Diastereoselective Friedel-Crafts reaction of α-trifluoromethyl imines derived from chiral amines

Article abstract of DOI:10.1016/S0957-4166(01)00402-5

The Friedel-Crafts reactions of chiral N-(2,2,2-trifluoroethylidene)-1-arylethylamines 1a and 1b with various electron-rich aromatic compounds were examined. The reactions proceeded readily at room temperature in the presence of BF₃·Et₂O. Substituted products 2-12 were obtained in low to very high stereoselectivities (up to 100% d.e.). The absolute configuration of compound 12 was determined by X-ray analysis. Moreover, the chiral auxiliary from compounds 3 and 12 was selectively removed by palladium-catalyzed hydrogenolysis.

Full text of DOI:10.1016/S0957-4166(01)00402-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2121–2127
Diastereoselective Friedel–Crafts reaction of a-trifluoromethyl
imines derived from chiral amines
Yuefa Gong* and Katsuya Kato
National Institute of Advanced Industrial Science and Technology, Hirate-cho, Kita-ku, 462-8510 Nagoya, Japan
Received 19 June 2001; accepted 28 August 2001
Abstract—The Friedel–Crafts reactions of chiral N-(2,2,2-trifluoroethylidene)-1-arylethylamines 1a and 1b with various electron-
rich aromatic compounds were examined. The reactions proceeded readily at room temperature in the presence of BF3·Et2O.
Substituted products 2–12 were obtained in low to very high stereoselectivities (up to 100% d.e.). The absolute configuration of
compound 12 was determined by X-ray analysis. Moreover, the chiral auxiliary from compounds 3 and 12 was selectively removed
by palladium-catalyzed hydrogenolysis. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ated amines is still of great interest. Some of the main
procedures developed recently are the asymmetric
nucleophilic addition of chiral sulfoxides to N-anisyl
a-trifluoromethyl imines,13 the enantioselective 1,3-
hydrogen shift of perfluroalkylated imines bearing a
chiral 1-phenylethyl group14 and the stereoselective
nucleophilic addition of TMSCF3 to chiral N-(tert-
butylsulfinyl)imines.15 In addition, the enzymatic reso-
lution of ( )-1-phenyl-2,2,2-trifluoroethyamine has been
reported.16
The development of diastereo- and enantioselective syn-
thetic methods for the preparation of amines remains
an important goal in modern organic synthesis and
various methods have been investigated,1 with the addi-
tion of nucleophiles to imines being one of the most
important.2
Nucleophilic
addition
of
some
organometallic reagents to an imine bearing a chiral
auxiliary affords the amine in high stereoselectivity
(>99% d.e).3 The inexpensive and commercially avail-
able optically active 1-phenylethylamine and 1-(1-naph-
thyl)ethylamine are widely used and efficient chiral
auxiliaries.4
In contrast to the considerable progress with method-
ologies for nucleophilic additions to imines, there have
been only very few reports regarding the reaction of
aromatic compounds with imines, according to our
knowledge, only the Cu(I)-catalyzed enantioselective
substitution of pyrrole, indole and N,N-dimethylanili-
nes with N-tosylimino or N-ethoxycarbonylimino esters
of ethyl glyoxylate has been reported.17 Although the
Friedel–Crafts reaction with hexafluoroisopropyliden-
imine, was first reported in 1968,18 the reaction has a
narrow spectrum of application because of the vigorous
reaction conditions. Our recent work demonstrated that
N-alkyl a-trifluoromethylated imines are reactive
enough to undergo BF3-catalyzed Friedel–Crafts reac-
tion with various electron-rich heteroaromatic com-
pounds and benzene derivatives at room temperature.19
We therefore realized that it is possible to directly
synthesize chiral 1-aryl-2,2,2-trifluoroethylamines by
using a-trifluoromethylated imines bearing a chiral aux-
illiary. In the study reported herein, we carried out the
Friedel–Crafts reaction by choosing chiral imine 1,
which is useful in the preparation of a-trifluoromethyl-
ated amino acids,20 as the starting material. Subse-
a-Trifluoromethylated amines are important building
blocks for pharmaceutical research due to their unusual
physical, chemical and biological properties.5 To date,
literature reports regarding the preparation of a-trifl-
uoromethylated amines mainly involve (1) the reductive
amination of a-trifluoromethylated ketones;6 (2) the
1,3-hydrogen shift of N-benzyl perfluroalkylated
imines;7 (3) ene reactions of N-tosyl trifluoromethylated
imines8 and (4) nucleophilic additions of trimethyl(trifl-
uoromethyl)silane to nitrones,9 imines10 and N-tosyl
aldimines.11 In addition, trifluoroacetimidoyl halides
are very useful in preparing a-trifluoromethylated
amine derivatives.12
Because of its importance in the drug industry, the
direct asymmetric synthesis of chiral a-trifluoromethyl-
* Corresponding author. Fax: +81 (52) 911-2428; e-mail: gong-yf@
aist.go.jp; katsuya-kato@aist.go.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00402-5

2122
Y. Gong, K. Kato / Tetrahedron: Asymmetry 12 (2001) 2121–2127
quent experiments clearly showed that the Friedel–
Crafts reaction with chiral imine 1 is an efficient way to
prepare N-alkyl 1-aryl-2,2,2-trifluoroethylamines with
high diastereoselectivity. Our new preparative method
also has the advantage of directly introducing trifl-
uoromethyl and amine functional groups into the aro-
matic compound stereoselectively at the same time.
BF3·Et2O (entries 1–3). The same conditions were used
for the corresponding reaction of reactive pyrrole and
(N,N-dimethyl)aniline, yielding good yields of products
4 and 5 (Fig. 1), respectively (entries 5 and 9). No
substitution reaction occurred with (N,N-dimethyl)-4-
methylaniline (entry 10), and the reactions with thio-
phene, phenols and 2-naphthol with 1a went very
slowly under these conditions (entries 7 and 8). There-
fore, about 100 mol% of BF3·Et2O was used in these
reactions. As a consequence, the yields of substituted
products 6 and 8–12 (Fig. 1) were markedly improved
(entries 8, 11–13). Similar reactions of 1b with indole,
pyrrole and 2-naphthol were carried out under the same
conditions, respectively (entries 4, 6 and 14).
2. Results and discussion
Chiral imines 1a and 1b were prepared by refluxing
trifluoroacetaldehyde ethyl hemiacetal and (S)-1-
phenylethylamine or (R)-1-(1-naphthyl)ethylamine in
toluene. The imines were easily obtained by removal of
the solvent under reduced pressure and were used with-
out purification.
The substituted product was easily separated from the
unreacted starting materials by column chromatogra-
phy, but it was difficult to separate the diastereomers of
the product using this method. Diastereomer analysis
was therefore carried out by 19F NMR because the
chemical shifts of the fluorine atoms are easily distin-
guished. The diastereomer ratios found are given in
Table 1. In addition, products 2–5 and 12 were also
analyzed by HPLC. The ratios found were consistent
with those in Table 1.
The reactions of chiral imine 1 with various aromatic
compounds were examined in the presence of BF3·Et2O
because the a-trifluoromethylimine did not react with
aromatic compounds such as indole in the absence of a
Lewis acid. The results are given in Table 1.
The reaction of 1a with indole proceeded smoothly in
CH2Cl2 at 10°C, giving the substituted product 2
(Scheme 1). The yield of 2 depended markedly on the
molar ratio of indole to BF3·Et2O, a high yield of 2
being obtained with an addition about 50 mol% of
On the basis of these results, we considered that the
main factors affecting the diastereoselectivity of the
substitution are the steric hindrance of the reactants
Table 1. Reaction of arenes with imine 1 in CH2Cl2 at 10°C
Product (%)b
anti:sync
[h]2D0 (CHCl3)d
a
Entry
Arene
Imine
BF3 (mol%)
Time (h)
1
2
3
4
5
6
7
8
Indole
Indole
Indole
Indole
Pyrrole
Pyrrole
Thiophene
Thiophene
PhNMe2
4-PhMeNMe2
Phenol
1a
1a
1a
1b
1a
1b
1a
1a
1a
1a
1a
10
20
50
50
50
50
50
100
50
50
4
4
4
4
4
2 (21)
2 (54)
2 (94)
3 (92)
4 (78)
5 (82)
6 (18)
6 (46)
7 (68)
None
8 (57)
9 (10)
10 (52)
11 (86)
12 (71)
95:5
92:8
9:1
\99:1
78:22
82:18
64:36
64:36
4:1
−10.2
+5.6
−11.4
+7.4
−4.5
−4.5
−18.0
4
48
48
12
12
48
9
10
11
100
1:1
97:3
97:3
89:11
\99:1
−7.8
−3.5
−10.2
−2.3
12
13
14
4-Cresol
2-Naphthol
2-Naphthol
1a
1a
1b
100
100
100
60
48
48
−18.9
a Molar ratio of BF3:arene.
b Isolated yields.
c Determined by 19F NMR.
d Data for isolated products.
F3C
H
CF3 CH3
CF3 CH3
BF3-Et2O, 10 oC
CH3
N
N
H
N
H
+
+
CH2Cl2
N
H
N
H
N
H
2b (syn)
1
2a (anti)
Scheme 1.

Y. Gong, K. Kato / Tetrahedron: Asymmetry 12 (2001) 2121–2127
2123
CF3 CH3
H
N
CF3 CH3
CF3 CH3
CF3 CH3
H
N
S
N
H
N
H
N
H
N
H
N
H
3a
4
6
5
OH CF3 CH3
OH CF3 CH3
OH CF3 CH3
CF3 CH3
N
H
N
H
N
H
N
H
R
R'
12
7: R = Me2N; 8: R = OH
9: R' = H; 10: R' = Me
11
F3C NH2
OH
F3C NHCH3
OH
15
16
Figure 1.
most preferable conformer of the imine (TS I, Fig. 2).
The arene therefore prefers to attack the carbon center
of CꢀN bond from the re face because there is less
steric hindrance than from the si face, and the (1R,1%S)
diastereomer (anti isomer) is the main product. The
reaction of a less reactive arene has a late transition
state, in which the arene molecule is much closer to the
carbon center of the CꢀN bond. In this case, the attack
of the arene molecule from the less hindered side (si
face, TS (II)) becomes more important, the transition
state (II) being competitive in energy to the TS (I),
which results in lowered the diastereoselectivity.
and the reactivity of arenes toward electrophile. For
instance, high diastereoselectivity was observed in the
reaction with the bulky indole (entry 3) as compared to
that with the pyrrole (entry 5). Similarly, the reaction of
bulky imine 1b gave a higher diastereoselectivity than
that using the imine 1a (entries 3–6). In contrast, the
effect of the reactivity of aromatic compounds on
diastereoselectivity was clearly shown by comparing the
results for the reactions with pyrrole and with thio-
phene. With thiophene the reaction proceeded much
more slowly than that with pyrrole under the same
conditions (entries 5 and 7), and afforded amine 6 with
lower diastereoselectivity (Table 1). Similarly, the reac-
tion of 1a with (N,N-dimethyl)aniline provided only
p-substituted amine 7 in the anti:syn ratio of 4:1 (entry
9), whereas the corresponding reaction with phenol
gave p-substituted amine 8 without diastereoselectivity
(entry 11). The high electrophilic reactivity of aromatic
compounds clearly favors the diastereoselective forma-
tion of amines.
Another problem is the formation of the o-substituted
product 9 with high diastereoselectivity in the reaction
with phenol (entry 11). As shown in Table 1, p-substi-
tution occurred preferentially, indicative that the reac-
tivity of the o-position is much lower than that of the
p-position. Because of the formation of p-substituted
product 8 without diastereoselectivity, the transition
state (I) for p-substitution may be very close in energy
to the transition state (II). A low diastereoselective
o-substitution therefore was estimated, although the
steric hindrance at the o-position is somewhat greater
than that at the p-position. On the basis of this analy-
sis, we speculate that the highly diastereoselective for-
mation of the o-substituted product might proceed via
A plausible explanation for the effect of reactivity on
diastereoselectivity, based on the Hammond postulate,
can be proposed. In the case of a reactive arene, the
reaction passes through an early transition state, which
should be rather close in energy to the reactant, so that
its geometry is predicted to resemble the energetically
F3B
CF3
F3B
CF3
(re)
F3B
CF3
N
N
(si)
N
H
H3C
Ph
Ph
H
H3C
Ph
H
H
H
O
R
H
(re)
H
Me
TS (II)
TS (III)
TS (I)
Figure 2. Transition state models for the diastereoselective Friedel–Crafts reaction of imine.

2124
Y. Gong, K. Kato / Tetrahedron: Asymmetry 12 (2001) 2121–2127
of 11 was converted to products under the same condi-
tions, indicative that removal of the chiral 1-
phenylethyl group from 11 was much more difficult
than that of the chiral 1-(a-naphthyl)ethyl group from
12. In this case, compound 15 was the main product,
and small amounts of 1-(2,2,2-trifluoroethyl)-naph-
thalen-2-ol and the N-methylated product 16 also were
detected by 19F NMR and MS analyses. The mecha-
nism by which the N-methylated products 14 and 16
are formed is now under investigation.
3. Conclusion
We consider that the BF3-catalyzed highly diastereose-
lective Friedel–Crafts reaction with chiral a-trifl-
uoromethyl imines is a new method to prepare chiral
N-alkyl 1-aryl-2,2,2-trifluoroethylamines. The dia-
stereoselectivity was obviously affected by steric factors
and the reactivity of the aromatic compound. The
unexpectedly high diastereoselectivity for o-substitution
products of phenols and 2-naphthol might be attributed
to the six-membered transition state (III). Selective
removal of the chiral auxilliary by palladium-catalyzed
hydrogenolysis allows us to prepare chiral 1-aryl-2,2,2-
trifluoroethyl amines conveniently. The practical use of
compounds 11 and 12 as the chiral auxiliary and the
bioactivity of chiral amines 13–16 is now being
investigated.
Figure 3. X-Ray structure of compound 12.
a six-membered transition state (III), as shown in Fig.
2. Diastereoselective o-substitution was also observed
in the corresponding reaction with p-cresol (entry 12).
In addition, only the 1-substituted products 11 and 12
were obtained in high diastereoselectivity in the respec-
tive reactions of 1a and 1b with 2-naphthol (entries 13
and 14). The absolute configuration of 12 is shown to
be (1S,1%R), as determined by X-ray crystallography
analysis (Fig. 3).21 This configuration is consistent with
that deduced from Fig. 2.
4. Experimental
4.1. General
IR spectra were recorded on a Shimadzu FTIR-8600PC
instrument. H NMR spectra were recorded with tetra-
1
We also investigated the removal of the chiral auxiliary
from the amines listed in Fig. 1 by palladium-catalyzed
hydrogenolysis. Hydrogenolysis of amine 3a or 12 was
carried out in methanol at room temperature under a
hydrogen atmosphere in the presence of Pd/C. Under
these conditions, the reaction of 3a proceeded readily,
and the chiral 1-(a-naphthyl)ethyl group was removed
methylsilane (TMS) as an internal standard at 90 MHz
on a Hitachi R-90H FT spectrometer and at 299.95
MHz on a Varian INOVA-300 FT spectrometer. 19F
NMR spectra were recorded with hexafluorobenzene as
an internal standard at 84.7 and at 282.22 MHz on the
same spectrometers. Mass spectra (70 eV) were mea-
sured on a Shimadzu QP-5000 instrument. High-resolu-
selectively,
yielding
2,2,2-trifluoro-1-(1H-indol-3-
yl)ethyl-amine 13 (86%) and a N-methylated product
methyl-[2,2,2-trifluoro-1-(1H-indol-3-yl)ethyl]-amine 14
(8%) (Scheme 2). A similar reaction of 12 gave 1-(1-
amino-2,2,2-trifluoro)ethyl-naphthalen-2-ol 15 (72%)
and 1-(2,2,2-trifluoro-1-methylamino)ethyl-naphthalen-
2-ol 16 (20%). HPLC analysis showed that no
tion mass spectra were measured on
a JEOL
JMS-SX102A MS spectrometer. Melting points were
measured in a glass capillary on a heating block, and
are uncorrected. HPLC analysis was performed in a
Shimatzu LC-10VP apparatus equipped with a chiral
column (Daicel OD-R). Optical rotations were mea-
sured in CHCl3 or EtOH solution in a 1 dm cell with a
JASCO DIP-370 digital polarimeter.
detectable
racemization
occurred
during
the
hydrogenolysis of 3a or 12. In contrast, only about 20%
CF3 CH3
CF3
NH2
CF3
NHCH3
N
H
H2, Pd/C
+
N
H
MeOH, rt, 72 h
N
H
13
N
H
14
3a
Scheme 2.

Y. Gong, K. Kato / Tetrahedron: Asymmetry 12 (2001) 2121–2127
2125
4.2. Preparation of imines 1a and 1b
4.3.3. (1-Phenylethyl)-[2,2,2-trifluoro-1-(1H-pyrrol-2-yl)-
ethyl]-amine, (1R,1%S)-4 (major isomer). Colorless oil.
IR (KBr) wmax=3422, 3030, 2968, 2868, 1456, 1362,
1263, 1175, 1136, 1113, 727, 702 cm−1. 1H NMR
(CDCl3) l 1.34 (d, J=6.6 Hz, 3H, CH3), 1.86 (s, br,
1H, NH), 3.62 (q, J=6.6 Hz, 1H, CH3CH), 3.96 (q,
J=7.3 Hz, 1H, CF3CH), 6.14 (m, 2H, ArH), 6.81 (m,
1H, ArH), 7.29 (s, 5H, PhH), 8.36 (br, 1H, NH). 19F
NMR (CDCl3) l 87.16 (d, J=7.3 Hz, 3F, CF3). MS
m/z 268 (M+, 23), 201 (27), 199 (34), 120 (60), 105
(100). Anal. calcd for C14H15F3N2: C, 62.68; H, 5.64; N,
10.44. Found: C, 62.53; H, 5.72; N, 10.29%. (1S,1%S)-4
Trifluoroacetaldehyde ethyl hemiacetal (4.32 g, 30
mmol) was added to a solution of (S)-1-phenylethyl-
amine (3.63 g, 30 mmol) or (R)-1-(1-naph-
thyl)ethylamine (0.51 g, 30 mmol) in toluene (25 mL)
,
dried over 4 A molecular sieves. The mixture was
stirred at room temperature for 15 min, and then
stirred under reflux for 2 h. The solvent was evaporated
under reduced pressure giving the imine as a crude oil.
This imine was used without purification.
1
(minor isomer): H NMR (CDCl3) l 1.36 (d, J=6.6 Hz,
3H, CH3), 4.10 (q, J=7.3 Hz, 1H, CF3CH). 19F NMR
(CDCl3) l 88.27 (d, J=7.3 Hz, 3F, CF3).
4.3. General procedure for the Friedel–Crafts reaction
with imine 1
Boron trifluoride etherate complex (0.21 g, 1.5 mmol)
was added to a solution of indole (0.35 g, 3 mmol) and
imine 1a (0.60 g, 3 mmol) in dried CH2Cl2 (10 mL) at
0°C, and the mixture stirred at 10°C for 4 h. Distilled
water (10 mL) was added, and the mixture neutralized
with saturated aqueous NaHCO3. The organic layer
was separated, and the aqueous layer extracted twice
with ethyl acetate. The organic phases were combined,
dried over anhydrous MgSO4, and subjected to evapo-
ration under reduced pressure. The residue was purified
by silica gel column chromatography (eluted with 1:5
(v/v) of ethyl acetate:hexane) giving 2 as a colorless oil
in 94% yield.
4.3.4. [1-(1-Naphthyl)ethyl]-[2,2,2-trifluoro-1-(1H-pyrrol-
2-yl)ethyl]amine, (1S,1%R)-5 (major isomer). White crys-
tals, mp 69–71°C. IR (KBr) wmax=3439, 3333, 3030,
2982, 2961, 1595, 1515, 1373, 1360, 1259, 1188, 1176,
1
1113, 800, 783, 731 cm−1. H NMR (CDCl3) l 1.46 (d,
J=6.6 Hz, 3H, CH3), 2.03 (s, br, 1H, NH), 4.04 (q,
J=7.5 Hz, 1H, CF3CH), 4.56 (q, J=6.6 Hz, 1H,
CH3CH), 6.06 (m, 1H, ArH), 6.17 (m, 1H, ArH), 6.78
(m, 1H, ArH), 7.25–7.96 (m, 7H, NpH), 8.36 (br, 1H,
NH). 19F NMR (CDCl3) l 87.45 (d, J=7.3 Hz, 3F,
CF3). MS m/z 318 (M+, 18), 251 (8), 170 (10), 155 (100).
Anal. calcd for C18H17F3N2: C, 67.91; H, 5.38; N, 8.80.
Found: C, 67.68; H, 5.47; N, 8.77%. (1R,1%R)-5 (minor
isomer): 19F NMR (CDCl3) l 88.21 (d, J=7.3 Hz, 3F,
CF3).
The Friedel–Crafts reactions of other arenes were com-
pleted in the same way. The spectrum data for all the
main diastereomers are listed below. Only the distin-
guishable NMR data of the minor diastereomer is given
below.
4.3.5.
(1-Phenylethyl)-(2,2,2-trifluoro-1-thiophen-2-yl-
ethyl)amine, (1R,1%S)-6 (major isomer). Colorless oil. IR
(KBr) wmax=3440, 3030, 2966, 2928, 1558, 1541, 1508,
1
1456, 1375, 1338, 1261, 1163, 1136, 1119, 702 cm−1. H
NMR (CDCl3) l 1.38 (d, J=6.6 Hz, 3H, CH3), 1.90 (s,
br, 1H, NH), 4.10 (q, J=6.6 Hz, 1H, CH3CH), 4.26 (q,
J=7.7 Hz, 1H, CF3CH), 6.99 (m, 2H, ArH), 7.29 (s,
6H, ArH and PhH). 19F NMR (CDCl3) l 88.00 (d,
J=7.7 Hz, 3F, CF3). MS m/z 285 (M+, 5), 270 (100),
216 (24), 165 (99), 105 (96). Anal. calcd for
C14H14F3NS: C, 58.93; H, 4.95; N, 4.91. Found: C,
4.3.1. (1-Phenylethyl)-[2,2,2-trifluoro-1-(1H-indol-3-yl)-
ethyl]-amine, (1R,1%S)-2 (major isomer). Colorless oil.
IR (KBr) wmax=3420, 3030, 2966, 2928, 1558, 1456,
1
1340, 1271, 1172, 1115, 764, 744, 702 cm−1. H NMR
(CDCl3) l 1.31 (d, J=6.8 Hz, 3H, CH3), 1.92 (s, br,
1H, NH), 3.71 (q, J=6.8 Hz, 1H, CH3CH), 4.15 (q,
J=7.7 Hz, 1H, CF3CH), 7.13–7.65 (m, 5H, ArH), 7.28
(s, 5H, PhH), 8.20 (s, br, 1H, NH). 19F NMR (CDCl3)
l 87.64 (d, J=7.7 Hz, 3F, CF3). MS m/z 318 (M+, 31),
249(76), 198 (42), 145 (47), 106 (100). Anal. calcd for
C18H17F3N2: C, 67.91; H, 5.38; N, 8.80. Found: C,
67.75; H, 5.42; N, 8.51%. (1S,1%S)-2 (minor isomer): 19F
NMR (CDCl3) l 88.56 (d, J=7.7 Hz, 3F, CF3).
1
58.84; H, 5.18; N, 5.00%. (1R,1%S)-6 (minor isomer): H
NMR (CDCl3) l 1.34 (d, J=6.6 Hz, 3H, CH3), 3.80 (q,
J=6.6 Hz, 1H, CH3CH). 19F NMR (CDCl3) l 86.92
(d, J=7.7 Hz, 3F, CF3).
4.3.6. (1-Phenylethyl)-[2,2,2-trifluoro-1-(4-N,N-dimethyl-
aminophenyl)ethyl]-amine, (1R,1%S)-7 (major isomer).
Colorless oil. IR (KBr) wmax=3439, 3030, 2982, 2961,
2866, 1616, 1526, 1456, 1362, 1263, 1165, 1107, 813,
4.3.2. [1-(1-Naphthyl)ethyl]-[2,2,2-trifluoro-1-(1H-indol-
3-yl)ethyl]-amine, (1S,1%R)-3. White crystals, mp 115–
116°C. IR (KBr) wmax=3412, 3314, 3030, 2966, 2928,
1559, 1458, 1336, 1261, 1194, 1113, 806, 785, 748 cm−1.
1H NMR (CDCl3) l 1.40 (d, J=6.4 Hz, 3H, CH3), 2.10
(s, br, 1H, NH), 4.26 (q, J=7.1 Hz, 1H, CF3CH), 4.56
(q, J=6.4 Hz, 1H, CH3CH), 6.88–8.10 (m, 13H, NH
and ArH). 19F NMR (CDCl3) l 88.30 (d, J=7.1 Hz,
3F, CF3). MS m/z 368 (M+, 59), 299 (39), 251 (8), 198
(39), 170 (68), 156 (100). Anal. calcd for C22H19F3N2:
C, 71.73; H, 5.20; N, 7.60. Found: C, 72.03; H, 5.28; N,
7.43%.
1
764, 702 cm−1. H NMR (CDCl3) l 1.30 (d, J=6.8 Hz,
3H, CH3), 1.88 (s, br, 1H, NH), 2.92 (s, 6H, NCH3),
3.60 (q, J=6.8 Hz, 1H, CH3CH), 3.74 (q, J=7.9 Hz,
1H, CF3CH), 6.68 (d, 2H, J=8.6 Hz, ArH), 7.11 (d,
2H, J=8.6 Hz, ArH), 7.26 (s, 5H, PhH). 19F NMR
(CDCl3) l 87.24 (d, J=7.9 Hz, 3F, CF3). MS m/z 322
(M+, 41), 253 (72), 202 (62), 149 (100), 105 (93). Anal.
calcd for C18H21F3N2: C, 67.06; H, 6.57; N, 8.69.
Found: C, 66.89; H, 6.63; N, 8.65%. (1S,1%S)-7 (minor
1
isomer): H NMR (CDCl3) l 1.33 (d, J=6.8 Hz, 3H,
CH3), 2.90 (s, 6H, NCH3), 3.94 (q, J=7.9 Hz, 1H,

2126
Y. Gong, K. Kato / Tetrahedron: Asymmetry 12 (2001) 2121–2127
CF3CH), 6.65 (d, 2H, J=8.6 Hz, ArH), 7.24 (s, 5H,
PhH). 19F NMR (CDCl3) l 88.59 (d, J=7.9 Hz, 3F,
CF3).
calcd for C20H18F3NO: C, 69.56; H, 5.25; N, 4.06.
Found: C, 69.48; H, 5.29; N, 4.29%. (1S,1%S)-11 (minor
isomer): 19F NMR (CDCl3) l 88.84 (d, J=7.5 Hz, 3F,
CF3).
4.3.7.
4-[2,2,2-Trifluoro-1-(1-phenylethylamino)ethyl]-
phenol, (1R,1%S)-8. Colorless oil. IR (KBr) wmax=3366,
4.3.11. 1-[2,2,2-Trifluoro-1-(1-naphth-1-yl-ethylamino)-
ethyl]-naphth-2-ol, (1S,1%R)-12. White crystals, mp
175°C. IR (KBr) wmax=3340, 3313, 3058, 2988, 1624,
1603, 1520, 1470, 1452, 1381, 1259, 1165, 1109, 950,
3030, 2972, 2866, 1616, 1600, 1518, 1474, 1364, 1261,
1171, 1121, 827, 764, 702 cm−1. H NMR (CDCl3) l
1
1.29 (d, J=6.3 Hz, 3H, CH3), 2.05 (s, 1H, NH), 3.57 (q,
J=6.3 Hz, 1H, CH3CH), 3.90 (q, J=7.3 Hz, 1H,
CF3CH), 6.83 (d, 2H, J=8.3 Hz, ArH), 7.15 (d, 2H,
J=8.3 Hz, ArH), 7.25 (s, 5H, PhH). 19F NMR
(CDCl3) l 87.45 (d, J=7.9 Hz, 3F, CF3). MS m/z 295
(M+, 13), 280 (100), 226 (67), 175 (52), 122 (50), 106
(96). Anal. calcd for C16H16F3NO: C, 65.08; H, 5.46; N,
4.74. Found: C, 65.04; H, 5.63; N, 4.75%. (1S,1%S)-8:
1H NMR (CDCl3) l 1.32 (d, J=6.3 Hz, 3H, CH3), 4.13
(q, J=7.3 Hz, 1H, CF3CH), 6.76 (d, 2H, J=8.3 Hz,
ArH). 19F NMR (CDCl3) l 88.50 (d, J=7.9 Hz, 3F,
CF3).
1
864, 827, 800, 783, 752 cm−1. H NMR (CDCl3) l 1.66
(d, J=6.8 Hz, 3H, CH3), 2.80 (d, br, J=11.6 Hz, 1H,
NH), 4.70 (dq, J=11.6 Hz, 6.8 Hz, 1H, CH3CH), 4.87
(q, J=7.7 Hz, 1H, CF3CH), 6.83–7.85 (m, 13H, ArH),
11.98 (s, 1H, ArOH). 19F NMR (CDCl3) l 88.33 (d,
J=7.7 Hz, 3F, CF3). MS m/z 395 (M+, 48), 241 (12),
177 (17), 155 (100), 128 (21). Anal. calcd for
C24H20F3NO: C, 72.90; H, 5.10; N, 3.54. Found: C,
72.78; H, 5.12; N, 3.64%.
4.4. Synthesis of (S)-2,2,2-trifluoro-1-(1H-indol-3-yl)-
ethylamine, 13
4.3.8. 2-[2,2,2-Trifluoro-1-(1S-phenylethylamino)ethyl]-
phenol, (1R,1%S)-9 (major isomer). Colorless oil. IR
(KBr) wmax=3327, 3032, 2972, 2880, 1618, 1589, 1491,
1473, 1456, 1381, 1364, 1267, 1173, 1128, 758, 700
cm−1. 1H NMR (CDCl3) l 1.44 (d, J=6.6 Hz, 3H,
CH3), 3.90 (q, J=6.6 Hz, 1H, CH3CH), 4.45 (q, J=7.7
Hz, 1H, CF3CH), 6.73–7.25 (m, 4H, ArH), 7.26 (s, 5H,
PhH). 19F NMR (CDCl3) l 87.96 (d, J=7.7 Hz, 3F,
CF3). MS m/z 295 (M+, 20), 280 (14), 191 (8), 122 (15),
105 (100). Anal. calcd for C16H16F3NO: C, 65.08; H,
5.46; N, 4.74. Found: C, 64.99; H, 5.68; N, 4.66%.
(1S,1%S)-9 (minor isomer): 19F NMR (CDCl3) l 87.23
(d, J=7.7 Hz, 3F, CF3).
A mixture of 3a (0.42 g, 1.14 mmol) and palladium on
charcoal (5%, 0.42 g) in methanol (10 mL) was stirred
for 72 h under a hydrogen atmosphere at room temper-
ature. The reaction mixture was filtered through a
Celite pad, and the filtrate concentrated by evaporation
under reduced pressure. The residue was isolated on a
silica gel column eluted with ethyl acetate/hexane (v/v:
1/5–1/2). The first eluted material was 1-ethylnaph-
thalene (0.16 g, 90% from 3a), the second methylamine
14 (0.021 g, 8% from 3a), and the third amine 13 (0.21
g, 86% from 3a). Compound 13: colorless needles
(recrystallization from CHCl3); [h]2D0=+0.7 (c 1.1,
1
EtOH). Mp 130–131°C. H NMR (acetone-d6) l 2.30
4.3.9.
4-Methyl-2-[2,2,2-trifluoro-1-(1S-phenylethyl-
(s, br, 2H, NH2), 4.84 (q, J=7.7 Hz, 1H, CF3CH),
7.10–7.60 (m, 4H, ArH), 7.75 (m, 1H, ArH), 10.35 (s,
br, 1H, NH). 19F NMR (acetone-d6) 87.42 (d, J=7.7
Hz, 3F, CF3). MS m/e 214 (M+, 33), 197 (44), 145 (100),
118 (76). Anal. calcd for C10H9F3N2: C, 56.06; H, 4.24;
N, 13.08. Found: C, 56.34; H, 4.25; N, 12.82%. Com-
pound 14: white needles, [h]2D0=+3.6 (c 0.5, CHCl3).
amino)ethyl]-phenol, (1R,1%S)-10 (major isomer). White
crystals, mp 101–103°C. IR (KBr) wmax=3340, 3304,
3022, 2978, 2922, 1600, 1504, 1448, 1363, 1269, 1151,
1124, 1113, 820, 762, 700 cm−1. H NMR (CDCl3) l
1
1.47 (d, J=6.8 Hz, 3H, CH3), 2.21 (s, 3H, ArCH3), 2.27
(s, br, 1H, NH), 3.70 (q, J=6.8 Hz, 1H, CH3CH), 3.87
(q, J=7.7 Hz, 1H, CF3CH), 6.58 (s, 1H, ArH), 6.80 (d,
1H, J=8.3 Hz, ArH), 7.15 (m, 3H, PhH and ArH),
7.33 (m, 3H, PhH), 10.40 (s, 1H, ArOH). 19F NMR
(CDCl3) l 87.19 (d, J=7.7 Hz, 3F, CF3). MS m/z 309
(M+, 38), 205 (22), 136 (42), 105 (100). Anal. calcd for
C17H18F3NO: C, 66.01; H, 5.87; N, 4.53. Found: C,
66.06; H, 5.93; N, 4.63%. (1S,1%S)-10 (minor isomer):
19F NMR (CDCl3) l 87.99 (d, J=7.7 Hz, 3F, CF3).
1
Mp 102–103°C. H NMR (CDCl3) l 1.78 (s, br, 1H,
CH3NH), 2.50 (s, 3H, CH3), 4.39 (q, J=7.7 Hz, 1H,
CF3CH), 7.15–7.44 (m, 4H, ArH), 7.70 (m, 1H, ArH),
8.42 (s, br, 1H, NH). 19F NMR (CDCl3) 87.90 (d,
J=7.7 Hz, 3F, CF3). MS m/e 228 (M+, 39), 198 (19),
159 (100), 117 (34). Anal. calcd for C11H11F3N2: C,
57.89; H, 4.86; N, 12.28. Found: C, 57.84; H, 4.85; N,
12.23%.
4.3.10. 1-[2,2,2-Trifluoro-1-(1-phenylethylamino)ethyl]-
naphth-2-ol, (1R,1%S)-11 (major isomer). White crystals,
mp 112–113°C. IR (KBr) wmax=3340, 3298, 3059, 3030,
2968, 2930, 1622, 1601, 1585, 1521, 1470, 1454, 1379,
1263, 1240, 1180, 1163, 1113, 953, 874, 820, 750, 698
cm−1. 1H NMR (CDCl3) l 1.53 (d, J=6.8 Hz, 3H,
CH3), 2.45 (d, br, J=12.1 Hz, 1H, NH), 3.74 (dq,
J=12.1 Hz, 6.8 Hz, 1H, CH3CH), 4.86 (q, J=7.5 Hz,
1H, CF3CH), 6.93–7.35 (m, 4H, ArH), 7.27 (s, 5H,
PhH), 7.77 (m, 2H, ArH), 11.85 (s, 1H, ArOH). 19F
NMR (CDCl3) l 88.27 (d, J=7.5 Hz, 3F, CF3). MS
m/z 345 (M+, 54), 241 (20), 172 (75), 105 (100). Anal.
4.5. Synthesis of (S)-1-(1-Amino-2,2,2-trifluoro-ethyl)-
naphthalen-2-ol, 15
Compound 12 (0.25 g, 0.63 mmol) was hydrogenated in
methanol (10 mL) in the presence of palladium on
charcoal (5%, 0.16 g) according to the same procedures.
The residue was isolated by silica gel column chro-
matography, eluting with ethyl acetate/hexane (v/v: 1/
5–1/3). The first eluted material was 1-ethylnaphthalene
(0.090 g, 91% from 12), the second methylamine 16
(0.032 g, 20% from 12), and the third amine 15 (0.11 g,
72% from 12). Compound 15: colorless needles, [h]2D0=

Y. Gong, K. Kato / Tetrahedron: Asymmetry 12 (2001) 2121–2127
2127
1
+3.3 (c 0.6, CHCl3). Mp 106–107°C. H NMR (CDCl3)
l 2.02 (s, br, 2H, NH2), 5.60 (q, J=7.0 Hz, 1H,
CF3CH), 7.11 (d, J=9.0 Hz, 1H, ArH), 7.39 (m, 3H,
ArH), 7.76 (d, J=8.8 Hz, 2H, ArH), 11.13 (s, br, 1H,
ArOH). 19F NMR (CDCl3) 86.66 (d, J=7.0 Hz, 3F,
CF3). MS m/e 241 (M+, 31), 196 (28), 172 (100), 146
(22), 127 (55). Anal. calcd for C12H10F3NO: C, 59.75;
H, 4.18; N, 5.81. Found: C, 59.80; H, 4.17; N, 5.76%.
Compound 16: colorless needles, [h]2D0=+1.0 (c 0.8,
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Soloshonok, V. A., Ed.; John and Wiley & Sons:
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1992, 2, 219–222; (d) Shirlin, D.; Tarnus, C.; Baltzer, S. J.
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Kitazume, T.; Yamazaki, T. J. Fluorine Chem. 1997, 83,
15–19; (b) Wang, Y.; Mosher, H. S. Tetrahedron Lett.
1991, 32, 987–990.
1
CHCl3). Mp 135–136°C. H NMR (CDCl3) l 2.51 (s,
3H, CH3), 5.13 (q, J=7.2 Hz, 1H, CF3CH), 7.10 (d,
J=9.0 Hz, 1H, ArH), 7.39 (m, 3H, ArH), 7.78 (d,
J=8.6 Hz, 2H, ArH). 19F NMR (CDCl3) 88.12 (d,
J=7.2 Hz, 3F, CF3). MS m/e 255 (M+, 27), 196 (19),
186 (100), 177 (12), 146 (12). Anal. calcd for
C13H12F3NO: C, 61.17; H, 4.74; N, 5.49. Found: C,
61.19; H, 4.72; N, 5.44%.
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Enantiocontrolled Synthesis of Fluoro-organic Compounds: