An asymmetric synthesis of both enantiomers of 2,2,2-trifluoro-1-furan-2-yl-ethylamine and 3,3,3-trifluoroalanine from 2,2,2-trifluoro-1-furan-2-yl-ethanone

Article abstract of DOI:10.1016/S0957-4166(01)00410-4

The selective conversion of 2,2,2-trifluoro-1-furan-2-yl-ethanone into (E)- and (Z)-oximes and oxime ethers and subsequent oxazaborolidine-catalyzed enantioselective reduction using different amino alcohols furnished both enantiomers of the important chir

Full text of DOI:10.1016/S0957-4166(01)00410-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2309–2313
An asymmetric synthesis of both enantiomers of
2,2,2-trifluoro-1-furan-2-yl-ethylamine and 3,3,3-trifluoroalanine
from 2,2,2-trifluoro-1-furan-2-yl-ethanone
8
Ayhan S. Demir,* Ozge Sesenoglu and Zuhal Gerc¸ek-Arkin
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 30 July 2001; accepted 18 September 2001
Abstract—The selective conversion of 2,2,2-trifluoro-1-furan-2-yl-ethanone into (E)- and (Z)-oximes and oxime ethers and
subsequent oxazaborolidine-catalyzed enantioselective reduction using different amino alcohols furnished both enantiomers of the
important chiral building block 2,2,2-trifluoro-1-furan-2-yl-ethylamine with e.e. of up to 88%. Oxidation of the furan ring afforded
both enantiomers of 3,3,3-trifluoroalanine in 91–93% yields. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
As we reported earlier, furyl alkyl ketones can be used
as starting materials for the enantioselective synthesis
of both enantiomers of a-amino acids. Oxime ether
formation and oxazaborolidine-catalyzed enantioselec-
tive reduction followed by oxidation of the furan ring
furnished the a-amino acids in good yields and high
enantiomeric purities (Scheme 1).5
The polyhalogenated alanine analogue 3,3,3-trifluoro-
alanine is known to be a potent inhibitor of PLP-con-
taining enzymes.1 Several methods have been published
for the synthesis of 3,3,3-trifluoroalanine and its deriva-
tives but few examples have been reported for the
asymmetric synthesis of these compounds.2 Uneyama
described the synthesis of enantiomerically enriched
3,3,3-trifluoroalanine (up to 62% e.e.) by the asym-
metric reduction of 2-(N-arylimino)-3,3,3-trifluoro-
propanoic acid esters with a chiral oxazaborolidine
catalyst followed by oxidative removal of the N-aro-
matic moiety with retention of configuration.3 The
asymmetric reduction of imino esters using (S)-reduc-
tants afforded the (S)-configured amino esters together
with the (R)-configured amino alcohol. It was found
that the use of the oxazaborolidine in combination with
catecholborane completely suppressed the formation of
amino alcohol and the amino ester was obtained in 63%
e.e. Bravo et al. have developed several synthetic routes
using chiral sulfoxides as stereocontrolling elements for
the synthesis of fluorinated alanines. Forming the chiral
fluoroalkyl(sulfinyl)methyl imines and then reducing
these compounds stereoselectively gave the correspond-
ing amines with diastereomeric ratios (d.r.) of up to
93:7. The amines were then transformed into fluoroala-
nines in good yield.4
In connection with our reported preliminary results, we
describe herein the enantioselective synthesis of 2,2,2-
trifluoro-1-furan-2-yl-ethylamine and 3,3,3-trifluoroala-
nine starting from 2,2,2-trifluoro-1-furan-2-yl-ethanone.
2. Results and discussion
2,2,2-Trifluoro-1-furan-2-yl-ethanone 1 was synthesized
using the literature procedure.6 As illustrated in Scheme
2, the ketone 1 was converted to oxime 2 using
H2NOH.HCl/NaOAc in EtOH. Oxime 2 was obtained
in 92% yield as a mixture of diastereomers ((E)/(Z)
ratio: 28:72) (mp 104–106°C). The chromatographic
separation of isomers gave pure (E)-isomer (mp 100–
102°C, 24%) and (Z)-isomer (mp 110–111°C, 70%) as
colorless solids which had intense fresh bread-like odor.
The reaction of 2 ((E)/(Z) mixture) with hydrogen
NH2
NH2
O
OH
O
O
R
*
R
*
R
O
* Corresponding author. E-mail: asdemir@metu.edu.tr
Scheme 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00410-4

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A. S. Demir et al. / Tetrahedron: Asymmetry 12 (2001) 2309–2313
this conversion. The O-benzyl oximes were purified by
O
O
O
flash column chromatography and isolated as viscous
oils. Compounds 3 were also synthesized from ketones
and O-benzyl hydroxylamine hydrochloride. This pro-
cedure gave a mixture of isomers which were separated
by flash column chromatography to afford the (E)- and
(Z)-oxime ethers in 28 and 36% yields, respectively.
CF3
1
a
OH
OH
HO
O
N
N
N
b
b
O
CF3
CF3
CF3
(Z)-2
(E)-2
2
Oxime ethers are a class of readily available compounds
for the conversion of carbonyl groups to amines. One
of the most important works in this area was reported
by Itsuno et al.7 who showed that acetophenone oxime
ethers can be converted into amines with high e.e.s
using BH3–oxazaborolidine complexes. The enantiose-
lective reduction of (Z)-3 and (E)-3 was carried out
with BH3 in the presence of oxazaborolidine complexes8
prepared from different chiral amino alcohols using the
following procedure: A solution of borane (20 mmol) in
THF (20 mL) was added under argon dropwise to a
solution of (−)-(1R,2S)-norephedrine (10 mmol) in
THF (10 mL) at −20°C. The resulting mixture was
allowed to warm to −5°C and stirred at this tempera-
ture for 16 h before the oxime ether (Z)-3 (8 mmol) in
THF (10 mL) was added dropwise. The resulting solu-
tion was stirred at 30°C for 48 h (monitored by TLC)
and was decomposed by slow addition of 2 M aqueous
HCl. The product amine (S)-4 was obtained in 80%
yield and 76% e.e. after purification of the crude
product by bulb-to-bulb distillation and converted to
its hydrochloride salt using methanolic hydrogen chlo-
ride. Under similar conditions using the (E)-oxime
ether, (E)-3 furnished amine (R)-4 in 74% yield and
73% e.e. Different amino alcohols were used in the
reduction reaction and as shown in Table 1 the (R)-
and (S)-amine are obtained in 73–80% yields and 73–
88% e.e. The highest e.e. was found with amino alcohol
8.
d
d
c
BnO
O
OBn
N
N
NH2
CF3
g
O
O
CF3
(E)-3
CF3
(Z)-3
+
(_)-
4
e
e
NH2
NH2
O
NH2
CF3
NH2
CF3
f
f
O
O
OH
HO
F3C
F3C
O
(S)-4
(S)-5
(R)-4
(R)-5
Scheme 2. (a) H2NOHHCl, NaOAc, EtOH; (b) separation;
(c) HCl(g), MeOH; (d) NaH, BnBr, DMF; (e) BH3·THF, cat.;
(f) O3, MeOH, −78°C.
chloride in ether furnished oxime 2 with an (E)/(Z)
ratio of 4:1, which was purified by recrystallization. The
1
(E)- and (Z)-isomers were identified by their H and
13C NMR spectra (the (Z)-isomer displays a multiplet
for the C(3) proton of the furan ring at 6.84 ppm and
the (E)-isomer displays the multiplet for the same pro-
ton at 7.58 ppm. Additionally, the 13C NMR shift for
carbon C(3) of the (Z)-isomer is 114.9 ppm, whereas
for the (E)-isomer the shift is 121.4 ppm). The purity of
the ((E)- and (Z)-isomers was confirmed by glc analysis
of the corresponding O-benzyl ether derivatives of the
oximes.
The best enantiomeric purity was obtained when the
ratio of borane:amino alcohol:oxime ether was ca.
2.5:1.25:1.0. An excess of borane relative to the amino
alcohol led to product with low enantiomeric purities.
The oximes were converted to the O-benzyl oximes
(E)-3 and (Z)-3 using NaH and benzyl bromide in
94–96% yields. No isomerization was observed during
Table 1. Enantioselective synthesis of (S)-4 and (R)-4 using different amino alcohols

A. S. Demir et al. / Tetrahedron: Asymmetry 12 (2001) 2309–2313
2311
The amines were characterized by NMR and IR. The
enantiomeric purity of the products was determined via
preparation of the Mosher amide and analysis by 19F
NMR, or via analysis of the N-acetyl derivative by
HPLC on a chiral stationary phase column compared
to racemic product, which was synthesized from (Z)-3
using BH3·SMe2. The absolute configuration of (S)-4
and (R)-4 was found by comparison of the specific
rotation values with known data.9 The amino alcohols
used for the preparation of the oxazaborolidines were
recovered in 93–95% yields during the work up proce-
dure as their HCl salts.
(70 mL) and stirred under reflux for 12 h. The reaction
was monitored by TLC. After 12 h the hot solution was
filtered and ethanol was evaporated. The remaining
solid was dissolved in water and extracted with diethyl
ether. The ether layer was washed with water and brine
and dried over anhydrous MgSO4. Evaporation of the
solvent afforded 8.2 g (92%) of 2 as an isomeric mix-
ture. Mp 104–106°C. IR(KBr): 3650, 2980–2990, 1550
1
cm−1. H NMR (CDCl3): l ppm 6.50–6.71 (m, E- and
Z-oxime of C-4 H, furan), 6.80–7.61 (m, Z-oxime C-3
H, furan), 7.5–7.6 (m, Z- and E-oxime C-5 H and
E-oxime C-3 H, furan).
The reduction of oxime ether (Z)-3 under similar condi-
tion with catalytic amount of oxazaborolidine com-
plexes prepared with amino alcohol (S)-8 (0.1–0.2
equiv.) afforded products with e.e. of 15–22%.
Purification of 8.0 g of the crude product by flash
column chromatography (flash silica, EtOAc/n-hexane,
1:4) gave (Z)-2 (5.60 g, 70%) as a colorless solid, mp
110–111°C, 1H NMR (CDCl3): l 6.49 (m, 1H), 6.84 (m,
1H), 7.54 (m, 1H), 10.54 (br.s, 1H). 13C NMR (CDCl3):
l 112.2, 114.9 118.3 (q, J=280 Hz), 138.6 (q, J=32
Hz), 143.7, 145.4. Anal. calcd for C6H4F3NO2 (179.1):
C, 40.24; H, 2.25; N, 7.82. Found: C, 40.39; H, 2.38; N,
7.68%. The purification also afforded (E)-2 (1.92 g,
24%) as the minor product, colorless solid, mp 100–
The effect of the O-protecting group on the reduction
of oxime ethers 3 was investigated. The reduction was
carried out on a (Z)-O-methyl oxime and determina-
tion of the e.e.s of the product amines showed low
selectivity (32% e.e.). As shown in Scheme 2, the amines
(S)- and (R)-4 are converted into 3,3,3-trifluoroalanine
by oxidation of the furan ring with ozone in 91–93%
yields.
1
102°C, H NMR (CDCl3): l 6.59 (m, 1H), 7.55 (m,
1H), 7.58(m, 1H), 9.74 (br. S, 1H). 13C NMR (CDCl3):
l 112.5, 120.5 (q, J=273 Hz), 121.4, 137.9 (q, J=33
Hz), 140.7, 144.5. Anal. calcd for C6H4F3NO2 (179.1):
C, 40.24; H, 2.25; N, 7.82. Found: C, 40.44; H, 2.47; N,
7.61%.
3. Conclusion
2,2,2-Trifluoro-1-furan-2-yl-ethanone 1 was converted
into its (E)- and (Z)-oxime selectively in good yield and
oxazaborolidine-catalyzed enantioselective reduction of
the corresponding O-benzyl oxime ethers afforded both
enantiomers of 2,2,2-trifluro-1-furan-2-yl-ethylamine in
good yield with e.e. of up to 88%. Both enantiomers of
3,3,3-trifluoroalanine were then obtained in high yield
by oxidation of the furan ring with ozone. The chirality
of the amine products is controlled by appropriate
choice of geometrical isomer of the O-benzyloxime.
4.3. Isomerization of oxime
Oxime 2 (1.79 g, 10 mmol) ((E)/(Z) mixture) was
suspended in dry ether (50 mL) and HCl gas was
bubbled through the solution at 0°C The reaction was
monitored by TLC. Initially a clear solution was seen
and then a white precipitate formed. Evaporation of
solvent gave oxime 2 with an (E)/(Z) ratio of 4:1.
Separation of the isomers by flash column chromatog-
raphy (silica gel, EtOAc/hexane 1:4) furnished E-2
(1.33 g) and Z-2 (0.32 g).
4. Experimental
4.4. 2,2,2-Trifluoro-1-furan-2-yl-ethanone-O-benzyl
oxime 3
4.1. General methods
To a suspension of NaH (mineral oil removed by
washing with hexane, 35 mmol) in DMF (100 mL)
under argon atmosphere at 0°C was slowly added
oxime 2 (25 mmol) over 30 min. Benzyl bromide (26
mmol) was added and the mixture stirred for 10 h at rt
(the reaction was monitored by TLC). After addition of
water (50 mL) the mixture was extracted with ethyl
acetate. The organic layer was washed with water and
brine and dried over MgSO4. The crude product was
purified by flash column chromatography (flash silica,
EtOAc/n-hexane, 1:4).
NMR spectra were recorded on a Bruker DPX 400.
Column chromatography was conducted on silica gel
60 (mesh size 40–63 mm). Enantiomeric excesses were
determined by HPLC analysis using a Thermo Quest
(TSP) GC–LC–MS equipped with an appropriate opti-
cally active column, as described in the footnotes of the
corresponding Tables. Optical rotations were measured
with Bellingham & Stanley P20 polarimeter or with
Perkin–Elmer 241 polarimeter. Elemental analyses were
performed at the Middle East Technical University
Analysis Center.
4.5. (Z)-2,2,2-Trifluoro-1-furan-2-yl-ethanone-O-benzyl
oxime (Z)-3
4.2. 2,2,2-Trifluoro-1-furan-2-yl-ethanone oxime 2
2,2,2-Trifluoro-1-furan-2-yl-ethanone
mmol), NH2OH·HCl (4.16 g, 60 mmol) and CH3CO2-
1
(8.20 g, 50
Yellow oil, (6.07 g, 96%), IR (neat): 3010–2820, 1590
1
cm−1, H NMR(CDCl3): l 5.41 (s, 2H, benzyl CH2),
Na (4.92 g, 60 mmol) were mixed in absolute ethanol
6.45 (dd, 1H, C-4 H, furan, J=1.5 Hz and 3 Hz), 6.75

2312
A. S. Demir et al. / Tetrahedron: Asymmetry 12 (2001) 2309–2313
(dd, 1H, C-3 H, furan, J=0.7 Hz and 2.6 Hz), 7.21–
7.42 (m, 5H, phenyl), 7.50–7.61 (m, 1H, C-5 H furan).
Anal. calcd for C13H10F3NO2 (269.07): C, 58.00; H,
3.74; N, 5.20. Found: C, 58.23; H, 3.97; N, 5.11%.
(R)-enantiomer with 86% e.e., (lit.4b [h]D20=+15.4 (c
0.78, MeOH) for (R)-enantiomer with >99% e.e.; lit.3
[h]2D0=+6.8 (c 0.76, MeOH) for (R)-enantiomer with
1
62% e.e.), H NMR (400 MHz, D2O): 4.34 (q, J=10
Hz, 1H) data of the products are in agreement with the
published data.3,4b
4.6. (E)-2,2,2-Trifluoro-1-furan-2-yl-ethanone-O-benzyl
oxime (E)-3
4.12. Synthesis of ( )-2,2,2-trifluoro-1-furan-2-yl-ethyl-
amine ( )-4
Yellow oil, (5.94 g, 94%), IR (neat): 3010–2800, 1590
1
cm−1, H NMR (CDCl3): l ppm 5.40 (s, 2H, benzyl
To a solution of (Z)-3 (1.35 g, 5 mmol) in abs. THF (25
mL) was added BH3·SMe2 (12 mmol) drop wise during
1 h. Then the mixture was stirred for 36 h at rt and
hydrolyzed with 2N aqueous HCl and extracted with
ether. The water layer was separated basified with
ammonium hydroxide solution and extracted with
ether. The organic layer was separated, washed with
water and dried over anhydrous MgSO4. The crude
product was purified by bulb-to-bulb distillation to
afford the product ( )-4 (0.73 g, 88%).
CH2), 6.45 (dd, 1H, C-4 H, furan, J=1.5 Hz and 3 Hz),
7.31–7.52 (m, 7H, C-3, C-5 H furan, phenyl H). Anal.
calcd for C13H10F3NO2 (269.07): C, 58.00; H, 3.74; N,
5.20. Found: C, 58.16; H, 3.86; N, 5.31%.
4.7. 2,2,2-Trifluoro-1-furan-2-yl-ethylamine 4
A solution of borane (20 mmol) in THF (20 mL) was
added under argon dropwise to a solution of amine (10
mmol) in THF (10 mL) at −20°C. The resulting mixture
was allowed to warm to −5°C and stirring continued at
this temperature for 16 h. A solution of the oxime ether
(8 mmol) in THF (10 mL) was added dropwise. The
resulting solution was stirred at 30°C for 48 h (moni-
tored by TLC) and was decomposed by slow addition
of aqueous 2 M HCl. The product amine was separated
from the residue of amines by bulb-to-bulb distillation
and converted to its HCl salts using HCl(g)/MeOH.
Acknowledgements
Financial support by the Turkish Scientific and Techni-
cal Research Council (TUBITAK), Turkish State Plan-
ning Organization (for GC–LC–MS) and Middle East
Technical University (AFP 2001) is gratefully
acknowledged.
4.8. (S)-2,2,2-Trifluoro-1-furan-2-yl-ethylamine (S)-4
References
1H NMR (CDCl3): l ppm 1.82 (s, 2H), 4.2–4.7 (m, 1H),
6.21–6.48 (m, 2H), 7.22–7.51 (m, 1H).
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