Nucleophilic replacement of p-(1-chloro-2,2,2-trifluoroethyl)phenols: Novel synthesis of β-trifluoromethyl-tyrosine

Article abstract of DOI:10.1016/S0022-1139(03)00004-6

Three para -(1-chloro-2,2,2-trifluoroethyl)phenols 2a-c were prepared by selective α-chlorination of the corresponding alcohols 1a-c. Substitution of 2a by active methylene compound 4 proceeds smoothly in the presence of an appropriate base at room temper

Full text of DOI:10.1016/S0022-1139(03)00004-6

Journal of Fluorine Chemistry 121 (2003) 141–146
Nucleophilic replacement of p-(1-chloro-2,2,2-trifluoroethyl)phenols:
novel synthesis of b-trifluoromethyl-tyrosine
Yuefa Gonga, Katsuya Katob,*
aDepartment of Chemistry, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
bNational Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimoshidami,
Moriyama-ku, Nagoya 463-8510, Japan
Received 16 November 2002; accepted 20 December 2002
Abstract
Three para-(1-chloro-2,2,2-trifluoroethyl)phenols 2a–c were prepared by selective a-chlorination of the corresponding alcohols 1a–c.
Substitution of 2a by active methylene compound 4 proceeds smoothly in the presence of an appropriate base at room temperature, giving
substituted products 5–9 in good yields. On the basis of this finding, both the important b-trifluoromethyl-tyrosine 15 and its derivatives have
been successfully synthesized.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Nucleophilic replacement; Trifluoromethyl-tyrosine; Amino acid
1. Introduction
midomalonate in the presence of sodium ethoxide or sodium
hydride [20]. We therefore used 4-(1-hydroxy-2,2,2-trifluor-
oethyl)phenol as the starting material to synthesize the
interesting fluorinated tyrosine derivative, b-trifluoro-
methyl-tyrosine. The 4-(1-hydroxy-2,2,2-trifluoroethyl)phe-
nol readily obtained from phenol and trifluoroacetaldehyde
ethyl hemiacetal [21,22] does not, however, react with
diethyl 2-acetoamidomalonate under the same conditions,
mainly because of the poor leaving ability of the side-chain
hydroxyl group. For this reason, we have tried to selectively
convert this hydroxyl group into a good leaving group, such
as an acetoxy or a halogen group, but it is difficult to
selectively acylate the side-chain hydroxyl group in acetic
anhydride because of competitive acylation of the phenolic
group. Selective chlorination of the side-chain hydroxyl
group was made possible by the use of the common chlor-
ination agent, SOCl2 and pyridine. The substitution of para-
or ortho-(1-chloro-2,2,2-trifluoroethyl)phenols by various
nucleophiles and a convenient method for preparing b-
trifluoromethyl-tyrosine are reported.
Preparation of fluorine-substituted compounds is of inter-
est because of the striking effects that selective fluorine
substitution has on bioactive molecules’ bioactivity [1–3].
Lately, the preparation and bioactivities of fluorinated
amines and amino acids have become of great interest,
and several studies have been published. a-Trifluoromethy-
lated amines have been prepared by reductive amination of
trifluoromethyl ketones [4–6], the nucleophilic addition of
trimethyl(trifluoromethyl)silane to aldimines [7–10], the ene
reaction of N-tosyl trifluoromethylated imine [11], and the
Friedel-Crafts reaction of N-alkyl trifluoromethylated imi-
nes or hemiaminals [12,13]. Of the a-amino acids, fluori-
nated phenylalanine [14,15] and fluorinated threonine
[16,17] have been studied in detail. In addition, methods
for the preparation of fluorinated b-amino acids, the Refor-
matsky reaction of aldimine with ethyl bromodifluoroacetate
[18] and nucleophilic addition to trifluoromethylated imine
[19], have been established.
Recently, we reported the easy preparation of b-trifluor-
omethyl-N-acetyltryptophan by the substitution reaction of
2,2,2-trifluoro-1-(indol-3-yl)ethanol and diethyl 2-acetoa-
2. Results and discussion
Three para-(1-chloro-2,2,2-trifluoroethyl)phenols, 2a–c,
were prepared by the reactions of the corresponding alcohols
1a–c with SOCl2 and pyridine (Scheme 1). First, substitution
* Corresponding author. Fax: þ81-52-736-7275.
E-mail address: katsuya-kato@aist.go.jp (K. Kato).
0022-1139/03/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00004-6

142
Y. Gong, K. Kato / Journal of Fluorine Chemistry 121 (2003) 141–146
the target compounds b-trifluoromethylated tyrosine and
tyramine. Substituted product 10b (Fig. 1) was generated
with nitromethane, but only in about 20% yield (Entry 8).
Product analysis showed that the low yield mainly was due
to the formation of side-products caused by condensation of
2b in the presence of the base. The same side-products
were produced in the reaction with ethyl (benzhydrylidene-
amino)acetate, giving product 11 in 55% yield (Entry 9). In
contrast, a 70% yield of product 12 was obtained with
ethyl nitroacetate (Entry 10). A low yield of substituted
product 10c, a useful precursor of b-trifluoromethylated
dopamine was obtained when 4-(1-chloro-2,2,2-trifluor-
oethyl)-2-methoxy-phenol 2c was used in the reaction
with nitromethane (Entry 11), whereas with ethyl nitroace-
tate substituted product 13 was produced in high yield
(Entry 12).
Scheme 1.
reactions of 2a with the weakly acidic compounds 4 and
nitromethane were examined at room temperature in the
presence of an appropriate base. With diethyl malonate,
there was a high yield of substituted product 5 when sodium
hydride was the base (Table 1, Entry 1). Under the same
conditions, similar reactions of 2a with ethyl cyanoacetate,
ethyl benzoylacetate, ethyl (benzhydrylidene-amino)ace-
tate, and nitromethane gave the corresponding substituted
products 6, 8–10a in high yields (Entries 2 and 4–6). With
ethyl nitroacetate substituted product 7 was produced in high
yield when potassium carbonate was the base (Entry 3),
whereas no simple substituted product was detected in the
corresponding reaction of 2a with sodium cyanide (Entry 7).
It is very difficult for nucleophiles to substitute directly
for the chlorine atom in an alkyl chloride bearing a bulky
trifluoromethyl group. In fact, we found that no substitution
reaction occurred between 1-chloro-2,2,2-trifluoroethylben-
zene and diethyl malonate in the presence of sodium
hydride. The above replacement therefore probably pro-
ceeds along a pathway via the generation and reaction of
quinone methides.
The benzhydrylidene group next was removed from pro-
ducts 9 and 11. When a mixture of 9 (3.0 mmol), 4N aqueous
HCl (5.0 l), and acetic acid (8.0 ml) was stirred at room
temperature for 24 h, the b-trifluoromethyl-tyrosine analo-
gue 14 was afforded in 87% yield (Scheme 2). Under
the same conditions, hydrolysis of 11 gave b-trifluoro-
methyl-tyrosine 15 in 85% yield. Moreover, tyrosine 15
was obtained in 83% yield when nitro compound 12 was
hydrogenated in methanol in the presence of a catalytic
amount of palladium–charcoal under a hydrogen atmo-
sphere (Scheme 3). Palladium-catalyzed hydrogenation of
10c and 13 gave the corresponding reduction products 16
and 17, respectively, in 77 and 79% yields.
1
Stereochemical analysis of substituted products 6–9 by H
and 19F NMR showed that anti-isomer formation was some-
what more preferential than syn-isomer formation, albeit in
low ratios (Entries 2–5).
Based on these findings, the reactions of 4-(1-chloro-
2,2,2-trifluoroethyl)phenol 2b with nitromethane, ethyl
(benzhydrylidene-amino)acetate, and ethyl nitroacetate
were investigated under the above conditions to obtain
Table 1
Reaction of (1-chloro-2,2,2-trifluoroethyl)phenol with various nucleophiles
Entry
Substrate
Nucleophile
Conditions
Product (yield %)
anti:syn
1
2
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2b
3a
3a
3b
CH2(CO2Et)2
NCCH2CO2Et
O2NCH2CO2Et
PhCOCH2CO2Et
Ph2CH¼NCH2CO2Et
CH3NO2
NaH/toluene, RT, 6 h
NaH/THF, RT, 6 h
K2CO3/DMF, RT, 36 h
NaH/THF, RT, 8 h
NaH/THF, RT, 8 h
NaH/THF, RT, 8 h
DMF, RT, 36 h
5 (80)
6 (97)
7 (87)
66:34
55:45
57:43
58:42
3
4
8 (88)
9 (80)
5
6
10a (87)
None
7
NaCN
CH3NO2
8
NaH/THF, RT, 8 h
NaH/THF, RT, 8 h
K2CO3/DMF, RT, 36 h
NaH/THF, RT, 8 h
K2CO3/DMF, RT, 36 h
CH2Cl2, 0–5 8C, 8 h
CH2Cl2, 0–5 8C, 8 h
CH2Cl2, 0–5 8C, 8 h
CH2Cl2, 0–5 8C, 8 h
10b (20)
11 (55)
12 (70)
10c (30)
13 (85)
18 (61)
19 (43)
20a (51)
20b (62)
9
Ph2CH¼NCH2CO2Et
O2NCH2CO2Et
CH3NO2
65:35
61:39
10
11
12
13
14
15
16
O2NCH2CO2Et
PhCH(CH3)NH2
NH3 (aq)
64:36
74:26
PhCH(CH3)NH2
PhCH(CH3)NH2
>99:1
>99:1

Y. Gong, K. Kato / Journal of Fluorine Chemistry 121 (2003) 141–146
143
Fig. 1. Structures of substituted products of p- and o-(1-chloro-2,2,2-trifluoroethyl)phenols with nucleophiles.
In addition to the C-centered nucleophiles, substitution of
2b with an N-centered nucleophile was examined. The
addition of 2b (5.0 mmol) to an excess of 1-phenylethyla-
mine (15.0 mmol) in dichloromethane at 0–5 8C gave N-
alkyl 1-aryl-2,2,2-trifluoroethylamine, 18, in 61% yield
(Scheme 4). The diastereomer ratio determined by 19F
NMR was 74:26 (Entry 13). The corresponding reaction
of 2-(1-chloro-2,2,2-trifluoroethyl)phenol, 3a (Fig. 1),
readily obtained in high yield by the chlorination of
2-(1-hydroxy-2,2,2-trifluoroethyl)phenol with SOCl2 and
pyridine, was investigated under these conditions because
of the importance of o-aminoalkylphenols in asymmetric
synthesis. The reaction of 3a with ammonia afforded
a-trifluoromethylamine, 19, in 43% yield (Entry 14). A
similar reaction with (S)-1-phenylethylamine produced a
moderate yield of N-alkyl 1-aryl-2,2,2-trifluoroethylamine,
20, in high diastereoselectivity (up to 99:1) (Entry 15).
High diastereoselectivity also occurred in the correspond-
ing reaction of 2-(1-chloro-2,2,2-trifluoroethyl)-p-cresol,
3b (Entry 16).
In conclusion, we consider that the substitution reaction
of para- and ortho-(1-chloro-2,2,2-trifluoroethyl)phenols
using various nucleophiles is an efficient, novel method
for preparing b-trifluoromethyl-tyrosine, dopamine, and
a-trifluoromethylamines.
Scheme 2.
3. Experimental
3.1. General
All the starting materials were obtained commercially and
used without purification. Tetrahydrofuran was treated with
1
˚
sodium wires and preserved on 4 A molecular sieves. H
NMR spectra were recorded with tetramethylsilane (TMS)
as the internal standard at 90 MHz by a Hitachi R-90H FT
spectrometer and at 299.95 MHz by a Varian INOVA-300
FT spectrometer. 19F NMR spectra were recorded, at 84.7
and 282.22 MHz, respectively, by the same spectrometers
with hexafluorobenzene as the internal standard. Mass spec-
tra (70 eV) were measured with a Shimadzu QP-5000
instrument, and high-resolution mass spectra with a JEOL
JMS-SX102A MS spectrometer. Melting points, measured
in a glass capillary tube on a heating block, are uncorrected.
Scheme 3.
Scheme 4.

144
Y. Gong, K. Kato / Journal of Fluorine Chemistry 121 (2003) 141–146
3.2. Preparation of p-(1-chloro-2,2,2-trifluorethyl)
phenols 2a–c
J ¼ 8:6 Hz). MS m/z 362 (Mþ, 27), 314 (24), 288 (36), 271
(29), 269 (100), 241 (72), 215 (23), 203 (76), 175 (30), 153
(22). HRMS. Anal. calcd: 362.1341. Found: 362.1340.
2-Cyano-4,4,4-trifluoro-3-(4-hydroxy-3,5-dimethyl-phe-
nyl)-butyric acid ethyl ester (6): a colorless oil. Main
isomer: 1H NMR (CDCl3) d 7.05 (2H, s), 4.91 (1H, s,
br), 4.23 (2H, q, J ¼ 7:0 Hz), 4.15 (1H, d, J ¼ 7:2 Hz),
3.94 (1H, m), 2.23 (6H, s), 1.23 (3H, t, J ¼ 7:0 Hz). 19F
NMR (CDCl3) d 93.81 (3F, d, J ¼ 7:9 Hz). MS m/z 315
(Mþ, 9), 203 (100), 153 (9). HRMS. Anal. calcd: 315.1082.
Found: 315.1080. Minor isomer (distinguishable data): 1H
NMR (CDCl3) d 6.97 (2H, s). 19F NMR (CDCl3) d 95.15
(3F, d, J ¼ 7:9 Hz).
A
mixture of 4-(1-hydroxy-2,2,2-trifluoroethyl)-2,6-
dimethyl-phenol 1a (2.20 g, 10 mmol) and thionyl chloride
(1.67 g, 14 mmol) in dry toluene (15 ml) was cooled to 0–
5 8C in an ice–water bath. Pyridine (0.79 g, 10 mmol) was
added slowly to keep the reaction temperature below 10 8C.
This reaction mixture was stirred at 0–5 8C for 1 h then
heated at 70 8C for 2 h with continuous stirring. After being
cooled, it was poured into about 20 g of ice–water and stirred
for another 30 min. The organic layer was separated, and the
aqueous layer treated twice with ethyl acetate. The com-
bined organic layer was dried over sodium sulfate then
evaporated under reduced pressure, giving an oily residue.
It was purified by silica gel column chromatography (hex-
ane:ethyl acetate: 7:1 (v/v)), yielding 2.26 g (95%) of
chlorinated product 2a as a colorless oil. The same proce-
dures were used to prepare 2b, 2c, 3a, and 3b, the yields
being 91% for 2b, 95% for 2c, 90% for 3a, and 81% for 3b.
4,4,4-Trifluoro-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-
nitro-butyric acid ethyl ester (7): minor isomer first diluted
with hexane:ethyl acetate (1:5 (v/v)): colorless grains, mp
1
84–86 8C. H NMR (CDCl3) d 6.94 (2H, s), 5.65 (1H, d,
J ¼ 11:0 Hz), 4.80 (1H, s, br), 4.40 (1H, m), 4.34 (2H, q,
J ¼ 7:2 Hz), 2.21 (6H, s), 1.34 (3H, t, J ¼ 7:2 Hz). 19F
NMR (CDCl3) d 95.51 (3F, d, J ¼ 7:9 Hz). Main isomer
(second fraction) diluted with hexane:ethyl acetate (1:5 (v/
v)): a yellowish oil. 1H NMR (CDCl3) d 6.93 (2H, s),
5.69 (1H, d, J ¼ 10:8 Hz), 5.14 (1H, s), 4.43 (1H, m),
3.96 (2H, q, J ¼ 7:0 Hz), 2.20 (6H, s), 0.96 (3H, t,
3.3. General procedures for nucleophilic replacement
with 2a–c
Procedure (A): Diethyl malonate (0.88 g, 5.5 mmol) was
added to a suspension of sodium hydride (60%, 0.22 g,
5.5 mmol) in dried toluene (25 ml) and stirred at 0–5 8C
for 30 min. A solution of compound 2a (1.19 g, 5.0 mmol) in
toluene (10 ml) was added, and the whole stirred at room
temperature for 6 h. The reaction mixture then was poured
into distilled water (15 ml) and neutralized with dilute
aqueous HCl. The organic layer was separated, and the
aqueous layer treated twice with ethyl acetate. The organic
phases were combined, dried over anhydrous MgSO4, and
evaporated under reduced pressure. The residue was purified
by silica gel column chromatography. Elution with hexa-
ne:ethyl acetate (7:1 (v/v)) gave 1.45 g of product 5 in 80%
yield.
Procedure (B): A mixture of ethyl nitroacetate (0.73 g,
5.5 mmol) and potassium carbonate (1.38 g, 10.0 mmol)
was stirred in dry DMF (20 ml) at room temperature for
30 min. Compound 2a (1.19 g, 5.0 mmol) was added, and
the whole stirred vigorously for 36 h. The reaction mixture,
worked-up as above, gave 1.46 g (87%) of product 7.
Procedure (A) was followed when the ethyl cyanoacetate,
ethyl benzoylacetate, ethyl (benzhydrylidene-amino)acetate
and nitromethane reactions with 2a, 2b, or 2c took place in
THF. Procedure (B) was followed when ethyl nitroacetate
was used. The products obtained and their spectral data
follow.
J ¼ 7:0 Hz). 19F NMR (CDCl3)
d 93.34 (3F, d,
J ¼ 7:9 Hz). MS m/z 335 (Mþ, 33), 288 (44), 243 (84),
215 (100), 203 (23), 175 (15), 147 (11). HRMS. Anal. calcd:
335.0981. Found: 335.0981.
2-Benzoyl-4,4,4-trifluoro-3-(4-hydroxy-3,5-dimethyl-
phenyl)-butyric acid ethyl ester (8): main isomer (first
1
fraction): a yellowish oil. H NMR (CDCl3) d 7.92 (2H,
d, J ¼ 7:2 Hz), 7.43 (3H, m), 6.87 (2H, s), 5.40 (1H, s, br),
5.25 (1H, d, J ¼ 11:4 Hz), 4.48 (1H, m), 4.17 (2H, q,
J ¼ 7:2 Hz), 2.05 (6H, s), 1.18 (3H, t, J ¼ 7:2 Hz). 19F
NMR (CDCl3) d 94.48 (3F, d, J ¼ 8:8 Hz). Minor isomer
(second fraction): a yellowish oil. 1H NMR (CDCl3) d 8.14
(2H, d, J ¼ 7:2 Hz), 7.55 (3H, m), 7.05 (2H, s), 5.41 (1H, s,
br), 5.23 (1H, d, J ¼ 11:0 Hz), 4.55 (1H, m), 3.81 (2H, q,
J ¼ 7:0 Hz), 2.23 (6H, s), 0.84 (3H, t, J ¼ 7:0 Hz). 19F
NMR (CDCl3) d 94.07 (3F, d, J ¼ 8:8 Hz). MS m/z 394
(Mþ, 4), 301 (11), 243 (15), 203 (4), 105 (100), 77 (39).
HRMS. Anal. calcd: 394.1392. Found: 394.1387.
2-(Benzhydrylidene-amino)-4,4,4-trifluoro-3-(4-hydroxy-
3,5-dimethyl-phenyl)-butyric acid ethyl ester (9): a yellowish
1
oil. Main isomer: H NMR (CDCl3) d 7.42 (10H, m), 7.02
(2H, s), 4.63 (1H, d, J ¼ 4:8 Hz), 4.62 (1H, s, br), 4.08 (1H,
m), 3.92 (2H, q, J ¼ 7:0 Hz), 2.22 (6H, s), 0.88 (3H, t, J ¼
7:0 Hz). 19F NMR (CDCl3) d 95.65 (3F, d, J ¼ 8:3 Hz). MS
m/z 469 (Mþ, 0), 396 16), 280 (95), 266 (63), 250 (17),
238 (42), 202 (24), 193 (100), 165 (48), 105 (50), 77 (52).
Minor isomer (distinguishable data): 1H NMR (CDCl3)
d 6.79 (2H, s), 4.12 (2H, q, J ¼ 7:0 Hz), 2.15 (6H, s), 0.88
(3H, t, J ¼ 7:0 Hz). 19F NMR (CDCl3) d 97.44 (3F, d,
J ¼ 8:3 Hz).
2-[2,2,2-Trifluoro-1-(4-hydroxy-3,5-dimethyl-phenyl)-
ethyl]-malonic acid diethyl ester (5): a colorless oil. 1H
NMR (CDCl3) d 6.91 (2H, s), 4.92 (1H, s), 4.26 (2H, q,
J ¼ 7:2 Hz), 4.12 (1H, m), 4.09 (1H, d, J ¼ 7:0 Hz), 3.91
(2H, q, J ¼ 7:2 Hz), 2.20 (6H, s), 1.30 (3H, t, J ¼ 7:2 Hz),
0.96 (3H, t, J ¼ 7:2 Hz). 19F NMR (CDCl3) d 93.48 (3F, d,
2,6-Dimethyl-4-(2,2,2-trifluoro-1-nitromethyl-ethyl)phe-
nol (10a): colorless plates, mp 140–142 8C. 1H NMR

Y. Gong, K. Kato / Journal of Fluorine Chemistry 121 (2003) 141–146
145
(CDCl3) d 6.91 (2H, s), 4.87 (1H, d, J ¼ 6:2 Hz), 4.81 (1H,
d, J ¼ 5:5 Hz), 4.20 (1H, m), 2.24 (6H, s). 19F NMR
(CDCl3) d 92.63 (3F, d, J ¼ 7:8 Hz). MS m/z 263 (Mþ,
33), 217 (34), 216 (100), 203 (17), 153 (40), 147 (30). Anal.
calcd for C11H12F3NO3: C, 50.19; H, 4.60; N, 5.32. Found:
C, 50.11; H, 4.59; N, 5.23.
4-(2,2,2-Trifluoro-1-nitromethyl-ethyl)phenol (10b): a
yellowish oil. 1H NMR (CDCl3) d 7.19 (2H, d, J ¼
8:7 Hz), 6.84 (2H, d, J ¼ 8:7 Hz), 5.30 (1H, s, br), 4.89
(1H, d, J ¼ 6:1 Hz), 4.82 (1H, d, J ¼ 7:0 Hz), 4.26 (1H, m).
19F NMR (CDCl3) d 92.55 (3F, d, J ¼ 8:3 Hz). MS m/z 235
(Mþ, 13), 189 (18), 188 (100), 175 (16), 149 (24), 125 (75),
119 (69), 91 (46). HRMS. Anal. calcd: 235.0456. Found:
235.0455.
20 ml of ethyl acetate next was added, and the whole stirred
for several minutes. The organic layer was separated, and the
aqueous layer treated twice with ethyl acetate. The com-
bined organic phases were dried over anhydrous MgSO4 and
evaporated under reduced pressure. The residue was purified
in a silica gel column and eluted with hexane:ethyl acetate
(3:1 (v/v)), giving 0.71 g (85%) of b-trifluoromethyl-tyro-
sine ester 15.
Compound 9, hydrolyzed under the same conditions, gave
b-trifluoromethylated amino ester 14 in 87% yield.
2-Amino-4,4,4-trifluoro-3-(4-hydroxy-3,5-dimethyl-phe-
nyl)-butyric acid ethyl ester (14): colorless crystals, mp 130–
133 8C. Main isomer: 1H NMR (CDCl3) d 6.93 (2H, s), 4.12
(2H, q, J ¼ 7:0 Hz), 4.04 (1H, d, J ¼ 6:8 Hz), 3.65 (1H, m),
2.22 (6H, s), 1.65 (2H, s, br), 0.95 (3H, t, J ¼ 7:0 Hz). 19F
NMR (CDCl3) d 95.48 (3F, d, J ¼ 9:2 Hz). MS m/z 305 (Mþ,
5), 203 (4), 184 (8), 116 (22), 102 (38), 74 (100). Minor
isomer (distinguishable data): 1H NMR (CDCl3) d 4.20 (2H,
q, J ¼ 7:0 Hz), 1.28 (3H, t, J ¼ 7:0 Hz). 19F NMR (CDCl3)
d 98.14 (3F, d, J ¼ 9:2 Hz). Anal. calcd for C14H18F3NO3:
C, 55.08; H, 5.94; N, 4.59. Found: C, 55.02; H, 5.92; N, 4.53.
2-Amino-4,4,4-trifluoro-3-(4-hydroxy-phenyl)-butyric
acid ethyl ester (15): colorless crystals, mp 122–125 8C.
Main isomer: 1H NMR (CDCl3) d 7.22 (2H, d, J ¼ 8:4 Hz),
6.79 (2H, d, J ¼ 8:4 Hz), 4.10 (1H, d, J ¼ 6:3 Hz), 3.69
(1H, m), 4.18 (2H, q, J ¼ 7:2 Hz), 2.20 (2H, br), 1.26 (3H, t,
J ¼ 7:2 Hz). 19F NMR (CDCl3) d 95.36 (3F, d, J ¼ 9:4 Hz).
MS m/z 277 (Mþ, 1), 204 (13), 175 (5), 135 (8), 116 (22), 102
(87), 74 (100). Anal. calcd for C12H14F3NO3: C, 51.99; H,
5.09; N, 5.05. Found: C, 51.03; H, 5.08; N, 4.98. Minor
isomer (distinguishable data): 1H NMR (CDCl3) d 6.72 (2H,
d, J ¼ 8:4 Hz), 3.94 (2H, q, J ¼ 7:2 Hz), 1.08 (3H, t,
J ¼ 7:2 Hz). 19F NMR (CDCl3) d 97.91 (3F, d, J ¼ 9:4 Hz).
2-Methoxy-4-(2,2,2-trifluoro-1-nitromethyl-ethyl)phenol
1
(10c): colorless plates, mp 78–79 8C. H NMR (CDCl3) d
6.94 (1H, d, J ¼ 8:4 Hz), 6.82 (1H, d, J ¼ 8:4 Hz), 6.77
(1H, s), 4.90 (1H, d, J ¼ 4:6 Hz), 4.82 (1H, d, J ¼ 6:6 Hz),
4.20 (1H, m), 3.89 (3H, s). 19F NMR (CDCl3) d 92.69 (3F, d,
J ¼ 8:6 Hz). MS m/z 265 (Mþ, 40), 219 (29), 218 (100), 203
(34), 155 (28), 175 (12), 135 (32), 109 (41). Anal. calcd for
C10H10F3NO4: C, 45.29; H, 3.80; N, 5.28. Found: C, 45.12;
H, 3.79; N, 5.18.
4,4,4-Trifluoro-3-(4-hydroxy-phenyl)-2-nitro-butyric acid
ethyl ester (12): a colorless oil. Main isomer: 1H NMR
(CDCl3) d 7.21 (2H, d, J ¼ 8:6 Hz), 6.83 (2H, d, J ¼ 8:6
Hz), 5.66 (1H, d, J ¼ 10:8 Hz), 5.50 (1H, s, br), 4.50 (1H, dq,
J ¼ 10:8 and 8.8 Hz), 3.96 (2H, q, J ¼ 7:2 Hz), 0.99 (3H, t,
J ¼ 7:2 Hz). 19F NMR (CDCl3) d 93.31 (3F, d, J ¼ 8:8 Hz).
MS m/z 307 (Mþ, 10), 261 (11), 260 (44), 231 (11), 215 (93),
187 (100), 175 (31), 147 (51), 125 (39), 119 (47), 109 (30), 91
(50). HRMS. Anal. calcd: 307.0668. Found: 307.0666. Minor
isomer (distinguishable data): 1H NMR (CDCl3) d 4.36 (2H, q,
J ¼ 7:2 Hz), 1.35 (3H, t, J ¼ 7:2 Hz). 19F NMR (CDCl3) d
95.39 (3F, d, J ¼ 8:8 Hz).
3.5. Preparation of b-trifluoromethyl-tyrosine 15
via palladium-catalyzed hydrogenolysis
4,4,4-Trifluoro-3-(4-hydroxy-3-methoxy-phenyl)-2-nitro-
butyric acid ethyl ester (13): a colorless oil. Main isomer: 1H
NMR (CDCl3) d 6.94 (1H, d, J ¼ 7:0 Hz), 6.84 (1H, d,
J ¼ 7:0 Hz), 6.80 (1H, s), 5.67 (1H, d, J ¼ 10:6 Hz), 4.54
(1H, m), 4.05 (2H, q, J ¼ 7:0 Hz), 3.91 (3H, s), 0.99 (3H, t,
J ¼ 7:0 Hz). 19F NMR (CDCl3) d 93.34 (3F, d, J ¼ 8:9 Hz).
MS m/z 337 (Mþ, 11), 290 (16), 245 (15), 217 (100), 203
(8), 177 (12), 145 (12), 127 (10). HRMS. Anal. calcd:
337.0773. Found: 337.0772. Minor isomer (distinguishable
A mixture of nitro compound 12 (0.61 g, 2.0 mmol) and
5% palladium-charcoal (0.42 g) in methanol (10 ml) was
stirred for 24 h at room temperature under a hydrogen
atmosphere then filtered through a Celite pad, and the filtrate
concentrated by evaporation under reduced pressure. The
residue was separated by elution through a silica gel column
with hexane:ethyl acetate/hexane (from 4:1 to 2:1 (v/v)),
giving 0.46 g (83%) of b-trifluoromethyl-tyrosine ester 15.
Pd-catalyzed hydrogenolysis of nitro compounds 10c and
13, done by the same procedures, gave amine 16 in 77%
yield and amino ester 17 in 79% yield.
1
data): H NMR (CDCl3) d 4.37 (2H, q, J ¼ 7:0 Hz), 1.35
(3H, t, J ¼ 7:0 Hz). 19F NMR (CDCl3) d 95.42 (3F, d,
J ¼ 8:9 Hz).
3.4. Preparation of b-trifluoromethyl-tyrosine 15 via
acid-catalyzed hydrolysis
4-(1-Aminomethyl-2,2,2-trifluoro-ethyl)-2-methoxy-phe-
nol (16): colorless crystals, mp 103–105 8C. 1H NMR
(CDCl3) d 6.93 (1H, d, J ¼ 7:7 Hz), 6.85 (1H, s), 6.74
(1H, d, J ¼ 7:7 Hz), 3.89 (3H, s), 3.10–3.45 (3H, m),
2.40 (2H, br). 19F NMR (CDCl3) d 93.25 (3F, d,
J ¼ 9:9 Hz). MS m/z 235 (Mþ, 11), 206 (100), 205 (25),
186 (89), 171 (29). Anal. calcd for C10H12F3NO2: C, 51.07;
H, 5.14; N, 5.96. Found: C, 51.04; H, 5.14; N, 5.93.
A mixture of compound 11 (1.32 g, 3.0 mmol), 4N aqu-
eous HCl (5.0 ml), and acetic acid (8.0 ml) was vigorously
stirred at room temperature for 24 h. After the reaction
ended, 10 ml of cold water was added and the mixture
neutralized with saturated aqueous NaHCO3 solution. About

146
Y. Gong, K. Kato / Journal of Fluorine Chemistry 121 (2003) 141–146
[2] R. Filler, Y. Kobayashi, L.M. Yagupolskii, Organofluorine Com-
2-Amino-4,4,4-trifluoro-3-(4-hydroxy-3-methoxy-phe-
nyl)-butyric acid ethyl ester (17): a yellowish oil. Main
isomer: H NMR (CDCl3) d 6.85 (3H, s), 3.44–4.30 (6H,
pounds in Medicinal Chemistry and Biomedical Applications,
Elsevier, Amsterdam, 1993.
1
[3] B.E. Smart, J. Fluorine Chem. 109 (2001) 3–11.
[4] S. Watanabe, T. Fujita, M. Sakamoto, H. Hamano, T. Kitazume,
T. Yamazaki, J. Fluorine Chem. 83 (1997) 15–19.
[5] K. Kato, Y. Gong, T. Saito, H. Kimoto, Enantiomer 5 (2000) 521–
524.
m), 3.87 (3H, s), 1.26 (3H, t, J ¼ 7:0 Hz). 19F NMR (CDCl3)
d 95.42 (3F, d, J ¼ 9:3 Hz). MS m/z 307 (Mþ, 3), 306 (13),
232 (6), 205 (100), 186 (13), 155 (11), 116 (31). Anal. calcd
for C13H16F3NO4: C, 50.82; H, 5.25; N, 4.56. Found: C,
50.58; H, 5.13; N, 4.33. Minor isomer (distinguishable data):
1H NMR (CDCl3) d 1.09 (3H, t, J ¼ 7:0 Hz). 19F NMR
(CDCl3) d 98.02 (3F, d, J ¼ 9:3 Hz).
[6] T. Ono, V.P. Kukhar, V.A. Soloshonok, J. Org. Chem. 61 (1996)
6563–6569.
[7] D.W. Nelson, R.A. Easley, B.N. Pintea, Tetrahedron Lett. 40 (1999)
25–28.
[8] J.C. Blazejewski, E. Anselmi, M.P. Wilmshurst, Tetrahedron Lett. 40
(1999) 5475–5478.
3.6. Reaction of p-(1-chloro-2,2,2-trifluoro-ethyl)phenol
2b with 1-phenylethylamine
[9] G.K.S. Prakash, M. Mandal, G.A. Olah, Synlett (2001) 77–78.
[10] G.K.S. Prakash, M. Mandal, G.A. Olah, Angew. Chem. Int. Ed. 40
(2001) 589–590.
Compound 2b (1.05 g, 5.0 mmol) was added slowly with
continuous stirring to a solution of 1-phenylethylamine
(1.81 g, 15.0 mmol) in dichloromethane (25 ml) at 0–
5 8C, and the whole stirred for 8 h. The solvent was removed
under reduced pressure, and the oily residue separated by
silica gel column chromatography with hexane:ethyl acetate
(5:1 (v/v)) as the eluting solvent gave 0.90 g of N-alkyl
1-aryl-2,2,2-trifluoroethylamine 18 in 61% yield.
The same procedures were followed for the corresponding
reactions of 3a and 3b with 1-phenylethylamine. Products
20a and 20b were obtained, respectively, in 51 and 62%
yields.
[11] I. Kumadaki, S. Jonoshita, A. Harada, M. Omote, A. Ando, J.
Fluorine Chem. 97 (1999) 61–63.
[12] Y. Gong, K. Kato, H. Kimoto, Synlett (2000) 1058–1060.
[13] Y. Gong, K. Kato, J. Fluorine Chem. 108 (2001) 83–86.
[14] A.I. Ayi, M. Remli, R. Guedj, J. Fluorine Chem. 18 (1981) 93–96.
[15] T. Tsushima, J. Nishikawa, T. Sato, H. Tanida, K. Tori, T. Tsuji, S.
Misaki, M. Suefuji, Tetrahedron Lett. 21 (1980) 3593–3594.
[16] T. Kitazume, J. Lin, T. Yamazaki, Tetrahedron: Asymmetry 2 (1991)
235–238.
[17] T. Yamazaki, J. Haga, T. Kitazume, Bioorg. Med. Chem. Lett. 1
(1991) 271–276.
[18] S. Marcotte, X. Pannecoucke, C. Feasson, J.C. Quirion, J. Org.
Chem. 64 (1999) 8461–8464.
[19] P. Bravo, F. Guidetti, F. Viani, M. Zanda, A.L. Markovsky, A.E.
Sorochinsky, I.V. Soloshonok, V.A. Soloshonok, Tetrahedron 54
(1998) 12789–12806.
[20] Y. Gong, K. Kato, H. Kimoto, Tetrahedron Lett. 40 (1999) 5743–
5744.
References
[21] Y. Gong, K. Kato, H. Kimoto, Synlett (1999) 1403–1404.
[22] Y. Gong, K. Kato, H. Kimoto, Bull. Chem. Soc. Jpn. 73 (2000)
377–383.
[1] J.T. Welch, Selective Fluorination in Organic and Bioorganic
Chemistry, ACS Series 456, Maple Press, New York, 1991.