2-Trifluoromethyl-2-methyl-4-phenyloxazolidine: A new chiral auxiliary for highly diastereoselective enolate alkylation

Article abstract of DOI:10.1016/j.jfluchem.2011.02.020

The alkylation reactions of an amide sodium enolate derived from a C-2 disubstituted trifluoromethylated oxazolidine (Fox) chiral auxiliary occurred in good yields with a very high diastereoselectivity (>98% de). Compared to the C-2 monosubstituted trifluoromethyl analogue, this chiral auxiliary is much more stable towards bases at temperature over -35 °C because the dehydrofluorination reaction is avoided. However asymmetric enolates quaternarization was not successfully achieved with this new chiral auxiliary.

Full text of DOI:10.1016/j.jfluchem.2011.02.020

Journal of Fluorine Chemistry 134 (2012) 122–127
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
2-Trifluoromethyl-2-methyl-4-phenyloxazolidine: A new chiral auxiliary for
highly diastereoselective enolate alkylation§
*
Arnaud Tessier, Julien Pytkowicz, Thierry Brigaud
´
Universite de Cergy-Pontoise, Laboratoire SOSCO, F-95000 Cergy-Pontoise, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The alkylation reactions of an amide sodium enolate derived from a C-2 disubstituted trifluoromethy-
lated oxazolidine (Fox) chiral auxiliary occurred in good yields with a very high diastereoselectivity
(>98% de). Compared to the C-2 monosubstituted trifluoromethyl analogue, this chiral auxiliary is much
more stable towards bases at temperature over À35 8C because the dehydrofluorination reaction is
avoided. However asymmetric enolates quaternarization was not successfully achieved with this new
chiral auxiliary.
Received 27 January 2011
Received in revised form 11 February 2011
Accepted 27 February 2011
Available online 16 March 2011
Keywords:
ß 2011 Elsevier B.V. All rights reserved.
Alkylation reaction
Oxazolidines
Organofluorine chemistry
Stereoselective synthesis
1. Introduction
fluorine–metal and p electron–metal interactions [7]. Moreover
the trifluoromethyl group stabilizes the oxazolidine ring and
prevents the ring opening because of its strong electron
withdrawing effect. We also recently reported that the trans-
Fox proved to be an excellent chiral auxiliary for molecular
oxygen oxidation of enolates [8] and could also be used for aldol
reactions [9] (Scheme 1).
During our investigations we found that a limitation of the use
of Fox chiral auxiliary was the dehydrofluorination reaction
occurring over À50 8C. This side reaction led to partial degradation
of the Fox-amide starting material. As most of the reactions were
performed at À78 8C, this side reaction could be easily circum-
vented [5–9]. However in order to experiment reactions requiring
The asymmetric alkylation reaction of enolates is one of the
most extensively used reactions for the synthesis of chiral
compounds. Several chiral auxiliaries such as oxazolidinones [1]
and related heterocyclic structures [2], sultames [3] and amino
alcohols [4] are most commonly used for this reaction. We
recently reported that the trans 2-trifluoromethyloxazolidine
(trans-Fox) is a useful chiral auxiliary for highly diastereoselec-
tive amide enolates alkylation [5,6] and we could rationalize that
the trifluoromethyl and the phenyl groups are playing a crucial
role in the diastereoselectivity because of the existence of
higher temperatures such as for example
a-quaternarization
reactions, we became interested in a chiral auxiliary stable towards
basic conditions at higher temperatures. We designed that C-2
disubstituted chiral fluorinated oxazolidines would be valuable
candidates (Scheme 2).
§
The group ‘‘organofluorine chemistry and asymmetric synthesis’’ of the
laboratory SOSCO (Synthe`se Organique Se´lective et Chimie bioOrganique) of the
University of Cergy-Pontoise (North Paris) was founded in 2002 and is animated by
five permanent researchers: Thierry Brigaud (Professor), Julien Pytkowicz, Gre´gory
Chaume, Nathalie Lensen and Evelyne Chelain (Assistant Professors). The recent
major accomplishments of the group are dealing with the synthesis of
2. Results and discussion
trifluoromethylated
a- and b-amino acids, amino alcohols and diamines in
enantiopure form. More recently, we reported the efficient incorporation of these
fluorinated amino acids into peptides. We are now involved in the synthesis of
biologically relevant fluorinated amino acid containing peptides, the synthesis of
enantiopure fluorinated pseudoprolines, their incorporation into peptides and their
conformational analysis. In other respect, we recently reported the outstanding
performance of fluorinated oxazolidines as chiral auxiliaries for highly diaster-
eoselective amide enolates alkylation, molecular oxygen oxidation. It was
rationalized that the trifluoromethyl and the phenyl groups were playing a crucial
The oxazolidine (S)-1 was very conveniently obtained by
condensation of trifluoromethyl acetone with (R)-phenylglycinol
under PPTS acidic catalysis [10]. Interestingly, as already reported
in the literature [11], the only (S)-1 diastereoisomer was obtained
in this reaction (Scheme 3). In order to evaluate the performance of
the other diastereomer as a chiral auxiliary, we were also
interested in the preparation of the (R)-1 compound. This was
achieved by BF3ÁOEt2 promoted partial isomerization of (S)-1 into
(R)-1 (Scheme 3).
role in the diastereoselectivity because of the existence of fluorine–metal and
electron–metal interactions.
p
* Corresponding author. Fax: +33 1 34 25 73 81.
E-mail address: thierry.brigaud@u-cergy.fr (T. Brigaud).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.02.020

A. Tessier et al. / Journal of Fluorine Chemistry 134 (2012) 122–127
123
O
F3C
HN
CF3
O
O
CF3
O
R1
O
R1
H2N
Ph
OH
1) NaHMDS
2) R2X
O
PPTS (cat.)
Tol., Dean-Starck
N
N
R2
Ph
CF3
Ph
Ph
(S)-1
73%
R2= aliphatic , allyl,
benzyl
trans-Fox
56-86% yield
>99% de
F3C
HN
F3C
CF3
O
O
O
BF3.Et2O
HN
Ph
O
CF3
O
HN
Ph
CF3
R1
R
1) NaHMDS
N
CH2Cl2
74%
N
O
O
Ph
2) O2, P(OEt)3
3) 1N HCl
OH
Ph
trans-Fox
Ph
(S)-1
(S)-1
(R)-1
45
: 55
94 to >98% de
Scheme 3.
O
OH
O
CF3
O
The N-propanoyl Fox-amides (S)-2 and (R)-2 were obtained
through the reaction of the Fox chiral auxiliary (S)-1 with
propanoyl chloride. As we already reported [5], a highly reactive
acyl chloride is required for this reaction because of the
deactivation of the nitrogen atom of (S)-1 due to the electron-
withdrawing effect of the trifluoromethyl group. In similar
conditions, this reaction proved to be less efficient with (S)-1
than with the fluoral-based Fox chiral auxiliary and the N-
propanoylated Fox (S)-2 and (R)-2 were obtained in only 18–32%
yield when the reaction was carried out in the presence of a solvent
(Table 1, entries 1–4). This should be explained by the increased
steric hindrance caused by the quaternarization of the C-2 carbon
of the oxazolidine. The yield of the propanoylation reaction was
significantly improved when the reaction was performed without
solvent at 60 8C (Table 1, entries 5–7). It should be noticed that in
any cases an isomerization of (S)-1 into (R)-1 occurred in these
reaction conditions by a reversible ring opening reaction prior to
the propanoylation reaction to give a nearly 50:50 diastereomeric
mixture of (S)-2 and (R)-2. We already recently reported such
isomerization during the benzoylation reaction of other hindered
fluorinated oxazolidines [12]. The N-propanoyl oxazolidines are
very conveniently separated by silica gel chromatography and do
not undergo epimerization after isolation. Because of the
epimerization reaction of the starting oxazolidine, it became
useless to isolate both (S)-1 and (R)-1 oxazolidines before the
acylation reaction. Thus, starting from a 45:55 diastereomeric
mixture of (S)-1 and (R)-1, the N-propanoyl oxazolidines (S)-2 and
(R)-2 were prepared in high yield (91%) as a 50:50 mixture by
CF3
O
1) DIPEA, Bu2BOTf
N
Ph
N
2) PhCHO
3) H2O
Ph
Ph
(Syn,R,R)
trans-Fox
Syn:Anti = 95:5 dr
(Syn,R,R):(Syn,S,S) = 90:10 dr
Scheme 1.
O
O
CF3
CF2
R
R
NaHMDS or LDA
Temp. > -50°C
N
N
Degradation
O
O
Ph
Ph
O
CF3
R
2
N
Dehydrofluorination will be avoided
O
Ph
C-2 disubstituted
Fox chiral auxiliary
Scheme 2.
Table 1
Synthesis of N-propanoyloxazolidines (S)-2 and (R)-2.
O
F3C
O
O
F3C
N
CF3
O
HN
Ph
O
Cl
(2-3 equiv.)
N
O
Ph
Ph
(S)-2
(S)-1
(R)-2
.
Entry
Solvent
Reaction conditions
DMAP (cat.) 4 days, 80 8C
DMAP (cat.), TEA, 4 days, 80 8C
NaH, KI, 3 days, 80 8C
3 days, 60 8C
16 h, 60 8C
67 h, 60 8C
36 h, 50 8C
Yields (%)
(S)-2:(R)-2 dr
1
2
THF
DMF
THF
Pyr.
No
31
28
35:65
41:59
38:62
29:71
54:46
54:46
50:50
3
18
4a
5
32
61b
79b
91b
6
7c
No
No
a
5 equiv. of EtCOCl.
b
c
Total yield of all separated diastereomers.
Reaction performed from a 45:55(S)-1:(R)-1 dr mixture and 9 equiv. of EtCOCl.

124
A. Tessier et al. / Journal of Fluorine Chemistry 134 (2012) 122–127
Table 2
Quaternarization reactions attempts.
O
O
Ph
F3C
1) NaHMDS, Temp. > -35 °C
Unreacted starting material
N
N
O
H
R = Bn (S,R)-4
R
R
2) RX
Ph
R = Et (S,R)-5
Ph
R = Bn (S)-6
R = Et (S)-7
R = Bn (S,R)-4
R = Et (S,R)-5
.
Entry
1
Starting material
RX
EtI
Reaction conditions
Products
(S, R)-4
(S, R)-5
(S, R)-5
Deprotonation: À15 to 0 8C, 2 h
Alkylation: À78 to À50 8C, 2 h
Deprotonation: À35 8C, 3 h
(S, R)-4:(S)-6 ratio = 93:7
(S, R)-5:(S)-7 ratio = 95:5
(S, R)-5:(S)-7 ratio = 56:44
2
3
BnBr
BnBr
Alkylation: À78 to À35 8C, 3 h
Deprotonation: room temp, 2 h
Alkylation: À78 to À40 8C, 4 h
reaction with propanoyl chloride (9 equiv.) without solvent at
60 8C (Table 1, entry 6). (S)-2 and (R)-2 were isolated by silica gel
chromatography.
Because of the epimerization of the C-2 center of the
oxazolidine ring during the acylation reaction, the configuration
of the newly formed N-propanoylated oxazolidines had to be
confirmed. This was achieved by the removal of the side chain of
(S)-2 by a treatment with lithium aluminium hydride [5] giving the
(S)-1 diastereomer in 83% yield (Scheme 4).
deprotonation reaction could be performed over À35 8C. Unfortu-
nately the alkylation reaction of the amide side chain did not occur
and the only new products obtained were the amides (S)-6 and (S)-
7 resulting from the degradation of the chiral auxiliary. The fact
that no epimerization reaction of the amide side chain was
detected even at room temperature (Table 2, entry 3) suggests that
the deprotonation of the side chain to generate the enolate failed
probably because of a great steric hindrance.
In order to isolate the enamide (S)-6 and to confirm its base
promoted formation, the oxazolidine (S, R)-4 was treated with
NaHMDS at 5 8C for 2 h. In these conditions (S)-6 was obtained in 25%
isolated yield together with 62% of unreacted (S, R)-4 starting material
(Scheme 6). The postulated mechanism of the formation of (S)-6
involving the deprotonation at the benzylic position of the chiral
auxiliary is depicted in Scheme 6. This result confirms that the C-2
disubstituted chiral auxiliary (R)-1 is not suitable, in these conditions,
In order to assess the performance of both (S)-1 and (R)-1
oxazolidines as chiral auxiliaries for the asymmetric alkylation
reactions, the sodium enolates of (S)-2 and (R)-2 were submitted to
the benzylation reaction with benzyl bromide (Scheme 5). The (S)-1
Fox proved to be a very inefficient chiral auxiliary as the reaction of
(S)-2 gave the corresponding (S)-3 benzylated compound as a 59:41
diastereomeric mixture. However, the benzylation reaction of the
sodium enolate of (R)-2 proceeded in good yield (80%) to give the
amide (S, R)-4 with a complete diastereoselectivity. The ethylation
reaction was also achieved in a completely diastereoselective
manner to give the corresponding (S, R)-5 compound in 66% yield.
After removal of the chiral auxiliary (vide infra) the absolute
configuration of the newly formed asymmetric centre was assigned
to be (S). Intriguingly, conversely to our previously reported fluoral-
based Fox chiral auxiliary [5–8], the C-2 quaternarized chiral
auxiliary (R)-1 giving the best diastereoselectivity is bearing the
trifluoromethylgroup inthe relativecis positiontothephenylgroup.
According to this observation, we cannot propose similar transition
states to explain the high level of diastereoselectivity.
The stereoselective formation of quaternary asymmetric
centres is a challenge in organic synthesis. As the main problem
for this reaction is the control of the configuration of the enolate,
several reported methods of the literature involved cyclic enolate
to solve this drawback [13]. In order to investigate the use of the
Fox chiral auxiliary (R)-1 for asymmetric quaternarization reac-
tions, the compound (S, R)-4 and (S, R)-5 were submitted to the
sequence NaHMDS deprotonation and reaction with an haloge-
nated compound (Table 2). As the dehydrofluorination reaction at
the C-2 centre of the chiral auxiliary was impossible, the
for the asymmetric
a-quaternarization of amide enolates. The side
reaction resulting from the basic decomposition of the chiral auxiliary
could possibly be avoided by replacing the phenyl group of the Fox
chiral auxiliary by a more hindered tert-butyl group.
However, as this chiral auxiliary is efficient for highly
diastereoselective monoalkylations of enolates, we investigate
its removal in order to get an enantiopure hydroxy compound and
to assign its absolute configuration. To this end, the amide (S, R)-4
was treated by a reductive sequence we already reported involving
the formation of an intermediate aldehyde and its reduction into
an hydroxy compound [5–8]. According to this procedure, the
hydroxy compound (S)-8 was obtained in 72% isolated yield
(Scheme 7). The (S) configuration of 8 and its enantiomeric purity
O
F3C
N
O
F3C
N
1) NaHMDS, -78°C
2) BnBr
O
O
Ph
Ph
Ph
(S)-2
(S)-3 71 %
59 : 41 dr
O
N
CF3
O
N
CF3
1) NaHMDS, -78°C
2) RX
O
O
O
F3C
N
F3C
HN
R
1) LAH (4 equiv.)
Ph
Ph
O
O
2) 1N HCl
(R)-2
RX = BnBr
RX = EtI
(S,R)-4 80 % (>98% de)
(S,R)-5 66 % (>98% de)
Ph
(S)-2
Ph
83%
(S)-1
Scheme 4.
Scheme 5.

A. Tessier et al. / Journal of Fluorine Chemistry 134 (2012) 122–127
125
O
CF3
O
of phosphomolybdic acid in ethanol followed by heating. Mass
spectra (MS) were obtained on a GC/MS apparatus HP 5973 MSD
with an HP 6890 Series GC. Ionization was obtained by electronic
impact (EI 70 eV). Infrared spectra (IR) were obtained by Fourier-
O
Ph
1) NaHMDS, 5°C, 2h
2) NH4Cl sat
N
(S,R)-4
N
H
62 %
Ph
Ph
Ph
¨
(S)-6
25%
transformation on BRUCKER TENSOR 27, wavenumbers are given
in cmÀ1. Elemental analyses were performed by the CNRS analysis
central service. Optical rotations are reported as their specific
rotations determined using a JASCO DIP-370 polarimeter. Melting
points were obtained on a Bu¨chi apparatus and are uncorrected.
(S,R)-4
O
CF3
O
O
CF3
N
N
O
Ph
Ph
4.1. (2S, 4R)-2-methyl-2-trifluoromethyl-4-phenyloxazolidines (S)-1
Ph Ph
H
N(SiHMe3)2
To a solution of (R)-phenylglycinol (6 g, 43.7 mmol) in toluene
at room temperature (100 mL) was slowly added trifluoroacetone
(5.14 g, 45.9 mmol) and PPTS (2.2 g, 8.7 mmol). The flask was
equipped with a Dean-Stark apparatus and the solution was
warmed to reflux for 20 h. The solution was cooled down to 0 8C
and the resulting PPTS precipitate was filtered off. The flask and the
precipitate were washed with Et2O (30 mL) and the combined
organic layers were concentrated under reduced pressure. The
crude mixture was purified by filtration through a short pad of
silica gel (25 g, cyclohexane/ethyl acetate: 90/10) to afford
- CH3COCF3
Hydrolysis
(S,R)-4
O
Ph
N
H
Ph
(S)-6
Scheme 6.
oxazolidines (S)-1 (7.37 g, 73%) as a yellow oil.
23
(S)-1, [a D
]
À23.2 (c = 1.8, CHCl3); IR (neat): 3356, 3033, 2999,
1458, 1338, 1156 cmÀ1; 1H NMR (250 MHz, CDCl3):
d = 1.63 (s, 3H),
O
CF3
O
1) LAH (4 equiv)
-10°C
CF3
OH
2.29 (d, 1H, 3J = 6.2 Hz), 3.82 (t, 1H, 3J = 2J = 7.9 Hz), 4.40 (dd, 1H,
2J = 7.9, 3J = 7.6 Hz), 4.59 (dd, 1H, 3J = 7.9 Hz, 3J = 7.6 Hz), 7.20–7.50
OH
HN
N
2) Sat NH4Cl
3) LAH, 0°C
Ph
(m, 5H); 13C NMR (62.9 MHz, CDCl3):
d
= 20.6, 62.0, 73.6, 94.2 (q, 2JC–
Ph
Ph
(R)-9 (53%)
Ph
1
(S)-8
(72 %, >98% ee)
F = 30.8 Hz), 124.8 (q, JC–F = 287.2 Hz), 126.7, 128.2, 128.9, 138.8;
19F NMR (235.35 MHz, CDCl3):
int.): 232, 200, 162 (100), 132, 120, 77.3; Anal. calcd for C11H12F3NO:
C, 57.14; H, 5.23; N, 6.06. Found: C, 56.80; H, 5.05; N, 5.85.
(S,R)-4
d
À82.9 (3 F, s,CF3); EIMS, m/z (rel.
Scheme 7.
were assigned by Mosher’s ester derivatization experiment [13].
Unfortunately the chiral auxiliary (R)-1 was also reduced into the
amino alcohol (R)-9 in these conditions. However, as we already
reported [6,8] it is anticipated that the use of sodium borohydride
for the reduction of the intermediate aldehyde into (S)-8 would
avoid the reduction of the oxazolidines.
4.2. (2R, 4R)-2-methyl-2-trifluoromethyl-4-phenyloxazolidines (R)-1
To a solution of oxazolidines (S)-1 (1 g, 4.3 mmol) in CH2Cl2
(15 mL) was added BF3ÁOEt (1.1 mL, 8.6 mmol). After 24 h stirring
at room temperature, the reaction mixture was poured into a sat
NaHCO3 solution. The organic layer was extracted with dichlor-
omethane (3 Â 30 mL). The combined organic layers were dried
over magnesium sulfate and concentrated under reduced pressure.
Purification of the crude mixture by flash chromatography
(cyclohexane/ethyl acetate: 90/10) afforded 0.74 g (74%) of a
45:55 mixture of (S)-1 and (R)-1. A pure analytical sample of (R)-1
3. Conclusion
In summary we demonstrated that a C-2 disubstituted Fox
chiral auxiliary is suitable for highly diastereoselective amide
enolate alkylation reactions. This chiral auxiliary is stable in basic
conditions, even at room temperature, but failed to allow
diastereoselective quaternarization reactions.
was obtained.
23
(R)-1, [
a
]
D
À49.2 (c = 0.5; CHCl3); 1H NMR (250 MHz, CDCl3):
d
= 2.36 (s, 3H), 3.71 (dd, 1H, 1H, 2J = 9.2 Hz, 3J = 8.7 Hz), 4.28 (dd,
1H, 2J = 9.2, 3J = 7.6 Hz), 4.59 (ddd, 1H, 3J = 8.7 Hz, 3J = 7.6 Hz,
3J = 6.2 Hz), 7.10–7.40 (m, 5H); 13C NMR (62.9 MHz, CDCl3):
4. Experimental
2
1
d
= 21.5, 60.8, 75.0, 92.8 (q, JC–F = 30.8 Hz), 124.5 (q, JC–
F = 287.0 Hz), 126.8, 127.7, 128.6, 138.9; 19F NMR (235.35 MHz,
CDCl3):
À83.3 (3 F, s,CF3).
General: Unless otherwise mentioned, all the reagents were
purchased from commercial source. THF was distilled under
nitrogen from sodium/benzophenone prior to use. 1H NMR
(400.00 MHz), 13C NMR (100.50 MHz) and 19F NMR
(376.20 MHz) were measured on a JEOL 400 or a Bru¨ker Advance
250 spectrometer. Chemical shifts of 1H NMR were expressed in
d
4.3. (4R)-2-trifluoromethyl-2-methyl-4-phenyl-3-
propanoyloxazolidine (S)-2 and (R)-2
parts per million downfield from tetramethylsilane (
CDCl3. Chemical shifts of 13C NMR were expressed in parts per
million downfield from CDCl3 as internal standard ( = 77.0).
Chemical shifts of 19F NMR were expressed in parts per million
downfield from C6F6 as internal standard (
constants are reported in hertz. Column chromatography was
performed on Merck Kieselgel 60 (0.040–0.063 mm), employing
mixture of specified solvent as eluent. Thin-layer chromatography
(TLC) was performed on Merck silica gel (Merck 60 PF254) plates.
Silica TLC plates were visualized under UV light, by a 10% solution
d
= 0) in
To oxazolidine (R)-1 (7.00 g, 30.3 mmol) was added propanoyl
chloride (7.38 mL, 84.6 mmol). After 36 h stirring at 50 8C the
mixture was cooled down to room temperature and 1 N HCl
solution (50 mL) was added. The aqueous solution was extracted
with CH2Cl2 (3 Â 100 mL). The combined organic layers were
successively washed with a 1 N NaOH solution (50 mL), brine
(50 mL) and were dried over MgSO4. The resulting crude mixture
(9.4 g) was purified by flash column chromatography (cyclohex-
ane/ethyl acetate: 90/10 to 80/20) affording diastereomerically
pure (S)-2 (3.13 g, 36%) and pure (R)-2 (3.36 g, 39%).
d
d
= À164.9). Coupling

126
A. Tessier et al. / Journal of Fluorine Chemistry 134 (2012) 122–127
(2S, 4R)-2-trifluoromethyl-2-methyl-4-phenyl-3-propanoyloxazo-
solution (30 mL), extracted with diethyl ether (2 Â 50 mL) and
dichloromethane (50 mL). The combined organic layers were dried
over MgSO4, evaporated under reduced pressure and the resulting
crude mixture (1.29 g) was purified by flash column chromatog-
raphy (cyclohexane/ethyl acetate: 95/5) to give (S, R)-4 (0.84 g,
23
lidine (S)-2, white solid; m.p.: 78 8C; [
a
]
À51.7 (c = 1.8, CHCl3);
D
IR (neat): 2986, 2915, 1661, 1396, 1303, 1164, 1078, 1046,
701 cmÀ1 1H NMR (250 MHz, CDCl3): = 0.85 (t, 3H, 3J = 7.3 Hz),
;
d
1.85 (dq, 1H, 2J = 16.7 Hz, 3J = 7.3 Hz), 2.00 (s, 3H), 2.15 (dq, 1H,
2J = 16.7 Hz, 3J = 7.3 Hz), 3.85 (dq, 1H, 2J = 8.6 Hz, 5J = 1.75 Hz), 4.45
(ddq, 1H, 2J = 8.6 Hz, 3J = 7.0 Hz, 5J = 1.45 Hz), 4.96 (d, 1H,
80%) as a single diastereomer.
23
(S, R)-4, white solid; m.p.: 61 8C; [
a
]
À89.4 (c = 2.5,
D
3J = 7.0 Hz), 7.16–7.27 (m, 5H); 13C NMR (62.9 MHz, CDCl3):
CHCl3); IR (neat): 2982, 2913, 1663, 1373, 1168, 1146, 1103,
701 cmÀ1 1H NMR (250 MHz, CDCl3):
= 0.77 (d, 3H,
2
d
= 8.5, 19.4, 29.5, 61.9, 73.8, 94.4 (q, JC–F = 31.2 Hz), 124.6 (q,
;
d
1JC–F = 293.5 Hz), 125.7, 128.3, 129.3, 141.6, 172.5; 19F NMR
(235.35 MHz, CDCl3):
3J = 6.2 Hz), 1.62 (s, 3H), 2.55 (dd, 1H, 2J = 11.7 Hz, 3J = 4.5 Hz),
2.67 (m, 1H), 2.85 (dd, 1H, 2J = 11.7 Hz, 3J = 9.1 Hz), 3.77 (tq, 1H,
J = 8.5 Hz, 5J = 1.3 Hz), 4.06 (dd, 1H, 2J = 8.5 Hz, 3J = 5.8 Hz), 4.35
d
À76.7 (s, 3 F, CF3); EIMS, m/z (rel. int.):
287 (2), 230 (1), 218 (65), 200 (8), 175 (9), 162 (100), 130 (5), 120
(43), 103 (7); Anal. calcd for C14H16F3NO2: C, 58.53; H, 5.61; N,
4.88. Found: C, 58.68; H, 5.53; N, 4.82.
(m, 1H), 7.15–7.33 (m, 10H); 13C NMR (62.9 MHz, CDCl3):
2
d
= 17.65, 19.2, 41.6, 42.0, 61.9, 73.1, 94.7 (q, JC–F = 32.1 Hz),
(2R, 4R)-2-trifluoromethyl-2-methyl-4-phenyl-3-propanoyloxa-
124.2 (q, 1JC–F = 291 Hz), 126.0, 126.8, 128.4, 128.6, 129.1, 129.3,
138.8, 139.7, 176.3; 19F NMR (235.35 MHz, CDCl3):
F, CF3); EIMS, m/z (rel. int.): 377 (9), 362 (2), 308 (3), 265 (37),
250 (15), 162 (34), 146 (11), 119 (60), 91 (100), 77 (9); Anal.
calcd for C21H22F3NO2: C, 66.82; H, 5.88; N, 3.71. Found: C,
66.56; H, 5.99; N, 3.63.
23
zolidine (R)-2, yellow oil; [
a
]
D
À79.29 (c = 3.15; CHCl3); IR
d
À77.3 (s, 3
(neat): 2981, 2912, 1680, 1380, 1270, 1168, 1150, 1106, 701 cmÀ1
1H NMR (250 MHz, CDCl3): = 0.95 (t, 3H, 3J = 7.3 Hz), 1.88 (s, 3H),
1.89 (dq, 1H, 2J = 16.9 Hz, 3J = 7.3 Hz), 2.12 (dq, 1H, 2J = 16.9 Hz,
3J = 7.3 Hz), 3.99 (dd, 1H, 2J = 8.9 Hz, 3J = 8.3 Hz), 4.46 (dd, 1H,
2J = 8.9 Hz, 3J = 8.3 Hz), 5.06 (t, 1H, 3J = 8.3 Hz), 7.30–7.40 (m, 5H);
;
d
13C NMR (62.9 MHz, CDCl3):
d
= 8.6, 20.0, 29.9, 62.5, 73.8, 94.8 (q,
4.6. (2R, 4R)-2-trifluoromethyl-2-methyl-3-[(S)-2-methylbutanoyl]-
2JC–F = 32.1 Hz), 124.5 (q, JC–F = 290.8 Hz), 126.1, 128.5, 129.4,
4-phenyloxazolidine (S, R)-5
1
138.4, 173.7; 19F NMR (235.35 MHz, CDCl3):
d
À78.0 (s, 3 F); EIMS,
m/z (rel. int.): 287 (6), 230 (5), 218 (10), 200 (19), 175 (81), 162
(100), 146 (16), 120 (61), 103 (14); Anal. calcd for C14H16F3NO2: C,
58.53; H, 5.61; N, 4.88. Found: C, 58.40; H, 5.59; N, 4.48.
To a solution of oxazolidine (R)-2 (0.58 g, 2 mmol) in THF
(10 mL) under argon atmosphere at À78 8C was added a solution of
NaHMDS (1.9 mL, 2 M in THF, 3.8 mmol). The reaction mixture was
stirred for 2 h at this temperature and ethyl iodide (0.3 mL,
3.81 mmol) was added. The reaction mixture was stirred for 3.5
additional hours at À78 8C, quenched with a saturated NH4Cl
solution (30 mL), extracted with diethyl ether (2 Â 40 mL) and
dichloromethane (40 mL). The combined organic layers were dried
over MgSO4, evaporated under reduced pressure and the resulting
crude mixture (0.61 g) was purified by flash column chromatogra-
phy (cyclohexane/ethyl acetate: 90/10) to give (S, R)-5 (0.44 g, 66%)
4.4. (2S, 4R)-2-trifluoromethyl-2-methyl-3-[2-methyl-3-
phenylpropanoyl]-4-phenyloxazolidine (S)-3
The oxazolidine (S)-2 (0.33 g, 1.14 mmol) was dissolved in THF
(9 mL) under argon atmosphere. The solution was cooled down to
À78 8C and NaHMDS was added dropwise (1.07 mL, 2 M in THF,
2.14 mmol). The reaction mixture was stirred for 1.5 h at this
temperature and benzyl bromide (0.26 mL, 2.14 mmol) was added
slowly. The reaction mixture was stirred for 2 additional hours at
À78 8C, quenched with a saturated NH4Cl solution (15 mL),
extracted with diethyl ether (2 Â 30 mL) and dichloromethane
(30 mL). The combined organic layers were dried over MgSO4,
evaporated under reduced pressure and the resulting crude
mixture (0.47 g) was purified by flash column chromatography
as a single diastereomer.
23
(S, R)-5, yellow oil; [
a
]
À74.9 (c = 2.6, CHCl3); IR (neat):
1H NMR
= 0.70 (d, 3H, 3J = 6.2 Hz), 0.89 (t, 3H,
D
2970, 2936, 2877, 1674, 1168, 1143, 1104 cmÀ1
(250 MHz, CDCl3):
;
d
3J = 7.4 Hz), 1.33 (m, 1H), 1.61 (m, 1H), 1.87 (s, 3H), 2.27 (m,
1H), 4.00 (dd, 1H, 2J = 10.3 Hz, 3J = 8.2 Hz), 4.47 (dd, 1H,
2J = 10.3 Hz, 3J = 8.2 Hz), 5.14 (t, 1H, 3J = 8.2 Hz), 7.26–7.40 (m,
(cyclohexane/ethyl acetate: 98/2 to 95/5) to give
diastereomeric mixture of (S)-3 (0.305 g, 71%) as a yellow oil.
a
59:41
5H); 13C NMR (62.9 MHz, CDCl3):
62.3, 73.3, 94.5 (q, 2JC–F = 31.8 Hz), 124.3 (q, 1JC–F = 291 Hz), 126.0,
128.2, 129.1, 138.5, 177.0; 19F NMR (235.35 MHz, CDCl3):
(s, 3 F, CF3); EIMS, m/z (rel. int.): 315 (4), 287 (3), 246 (6), 203 (56),
188 (40), 175 (7), 162 (65), 146 (12), 120 (29), 103 (13), 85 (48), 57
(100); Anal. calcd for C16H20F3NO2: C, 60.94; H, 6.39; N, 4.44.
Found: C, 61.17; H, 6.52; N, 4.33.
d = 11.7, 16.3, 19.7, 28.0, 40.6,
(S)-3 major diast, 1H NMR (250 MHz, CDCl3):
d
= 0.74 (d, 3H,
d
À77.4
3J = 6.3 Hz), 2.08 (s, 3H), 2.00–2.20 (m, 1H), 2.55–2.75 (m, 2H), 2.85
(dd, 1H, 2J = 11.7 Hz, 3J = 9.1 Hz), 3.80–4.30 (m, 2H), 4.60 (m, 1H),
7.11–7.50 (m, 10H); 19F NMR (235.35 MHz, CDCl3):
EIMS, m/z (rel. int.): 377 (16), 362 (5), 308 (3), 265 (25), 250 (15),
d
À76.5 (s, 3 F);
162 (46), 119 (58), 91 (100).
(S)-3 minor diast, 1H NMR (250 MHz, CDCl3):
d
= 1.15 (d, 3H,
4.7. (S)-2-methyl-N-(1-phenylvinyl)-3-phenylpropanamide (S)-6
3J = 6.7 Hz), 2.13 (s, 3H), 2.00–2.20 (m, 1H), 2.41 (dd, 1H,
2J = 13.4 Hz, 3J = 7.3 Hz), 2.95 (dd, 1H, 2J = 13.4 Hz, 3J = 3.5 Hz),
3.80–4.30 (m, 2H), 5.05 (m, 1H), 7.11–7.50 (m, 10H); 19F NMR
To a solution of oxazolidine (S, R)-4 (0.14 g, 0.37 mmol) in THF
(6 mL) under argon atmosphere at 0 8C was added a solution of
NaHMDS (0.32 mL, 2 M in THF, 0.65 mmol). The reaction mixture
was stirred for 2 h at 5 8C. The reaction mixture was quenched with
a saturated NH4Cl solution (15 mL) extracted with diethyl ether
(2 Â 25 mL) and dichloromethane (25 mL). The combined organic
layers were dried over MgSO4, evaporated under reduced pressure
and the resulting crude mixture (0.14 g) was purified by flash
column chromatography (cyclohexane/ethyl acetate: 95/5) to give
unreacted (S, R)-4 (0.9 g, 62%) and (S)-6 (0.036 g, 25%). 1H NMR
(235.35 MHz, CDCl3):
(49), 362 (13), 308 (4), 265 (8), 250 (7), 162 (50), 119 (62), 91 (100).
d
À76.47 (s, 3 F); EIMS, m/z (rel. int.): 377
4.5. (2R, 4R)-2-trifluoromethyl-2-methyl-3-[(S)-2-methyl-3-
phenylpropanoyl]-4-phenyloxazolidine (S, R)-4
To a solution of oxazolidine (R)-2 (0.8 g, 2.78 mmol) in THF
(20 mL) under argon atmosphere at À78 8C was added a solution of
NaHMDS (2.65 mL, 2 M in THF, 5.3 mmol). The reaction mixture
was stirred for 2 h at this temperature and benzyl bromide
(0.63 mL, 5.29 mmol) was added. The reaction mixture was stirred
for 4 additional hours at À78 8C, quenched with a saturated NH4Cl
(250 MHz, CDCl3):
d
= 1.27 (d, 3H, 3J = 6.7 Hz), 2.58 (m, 1H), 2.75
(dd, 1H, 2J = 13.4 Hz, 3J = 5.8 Hz), 2.99 (dd, 1H, 2J = 13.4 Hz,
3J = 9.1 Hz), 5.04 (s, 1H), 5.80 (s, 1H,), 6.55 (sl, 1H), 7.03 (m, 2H),
7.22–7.27 (m, 8H).

A. Tessier et al. / Journal of Fluorine Chemistry 134 (2012) 122–127
127
(d) S.G. Davies, H.J. Sanganee, Tetrahedron: Asymmetry 6 (1995) 671–674;
(e) T. Hintermann, D. Seebach, Helv. Chim. Acta 81 (1998) 2093–2126;
(f) C.L. Gibson, K. Gillon, S. Cook, Tetrahedron Lett. 39 (1998) 6733–6736;
4.8. (S)-2-methyl-N-(1-phenylvinyl)-butanamide (S)-7
To a solution of oxazolidine (S, R)-5 (0.13 g, 0.42 mmol) in THF
(6 mL) under argon atmosphere at À78 8C was added a solution of
NaHMDS (0.40 mL, 2 M in THF, 0.79 mmol). The reaction mixture
was stirred for 2 h at 0 8C and benzyl bromide (0.095 mL,
0.79 mmol) was added at À788. The reaction mixture was stirred
for 4 additional hours at À78 to À40 8C, quenched with a saturated
NH4Cl solution (15 mL) extracted with diethyl ether (2 Â 25 mL)
and dichloromethane (25 mL). The combined organic layers were
dried over MgSO4, evaporated under reduced pressure and the
resulting crude mixture (0.61 g) was purified by flash column
chromatography (cyclohexane/ethyl acetate: 90/10) to give 0.12 g
of a 56/44 mixture of (S, R)-5 and (S)-7.
(g) C.A. De Parrodi, A. Clara-Sosa, L. Pe´rez, L. Quintero, V. Maranon, R.A. Toscano,
J.A. Avina, S. Rojas-Lima, E. Juaristi, Tetrahedron: Asymmetry 12 (2001) 69–79;
(h) C.A. De Parrodi, E. Juaristi, L. Quintero, A. Clara-Sosa, Tetrahedron: Asymmetry
8 (1997) 1075–1082;
(i) A.K. Ghosh, H. Cho, M. Onishi, Tetrahedron: Asymmetry 8 (1997) 821–824;
(j) A. Sudo, K. Saigo, Tetrahedron: Asymmetry 6 (1995) 2153–2156;
(k) K. Kimura, K. Murata, K. Otsuka, T. Ishizuka, M. Haratake, T. Kunieda, Tetra-
hedron Lett. 33 (1992) 4461–4464;
(l) H. Matsunaga, K. Kimura, T. Ishizuka, M. Haratake, T. Kunieda, Tetrahedron
Lett. 32 (1991) 7715–7718;
(m) T. Nakamura, N. Hashimoto, T. Ishizuka, T. Kunieda, Tetrahedron Lett. 38
(1997) 559–562;
(n) N. Hashimoto, T. Ishizuka, T. Kunieda, Tetrahedron Lett. 35 (1994) 721–724;
(o) M.R. Banks, A.J. Blake, J.I.G. Cadogan, I.M. Dawson, I. Gosney, K.J. Grant, G.
Suneel, P.K.G. Hodgson, K.S. Knight, G.W. Smith, Tetrahedron 48 (1992) 7979–
8006;
(p) T.-H. Yan, V.-V. Chu, T.-C. Lin, C.-H. Wu, L.-H. Liu, Tetrahedron Lett. 32 (1991)
4959–4962.
(S)-7, 1H NMR (250 MHz, CDCl3):
d
= 0.97 (t, 3H, 3J = 7.4 Hz),
1.22 (d, 3H, 3J = 7.0 Hz), 1.45 (m, 1H), 1.75 (m, 1H), 2.20 (m, 1H),
5.09 (sl, 1H), 5.91 (s, 1H), 6.85 (s, 1H), 7.28–7.36 (m, 5H).
[2] For review and examples see:
(a) D.J. Ager, I. Prakash, D.R. Schaad, Chem. Rev. 96 (1996) 835–875;
(b) G. Cardillo, A. D’Amico, M. Orena, S. Sandri, J. Org. Chem. 53 (1988) 2354–
2356;
4.9. Removal of the chiral auxiliary
(c) K. Yokoyama, T. Ishizuka, N. Ohmachi, T. Kunieda, Tetrahedron Lett. 39 (1998)
4847–4850;
(d) A. Studer, T. Hintermann, D. Seebach, Helv. Chim. Acta 78 (1995) 1185–1206;
(e) K.S. Chu, G.R. Negrete, J.P. Konopelski, F.J. Lakner, N.-T. Woo, M.M. Olmstead, J.
Am. Chem. Soc. 114 (1992) 1800–1812;
(f) S.G. Davies, D.J. Dixon, G.J.-M. Doisneau, J.C. Prodger, H.J. Sanganee, Tetrahe-
dron: Asymmetry 13 (2002) 647–658;
(g) S.G. Davies, G.J.-M. Doisneau, J.C. Prodger, H.J. Sanganee, Tetrahedron Lett. 35
(1994) 2373–2376;
(h) S.G. Davies, D.J. Dixon, Synlett (1998) 963–964;
(i) A. Abiko, O. Moriya, S.A. Filla, S. Masamune, Angew. Chem. Int. Ed. Engl. 34
(1995) 793–795;
(j) A. Abiko, J.-F. Liu, G. Wang, S. Masamune, Tetrahedron Lett. 38 (1997) 3261–
3264;
(k) S. Najdi, D. Reichlin, M.J. Kurth, J. Org. Chem. 55 (1990) 6241–6244;
(l) M. Enomoto, Y. Ito, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 26 (1984)
1343–1344;
To a solution of (S, R)-4 (297 mg, 0.79 mmol) in anhydrous
diethyl ether (7 mL) under argon at À10 8C was added LAH
(120 mg, 3.15 mmol). The mixture was stirred for 2 h at À10 8C and
was quenched by a dropwise addition of a NaCl saturated solution
(10 mL). The mixture was then vigorously stirred for 2.5 h at room
temperature. The aqueous layer was extracted with diethyl ether
(2 Â 20 mL). The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. To this resulting crude
material (310 mg) in solution in anhydrous diethyl ether was
added LAH (55 mg, 1.46 mmol). The mixture was stirred for 1.5 h at
0 8C and was quenched by a dropwise addition of a 1 N HCl solution
(5 mL). The mixture was stirred at room temperature. The aqueous
layer was extracted with diethyl ether (2 Â 10 mL). The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The crude mixture (220 mg) was purified by
silica gel chromatography (cyclohexane:ethylacetate 98/2 to 95/5)
to afford (S)-8 as a colorless oil (85 mg, 72%) and (R)-9 (97 mg,
52%).
(m) Y. Kawanami, Y. Ito, T. Kitagawa, Y. Taniguchi, T. Katsuki, M. Yamaguchi,
Tetrahedron Lett. 25 (1985) 857–860;
(n) D. Tanner, C. Birgersson, A. Gogoll, K. Luthman, Tetrahedron 50 (1994) 9797–
9824;
(o) K.-S. Jeong, K. Parris, P. Ballester, J. Rebek, Angew. Chem. Int. Ed. Engl. 29
(1990) 555–556;
(p) G.-J. Lee, T.K. Kim, J.N. Kim, U. Lee, Tetrahedron: Asymmetry 13 (2002) 9–12;
(q) R.K. Boeckman, D.J. Boehmler, R.A. Musselman, Org. Lett. 3 (2001) 3777–3780.
[3] (a) W. Oppolzer, R. Moretti, S. Thomi, Tetrahedron Lett. 30 (1989) 5603–5606;
(b) W. Oppolzer, I. Rodriguez, C. Starkemann, E. Walther, Tetrahedron Lett. 31
(1990) 5019–5022;
The characterization data of (S)-8 were in accordance with the
literature data [5,14].
(c) J. Lin, W.H. Chan, A.W.M. Lee, W.Y. Wong, Tetrahedron 55 (1999) 13983–
13998.
[4] (a) A.G. Myers, B.H. Yang, H. Chen, J.L. Gleason, J. Am. Chem. Soc. 116 (1994)
9361–9362;
4.10. (R)-2-(2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol
(R)-9
(b) A.G. Myers, B.H. Yang, H. Chen, L. McKinstry, D.J. Kopecky, J.L. Gleason, J. Am.
Chem. Soc. 119 (1997) 6496–6511;
(c) A.G. Myers, J.L. Gleason, T. Yoon, D.W. Kung, J. Am. Chem. Soc. 119 (1997)
6496–6511.
1H NMR (250 MHz, CDCl3):
d
= 1.20 (d, 3H, 3J = 6.9 Hz), 3.09
(hept, 1H, 3J = 6.9 Hz), 3.51 (dd, 1H, 2J = 10.8, 3J = 9.3 Hz), 3.73 (dd,
1H, 2J = 10.8, 3J = 4.2 Hz), 4.07 (dd, 1H, 3J = 9.3, 3J = 4.2 Hz), 7.21–
[5] A. Tessier, J. Pytkowicz, T. Brigaud, Angew. Chem. Int. Ed. 45 (2006) 3677–3681.
[6] A. Tessier, N. Lahmar, J. Pytkowicz, T. Brigaud, J. Org. Chem. 73 (2008) 3970–3973.
[7] G. Sini, A. Tessier, J. Pytkowicz, T. Brigaud, Chem. Eur. J. 14 (2008) 3363–3370.
[8] H. Lubin, A. Tessier, G. Chaume, J. Pytkowicz, T. Brigaud, Org. Lett. 12 (2010) 1496–
1499.
7.34 (m, 5H); 19F NMR (235.35 MHz, CDCl3):
3J = 6.9 Hz).
d
À76.8 (d, 3F,
Acknowledgement
[9] A. Tessier, J. Pytkowicz, T. Brigaud, J. Fluorine Chem. 130 (2009) 1140–1144.
[10] F. Huguenot, T. Brigaud, J. Org. Chem. 71 (2006) 7075–7078.
[11] A. Ishii, M. Kanai, Y. Katsuhara, in: V.A. Soloshonok (Ed.), ACS Symposium Series,
vol. 911, American Chemical Society, Washington, 2005, pp. 368–377.
[12] G. Chaume, O. Barbeau, P. Lesot, T. Brigaud, J. Org. Chem. 75 (2010) 4135–4145.
[13] (a) M.D. Groaning, A.I. Meyers, Tetrahedron 56 (2000) 9843–19843;
(b) A.G. Schultz, Chem. Commun. (1999) 1263–1271;
(c) S.B. Hoyt, L.E. Overman, Org. Lett. 2 (2000) 3241–3244;
(d) D. Enders, P. Teschner, G. Raabe, J. Runsink, Eur. J. Org. Chem. (2001) 4463–
4477;
The authors thank Central Glass Company for their financial
support and the gift of trifluoroacetone.
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