfinates 4
calcimimetic (R)-(+)-NPS R-568 (1) in six high-yielding were stable as no decomposition of these sulfinates was de-
steps starting from (S)-(isopropylsulfinyl)imine.[15c]
tected after storage for several months at 4 °C.
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FULL PAPER
The preparation of N-sulfinylimines 6–9 required a two- Table 1. Nucleophilic trifluoromethylation of N-sulfinylimines 6–
9.[a]
step one-pot synthesis that involved the condensation of
LHMDS with sulfinate SS-4 leading to the sulfinamide 5
followed by condensation with a suspension of CsF and the
aldehyde in THF (Scheme 2).
Scheme 2. Synthesis of N-(isopropylsulfinyl)imines 6–9.
Note that the synthesis of N-sulfinylimines 6–9 using sul-
[a] All reactions were conducted in toluene as solvent at –50 °C. [b]
finate SS-4 as the sulfinylating agent takes place efficiently
Major diastereoisomer. [c] Isolated yield. [d] Determined by NMR
under very mild reaction conditions as compared with the
procedures reported before for the synthesis of the 2-
methyl-2-propanesulfinamides I and p-toluenesulfinamides
II. Accordingly, the complete transformation of sulfinate
SS-4 to the silylated sulfinamide derivative 5 takes place at
0 °C in only 5 min and by condensation with the aldehyde,
the final sulfinylimine is generally obtained in high chemical
yield within one hour.
analysis of the crude.
methanol at 0 °C for 2 h provided, after addition of Et3N
and stirring overnight, the free amine R-14 in good yield
and with the R absolute configuration (Scheme 3).[20]
The condensation of Ruppert–Prakash’s reagent with
the N-sulfinylimines 6–9 using difluorotriphenylsilicate
(TBAT)[19] as a soluble fluoride source in toluene at –50 °C
afforded the corresponding trifluoromethylated sulfin-
amides in good-to-excellent yields. The results are compiled
in Table 1.
The diastereomeric excesses of the products were mea-
1
sured by H and 19F NMR analysis of the crude mixtures.
Scheme 3. Determination of the absolute configuration of tri-
fluoromethylated amines: synthesis of R-14.
As can be observed from Table 1, the trifluoromethylated
compounds 10–13 were obtained in excellent yields and in
short reaction times. Note that both N-(arylsulfinyl)- and
The stereochemical outcome of the addition of the tri-
N-(alkylsulfinyl)imines are equally reactive towards Rup- fluoromethyl group can be rationalized by a non-chelated
pert–Prakash’s reagent and afforded the corresponding sulf- Cram model in which the approach of the bulky trifluoro-
inamides with excellent diastereoselectivities (up to 92% de, methylating complex takes place on the less hindered Si
Table 1, entries 1 and 4), which is indicative of the highly face of the double bond (Figure 3).
stereochemical control exerted by the isopropylsulfinyl
With these results in hand we synthesized the calcimi-
group. On the other hand, in all cases, the diastereomeric metic analogues. First, (SS,R)-10 was desulfinylated to yield
trifluoromethylated sulfinamides can be easily separated, R-15, which was treated with 3-(2-chlorophenyl)-2-propenyl
which allows their preparation in optically pure form by chloride (16) in the presence of sodium carbonate to afford
flash chromatography.
amide R-17 in excellent yield (Scheme 4). In contrast to the
To determine the absolute configurations of the amides corresponding methylated amide, which can be easily hy-
obtained and thus the sense of asymmetric induction, the drogenated, the α,β-unsaturated trifluoromethylated amide
synthesis of a known trifluoromethylamine was sought. De- R-17 was inactive towards palladium-catalysed hydrogena-
sulfinylation of N-sulfinamide (SS,R)-11 with 4  HCl in tion in all the solvents and hydrogen pressures assayed. This
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Enantiodivergent Approach to Trifluoromethylated Amines
presence of TBTU in DMF. Finally, the treatment of R-19
with DIBALH in THF afforded the desired trifluorometh-
ylated analogue of NPS R-568 in good yield (Scheme 4).
Then, starting from sufinate RS-4 and following the same
synthetic route we were able to obtain the other enantiomer
with the same absolute configuration as the biologically
active calcimimetic NPS R-568 (S-2) in 30% overall yield
(Scheme 5).
Conclusions
The results presented in this work show that besides the
advantage of lower molecular weight, the isopropylsulfinyl
group confers high chemical reactivity and excellent
stereocontrol. The usefulness of this new chiral controller
has been demonstrated by a highly enantioselective synthe-
sis of trifluoromethyl-arylamines. Both enantiomers of the
calcimimetic drug R-(+)-NPS R-568 have been efficiently
obtained by the use of the “DAG methodology”, which
allows the synthesis of both sulfinylating agents in an
enantiodivergent and economic manner using DCGOH as
the sole chiral auxiliary in the whole process. The results
reported in this work demonstrate that the “DAG method-
ology” is the method of choice for the synthesis of a tri-
fluoromethylated analogue of a biologically active amine as
both enantiomers of the sulfinylimine intermediate are eas-
ily prepared in an enantiodivergent way.
Figure 3. Model explaining the stereochemical outcome of the tri-
fluoromethylation of the (isopropylsulfinyl)imines.
problem was solved by using the commercially available 3-
(2-chlorophenyl)-2-propionic acid (18) as the starting mate-
rial, which afforded the amide R-19 in good yield in the
Experimental Section
General Methods: Unless otherwise noted all reagents were ob-
tained from commercial suppliers and used without further purifi-
cation. All reactions were performed under dry argon using oven-
dried glassware and freshly distilled and dried solvents. THF and
dichloromethane were dried with molecular sieves. Isopropylsulf-
inyl chloride[18a] and TBAT[19] were prepared according to pre-
viously reported procedures. The reactions were monitored by thin-
layer chromatography (TLC) using silica gel GF254 (Merck) with
detection by charring with phosphomolybdic acid/EtOH. For flash
chromatography, 230–400 mesh silica gel (Merck) was used. Col-
umns were eluted with a positive air pressure. Chromatographic
eluents are given as volume-to-volume ratios (v/v). NMR spectra
were recorded with Bruker AMX500 (1H, 500 MHz) and Bruker
Avance DRX500 (1H, 500 MHz) spectrometers. Chemical shifts are
reported in ppm and coupling constants are reported in Hz. Rou-
Scheme 4. Enantioselective synthesis of trifluoromethylated ana-
logue of NPS R-568 (R-2).
1
tine H and 13C NMR spectra were referenced to the residual pro-
ton or carbon signals of the solvent, respectively. 19F NMR spectra
were referenced to CFCl3 as the internal standard. High-resolution
mass spectra were recorded with a Kratos MS-80RFA 241-MC
spectrometer. Optical rotations were determined with a Perkin–El-
mer 341 polarimeter.
(S)-(1,2:5,6-Di-O-Cyclohexylidene-α-D-glucofuranosyl) 2-Propane-
sulfinate (S-4): Diisopropylethylamine (DIPEA) (4.8 mL, 27.5
mmol) was added to a solution of 1,2:5,6-di-O-cyclohexylidene-α-
-glucofuranose (DCG, 3; 5 g, 15.27 mmol) in a mixture of toluene
(210 mL) and dichloromethane (20 mL). The solution was stirred
at –78 °C for 20 min before adding isopropylsulfinyl chloride
(2.5 mL, 27.5 mmol).[2] After 1 h at –78 °C, the reaction mixture
was hydrolysed with 10% aqueous HCl (100 mL), and the aqueous
Scheme 5. Enantioselective synthesis of the trifluoromethylated an-
alogue of NPS R-568 (S-2).
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I. Fernández, V. Valdivia, A. Alcudia, A. Chelouan, N. Khiar
FULL PAPER
phase was extracted with dichloromethane (3ϫ60 mL). The or-
ganic layer was washed with saturated aqueous NaHCO3 and satu-
rated aqueous NaCl and then dried with Na2SO4. After removing
the solvent under vacuum, sulfinate S-4 was obtained (6.5 g, quan-
titative yield) as an oil in 96% de; [α]2D0 = –52 (c = 0.6, acetone).
(20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 5 min
and transferred through a cannula to a second flask containing 3-
methoxybenzaldehyde (3.36 mL, 22.05 mmol, 1.5 equiv.) and CsF
(2.7 g, 17.64 mmol, 1.2 equiv.) in THF (15 mL) at 0 °C. After stir-
ring at 0 °C for 30 min, the reaction mixture was quenched with
1H NMR (500 MHz, CDCl3): δ = 5.87 (d, J = 3.5 Hz, 1 H, 1-H), saturated aqueous NH4Cl (1ϫ35 mL), and the aqueous layer was
4.70 (d, J = 2.5 Hz, 1 H, 3-H), 4.56 (d, J = 3.5 Hz, 1 H, 2-H), 4.29– extracted with AcOEt (4ϫ35 mL). The organic layer was washed
4.22 (m, 2 H, 4-H and 5-H), 4.16–3.92 (m, 2 H, 6-H and 6Ј-H), with saturated aqueous NaHCO3 and saturated aqueous NaCl and
2.77 [m, J = 7.0 Hz, 1 H, SOCH(CH3)2], 1.72–1.25 (m, 20 H, Cy), then dried with Na2SO4. The solvent was removed under reduced
1.22 [d, J = 7.0 Hz, 6 H, SOCH(CH3)2] ppm. 13C NMR (125 MHz, pressure and the residue was purified by flash chromatography (Ac-
CDCl3): δ = 113.1, 109.7, 104.6, 84.2, 80.7, 79.9, 72.0, 66.5, 60.4,
55.6, 36.4, 35.7, 34.6, 25.2, 24.8, 24.0, 23.8, 23.7, 23.5, 13.9 ppm.
HRMS: calcd. for C21H34O7S [M]+ 430.2025; found 430.2016 (δ =
2.0 ppm).
OEt/CH2Cl2, 1:30) to give S-6 (2.68 g, 81% yield) as a white solid;
m.p. 54 °C; [α]2D0 = +77 (c = 0.65, CHCl3). 1H NMR (CDCl3,
500 MHz): δ = 8.58 (s, 1 H, N=CHAr), 7.49–7.43 (m, 3 H, Ar),
7.11–7.09 (m, 1 H, Ar), 3.89 (s, 3 H, OCH3), 3.00 [m, J = 6.90 Hz,
1 H, CH(CH3)2], 1.35 [d, J = 6.95 Hz, 3 H, CH(CH3)2], 1.25 [d, J
= 6.85 Hz, 3 H, CH(CH3)2] ppm. 13C NMR (CDCl3, 125 MHz): δ
= 162.59 160.0, 135.3, 130.0, 122.6, 119.0, 113.0, 55.4, 53.9, 14.8,
13.50 ppm. HRMS: calcd. for C11H16NO2S [M]+ 226.0901; found
226.0895.
(R)-(1,2:5,6-Di-O-cyclohexylidene-α-D-glucofuranosyl) 2-Propane-
sulfinate (R-4): Pyridine (3.3 mL, 27.5 mmol) was added to a solu-
tion of 1,2:5,6-di-O-cyclohexylidene-α--glucofuranose (DCG, 3;
5 g, 15.27 mmol) in THF (200 mL). The solution was stirred at
–78 °C for 20 min before adding isopropylsulfinyl chloride (3.7 mL,
27.5 mmol). After 1 h at –78 °C, the reaction mixture was hydro-
lysed with 10% aqueous HCl (100 mL), and the aqueous phase was
extracted with dichloromethane (3ϫ60 mL). The organic layer was
washed with saturated aqueous NaHCO3 and saturated aqueous
NaCl and then dried with Na2SO4. After removing the solvent un-
der vacuum, sulfinate R-4 was obtained (6.4 g, quantitative yield)
as an oil in 80% de. The resulting mixture of diastereomers can be
separated by silica gel column chromatography (AcOEt/hexane,
(S)-N-[(E)-Benzylidene]-2-propanesulfinamide (S-7): 1  LHMDS in
THF (19 mL, 19 mmol, 1.5 equiv.) was added to a solution of sulf-
inate S-4 (5.45 g, 12.6 mmol, 1 equiv.) in THF (20 mL) at 0 °C.
The reaction mixture was stirred at 0 °C for 5 min and transferred
through a cannula to a second flask containing benzaldehyde
(2 equiv.) and CsF (1 equiv.) in THF (19 mL) at 0 °C. After stirring
at 0 °C for 30 min, the reaction mixture was quenched with satu-
rated aqueous NH4Cl (1ϫ35 mL), and the aqueous layer was ex-
tracted with AcOEt (4ϫ35 mL). The organic layer was washed
with saturated aqueous NaHCO3 and saturated aqueous NaCl and
finally dried with Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography (Ac-
OEt/CH2Cl2, 1:30) to give S-7 (1.84 g, 75% yield) as a white solid;
m.p. 37–39 °C; [α]2D0 = +54 (c = 0.5, CHCl3). 1H NMR (CDCl3,
500 MHz): δ = 8.60 (s, 1 H, N=CHPh), 7.83 (d, J = 7 Hz, 2 H,
Ph), 7.50–7.43 (m, 3 H, Ph), 2.95 [m, J = 6.8 Hz, 1 H, CH(CH3)2],
1.33 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.25 [d, J = 6.8 Hz, 3 H,
CH(CH3)2] ppm. 13C NMR (CDCl3, 125 MHz): δ = 162.6, 134.0,
132.5, 129.4, 128.9, 53.9, 14.8, 13.6 ppm. HRMS: calcd. for
C10H13NOS [M]+ 196.0796; found 196.0797.
1:7); [α]2D0 = +15 (c = 0.8, acetone). H NMR (CDCl3, 400 MHz):
1
δ = 5.87 (d, J = 3.5 Hz, 1 H, 1-H), 4.73 (d, J = 3.5 Hz, 1 H, 2-H),
4.69 (d, J = 1.3 Hz, 1 H, 3-H), 4.23–4.04 (m, 3 H, 4-H, 5-H, 6-H),
3.94–3.90 (m, 1 H, 6Ј-H) 2.79 [m, J = 7.0 Hz, 1 H, SOCH(CH3)2],
1.82–1.34 (m, 20 H, Cy), 1.24 [d, J = 7.0 Hz, 3 H, SOCH(CH3)2],
1.23 [d, J = 7.0 Hz, 3 H, SOCH(CH3)2] ppm. 13C NMR (CDCl3,
100 MHz): δ = 113.0, 110.0, 105.0, 83.3, 83.1, 81.2, 71.7, 67.5, 56.0,
36.6, 36.4, 35.6, 34.8, 25.1, 24.8, 24.0, 23.9, 23.8, 23.5, 13.8,
13.7 ppm. HRMS: calcd. for C21H34O7S [M]+ 430.2025; found
430.2020 (δ = 1.2 ppm).
(R)-N-[(E)-3-Methoxybenzylidene]-2-propanesulfinamide (R-6): 1 
LHMDS in THF (10.45 mL, 10.45 mmol, 1.5 equiv.) was added to
a solution of sulfinate R-4 (3 g, 6.97 mmol, 1 equiv.) in THF
(15 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min
and then transferred through a cannula to a second flask contain-
ing 3-methoxybenzaldehyde (1.7 mL, 13.94 mmol, 2 equiv.) and
CsF (1.05 g, 6.97 mmol, 1 equiv.) in THF (15 mL) at 0 °C. After
stirring at 0 °C for 1 h, the reaction mixture was quenched with
saturated aqueous NH4Cl (1ϫ35 mL), and the aqueous layer was
extracted with AcOEt (4ϫ35 mL). The organic layer was washed
with saturated aqueous NaHCO3 and saturated aqueous NaCl and
finally dried with Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography (Ac-
OEt/hexanes, 1:9), to give Rs-6 (1.3 g, 83% yield) as a white solid;
m.p. 50–51 °C; [α]2D0 = –74.8 (c = 1, CHCl3). 1H NMR (CDCl3,
500 MHz): δ = 8.55 (s, 1 H, N=CHAr), 7.40–7.38 (m, 3 H, Ar),
7.06 (d, J = 7 Hz, 1 H, Ar), 3.86 (s, 3 H, OCH3), 2.98 [m, J =
6.90 Hz, 1 H, CH(CH3)2], 1.32 [d, J = 6.95 Hz, 3 H, CH(CH3)2],
1.20 [d, J = 6.85 Hz, 3 H, CH(CH3)2] ppm. 13C NMR (CDCl3,
125 MHz): δ = 157.24, 154.80, 130.06, 124.8, 117.44, 113.87,
107.73, 50.22, 48.66, 9.64, 8.28 ppm. HRMS: calcd. for
C11H15NO2S [M]+ 225.0823; found 225.0823.
(S)-N-[(E)-Naphthalen-2-ylmethylene]-2-propanesulfinamide (S-8):
1  LHMDS in THF (6.96 mL, 6.96 mmol, 1.5 equiv.) was added
to a solution of sulfinate S-4 (2 g, 4.64 mmol, 1 equiv.) in THF
(8 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h
and transferred through a cannula to a second flask containing 2-
naphthaldehyde (1.26 mL, 9.30 mmol, 2 equiv.) and CsF (705 mg,
4.64 mmol, 1 equiv.) in THF (15 mL) at 0 °C. After stirring at 0 °C
for 1 h, the reaction mixture was quenched with saturated aqueous
NH4Cl (1ϫ25 mL), and the aqueous layer was extracted with Ac-
OEt (4ϫ25 mL). The organic layer was washed with saturated
aqueous NaHCO3 and with saturated aqueous NaCl and dried
with Na2SO4. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography (AcOEt/hexanes,
1:9), to give S-8 (0.93 g, 82% yield) as a yellow oil; [α]2D0 = +22.5
(c = 1, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 9.16 (s, 1 H,
N=CHAr), 9.02 (d, J = 8.55 Hz, 1 H, Ar), 8.05–8.03 (m, 2 H, Ar),
7.92 (d, J = 8.10 Hz, 1 H, Ar), 7.64 (t, J = 7.05 Hz, 1 H, Ar), 7.57
(t, J = 7.55 Hz, 2 H, Ar), 3.05 [m, J = 6.85 Hz, 1 H, CH(CH3)2],
1.35 [d, J = 6.90 Hz, 3 H, CH(CH3)2], 1.29 [d, J = 6.85 Hz, 3 H,
CH(CH3)2] ppm. 13C NMR (CDCl3, 125 MHz): δ = 157.31, 128.71,
128.15, 126.69, 126.04, 124.14, 123.67, 122.85, 121.34, 120.04,
119.15, 48.81, 9.57, 8.39 ppm. HRMS: calcd. for C14H15NOS
[M]+ 245.0874; found 245.0881.
(S)-N-[(E)-3-Methoxybenzylidene]-2-propanesulfinamide (S-6): 1 
LHMDS in THF (17.6 mL, 17.64 mmol, 1.2 equiv.) was added to
a solution of sulfinate S-4 (6.7 g, 14.7 mmol, 1 equiv.) in THF
1506
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1502–1509

Enantiodivergent Approach to Trifluoromethylated Amines
(S)-N-[(E)-Cyclohexylmethylene]-2-propanesulfinamide (S-9): 1 
LHMDS in THF (7.31 mL, 7.31 mmol, 1.5 equiv.) was added to a
solution of sulfinate S-4 (2.1 g, 4.87 mmol, 1 equiv.) in THF (8 mL)
at 0 °C. The reaction mixture was stirred at –78 °C for 1 h and
then transferred through a cannula to a second flask containing
cyclohexanecarbaldehyde (1.18 mL, 9.74 mmol, 2 equiv.) and CsF
(739 mg, 4.87 mmol, 1 equiv.) in THF (20 mL). After stirring at
0 °C for 1 h, the reaction mixture was quenched with saturated
aqueous NH4Cl (1ϫ30 mL), and the aqueous layer was extracted
with AcOEt (4ϫ30 mL). The organic layer was washed with satu-
rated aqueous NaHCO3 and with saturated aqueous NaCl and
dried with Na2SO4. The solvent was removed under reduced pres-
sure and the residue was purified by flash chromatography (AcOEt/
7S and following the general procedure as a unique diastereoisomer
in 86% yield; m.p. 80–83 °C; [α]2D0 = +24.2 (c = 0.5, CHCl3). 1H
NMR (CDCl3, 500 MHz): δ = 7.45–7.43 (m, 5 H, Ar), 4.93–4.87
(m, 1 H, CHCF3), 4.10 (d, J = 5.9 Hz, 1 H, NH), 2.88–2.78 [m, 1
H, CH(CH3)2], 1.31 [d, J = 6.95 Hz, 3 H, CH(CH3)2], 1.29 [d, J =
6.95 Hz, 3 H, CH(CH3)2] ppm. 13C NMR (CDCl3, 125 MHz): δ =
133.7, 129.6, 128.9, 128.0, 124.6 (q, J = 281.5 Hz), 60.34 (q, J =
30.8 Hz), 55.11, 15.49, 15.32 ppm. HRMS: calcd. for
C11H15NOF3S [M + H]+ 266.0826; found 266.0830.
(SS,R)-N-[2,2,2-Trifluoro-1-(naphthalen-2-yl)ethyl]-2-propanesulfin-
amide [(SS,R)-12]: The title compound was obtained starting from
imine S-8 and following the general procedure as a 85:15 mixture
of diastereomers in 85% yield as a white solid; m.p. 112–114 °C;
hexanes, 1:9) to give S-9 (0.98 g, 75% yield) as a yellow oil; [α]2D0
=
1
[α]2D0 = +131 (c = 1.2, CHCl3). H NMR (CDCl3, 500 MHz): δ =
+48 (c = 0.3, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 7.98 (d, J
= 4.60 Hz, 1 H, N=CHCy), 2.85 [m, J = 6.90 Hz, 1 H, CH(CH3)
2], 2.51–2.44 (m, 1 H, Cy), 1.94–1.87 (m, 2 H, Cy), 1.84–1.77 (m,
2 H, Cy), 1.74–1.66 (m, 2 H, Cy), 1.39–1.34 (m, 4 H, Cy), 1.26 [d,
J = 6.95 Hz, 3 H, CH(CH3)2] 1.17 [d, J = 6.85 Hz, 3 H, CH(CH3)
2] ppm. 13C NMR (CDCl3, 125 MHz): δ = 172.47, 53.08, 43.96,
29.32, 25.87, 25.34, 14.54, 13.11 ppm. HRMS: calcd. for
C10H20NOS [M + H]+ 202.1266; found 202.1260.
8.18 (d, J = 8.5 Hz, 1 H, Ar), 7.93 (dd, J = 8 and 3.5 Hz, 2 H, Ar),
7.72 (d, J = 7.5 Hz, 1 H, Ar), 7.65 (td, J = 7 and 1 Hz, 1 H, Ar),
7.57 (t, J = 7 Hz, 1 H, Ar), 7.52 (t, J = 7.7 Hz, 1 H, Ar), 5.81 (q,
J = 6 Hz, 1 H, CHCF3), 4.32 (d, J = 5 Hz, 1 H, NH), 2.74 [sept,
J = 7 Hz, 1 H, CH(CH3)2], 1.27 [d, J = 7 Hz, 3 H, CH(CH3)2],
1.24 [d, J = 7 Hz, 3 H, CH(CH3)2] ppm. 13C NMR (CDCl3,
125 MHz): δ = 133.94, 130.86, 130.37, 129.72, 129.17, 127.38,
126.32, 125.79, 125.10, 122.54, 55.06, 15.55, 14.98 ppm. 19F NMR
(CDCl3 , 400 MHz): δ = –73.43 ppm. HRMS: calcd. for
C15H17F3NOS [M + H]+ 316.0983; found 316.0976.
General Method for the Addition of the Trifluoromethyl Anion to N-
Sulfinylimines: CF3SiMe3 (4.58 mmol, 4.5 equiv.) was added
through a syringe to a suspension of the corresponding imine
(1.01 mmol, 1 equiv.) and TBAT (1.11 mmol, 1.1 equiv.) in toluene
(33 mL) under argon at –50 °C. After stirring overnight, the reac-
tion was quenched with saturated aqueous NH4Cl (30 mL) and
extracted with AcOEt (3ϫ20 mL). Finally, the organic layer was
dried with Na2SO4 and the solvent was removed under reduced
pressure. The residue obtained was purified by flash chromatog-
raphy (AcOEt/hexanes, 2:3) to give the corresponding trifluoro-
methyl-substituted amine.
(SS,R)-N-(1-Cyclohexyl-2,2,2-trifluoroethyl)-2-propanesulfinamide
[(SS,R)-13]: The title compound was obtained starting from imine
S-9 and following the general procedure as a 93:7 mixture of dia-
stereomers in 72% yield as a white solid; m.p. 98–100 °C; [α]2D0
=
+70.8 (c = 1.04, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 3.65
(d, J = 8.5 Hz, 1 H, NH), 3.55–3.51 (m, 1 H, CHCF3), 2.84–2.79
[m, 1 H, CH(CH3)2], 1.86–1.82 (m, 5 H, Cy), 1.70–1.68 (m, 3 H,
Cy), 1.46 (dq, J = 5 and 10 Hz, 1 H, Cy), 1.30 [d, J = 3.5 Hz, 3 H,
CH(CH3)2], 1.29 [d, J = 3.5 Hz, 3 H, CH(CH3)2], 1.08 (dq, J =
12.4 and 3 Hz, 1 H, Cy) ppm. 13C NMR (CDCl3, 125 MHz): δ =
125.45 (q, J = 280 Hz), 63.31 (q, J = 28 Hz), 55.61, 37.74, 29.94,
27.34, 26.05, 25.86, 25.67, 21.12, 15.60, 14.85 ppm. 19F NMR
(CDCl3, 400 MHz): δ = –73.10 ppm.
(RS,S)-N-[2,2,2-Trifluoro-1-(3-methoxyphenyl)ethyl]-2-propanesulf-
inamide [(RS,S)-10]: The title compound was obtained starting from
imine RS-6 and following the general procedure as a 96:4 mixture
of diastereoisomers in 96% yield as a slightly yellow oil; [α]2D0
=
1
–52.1 (c = 0.6, CHCl3). H NMR (CDCl3, 500 MHz): δ = 7.28 (t,
J = 8 Hz, 1 H, Ar), 7.01–6.98 (m, 2 H, Ar), 6.91 (dd, J = 8 and
2 Hz, 1 H, Ar), 4.82 (q, J = 7 Hz, 1 H, CHCF3), 4.53 (d, J =
6.5 Hz, 1 H, NH), 3.78 (s, 3 H, OCH3), 2.77 [hept, J = 7 Hz, 1 H,
CH(CH3)2], 1.24 [d, J = 7 Hz, 3 H, CH(CH3)2], 1.21 [d, J = 7 Hz,
3 H, CH(CH3)2] ppm. 13C NMR (CDCl3, 125 MHz): δ = 159.84,
135.13, 130.09, 124.63 (q, J = 280 Hz), 121.33, 114.67, 114.05,
60.13 (q, J = 31 Hz), 55.22, 54.91, 15.65, 15.08 ppm. 19F NMR
(CDCl3 , 400 MHz): δ = –74.70 ppm. HRMS: calcd. for
C12H16NO2F3S [M + H]+ 296.0932; found 296.0928.
(R)-2,2,2-Trifluoro-1-phenylethylamine (R-14): 4  HCl (0.7 mL,
2.71 mmol, 2 equiv.) was added to a solution of (SS,R)-11 (200 mg,
0.76 mmol, 1 equiv.) in MeOH (5 mL), under argon. After stirring
for 1 h 30 min, the MeOH solvent was evaporated under reduced
pressure to afford compound (R)-2,2,2-trifluoro-1-phenylethyl-
amine hydrochloride (150 mg, 93.5%) as a white solid; m.p. 235–
237 °C; [α]2D0 = –6.67 (c = 0.6, MeOH). 1H NMR (CD3OD,
500 MHz): δ = 7.63–7.55 (m, 5 H, Ar), 5.4 (q, J = 7.5 Hz, 1 H,
CHCF3), 4.87 (s, 3 H, NH3+Cl–) ppm. 13C NMR (CD3OD,
125 MHz): δ = 134.6, 133.1, 132.2, 132.0, 127.4 (q, J = 280.3 Hz),
59.3 (q, J = 32.6 Hz) ppm. HRMS: calcd. for: C8H9NF3Cl [M +
H]+ 176.0687; found 176.0676.
(SS,R)-N-[2,2,2-Trifluoro-1-(3-methoxyphenyl)ethyl]-2-propanesulf-
inamide [(SS,R)-10]: The title compound was obtained starting from
imine S-6 and following the general procedure as a unique dia-
stereoisomer in 95.4% yield as a slightly yellow oil; [α]2D0 = +50.7
(c = 2.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.31 (t, J =
7.9 Hz, 1 H, Ar), 7.01–6.91 (m, 3 H, Ar), 4.83–4.80 (m, 1 H,
CHCF3), 4.00 (d, J = 5.8 Hz, 1 H, NH), 3.81 (s, 3 H, OCH3), 2.77
[hept, J = 6.9 Hz, 1 H, CH(CH3)2], 1.26 [d, J = 7.0 Hz, 3 H,
CH(CH3)2], 1.25 [d, J = 6.7 Hz, 3 H, CH(CH3)2] ppm. 13C NMR
(125 MHz, CDCl3): δ = 160.0, 135.0, 130.3, 126.7 (q, J = 281 Hz),
120.10, 114.9, 114.0, 60.3 (q, J = 31 Hz), 55.3, 55.1, 15.5, 14.9 ppm.
19F NMR (400 MHz, CDCl3): δ = –74.57 ppm. HRMS: calcd. for
C12H17NO2F3S [M + H]+ 296.0932; found 296.0937.
Et3N (0.19 mL, 1.34 mmol) was added to a suspension of this prod-
uct (125 mg, 0.67 mmol) in diethyl ether (2 mL) under argon. After
stirring overnight, the slurry was filtered and the liquid portion
evaporated to afford R-14 (85 mg, 72%) as a yellow oil; [α]2D0
=
–17.44 (c = 3.4, EtOH). 1H NMR (CDCl3, 500 MHz): δ = 7.43–
7.38 (m, 5 H, Ar), 4.40 (q, J = 7.5 Hz, 1 H, CHCF3), 1.80 (br. s, 2
H, NH2) ppm. 13C NMR (CDCl3, 125 MHz): δ = 135.4, 128.9,
128.6, 127.8, 125.7 (q, J = 275 Hz), 57.9 (q, J = 25 Hz) ppm. 19F
NMR (400 MHz, CDCl3): δ = –73.48 ppm. HRMS: calcd. for:
C8H9NF3 [M – H]+ 174.0530; found 174.0529.
(R)-2,2,2-Trifluoro-1-(3-methoxyphenyl)ethylamine (R-15):
CF3CO2H (0.36 mL, 4.75 mmol) was added to a solution of sulfin-
amide (SS,R)-10 (124 mg, 0.42 mmol) in MeOH (5 mL) at 0 °C, and
(SS,R)-N-(2,2,2-Trifluoro-1-phenylethyl)-2-propanesulfinamide
[(SS,R)-11]: The title compound was obtained starting from imine
Eur. J. Org. Chem. 2010, 1502–1509
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1507

I. Fernández, V. Valdivia, A. Alcudia, A. Chelouan, N. Khiar
FULL PAPER
the reaction mixture was stirred overnight. The solvent was re-
moved under reduced pressure to give the corresponding ammo-
nium trifluoroacetate. The residue was passed through a cation-
exchange column (Isolute SPE SCX-2) to give the amine R-15
(59 mg, 69%) as a yellow oil; [α]2D0 = –108 (c = 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.35–7.32 (m, 1 H, Ar), 7.05–7.02
(m, 2 H, Ar), 6.95–6.94 (m, 1 H, Ar), 4.35 (q, J = 7.4 Hz, 1 H,
CHCF3), 3.81 (s, 3 H, OCH3), 1.78 (s, 2 H, NH2) ppm. 13C NMR
(125 MHz): δ = 159.8, 137.0, 129.7, 125.7 (q, J = 280 Hz), 121.5,
114.3, 113.6, 57.9 (q, J = 29.5 Hz), 55.2 ppm. 19F NMR (400 MHz,
CDCl3): δ = –77.2 ppm. HRMS: calcd. for: C9H11NOF3 [M +
H]+ 206.0802; found 206.0793.
HRMS: calcd. for C18H2ClF3NO [M + H]+ 358.1185; found
358.1184.
(S)-N-[2,2,2-Trifluoro-1-(3-methoxyphenyl)ethyl]-3-(2-chlorophen-
yl)-1-propylamine (S-2): Starting from amine S-19 and following
the same experimental procedure as described above, the title com-
pound was obtained in 63% yield; [α]2D0 = +27.4 (c = 0.4, acetone).
Acknowledgments
The authors thank the Spanish Ministerio de Ciencia e Innovación
(MICINN), the European Regional Development Fund (grant
numbers CTQ2007-61185 and CTQ2006-15515) and the Junta de
Andalucía (grant numbers P06-FQM-01852 and P07-FQM-2774)
for financial support. A. A. thanks the Ministerio de Educación y
Ciencia (MEC) for a Ramón y Cajal Contract, V. V. thanks the
Consejo Superior de Investigaciones Científicas (CSIC) for a pre-
doctoral I3P grant.
(S)-2,2,2-Trifluoro-1-(3-methoxyphenyl)ethylamine (S-15): Starting
from amine (RS,S)-10 and following the same experimental pro-
cedure as described above, the title compound was obtained in 64%
yield with identical physical data to those of its enantiomer R-15;
[α]2D0 = +95 (c = 0.6, CHCl3).
(R)-3-(2-Chlorophenyl)-N-[2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl]-
propanamide (R-19): A solution of amine R-15 (15 mg, 0.073 mmol)
and DIPEA (0.038 mL, 0.220 mmol) in DMF (1 mL) was added
through a cannula to a stirred solution of 3-(2-chlorophenyl)prop-
anoic acid (18; 13.43 mg, 0.073 mmol) and O-(benzotriazol-1-yl)-
N,N,NЈ,NЈ-tetramethyluronium tetrafluoroborate (TBTU;
23.44 mg, 0.073 mmol) in DMF (0.5 mL) at room temperature. Af-
ter stirring for 10 min, DMF was removed in vacuo, CH2Cl2
(15 mL) was added and the organic phase was washed with satu-
rated aqueous NaHCO3 (10 mL) and brine (10 mL) and then dried
(Na2SO4) and concentrated in vacuo. Purification of the residue by
flash chromatography (AcOEt/hexane, 1:5) gave the amide R-19
(59.3 mg, 76%) as a white solid; m.p. 98–100 °C; [α]2D0 = –13.6 (c =
0.5, acetone). 1H NMR (500 MHz, CDCl3): δ = 7.32–7.28 (m, 2 H,
Ar), 7.19–7.11 (m, 3 H, Ar), 6.94–6.88 (m, 3 H, Ar), 6.40 (d, J =
9.3 Hz, 1 H, NH), 5.74–5.66 (m, 1 H, CHCF3), 3.80 (s, 3 H,
OCH3), 3.12–3.05 (m, 2 H, CH2), 2.66–2.58 (m, 2 H, CH2) ppm.
13C NMR (125 MHz, CDCl3): δ = 171.5, 159.9, 137.7, 134.2, 133.7,
130.7, 129.5, 127.9, 127.0, 124.4 (q, J = 281 Hz), 120.0, 114.5,
113.9, 55.3, 54.1 (q, J = 31 Hz), 36.0, 29.3 ppm. 19F NMR
(400 MHz, CDCl3 ): δ = –74.3 ppm. HRMS: calcd. for
[1] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev. 2008, 37, 320; b) H.-J. Böhm, D. Banner, M. Kansy,
B. Kuhn, K. Müller, U. Obst-Sander, M. Stahl, ChemBioChem
2004, 5, 637; c) P. Jeschke, ChemBioChem 2004, 5, 570; d) B. D.
Roth, in: Progress in Medicinal Chemistry, vol. 40 (Eds.: F. D.
King, A. W. Oxford), Elsevier, Amsterdam, 2002; e) K. Drlica,
M. Malik, Curr. Top. Med. Chem. 2003, 3, 249; f) D. T. Wong,
F. P. Baymaster, E. A. Engleman, Life Sci. 1995, 57, 411.
[2] a) J. P. Begué, D. Bonnet-Delpon, J. Fluorine Chem. 2006, 127,
992; b) C. Isanbor, D. O’Hagan, J. Fluorine Chem. 2006, 127,
303; c) K. L. Kirk, J. Fluorine Chem. 2006, 127, 1013.
[3] K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881.
[4] a) I. Ojima, K. Kato, F. A. Jameison, J. Conway, K. Nakah-
ashi, M. Hagiawara, T. Miyamae, H. E. Radunz, Bioorg. Med.
Chem. Lett. 1992, 2, 219; b) D. Schirlin, C. Tarnus, S. Baltzer,
J. M. Rémy, Bioorg. Chem. Lett. 1992, 2, 651.
[5] a) W. H. Pirkle, K. A. Simmons, J. Org. Chem. 1981, 46, 3239;
b) Y. Wang, H. S. Mosher, Tetrahedron Lett. 1991, 32, 987; c)
J.-A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119; d) J. Ga-
wronski, N. Wascinska, J. Gajewy, Chem. Rev. 2008, 108, 5227.
[6] a) T. Billard, B. R. Langlois, Eur. J. Org. Chem. 2007, 891; b)
N. Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry
2008, 19, 2633.
C
1 8 H1 8 NO2 F3 Cl [M + H]+ 372.0978; found 372.0970.
C18H17NO2F3Cl: C 58.15, H 4.61, N 3.77; found C 57.97, H, 5.05,
N 3.63.
[7] G. K. S. Prakash, M. Mandal, G. A. Olah, Angew. Chem. Int.
Ed. 2001, 40, 589.
[8] J. A. Ellman, T.-D. Owens, T. P. Tang, Acc. Chem. Res. 2002,
(S)-3-(2-Chlorophenyl)-N-[2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl]-
propanamide (S-19): Starting from amine S-15 and following the
same experimental procedure as described above, the title com-
pound was obtained in 87% yield; [α]2D0 = +13.3 (c = 0.6, CDCl3).
35, 985.
[9] a) G. K. S. Prakash, M. Mandal, G. A. Olah, Org. Lett. 2001,
3, 2847; b) G. K. S. Prakash, M. Mandal, J. Am. Chem. Soc.
2002, 124, 6538.
[10] F. A. Davis, J. Org. Chem. 2006, 71, 8993.
(R)-N-[2,2,2-Trifluoro-1-(3-methoxyphenyl)ethyl]-3-(2-chlorophen-
yl)-1-propylamine (R-2): 1  DIBALH in THF (0.53 mL,
0.53 mmol) was added to a stirred solution of amide R-19 (50 mg,
0.133 mmol) in CH2Cl2 (2 mL) at room temperature. After stirring
overnight, the reaction was quenched by the addition of saturated
aqueous NH4Cl (2 mL). The mixture was filtered through a Celite
pad, adding CH2Cl2 (3ϫ10 mL), and the filtrate was concentrated
under vacuum. Purification of the residue by flash chromatography
(CH2Cl2/hexanes, 1:2) gave amine R-2 (10 mg, 66%), as a pale-
[11] G. K. S. Prakash, M. Mandal, G. A. Olah, Synlett 2001, 77.
[12] Y. Kawano, T. Mukaiyama, Chem. Lett. 2005, 34, 894.
[13] a) G. Liu, D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1997,
119, 9913; b) D. Morton, R. Stockman, Tetrahedron 2006, 62,
8869.
[14] a) I. Fernández, N. Khiar, Chem. Rev. 2003, 103, 3651; b) N.
Khiar, B. Suárez, B. V. Valdivia, I. Fernández, Synlett 2005,
2963; c) N. Khiar, R. Navas, B. Suárez, E. Álvarez, I.
Fernández, Org. Lett. 2008, 10, 3697.
[15] a) I. Fernández, V. Valdivia, B. Gori, F. Alcudia, E. Alvarez,
N. Khiar, Org. Lett. 2005, 7, 1307; b) I. Fernández, V. Valdivia,
M. Pernía, N. Khiar, Org. Lett. 2007, 9, 2215; c) I. Fernández,
V. Valdivia, N. Khiar, J. Org. Chem. 2008, 73, 745.
[16] a) N. Nagano, Pharmacol. Ther. 2006, 109, 339; b) S. J. Stedon,
J. Cunningham, Lancet 2005, 365, 2237; c) E. F. Nemeth, Curr.
Pharm. Des. 2002, 8, 2077; d) M. E. Steffey, J. Fox, B. C.
Van Wagenen, E. G. Delmar, M. F. Balandrin, E. F. Nemeth,
J. Bone Miner. Res. 1993, 8, S175; e) S. J. Silverberg, H. G.
1
yellow oil; [α]2D0 = –27.37 (c = 0.94, acetone). H NMR (500 MHz,
CDCl3): δ = 7.35–7.25 (m, 3 H, Ar), 7.15–7.11 (m, 3 H, Ar), 6.98–
6.89 (m, 3 H, Ar), 4.08 (q, J = 7.4 Hz, 1 H, CHCF3), 3.82 (s, 3 H,
OCH3), 2.79–2.71 (m, 2 H, CH2), 2.63 (t, J = 7.0 Hz, 2 H, CH2),
1.86–1.79 (m, 2 H, CH2) ppm. 13C NMR (125 MHz, CDCl3): δ =
159.8, 139.4, 133.9, 130.4, 129.7, 129.5, 125.4 (q, J = 28 Hz), 127.4,
126.8, 120.8, 114.3, 114.1, 64.6 (q, J = 28 Hz), 55.3, 47.1, 31.0,
29.8, 29.7 ppm. 19F NMR (400 MHz, CDCl3): δ = –74.4 ppm.
1508
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1502–1509

Enantiodivergent Approach to Trifluoromethylated Amines
Bone, T. B. Marriott, F. G. Locker, S. Thys-Jacobs, G. Dziem,
E. L. Kaatz, E. L. Sanguinetti, J. P. Bilezikian, New Engl. J.
Med. 1997, 337, 1506.
Alcudia, I. Fernández, J. Org. Chem. 2002, 67, 345; d) N.
Khiar, F. Alcudia, J. L. Espartero, L. Rodríguez, I. Fernández,
J. Am. Chem. Soc. 2000, 122, 7598.
[17] E. F. Nemeth, M. E. Steffey, L. G. Hammerland, B. C. P.
Hung, B. C. Van Wagenen, E. G. DelMar, M. Balandrin, Proc.
Natl. Acad. Sci. USA 1998, 95, 440.
[18] a) I. Fernández, N. Khiar, J. M. Llera, F. Alcudia, J. Org.
Chem. 1992, 57, 6789; b) N. Khiar, I. Fernández, F. Alcudia,
Tetrahedron Lett. 1994, 35, 5719; c) N. Khiar, C. S. Araujo, F.
[19] A. S. Pilcher, H. L. Ammon, P. DeShong, J. Am. Chem. Soc.
1995, 117, 5166.
[20] F. Gosselin, A. Roy, P. D. O’Shea, C.-Y. Chen, R. P. Volante,
Org. Lett. 2004, 6, 641.
Received: October 14, 2009
Published Online: February 3, 2010
Eur. J. Org. Chem. 2010, 1502–1509
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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