Stereoselective synthesis of trifluoromethyl-substituted 1,2-diamines by aza-Michael reaction with trans-3,3,3-trifluoro-1-nitropropene

Article abstract of DOI:10.1016/j.tet.2006.06.013

Aza-Michael addition of optically pure 4-phenyl-2-oxazolidinone to 3,3,3-trifluoro-1-nitropropene proceeds smoothly at low temperature with a high yield. Diastereoselectivity of the addition depends on the base used and lithiated species proved to be highly efficient affording 92% de. Optically pure 1,2-diamino-3,3,3-trifluoropropane is prepared in 58% yield from the aza-Michael addition product through a three-step procedure.

Full text of DOI:10.1016/j.tet.2006.06.013

Tetrahedron 62 (2006) 8109–8114
Stereoselective synthesis of trifluoromethyl-substituted 1,2-
diamines by aza-Michael reaction with trans-3,3,3-trifluoro-
1-nitropropene
a
Joel Turconi, Luc Lebeau, Jean-Marc Paris and Charles Mioskowski
a
b
a,
*
€
a
´
´
´
Laboratoire de Syntheꢀse Bioorganique associe au CNRS, Universite Louis Pasteur de Strasbourg, Faculte de Pharmacie,
74 route du Rhin, BP 24, 67401 Illkirch Cedex, France
bRhodia Recherches, Centre de Recherches et de Technologies de Lyon, 85 avenue des Freꢀres Perret, BP 62,
69192 Saint-Fons Cedex, France
Received 18 October 2005; revised 31 May 2006; accepted 2 June 2006
Available online 22 June 2006
Abstract—Aza-Michael addition of optically pure 4-phenyl-2-oxazolidinone to 3,3,3-trifluoro-1-nitropropene proceeds smoothly at low tem-
perature with a high yield. Diastereoselectivity of the addition depends on the base used and lithiated species proved to be highly efficient
affording 92% de. Optically pure 1,2-diamino-3,3,3-trifluoropropane is prepared in 58% yield from the aza-Michael addition product through
a three-step procedure.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(piperazines, imidazolines, imidazolidines, etc.) as well as
aliphatic amines4 (amino acids, amino alcohols, etc.). Chiral
1-trifluoromethyl-substituted 1,2-ethylenediamines espe-
cially gained our attention as promising building blocks for
the synthesis of optically active trifluoromethylated nitrogen
compounds. The synthesis of racemic 1,2-diamino-3,3,3-tri-
fluoropropane 1 has been reported only very recently by Sos-
novskikh et al.5 The authors prepared the compound
according to Scheme 1 by reduction of 2-amino-3,3,3-tri-
fluoro-1-nitropropene with lithium aluminum hydride, and
characterized 1 as bis-tosyl derivative.6 At the same time
For more than 50 years fluorinated compounds receive tre-
mendous interest as candidates for new pharmaceuticals and
agrochemicals.1 Today 16–17% of pharmaceuticals do incor-
porate fluorine and half of agrochemicals are fluorinated
molecules. During the past decade, the number of fluorinated
compounds developed by companies increased by a 2-fold
factor and more and more investigations are now focusing
toward chiral and optically pure fluorinated molecules.2
The synthesis of selectively fluorinated non-racemic chiral
compounds having sophisticated structures is generally real-
ized by fluorinating the final intermediate during the
synthetic sequence. The synthesis of organofluorine com-
pounds using fluorine-containing ‘building blocks’ is an
efficient alternative to the direct introduction of fluorine.
Although there has been recent general interest in the prepa-
ration and utilization of optically enriched and/or pure build-
ing blocks, there are, however, very few optically active and
synthetically usable fluorinated compounds that are commer-
cially available. Thus efforts, more than ever, are required to
developefficient methodologies to produce such compounds.
Scheme 1.
OH Me
1) Bn(Me)NH
2) Recryst.
O
N
F3C
Bn
F3C
(75% ee)
(>99.5% ee)
Ph3PCl2
Et3N
AgBF4
1,2-Ethylenediamines are key starting materials in the syn-
thesis of nitrogen-containing heterocyclic compounds3
Bn
Me
R1
N
Me
N
R1R2NH
Bn
N
Keywords: Perfluoroalkyl nitroalkene; Diastereoselective aza-Michael
addition; 3,3,3-Trifluoro-1-nitropropene; 4-Phenyl-2-oxazolidinone.
* Corresponding author. Tel.: +33 3 90 24 42 97; fax: +33 3 90 24 43 06;
e-mail: mioskow@aspirine.u-strasbg.fr
F3C
R2
F3C
BF4
2
Scheme 2.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.013

8110
J. Turconi et al. / Tetrahedron 62 (2006) 8109–8114
Ts
N
Ts
N
O
n-BuLi
O
MeOC(O)Cl
H2N
Ph
F3C
O
N
H
O
F3C
NaH
F3C
TsHN CF3
O
Scheme 3.
CF3
O
O
O
N
H
F3C
O
H
H
N
H
O
Et3N
LiCl
Ni
N
+
N
Ni
N
N
O
N
N
O
O
HCl
O
CF3
HOOC
N
H
NH2
Scheme 4.
Katagiri et al. described the synthesis of optically active
N,N0-substituted 1,2-diamino-3,3,3-trifluoropropanes 2 start-
ing from optically pure 2,3-epoxy-1,1,1-trifluoropropane
(Scheme 2).7 In 2003, Uneyama’s group developed an alter-
nate strategy involving N-tosylaziridines (Scheme 3).8 That
has to be paralleled with a work by Soloshonok, who
described aza-aldol reactions of chiral Ni(II) complex of
glycine with imines (Scheme 4).9 Prakash and Mandal devel-
oped a different route to access trifluoromethyl vicinal ethyl-
enediamine involving nucleophilic trifluoromethylation of
optically active (R)-N-tert-butanesulfinimines (Scheme 5).10
Last, Zanda et al. described the diastereoselective addition
of a-amino esters to 3,3,3-trifluoro-1-nitropropene (Scheme
6).11 The diastereoselectivity observed by Zanda is in the
range 23–84% depending on experimental conditions.
To the best of our knowledge, the literature do not disclose
any other report on the synthesis, either stereoselective or
not, of 1,2-diamino-2-perfluoroalkyl compounds. Herein we
report our results concerning the stereoselective synthesis of
1,2-diamino-3,3,3-trifluoropropane 1 by Michael addition
of amino compounds on prochiral trans-3,3,3-trifluoro-1-
nitropropene 4.
2. Results and discussion
The use of nitroalkenes as Michael acceptors has received
much attention due to the number of efficient methods for
converting nitro groups into amines, carbonyls, etc.12 Aza-
Michael reactions somewhat remained in the background
as b-aminonitroalkanes are reported as unstable com-
pounds.13,14 Nevertheless, some remarkable results have
been obtained concerning the addition of achiral, prochiral,
or chiral nitrogen nucleophiles to either achiral, prochiral, or
chiral nitroalkenes. Restricting our analysis to those dia-
stereocontrolled addition reactions we can only find some
15 examples.15–28 trans-3,3,3-Trifluoro-1-nitropropene 4 is
a highly reactive Michael acceptor and is regioselectively
attacked at the C2 position (Fig. 1).29 To the best of our
knowledge, the only aza-Michael reactions with 4 reported
so far in the literature concern pyrazole 5 and triazoles 6, ad-
ducts being obtained as pairs of enantiomers,30 and a-amino
esters as reported by Zanda et al.11
H
O
S
O
S
Ti(OEt)4
NBn2
+
NBn2
O
NH2
N
Bn
Bn
TMSCF3
TBAT
1) HCl
O
S
CF3
CF3
2) Pd/C, H2
NBn2
NH2
N
H
H2N
Bn
Bn
3
Scheme 5.
Intrigued by the diastereoselective potential of the aza-
Michael reaction with 2-perfluoroalkyl-1-nitroalkenes we
investigated the addition of a series of various chiral nitrogen
CF3
O
O
NO2
O
NO2
+
NH2
F3C
N
H
O
4
H2
R2
Pd(OH)2/C
N
O
R1
R2
R1
N
N
O
N
N
H
CF3
N
H
H
O
NH2
7-R-(–): R1 = Ph, R2 = H
N
H
5
6
7-S-(+): R1 = H, R2 = Ph
O
Scheme 6.
Figure 1.

J. Turconi et al. / Tetrahedron 62 (2006) 8109–8114
8111
nucleophiles to 4 to set up an access to enantiopure 1,2-di-
amino-2-perfluoroalkyl compounds.31 Remarkable results
were obtained with 4-phenyl-2-oxazolidinone 7 that is com-
mercially available as both R-(ꢀ) and S-(+) isomers
(Scheme 7). We studied the scope and the diastereoselectiv-
ity of the reaction as a function of experimental conditions
such as temperature, base used for nitrogen deprotonation
(or addition promoter), or solvent composition (Table 1).
case does not have drastic effects on conversion and yield
(Entry 11). Alternative addition conditions have been tested.
In the conditions described by Rawal et al., for the addition
of oxazolidinones to 3-butyn-2-one (N-methylmorpholine,
NMM)32 no reaction occurs (Entry 15). Bis(acetonitrile)pal-
ladium(II) chloride has been recently described to promote
the intramolecular addition of oxazolidinones to double
bonds in a high yield.33 However, in the conditions described
by Hirai et al. 4-phenyl-2-oxazolidinone does not add to 4
and is integrally recovered after work up of the reaction
mixture (Entry 16). The same negative results are obtained
using potassium fluoride on alumina as described by Blass
et al. for the addition of oxazolidinone to a series of various
electrophiles.34
O
O
Base
Ph
+
4
Ph
O
O
N
H
N
NO2
8
F3C
7-R-(–)
Scheme 7.
In all the experiments described herein a major diastereomer
formed as expected from earlier results obtained with non-
fluorinated nitroalkenes.21 As fluorinated substituents may
modify the stereochemical issue of diastereoselective reac-
tions,2 we were bent on determining the absolute configura-
tion of the reaction adduct. A single-crystal X-ray analysis
of compound 8 derived from (R)-(ꢀ)-4-phenyl-2-oxazolidi-
none showed that the chiral center that is created has an S ab-
solute configuration (Fig. 2). That result is in agreement with
those in the non-fluorinated series. The high level of asym-
metric induction can be explained by a metal-chelated
eight-membered transition state model (Fig. 3). Thus transi-
tion state TS-re suffers from steric repulsion between phenyl
and trifluoromethyl groups, which does not exist in TS-si.
Quite surprisingly the metal cation reveals extremely impor-
tant for the diastereoselectivity of the reaction. While K+
The conjugate addition of 4-phenyl-2-oxazolidinone lithium
or potassium salt to trans-3,3,3-trifluoro-1-nitropropene
4 proceeds smoothly and gets to completion within 15–
30 min at ꢀ78 ꢁC. Higher yields were invariably obtained
using n-butyllithium as a base instead of potassium tert-
butoxide. That is likely related to the size of the alkaline
counter-ion, which is consistent with the intermediate result
obtained with sodium hydride (Entry 14). Indeed trans-3,3,3-
trifluoro-1-nitropropene 4 is unstable under basic conditions
even at low temperature. Consequently the quicker the anion
from 7 adds to the nitroalkene precluding its degradation,
the better. That is equally consistent with the lower yield ob-
tained when no phase transfer catalyst is used (Entry 3, 42%
yield after 30 min). Due to the higher solubility of n-butyl-
lithium in the reaction mixture, lack of 18-crown-6 in that
Table 1. Conjugate addition of R-(ꢀ)-4-phenyl-2-oxazolidinone 7 on trans-3,3,3-trifluoro-1-nitropropene 4
Entrya
Compound 7
T (ꢁC)
Base
Conversionb (%)
Yieldc (%)
ded (%)
1
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
R-(ꢀ)
S-(+)
ꢀ100
ꢀ78
ꢀ78
ꢀ40
+25
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
NaH
NMM
PdCl2(MeCN)2
KF/Al2O3
t-BuOLi
PhMgCl
n-BuLi
66
68
64
65
44
28
60
80
100
100
100
100
100
71
55
54
42
45
28
8
48
74
83
91
83
85
84
54
—
—
—
86
0
64
58
56
52
50
50
50
92
92
92
92
86
92
70
—
—
—
92
—
92
2
3e
4
5
6
+50
7f
ꢀ78
ꢀ100
ꢀ78
ꢀ78
ꢀ78
ꢀ30
ꢀ78
ꢀ78
+25
+25
+25
ꢀ78
ꢀ78
ꢀ78
8
9
10g
11e
12
13h
14e,i
15j
16k
17l
18e
19
20
0
0
0
100
32
100
86
a
Unless otherwise stated, stoichiometric amounts of 4, 7, and 18-crown-6 were allowed to react in THF for 15 min before addition of aqueous ammonium
chloride and standard work up.
Conversion of oxazolidinone 7, evaluated by 1H NMR spectroscopy.
Based on isolated diastereomerically pure 8.
b
c
d
e
f
Evaluated by 1H and 19F NMR spectroscopies in the crude reaction mixture.
No 18-crown-6 was used and reaction time was extended to 30 min.
The reaction was carried out in DMF.
g
h
i
Nitroalkene 4 (1.5 equiv) was used.
The reaction was carried out in diethyl ether.
Anion was prepared for 1 h at 50 ꢁC.
Experimental conditions are as described elsewhere.32
Experimental conditions are as described elsewhere.33
Experimental conditions are as described elsewhere.34
j
k
l

8112
J. Turconi et al. / Tetrahedron 62 (2006) 8109–8114
analogue compounds21 revealed troublesome and inefficient
C(42)
(Scheme 8). Indeed catalytic reduction of the nitro group in 8
followed by a treatment of 9 with lithium in ammonia or so-
dium hydroxide did not afford diamine 13 as expected from
results in the non-fluorinated series. Instead was obtained
imidazolidone 10 that was then debenzylated to afford 4-tri-
fluoromethyl-2-imidazolidone 11. Further attempts to hydro-
lyze 11 for getting 1,2-diamino-3,3,3-trifluoropropane 13
invariably failed and complex mixtures of polar compounds
were obtained that could not be separated even after treat-
ment with acetyl chloride. To prevent the intramolecular re-
arrangement of aminocarbamate 9 into hydroxyurea 10, the
former was refluxed with ethylene diamine. We were then
able to obtain diamine 12 nearly quantitatively together
with 2-imidazolidone. Compound 12 was submitted to
hydrogenolysis and optically pure S-(ꢀ)-1,2-diamino-3,3,3-
trifluoropropane 13 was obtained. Debenzylation of 12,
however, proved difficult and despite many efforts for opti-
mizing the experimental conditions (varying the nature and
amount of catalyst used, hydrogen pressure, hydrogen
source, temperature, solvent, and pH), compound 13 was
never obtained in a yield better than 51%. About 40–45%
of starting material was recovered unchanged and could be
engaged in another hydrogenolysis cycle. Another debenzy-
lation procedure using ammonium persulfate35 proved inef-
ficient to form compound 13.
C(41)
C(39)
C(32)
C(28)
C(22)
C(31)
C(25)
O(12)
N(10)
F(6)
C(14)
O(8)
C(30)
C(38)
O(10)
N(9)
F(2)
F(7)
C(26)
O(9)
OH
O
H2
O
Ph
F3C
Ph
NaOH
Pd(OH)2/C
Figure 2. Structure of compound 8 resulting from the conjugate addition of
7-R-(ꢀ) on 4 as determined by X-ray crystal analysis.
O
N
N
8
NH
NH2
9
F3C
10
NH2
NH2
H2
Pd(OH)2/C
²
H2
Pd(OH)2/C
HO
HN
F3C
O
NH2
O
Ph
HN
NH2
NH
+
F3C
HN
NH
F3C
NH2
12
13
11
Scheme 8.
Figure 3.
3. Conclusion
yields medium diastereomeric excess (58% de, Entry 2), Na+
and especially Li+ give much better results (70% de and 92%
de, respectively; Entry14 and Entries 8–11, 13, respectively).
An additional experiment carried out with lithium tert-but-
oxide also gave 92% de indicating that the higher diastereo-
selectivity presumably results from a better fit between the
geometry of the eight-membered ring transition state and
the cation size (Entry 18). Diastereomeric excess obtained
with potassium tert-butoxide is roughly the same when the
reaction is carried out at +50 or ꢀ40 ꢁC (50–52% de, Entries
4–6). A slight improvement, however, is observed at lower
temperature and at ꢀ100 ꢁC, 68% de is obtained (Entry 1).
We tried to carry out the reaction at a temperature below
ꢀ100 ꢁC using a pentane/THF mixture. In that case, how-
ever, oxazolidine 7 proves only poorly soluble and does not
allow synthetically useful conversion.
We have described the first diastereoselective synthesis of
1,2-diamino-3,3,3-trifluoropropane 13. The title compound
is prepared in four steps starting from readily available opti-
cally pure 4-phenyl-2-oxazolidinone 7 and trans-3,3,3-tri-
fluoro-1-nitropropene 4. The synthetic route is versatile
and allows several intermediate function installations, espe-
cially on compounds 9 and 12. Consequently unambiguous
derivatization of one amino group or the other can be easily
achieved and makes these compounds valuable intermedi-
ates for the elaboration of chiral non-racemic sophisticated
fluorinated compounds.
4. Experimental
4.1. General procedure
The transformation of 8 into 1,2-diamino-3,3,3-trifluoropro-
pane 13 using the procedure described for non-fluorinated
1H, 13C, and 19F NMR chemical shifts d are reported in parts
per million relative to their standard reference (1H: CHCl3 at

J. Turconi et al. / Tetrahedron 62 (2006) 8109–8114
8113
7.27 ppm, HDO at 4.63 ppm, CD2HOD at 3.31 ppm; 13C:
CDCl3 at 77.0 ppm, CD3OD at 49.0 ppm; 19F: CFCl3 exter-
nal at 0.00 ppm). IR spectra were recorded in wave numbers
(cmꢀ1). Mass spectra (MS) and high-resolution mass spectra
(HRMS) were recorded at chemical ionization (CI) or in the
electro spray (ESI) mode. Mass data are reported in mass
units (m/z). Abbreviations: s, singlet; d, doublet; t, triplet;
q, quadruplet; m, multiplet; b, broad. trans-3,3,3-Trifluoro-
1-nitropropene was prepared according to the literature.36
3 M and extracted with ether. The organic layer is washed
with brine, dried over MgSO4, and reduced in vacuo to yield
imidazolidone 10 (241 mg, 60%) as a slightly yellow oil.
TLC Rf 0.65 (AcOEt). 1H NMR (CDCl3, 300 MHz) d 7.41–
7.27 (m, 5H); 6.30 (s, 1H); 4.63 (dd, J¼3.7, 8.1 Hz, 1H);
4.27 (dd, J¼8.1, 12.5 Hz, 1H); 4.04 (dd, J¼3.7, 12.5 Hz,
1H); 3.92 (m, 1H); 3.60 (t, J¼10.0 Hz, 1H); 3.50 (dd,
J¼3.7, 10.0 Hz, 1H). 13C NMR (CDCl3, 75 MHz) d 163.3;
137.7; 129.3; 128.6; 127.6; 125.3 (q, J¼281.2 Hz); 64.3;
63.6; 57.3 (q, J¼31.8 Hz); 39.4. 19F NMR (CDCl3,
188 MHz) d ꢀ76.3. IR (film, CsI) n 3317; 2924; 1706;
1497; 1451; 1392; 1280; 1172; 1143. MS (CI/NH3) m/z
275 [M+H]+; 292 [M+NH4]+. HRMS (ESI) m/z calcd for
C12H13F3N2NaO2 297.0821, found 297.0836. [a]2D0 ꢀ10
(c 7.5, CHCl3).
4.1.1. Synthesis of (L)-3-[2-(S)-(1-nitro-3,3,3-trifluoro-
propyl)]-[4-(R)-phenyl]-oxazolidin-2-one 8. A 1.6 M solu-
tion of n-butyllithium in hexane (370 mL, 0.61 mmol) is
added dropwise to (R)-4-phenyloxazolidin-2-one (100 mg,
0.61 mmol) in anhydrous THF (5 mL) at ꢀ78 ꢁC. Deproto-
nation is allowed to occur for 1 h before trans-3,3,3-tri-
fluoro-1-nitropropene 4 (112 mg, 0.79 mmol) in THF
(2 mL) is slowly added. The reaction mixture is stirred for
30 min at ꢀ78 ꢁC, saturated aqueous NH4Cl (3 mL) is added,
and the temperature is allowed to rise to room temperature.
The mixture is extracted with ether. The organic layer is
washed with water, brine, dried over Na2SO4, and reduced
under vacuum. The crude residue is purified by chromato-
graphy over silica gel (hexane/ethyl acetate 7:3) to yield 8
(169 mg, 91%) as a white solid. TLC Rf 0.5 (hexane/ethyl
acetate 7:3). mp 108 ꢁC. 1H NMR (CDCl3, 200 MHz)
d 7.57–7.31 (m, 5H); 5.49 (dd, J¼8.6, 14.4 Hz, 1H); 4.99
(t, J¼8.3 Hz, 1H); 4.78 (dd, J¼4.7, 14.4 Hz, 1H); 4.73 (t,
J¼8.5 Hz, 1H); 4.40 (m, 1H); 4.29 (t, J¼7.2 Hz, 1H). 13C
NMR (CDCl3, 50 MHz) d 156.9; 135.1; 130.7; 130.1;
128.3; 124.2 (q, J¼284.0 Hz); 71.0; 70.1; 61.8; 53.8 (q, J¼
31.9 Hz). 19F NMR (CDCl3, 188 MHz) d ꢀ71.2. IR (KBr)
n 2924; 1766; 1567; 1416; 1378; 1252; 1184; 1138. MS
(CI/NH3) m/z 322 [M+NH4]+; 339 [M+NH3+NH4]+; 626
[2M+NH4]+. HRMS (ESI) m/z calcd for C12H11F3N2NaO4
327.0569, found 327.0574. [a]2D0 ꢀ61 (c 0.88, CHCl3).
4.1.4. Synthesis of (D)-4-(S)-trifluoromethylimidazoli-
din-2-one 11. Compound 10 (100 mg, 0.36 mmol) and palla-
dium hydroxide 20% (100 mg) in dry methanol (8 mL) are
vigorously stirred under hydrogen pressure (60 bar) for
46 h at room temperature. The catalyst is removed by filtra-
tion over a Celite pad and washed with methanol. The filtrate
is reduced in vacuo and the residue is purified by silica gel
chromatography (AcOEt/MeOH 9:1) to yield compound 11
(11 mg, 21%) as a white powder. TLC Rf 0.45 (AcOEt/
MeOH 9:1). 1H NMR (CD3OD, 200 MHz) d 4.40 (m, 1H);
3.79 (t, J¼10.0 Hz, 1H); 3.55 (dd, J¼4.6, 10.0 Hz, 1H).
13C NMR (CD3OD, 75 MHz) d 165.8; 126.8 (q, J¼
278.0 Hz); 54.9 (q, J¼32.6 Hz); 41.7. 19F NMR (CD3OD,
188 MHz) d ꢀ81.8. IR (KBr) n 3233; 1724; 1494; 1457;
1273; 1176; 1143. MS (CI/NH3) m/z 172 [M+NH4]+; 189
[M+NH3+NH4]+. HRMS (ESI) m/z calcd for C4H5F3N2NaO
177.0252, found 177.0278. [a]2D0 +5 (c 0.83, MeOH).
4.1.5. Synthesis of 2-(1-aminomethyl-2,2,2-trifluoroethyl-
amino)-2-phenyl-ethanol 12. Oxazolidinone 9 (250 mg,
0.91 mmol) is stirred in refluxing freshly distilled ethylene
diamine for 18 h. Ethylene diamine is removed under vac-
uum and the residue is dissolved in HCl 1 M (15 mL), and
washed with ether. The pH of the aqueous phase is brought
to 14 with NaOH 6 M, and the solution is washed with ether.
The organic phase is then washed with brine and dried over
MgSO4 to yield compound 12 (169 mg, 75%) as a slightly
4.1.2. Synthesis of (L)-3-[2-(S)-(1-amino-3,3,3-trifluoro-
propyl)]-[4-(R)-phenyl]-oxazolidin-2-one 9. Compound 8
(570 mg, 1.88 mmol) and palladium hydroxide 20%
(53 mg) in dry methanol (20 mL) are vigorously stirred un-
der hydrogen pressure (30 bar) for 14 h at room temperature.
The catalyst is removed by filtration over a Celite pad and
washed with methanol. The filtrate is reduced in vacuo and
the residue is dried in the presence of P2O5 to yield com-
pound 9 (458 mg, 88%) as a colorless oil. 1H NMR
(CDCl3, 300 MHz) d 7.41–7.27 (m, 5H); 4.98 (dd, J¼7.3,
8.9 Hz, 1H); 4.69 (t, J¼8.9 Hz, 1H); 4.22 (dd, J¼7.5,
8.7 Hz, 1H); 3.85 (m, 1H); 3.64 (s, 2H); 3.36 (dd, J¼10.6,
13.7 Hz, 1H); 3.08 (dd, J¼4.7, 13.4 Hz, 1H). 13C NMR
(CDCl3, 75 MHz) d 158.3; 137.4; 129.4; 129.0; 127.9;
124.6 (q, J¼283.0 Hz); 70.9; 59.9; 58.2 (q, J¼29.3 Hz);
36.8. 19F NMR (CDCl3, 188 MHz) d ꢀ71.3. IR (film, CsI)
n 3369; 2923; 1755; 1534; 1416; 1363; 1245; 1177; 1131.
MS (CI/NH3) m/z 275 [M+H]+; 549 [2M+H]+. HRMS
(ESI) m/z calcd for C12H14F3N2O2 275.1007, found
275.1012. [a]2D0 ꢀ40 (c 1.25, CHCl3).
1
yellow oil. H NMR (CDCl3, 200 MHz) d 7.37–7.33 (m,
5H); 4.10 (dd, J¼4.2, 8.8 Hz, 1H); 3.73 (dd, J¼4.4,
10.8 Hz, 1H); 3.63 (dd, J¼8.6, 10.8 Hz, 1H); 2.93 (m, 1H);
2.89 (dd, J¼4.1, 13.9 Hz, 1H); 2.72 (dd, J ¼5.1, 13.0 Hz,
1H). 13C NMR (CDCl3, 50 MHz) d 140.1; 129.1; 128.4;
128.0; 67.8; 63.6; 57.7 (q, J¼25.6 Hz); 41.0. 19F NMR
(CDCl3, 188 MHz) d ꢀ73.6. IR (film, CsI) n 3344; 2926;
1670; 1602; 1454; 1358; 1264; 1134; 1071. MS (CI/NH3)
m/z 249 [M+H]+. HRMS (ESI) m/z calcd for C11H16F3N2O
249.1209, found 249.215. [a]2D0 ꢀ20 (c 0.50, CHCl3).
4.1.6. Synthesis of (D)-2-(S)-1,2-diamino-3,3,3-trifluoro-
propane 13. Compound 12 (1.20 g, 4.83 mmol) and palla-
dium hydroxide 20% (0.60 g) in THF/methanol 1:1
(80 mL) are vigorously stirred under hydrogen pressure
(60 bar) for 48 h at room temperature. The catalyst is re-
moved by filtration over a Celite pad and washed with meth-
anol. The filtrate is reduced in vacuo and the residue is
purified by column chromatography (CHCl3/MeOH/concd
NH4OH 12:4:1) to yield residual starting material (504 mg)
4.1.3. Synthesis of (L)-1-[2-hydroxy-1-(R)-phenylethyl]-
5-(S)-trifluoromethylimidazolidin-2-one 10. Compound 9
(400 mg, 1.46 mmol) and sodium hydroxide (400 mg,
9.76 mmol) are stirred in refluxing methanol (8 mL) for
2 h. The reaction mixture is neutralized at 0 ꢁC with HCl

8114
J. Turconi et al. / Tetrahedron 62 (2006) 8109–8114
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and compound 13 (316 mg, 88% based on recovered starting
material) as a brown liquid. TLC Rf 0.6 (CHCl3/MeOH/
concd NH4OH 12:4:1). 1H NMR (CDCl3, 200 MHz) d 3.39
(m, 1H); 3.16 (dd, J¼3.7, 12.8 Hz, 1H); 2.83 (dd, J¼9.5,
12.9 Hz, 1H). 13C NMR (CDCl3, 50 MHz) d 126.3 (q,
J¼280.0 Hz); 54.8 (q, J¼28.6 Hz); 40.6. 19F NMR (CDCl3,
188 MHz) d ꢀ78.3. IR (film, CsI) n 3373; 1558; 1411;
1269; 1161; 1016. MS (CI/NH3) m/z 129 [M+H]+; 146
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Supplementary data
ꢁ
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