Lewis acid activation of chiral 2-trifluoromethyl-1,3-oxazolidines. Application to the stereoselective synthesis of trifluoromethylated amines, α- and β-amino acids

Article abstract of DOI:10.1016/S0040-4039(02)00330-1

The reaction of chiral 2-trifluoromethyl-1,3-oxazolidines with various silylated nucleophiles under Lewis acid activation provides a stereoselective route to functionalized α-trifluoromethylamines. This methodology was successfully applied to the diastereoselective synthesis of trifluoromethylated homoallylic and propargylic amines, trifluoromethylated α-amino nitrile, β-aminoketone and β-aminoester. The α-amino nitrile and the β-amino ester were converted into (+)-3,3,3-trifluoroalanine and (+)-4,4,4-trifluoro-3-aminobutanoic acid in a one-step procedure.

Full text of DOI:10.1016/S0040-4039(02)00330-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2827–2830
Lewis acid activation of chiral 2-trifluoromethyl-1,3-oxazolidines.
Application to the stereoselective synthesis of trifluoromethylated
amines, a- and b-amino acids
Nicolas Lebouvier, Christophe Laroche, Florent Huguenot and Thierry Brigaud*
Laboratoire ꢀRe´actions Se´lectives et Applicationsꢁ, Associe´ au CNRS (UMR 6519), Universite´ de Reims Champagne-Ardenne,
Faculte´ des Sciences, BP 1039, 51687 Reims Cedex 2, France
Received 4 February 2002; revised 14 February 2002; accepted 15 February 2002
Abstract—The reaction of chiral 2-trifluoromethyl-1,3-oxazolidines with various silylated nucleophiles under Lewis acid activation
provides a stereoselective route to functionalized a-trifluoromethylamines. This methodology was successfully applied to the
diastereoselective synthesis of trifluoromethylated homoallylic and propargylic amines, trifluoromethylated a-amino nitrile,
b-aminoketone and b-aminoester. The a-amino nitrile and the b-amino ester were converted into (+)-3,3,3-trifluoroalanine and
(+)-4,4,4-trifluoro-3-aminobutanoic acid in a one-step procedure. © 2002 Elsevier Science Ltd. All rights reserved.
Trifluoromethylated amines are important building
blocks for the synthesis of bioactive compounds
because of the unique electron withdrawing properties
of the trifluoromethyl group.1 The development of
stereoselective methods for the synthesis of a-trifl-
uoromethylated amines is then a current challenge in
organofluorine chemistry.2 Most of the existing
stereoselective methods for their synthesis use reduction
or organometallics addition to fluorinated imino- or
enamino-compounds3 or direct trifluoromethylation of
a chiral sulfinylimine.4 A stereoselective approach
developed by Mikami et al. consists of lithium alu-
minum hydride reduction or organometallics reactions
with (R)-phenylglycinol and fluoral derived oxazolidi-
nes and hemiacetals.5 To achieve good yields and high
stereoselectivity this method requires the separation of
both oxazolidines diastereomer or the use of a large
excess of organometallic reagent for the reaction on the
hemiacetals. As a limitation, this reaction was only
described for phenyl, benzyl and methyl group intro-
duction. In order to investigate new potentialities of the
use of 2-trifluoromethyl-1,3-oxazolidines toward the
synthesis of enantiopure trifluoromethylamino com-
pounds, we undertook the study of their Lewis acid-
mediated reactions with silylated nucleophiles. This
methodology will provide a stereoselective strategy for
the introduction of various functionalized side chains.
Although several examples of nucleophilic addition to
trifluoromethyl-iminium ions and related reactions are
described in the literature,6 to our knowledge, no exam-
ple is reported with silylated nucleophiles in the asym-
metric series.
Chiral 2-trifluoromethyl-oxazolidines 1a,b were readily
prepared in high yield following the literature
procedure5a starting from (R)-(−)-phenylglycinol
(Scheme 1).
H
Ph
N
a
(R)-(-)-phenylglycinol
F3C
91%
O
1a (2S) + 1b (2R)
62 : 38
Scheme 1. Synthesis of 2-trifluoromethyl-1,3-oxazolidines. (a)
Trifluoroacetaldehyde ethylhemiacetal, PPTS 0.1 equiv., tolu-
ene, Dean Stark distillation.
The use of (R)-(−)-phenylglycinol as a chiral auxiliary
in the Strecker synthesis constitutes a highly stereoselec-
tive access to a-amino acids.7 Because of the great
interest of fluorine-containing amino acids,8 we carried
out the reaction of 1a,b with trimethylsilyl cyanide
promoted by Lewis acids (Table 1). The aminonitriles
2a,b were obtained in high yield with BF3·OEt2 (1.5
equiv.) or with a catalytic amount of TMSOTf as a
diastereomeric mixture. The major diastereomer 2a9
Keywords: fluorine; oxazolidines; iminium; asymmetric synthesis;
amino acids.
* Corresponding author. Tel.: (+33) 326 91 31 64; fax: (+33) 326 91 31
66; e-mail: thierry.brigaud@univ-reims.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00330-1

2828
N. Lebou6ier et al. / Tetrahedron Letters 43 (2002) 2827–2830
Table 1. Strecker reactions
and ion-exchange resin purification (Scheme 2). (R)-(+)-
3,3,3-Trifluoroalanine 3 was obtained in 70% overall
yield from 2a and 65% ee ([h]2D0 +10.0 (c 0.76, MeOH)
lit. data10a +15.4 (c 0.76, MeOH)). Although partial
racemization occurred during the purification process
on H+ resin with 7% NH3 elution,11 we can assume that
the configuration of 2a is (R,R).
(a) TMSCN (1.5 equiv.), Lewis acid, −78°C to rt, 12 h.
Entry
1a:1b
Lewis acid
Yield (%)a
2a:2bb
Ph
Ph
H
OH
1
2
3
62:38
87:13
20:80
BF3·OEt2 (1.5 equiv.)
TMSOTf (0.1 equiv.)
TMSOTf (0.1 equiv.)
91
87
84
83:17
81:19
83:17
N
N
a
F3C
CN
F3C
CN
2a
a Isolated yields.
b Determined by 19F NMR integration of the CF3 signals of each
diastereomer in the crude mixture. Both isomers can be separate by
silica gel chromatography.
NH2
b
F3C
CO2H
(R)-3 (70%)c
was separated by flash column chromatography. An
interesting feature of this reaction is that the same
diastereomeric ratio (2a:2b 83:17) was achieved irre-
spective of the starting oxazolidines 1a:1b mixture
(Table 1, entries 2 and 3). The major outcome of this
observation is that the reaction can be performed from
the diastereomeric mixture of oxazolidines avoiding a
separation step.
Scheme 2. Synthesis of (R)-(+)-3,3,3-trifluoroalanine. (a)
Pb(OAc)4, CH2Cl2:MeOH (2:1). (b) HCl conc., reflux, 4 h, H+
resin. (c) Overall yield from 2a.
The BF3·OEt2-promoted reaction of the diastereomeric
mixture of oxazolidines 1a,b was then extended to
various silylated nucleophiles (Scheme 3).12 The reac-
tions with allyltrimethylsilane, bis-trimethylsilyl-
acetylene, an enoxysilane and a ketene silyl acetal
proceeded in good yields. Bis-trimethylsilylacetylene
proved to be the less reactive and 4 days reflux in
CH2Cl2 were necessary to ensure a good transformation
of 1a,b. The control of the stereoselectivity increases
from bis-trimethylsilyl-acetylene (54:46), allyltrimethyl-
silane (70:30), ketene silyl acetal (84:16) to become
almost complete for the enoxysilane.13 This high
stereoselectivity may be attributed to a Lewis acid
coordination of the oxygen atom of the enoxysilane. It
should be noticed that in contrast to related reactions6d
no elimination of the amino group occurred. As for the
Strecker-type reaction, the configurations of the major
4a, 6a and 7a diastereomers are assumed to be (R,R)
resulting from the addition on the less hindered re face
of the iminium. This was confirmed for 7a giving
(R)-(+)-3-amino-4,4,4-trifluorobutanoic acid 814 in 90%
yield after removal of the chiral auxiliary and hydroly-
sis of the ester function in a one-pot procedure.
These results strongly suggest the formation of an
iminium as a key intermediate; the nucleophilic attack
taking place at the less hindered re face. The (R,R)
configuration of the major diastereomer 2a was first
assigned by comparison with literature NMR data7c in
the non-fluorinated series relating a strong shielding
effect of H-2 by the phenyl moiety in the major 2a
(R,R) isomer (Fig. 1).
Additional evidence of the (R,R) configuration of the
major diastereomer was obtained by converting 2a into
an enantioenriched sample of (R)-(+)-3,3,3-trifluoroala-
nine and comparison of its optical rotation with litera-
ture data.10 The removal of the chiral auxiliary and
hydrolysis of the nitrile function of pure 2a was effected
using lead tetraacetate followed by HCl conc. treatment
3.90 ppm
NC
H
Ph
CF3
F3C
H
OH
-
OBF3
HN
H
Further studies on the stereoselective synthesis of bioac-
tive a-trifluoromethyl amino compounds are now in
progress.
H
2a (R,R) major
re face attack
+
CN
Ph
CF3
OH
4.35 ppm
H
Acknowledgements
HN
H
2b (S,R) minor
The authors thank Professor Charles Portella for his
support, H. Bailla and S. Lanthony for their technical
assistance in the analytical aspects.
Figure 1.

N. Lebou6ier et al. / Tetrahedron Letters 43 (2002) 2827–2830
Ph
2829
Ph
H
OH
H
OH
Si
N
N
b
a
1a,b
F3C
F3C
63%
90%
4a (R,R) : 4b (R,S)
70 : 30f,g
5a : 5b
54 : 46f
73%
c
66%
d
Ph
Ph
H
N
OH
NH2
H
OH
N
CO2H
e
COPh
F3C
CO2Et
F3C
6a (R,R) (92%<de)f
90%h
F3C
(R)-(+)-3-amino-4,4,4-
trifluorobutanoic acid 8
7a (R,R) :7b (R,S)
84 : 16f,g
Scheme 3. Reactions of 1a,b with various silylated nucleophiles. (a) AllylTMS, CH2Cl2, BF3·OEt2. (b) Bis-trimethylsilyl-acetylene,
CH2Cl2, BF3·OEt2, reflux 4 days. (c) H2CꢀC(OTMS)Ph, CH2Cl2, BF3·OEt2. (d) H2CꢀC(OTMS)OEt, CH3CH2CN, BF3·OEt2, 1 h
30 min reflux. (e) Pb(OAc)4, CH2Cl2:MeOH (2:1) then HCl conc., reflux, 4 h, H+ resin. (f) Determined by 19F NMR integration
of the CF3 signals of each diastereomer in the crude mixture. (g) A pure fraction of both isomers was obtained after silica gel
chromatography separation. (h) Overall yield from a pure sample of 7a.
T. Org. Lett. 2000, 2, 1577–1579; (f) Blond, G.; Billard,
T.; Langlois, B. R. J. Org. Chem. 2001, 66, 4826–4830;
(g) Billard, T.; Langlois, B. R. J. Org. Chem. 2002, 67,
997–1000. For related reactions, see: (h) Crousse, B.;
Narizuka, S.; Bonnet-Delpon, D.; Be´gue´, J.-P. Synlett
2001, 679–681; (i) Crousse, B.; Be´gue´, J.-P.; Bonnet-Del-
pon, D. J. Org. Chem. 2000, 5009–5013; (j) Abouabdel-
lah, A.; Be´gue´, J.-P.; Bonnet-Delpon, D.; Nga, T. T. T. J.
Org. Chem. 1997, 62, 8826–8833; (k) Gong, Y.; Kato, K.;
Kimoto, H. Synlett 2000, 1058–1060.
References
1. Biomedical Frontiers of Fluorine Chemistry; Ojima, I.;
McCarthy, J. R.; Welch, J. T., Eds.; American Chemical
Society: Washington, DC, 1996.
2. (a) Enantiocontrolled Synthesis of Fluoro-organic Com-
pounds; Soloshonok, V. A., Ed.; Wiley: Chichester, 1999;
(b) Asymmetric Fluoroorganic Chemistry: Synthesis,
Applications, and Future Directions; Ramachandran, P.
V., Ed.; American Chemical Society: Washington, DC,
1999.
3. (a) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42,
2436–2439; (b) Wang, Y.; Mosher, H. S. Tetrahedron
Lett. 1991, 32, 987–990; (c) Abe, H.; Amii, H.; Uneyama,
K. Org. Lett. 2001, 3, 313–315; (d) Sakai, T.; Yan, F.;
Kashino, S.; Uneyama, K. Tetrahedron 1996, 52, 233–
244; (e) Enders, D.; Funabiki, K. Org. Lett. 2001, 3,
1575–1577; (f) Soloshonok, V. A.; Avilov, D. V.; Kukhar,
V. P.; Van Meervelt, L.; Mischenko, N. Tetrahedron Lett.
1997, 38, 4671–4674; (g) For a review on [1.3]-proton
shift, see: Soloshonok, V. A. in Ref. 2b, p. 74; (h) For a
review on the use of the sulfinyl chiral auxiliary, see:
Bravo, P.; Zanda, M. in Ref. 2a, p. 107. Bravo, P.;
Bruche, L.; Crucianelli, M.; Zanda, M. in Ref. 2b, p. 98.
4. (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org.
Lett. 2001, 3, 2847–2850; (b) Prakash, G. K. S.; Mandal,
M.; Olah, G. A. Angew. Chem., Int. Ed. Engl. 2001, 40,
589–590.
5. (a) Higashiyama, K.; Ishii, A.; Mikami, K. Synlett 1997,
1381–1382; (b) Higashiyama, K.; Ishii, A.; Miyamoto, F.;
Mikami, K. Tetrahedron Lett. 1998, 39, 1199–1202; (c)
Higashiyama, K.; Ishii, A.; Miyamoto, F.; Mikami, K.
Chem. Lett. 1998, 119–120.
6. (a) Fuchigami, T.; Ichikawa, S.; Konno, A. Chem. Lett.
1989, 1987–1989; (b) Fuchigami, T.; Nakagawa, Y.; Non-
aka, T. J. Org. Chem. 1987, 52, 5489–5491; (c)
Fuchigami, T.; Ichikawa, S. J. Org. Chem. 1994, 59,
607–615; (d) Xu, Y.; Dolbier, W. R. J. Org. Chem. 2000,
65, 2134–2137; (e) Takaya, J.; Kagoshima, H.; Akiyama,
7. (a) Inaba, T.; Kozono, I.; Fujita, M.; Ogura, K. Bull.
Chem. Soc. Jpn. 1992, 65, 2359–2365; (b) Chakraborty, T.
K.; Reddy, G. V.; Hussain, K. A. Tetrahedron Lett. 1991,
32, 7597–7600; (c) Chakraborty, T. K.; Hussain, K. A.;
Reddy, G. V. Tetrahedron 1995, 51, 9179–9190; (d) Dave,
R. H.; Hosangadi, B. D. Tetrahedron 1999, 55, 11295–
11308.
8. Fluorine-containing Amino Acids, Synthesis and Proper-
ties; Kukhar’, V. P.; Soloshonok, V A., Eds.; Wiley:
Chichester, 1995.
9. Data for 2a. Colorless liquid; [h]2D0 +203 (c 0.76, CHCl3);
3
1H NMR l 2.06 (s, 1H), 2.87 (d, JHH=13.4, 1H), 3.65
(dd, 2JHH=10.7, 3JHH=9.5, 1H), 3.82 (dd, 2JHH=10.7,
3JHH=3.8, 1H), 3.90 (dq, 3JHH=13.4, 3JHF=6.7, 1H),
3
3
4.13 (dd, JHH=9.5, JHH=3.8, 1H), 7.18–7.41 (5H); 19F
NMR l −74.2 (d, 3JHF=6.7); 13C NMR l 50.9 (q,
2JCF=34.5), 62.5, 66.9, 113.4, 121.6 (q, 1JCF=281.3),
126.8 (2C), 127.5 (2C), 129.2, 136.3; IR (neat) 3338, 3020,
2934, 1216, 1150; MS m/z 245 (M+1, 49), 227 (5), 218
(65), 213 (100). Anal. calcd for C11H11N2OF3: C, 54.10;
H, 4.54; N, 11.47. Found: C, 54.23; H, 4.52; N, 11.13%.
10. Enantiopure (R)-(+)-3,3,3-trifluoroalanine: (a) Arnone,
A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S. V.;
Zanda, M.; Caviccho, G.; Crucianelli, M. J. Org. Chem.
1996, 61, 3375–3387. Corrigenda: J. Org. Chem. 1996, 61,
9635. Enantioenriched 3,3,3-trifluoroalanine: (b) Sakai,
T.; Yani, F.; Uneyama, K. Synlett 1995, 753–754; (c)
Sakai, T.; Yani, F.; Kashino, S.; Uneyama, K. Tetra-
hedron 1996, 52, 233–244; (d) Crucianelli, M.; Battista,

2830
N. Lebou6ier et al. / Tetrahedron Letters 43 (2002) 2827–2830
1
2
N.; Bravo, P.; Volonterio, A.; Zanda, M. Molecules 2000,
CHCl3); H NMR l 1.78 (m, 2H), 3.24 (dd, JHH=12.5,
2
2
8
5, 1251–1258; (e) Ayhan, S. ; Demir, A. S.; Ozge, S.;
3JHH=2, 1H), 3.33 (d, JHH=12.5, 1H), 3.58 (dd, JHH
=
Zuhal, G.-A. Tetrahedron: Asymmetry 2001, 2309–2313.
11.3, 3JHH=7.9, 1H), 3.79 (dd, 2JHH=11.3, 3JHH=3.8,
3
3
3
11. 3,3,3-Trifluoroalanine is poorly stable at pH >6. Its par-
tial racemization had already been reported by Zanda et
al., see Ref. 10d.
1H), 4.04 (qd, JHF=7.2, JHH=2, 1H), 4.07 (dd, JHH=
2
3
7.9, JHH=3.8, 1H), 7.23–7.27 (5H), 7.49 (dd, JHH=7.3,
3JHH=5.2, 2H), 7.62 (tt, JHH=5.2, JHH=1.2, 1H), 7.95
3
4
(dt, 3JHH=7.3, 4JHH=1.2, 2H); 19F NMR l −74.9 (d,
1
12. Data for 4a: Colorless liquid; H NMR l 2.29–2.48 (m,
3JHF=7.2); 13C NMR l 38.6, 54.0 (q, JCF=28.6), 62.4,
2
4H), 3.00 (qdd, 3JHF=7.6, 3JHH=3.8, 3JHH=1.5, 1H),
67.0, 126.5 (q, 1JCF=274.7), 127.3, 127.7, 128.2, 128.6,
128.8, 133.9, 136.2, 140.4, 196.9; IR (neat) 3349, 3030,
2928, 1686, 1266; MS m/z 338 (M+1, 44), 320 (13), 306
(69), 186 (100). Anal. calcd for C18H18NO2F3: C, 64.09;
H, 5.38; N, 4.15. Found: C, 64.13; H, 5.59; N, 3.90%.
Compound 7a: Colorless liquid; [h]2D0 −16 (c 0.76,
CHCl3); 1H NMR l 1.27 (t, 3JHH=7.3, 3H), 2.53 (dd,
2JHH=16.2, 3JHH=8.4, 1H), 2.73 (dd, 2JHH=16.2,
3JHH=4.4, 1H), 3.57 (dd, 2JHH=11.0, 3JHH=8.2, 1H),
3
2
3.55 (m, 1H), 3.67 (dd, JHH=7.3, JHH=4.2, 1H), 4.01
(dd, 3JHH=8.0, 2JHH=4.2, 1H), 5.11 (dd, 3JHH=16.3,
2JHH=1.5, 1H), 5.13 (dq, 3JHH=9.1, 2JHH=4JHH=1.5,
1H), 5.52 (ddt, 3JHH=16.3, 3JHH=9.1, 3JHH=2.3, 1H),
7.23–7.27 (5H); 19F NMR l −74.8 (d, 3JHF=7.6); 13C
NMR l 33.9, 55.6 (q, 2JCF=27.6), 63.3, 67.0, 119.5, 128.0
(2C), 128.1 (2C), 128.2 (q, 1JCF=282.6), 128.7, 132.9,
139.5; IR (neat) 3355, 3084, 2930, 2875, 1264; MS m/z
260 (M+1, 35), 242 (9), 228 (86), 131 (100). Anal. calcd
for C13H15NOF3: C, 60.22; H, 6.22; N, 5.40. Found: C,
60.08; H, 6.23; N, 5.02%. Compound 5a: Colorless liquid;
1H NMR l 0.13 (s, 9H), 2.00–2.40 (m, 2H), 3.62 (dd,
2JHH=10.9, 3JHH=7.6, 1H), 3.76 (dd, 2JHH=10.9,
2
3
3.70 (m, 1H), 3.72 (dd, JHH=11.0, JHH=3.4, 1H), 4.00
3
3
3
(dd, JHH=8.2, JHH=3.4, 1H), 4.18 (q, JHH=7.3, 2H),
7.20–7.40 (5H); 19F NMR l −75.5 (d, 3JHF=8.1); 13C
2
NMR l 13.9, 34.5, 54.7 (q, JCF=28.5), 61.3, 62.3, 67.1,
125.9 (q, JCF=283.5), 127.3, 127.8, 128.5, 140.0, 170.9;
IR (neat) 3345, 3064, 2984, 1735, 1268; MS m/z 306
(M+), 274, 259, 104 (100). Anal. calcd for C14H18NO3F3:
C, 55.08; H, 5.94; N, 4.59. Found: C, 55.08; H, 5.89; N,
4.48%.
1
3
3
3JHH=4.4, 1H), 3.92 (q, JHF=6.5, 1H), 4.01 (dd, JHH
7.6, 3JHH=4.4, 1H), 7.31–7.41 (m, 5H); 19F NMR l
−75.3 (d, 3JHF=6.5); 13C NMR
−0.48, 51.8 (q,
=
l
2JCF=32.5), 63.4, 66.4, 91.8, 97.4, 123.8 (q, JCF=281.5),
127.3, 127.8, 128.8, 139.4; IR (neat) 3334, 3031, 2961,
2182, 1253, 1138; MS m/z 316 (M+1, 7), 284 (100), 214
(5), 121 (71). Anal. calcd for C15H20NOF3Si: C, 57.12; H,
6.39; N, 4.44. Found: C, 56.95; H, 6.03; N, 4.14%.
Compound 6a: Colorless liquid; [h]2D0 −27 (c 1.12,
1
13. The other diastereomer could not be discriminated from
other minor side products in the crude mixture.
14. Soloshonok, V. A.; Ono, T.; Soloshonok, I. V. J. Org.
Chem. 1997, 62, 7538–7539.