Asymmetric synthesis of α-monofluoromethyl- and α- difluoromethylbenzylamines through regioselective hydrogenolysis

Article abstract of DOI:10.1016/j.jfluchem.2005.01.009

Asymmetric synthesis of α-monofluoromethyl- and α- difluoromethylbenzylamines through regioselective hydrogenolysis is described. Hydrogenolysis of diastereomerically pure bis(α-methylbenzyl)amine derivatives having partially fluorinated methyl group at b

Full text of DOI:10.1016/j.jfluchem.2005.01.009

Journal of Fluorine Chemistry 126 (2005) 377–383
www.elsevier.com/locate/fluor
Asymmetric synthesis of a-monofluoromethyl- and
a-difluoromethylbenzylamines through
regioselective hydrogenolysis
a
a
a
Masatomi Kanai a, , Koji Ueda , Manabu Yasumoto , Yokusu Kuriyama ,
*
Kenjin Inomiya a, Takashi Ootsuka a, Yutaka Katsuhara a,
Kimio Higashiyama b, Akihiro Ishii a,
*
a Chemical Research Center, Central Glass Co. Ltd., Kawagoe, Saitama 350-1151, Japan
b Faculty of Pharmaceutical Science, Hoshi University, Shinagawa, Tokyo 142-8501, Japan
Received 13 December 2004; received in revised form 11 January 2005; accepted 13 January 2005
Available online 16 March 2005
Abstract
Asymmetric synthesis of a-monofluoromethyl- and a-difluoromethylbenzylamines through regioselective hydrogenolysis is described.
Hydrogenolysis of diastereomerically pure bis(a-methylbenzyl)amine derivatives having partially fluorinated methyl group at benzylic
position also proceeded with a high regioselectivity as well as in the case of a-trifluoromethyl group. Moreover, opposite asymmetric
induction was observed in reduction of chiral imines derived from partially fluorinated acetophenone and a-phenylethylamine.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Asymmetric synthesis; a-Monofluoromethylbenzylamine; a-Difluoromethylbenzylamine; Regioselective hydrogenolysis; Diastereomerically
pure bis(a-methylbenzyl)amine derivative; Partially fluorinated methyl group; Opposite asymmetric induction
1. Introduction
fluorinated a-methyl group (n = 1 or 2) has a similar effect.
If desirable hydrogenolysis at side ‘‘A’’ would occur,
optically active a-monofluoromethyl- and a-difluoro-
methylbenzylamines, which are novel and potentially
promising intermediates in medicinal chemistry [3], could
be obtained [4].
Recently we reported that highly regioselective hydro-
genolysis of diastereomerically pure bis(a-methylbenzyl)-
amine derivatives proceeded under influence of fluorine
atom or trifluoromethyl group on aromatic ring [1]. This
regioselective hydrogenolysis could be applied to a practical
asymmetric synthesis of fluorine or trifluoromethyl sub-
stituted a-phenylethylamines. In our research direction, we
are interested in a regioselective hydrogenolysis of bis-
(a-methylbenzyl)amine derivatives affected by partially
fluorinated a-methyl group (Scheme 1). Retarding effect of
a-trifluoromethyl group for hydrogenolytic cleavage at side
‘‘B’’ has been well-known [2]. However, to the best of our
knowledge, it has never been investigated whether partially
In this report, we disclose that partially fluorinated a-
methyl group also plays an important role in regioselective
hydrogenolysis.
2. Results and discussion
Preparation of diastereomerically pure bis(a-methylben-
zyl)amine derivatives having partially fluorinated a-methyl
group was first examined (Table 1).
Dehydration between corresponding partially fluorinated
acetophenone (1) [5] and commercially available (S)-a-
phenylethylamine was carried out in the presence of a
* Corresponding authors. Tel.: +81 49 246 3711; fax: +81 49 243 4201.
E-mail addresses: mkanai@cgco.co.jp (M. Kanai), aishii@cgco.co.jp
(A. Ishii).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.01.009

378
M. Kanai et al. / Journal of Fluorine Chemistry 126 (2005) 377–383
2 and X-ray analysis of analogous (R)-N-(2,2,2-trifluoro-1-
phenylethylidene)-2-phenylglycinol [8], where chiral aux-
iliary and trifluoromethyl group were located in trans
configuration [9].
Subsequent 1,3-asymmetric reduction of partially fluori-
nated imine (S-2) was examined. After screening of reducing
agents, sodium borohydride was found to be effective to give
diastereomeric mixture of bis(a-methylbenzyl)amine deri-
vative (S-3) with a reasonable diastereoselectivity (Table 1,
entries 1 and 2) [10]. In all entries, diastereomeric excess of
S-3 was easily improved to >99.0% by recrystallization of
organic acid salt in ca. 70% ( p-TsOH salt for S-F1-3 and S-
F3-3, phthalic acid salt for S-F2-3). Relative stereochemistry
of three major diastereomers was obviously determined to
be all syn (S,S) configuration by X-ray analysis of
corresponding organic acid salt (Fig. 2). Opposite asym-
metric induction was observed in comparison with that
observed in reduction of (S)-nonfluoroimine (S-F0-2), where
major diastereomer of S-F0-3 was anti (S,S) [11]. This
opposite sense was rationalized by a reaction mechanism
through a proposed transition state [12], and resulted from
opposite geometry of fluorinated imine (S-2) (Fig. 3).
Next, regioselective hydrogenolysis of diastereomeri-
cally pure bis(a-methylbenzyl)amine derivative (S,S-3) was
examined. When free base of S,S-F1-3 was used as a
substrate, unexpected linear secondary amine was obtained
(Table 2, entry 1) [13,14]. This by-product might be
produced via an aziridine intermediate as shown in Fig. 4. In
Scheme 1. Regioselective hydrogenolysis affected by partially fluorinated
a-methyl group.
catalytic amount of zinc chloride with azeotropic removal of
produced water. Expected (S)-monofluoroimine (S-F1-2)
was obtained in a good yield as a mixture of geometry,
whose ratio was determined to be 75:25 by 1H and 19F NMR
(entry 1). Configuration of major isomer was clarified to be
E by assignment using ROE technique of 1H NMR [6]
(Fig. 1). In minor isomer (Z), ROE correlation was observed
between methine proton of chiral auxiliary and methylene
proton of monofluoromethyl group, while not observed in
major isomer (E). In comparison with (S)-nonfluoroimine
(S-F0-2) derived from acetophenone and (S)-a-phenylethy-
lamine [7], where chiral auxiliary and methyl group were
located in cis configuration, opposite geometry was
observed for major isomer of S-F1-2. This indicated that
geometry of imine was strongly influenced by incorporating
a fluorine atom.
On the other hand, (S)-difluoroimine (S-F2-2) and (S)-
trifluoroimine (S-F3-2) were obtained as a sole isomer
(entries 2 and 3). These geometries also were determined to
be E configuration from a similarity of major isomer of S-F1-
Table 1
Preparation of diastereomerically pure bis(a-methylbenzyl)amine derivatives
Entrya
Substrate (1)
Yield of S-2
Geometry of S-2
Yield of S-3
Diastereomeric ratio of S-3
1
F1-1 (n = 1)
F2-1 (n = 2)
F3-1 (n = 3)
S-F1-2, 95%
S-F2-2, 99%
S-F3-2, 93%
E:Z = 75:25
E:Z = >99:1
E:Z = >99:1
S-F1-3, 90%
S-F2-3, 84%
S-F3-3, 89%
S,S:R,S = 67:33
S,S:R,S = 79:21
S,S:R,S = 77:23
2
3b
a
Dehydration scale: 50 mmol; reduction scale: 30 mmol.
b
According to Ref. [2]. Dehydration: (S)-a-phenylethylamine (1.5 equiv.), p-TsOH (0.1 equiv.); reduction: NaBH3CN (2.0 equiv.).
Fig. 1. ROE correlation of S-F1-2.

M. Kanai et al. / Journal of Fluorine Chemistry 126 (2005) 377–383
379
Fig. 2. Major diastereomer of S-3.
fact, desirable hydrogenolysis proceeded smoothly using its
p-TsOH salt, maybe due to decreased nucleophilicity of
nitrogen atom (entry 2).
Fig. 3. Transition state of 1,3-asymmetric reduction.
Interestingly, even in monofluorinated S,S-F1-3, a high
regioselectivity (97:3) was observed to produce (S)-a-
monofluoromethylbenzylamine (S-F1-4) in a good yield
without any racemization. Moreover, hydrogenolysis of S,S-
F2-3Áphthalic acid proceeded with an exclusive regioselec-
tivity (>99:1) to produce (S)-a-difluoromethylbenzylamine
(S-F2-4) (entry 3) as well as trifluoromethyl counterpart (S,S-
F3-3Á p-TsOH, entry 4). These high regioselectivities might
be governed by a difference between two carbon–nitrogen
bond strengths. Actually, a significant difference of bond
length was observed in X-ray analysis of organic acid salt of
S,S-3 (Table 3). On the other hand, steric effect at benzylic
position could not be completely excluded as a possible
factor, because Baltzly et al. reported that hydrogenolysis of
N-benzyl-a-methylbenzylamine proceeded with a high
regioselectivity [15]. However, considering steric hindrance
of fluorine atom [16] and regioselectivity of monofluoro-
substrate S,S-F1-3, it would be acceptable that this highly
regioselective hydrogenolysis was affected mainly by the
former bond strength factor.
Table 2
Regioselective hydrogenolysis of diastereomerically pure bis(a-methylbenzyl)amine derivatives
Entrya
Substrate
Conversionb
Regioselectivityb,c
Yieldd
e
e
1
S,S-F13 (n = 1)
ca. 25%
>99%g
>99%
–
–
2f
S,S-F1-3Áp-TsOH (n = 1)
S,S-F2-3Áphthalic acid (n = 2)
S,S-F3-3Áp-Ts0H (n = 3)
97:3g
84%
98%
95%
3
4h
a
>99:1
>99:1
>99%
1 mmol scale.
b
c
d
e
f
Determined by GC.
Ethylbenzene vs. fluorine substituted ethylbenzene.
Determined by internal reference method in 19F NMR.
Production of linear secondary amine.
In the presence of AcOH (5.0 equiv.).
g
h
Determined by GC of corresponding acetamide.
According to Ref. [2].

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M. Kanai et al. / Journal of Fluorine Chemistry 126 (2005) 377–383
Fig. 4. Side reaction via aziridine intermediate.
Table 3
saturated NH4Cl 30 mL (three times). Recovered organic
layer was washed with brine 50 mL. After removal of
solvent under a reduced pressure, crude product of partially
fluorinated imine (S-2) was obtained in the following yield.
Comparison of two carbon–nitrogen bond lengths
1
Geometrical ratio was determined by H and 19F NMR.
Trifluorinated imine (S-F3-2) was prepared according to Ref.
[2].
˚
C1-N (A)
˚
C2-N (A)
Organic acid salt
3.2.1. (S)-N-[(E)-2-fluoro-1-phenylethylidene]-2-phen-
ylethylamine (S-E-F1-2) and (S)-N-[(Z)-2-fluoro-1-
phenylethylidene]-2-phenylethylamine (S-Z-F1-2)
Total yield 95%. E:Z = 75:25.
S,S-Fr3Áp-TsOH
1.50 (1)
1.49 (1)
1.52 (2)
1.55 (1)
1.51 (1)
1.54 (2)
S,S-F2-3Áphthalic acid
S,S-F3-3Áp-TsOH
1
Major isomer (S-E-F1-2): H NMR, d 1.43 (d, 6.4 Hz,
In conclusion, we found that highly regioselective
hydrogenolysis of diastereomerically pure bis(a-methyl-
benzyl)amine derivatives proceeded under influence of
partially fluorinated methyl group at benzylic position to
provide an asymmetric synthesis of a-monofluoromethyl-
and a-difluoromethylbenzylamines. Moreover, we demon-
strated an instructive example that reaction path was
dramatically changed by incorporating a fluorine atom.
3H), 4.56 (q, 6.4 Hz, 1H), 5.12 (d, 47.2 Hz, 2H), 7.00–7.60
(Ar–H, 10H). 19F NMR, d +206.98 (t, 47.2 Hz, 1F).
1
Minor isomer (S-Z-F1-2): H NMR, d 1.58 (d, 6.6 Hz,
3H), 5.01 (q, 6.6 Hz, 1H), 5.31 (dd, 12.3 Hz, 46.1 Hz, 1H),
5.43 (dd, 12.3 Hz, 46.1 Hz, 1H), 7.00–7.60 (Ar–H, 10H). 19
NMR, d +208.31 (t, 46.1 Hz, 1F).
F
3.2.2. (S)-N-[(E)-2,2-difluoro-1-phenylethylidene]-2-
phenylethylamine (S-F2-2)
Yield 99%. E:Z = >99:1.
3. Experimental
S-E-F2-2: 1H NMR, d 1.42 (d, 6.6 Hz, 3H), 4.58 (q,
6.6 Hz, 1H), 6.21 (t, 56.0 Hz, 1H), 7.10–7.55 (Ar–H, 10H).
19F NMR, d +43.49 (dd, 332.4 Hz, 56.0 Hz, 1F), +44.35 (dd,
332.4 Hz, 56.0 Hz, 1F).
3.1. General
1H NMR (400 MHz), 13C NMR (100 MHz) and 19F NMR
(376 MHz) spectra were measured with a JEOL a-400 FT-
NMR spectrometer in CDCl3 solution with (CH3)4Si or C6F6
as an internal standard. GC analyses were carried out with a
Shimadzu GC-17A. High resolution mass spectra were
obtained with a Hitachi M-2500. Melting points were
measured with a Yanaco MP-J3 and were uncorrected. X-ray
analyses were measured with a Rigaku AFC7R diffract-
ometer. HPLC analyses were carried out with a Agilent 1100
Series.
3.2.3. (S)-N-[(E)-2,2,2-trifluoro-1-phenylethylidene]-2-
phenylethylamine (S-F3-2)
Yield 93%. E:Z = >99:1.
S-E-F3-2: 1H NMR, d 1.44 (d, 6.4 Hz, 3H), 4.54 (q,
6.4 Hz, 1H), 7.05–7.55 (Ar–H, 10H). 19F NMR, d +90.69
(s, 3F).
Sodium borohydride 30 mmol (1.0 equiv.) was added to a
solution containing crude product of partially fluorinated
imine (S-2) 30 mmol (1.0 equiv.) in methanol 30 mL at
<5 8C, and then solution was stirred for 12 h at room
temperature. Reaction mixture was quenched with 3N HCl
10 mL, and then alkalized with 3N NaOH 30 mL, followed
by extraction with toluene 50 mL (two times). Recovered
organic layer was washed with brine 30 mL. After removal
of solvent under a reduced pressure, crude diastereomeric
mixture of bis(a-methylbenzyl)amine derivative (S-3) was
obtained in the following yield. Diastereomeric ratio was
determined by GC (DB-5; length 30 M, i.d. 0.25 mm,
film 0.25 mm). Diastereomeric mixture of trifluorinated
3.2. Preparation of diastereomerically pure bis(a-methyl-
benzyl)amine derivatives (S,S-3)
A solution containing partially fluorinated acetophenone
(1) 50 mmol (1.0 equiv.), (S)-a-phenylethylamine 55 mmol
(1.1 equiv.) and zinc chloride 1.5 mmol (0.03 equiv.) in
toluene 50 mL was refluxed with azeotropic removal of
produced water for 24 h using a Dean–Stark trap. Reaction
mixture was washed with 1N NaOH 30 mL, and then with

M. Kanai et al. / Journal of Fluorine Chemistry 126 (2005) 377–383
381
bis(a-methylbenzyl)amine derivative (S-F3-3) was prepared
according to Ref. [2].
3.2.7. (aS)-a-(difluoromethyl)-N-[(S)-1-phenylethyl]benze-
nemethanamine (phthalic acid salt) (S,S-F2-3Áphthalic
acid)
3.2.4. (aS)-a-(fluoromethyl)-N-[(S)-1-
phenylethyl]benzenemethanamine (S,S-F1-3)
Recrystallization of organic acid salt was carried out from
a solution containing crude diastereomeric mixture of S-F2-3
(1.0 equiv.) and phthalic acid (1.0 equiv.) in i-propanol/n-
hexane mixed solvent (50/50, 2 mL/mmol).
Total yield 90%. S,S:R,S = 67:33.
Major isomer (S,S-F1-3): 1H NMR, d 1.37 (d, 6.7 Hz, 3H),
1.82 (br, 1H), 3.81 (q, 6.7 Hz, 1H), 4.04 (ddd, 4.4 Hz,
6.8 Hz, 16.6 Hz, 1H), 4.47 (ddd, 6.8 Hz, 9.0 Hz, 47.7 Hz,
1H), 4.53 (ddd, 4.4 Hz, 9.0 Hz, 47.7 Hz, 1H), 7.10–7.40
(Ar–H, 10H). 13C NMR, d 22.44, 55.15, 59.93 (d, 19.0 Hz),
86.39 (d, 174.4 Hz), 126.68, 127.03, 127.71, 127.88, 128.42,
128.59, 138.87, 144.97. 19F NMR, d +206.59 (dt, 16.6 Hz,
47.7 Hz, 1F). HRMS (EI), calculated for C16H18FN (Mꢀ+)
243.1422, found 243.1404.
mp, 174–176 8C.
X-ray, A colorless prismatic crystal of C48H46F4N2O8
having approximate dimensions of 0.45 mm  0.20 mm Â
0.50 mm was mounted on a glass fiber. All measurements
were made on a Rigaku AFC7R diffractometer with filtered
Cu Ka radiation (l =154178 A) and a rotating anode
generator. Crystal data of S,S-F2-3Áphthalic acid:
M = 854.89; monoclinic space group P1(#1), Z =1 with
a = 11.176(2)A, b = 11.193(2)A, c = 9.490(3)A, b =
111.96(2)o, V = 1090.2(4) A3, and Dcalc = 1.302 g/cm3.
All calculations were performed using the CrystalStructure
crystallographic software package. The structure was solved
by direct methods and expanded using Fourier techniques.
The non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were refined using the riding model. The
final R- and Rw-factors after full-matrix least squares
refinement were 0.096 and 0.107, respectively, based on
3664 observed reflections (I > 3.00 s(I)). Crystallographic
data have been deposited with Cambridge Crystallographic
Data Center as supplementary publication no. CCDC
258054.
3.2.5. (aS)-a-(fluoromethyl)-N-[(s)-1-phenylethyl]benze-
nemethanamine (p-toluenesulfonic acid salt) (S,S)-F1-3Áp-
TsOH
Recrystallization of organic acid salt was carried out from
a solution containing crude diastereomeric mixture of S-F1-3
(1.0 equiv.) and p-TsOH (1.0 equiv.) in i-propanol/n-hexane
mixed solvent (30/70, 4 mL/mmol).
mp, 195–197 8C.
X-ray, a colorless prismatic crystal of C92H104N4O12F4S4
having approximate dimensions of 0.20 mm  0.20 mm Â
0.25 mm was mounted on a glass fiber. All measurements
were made on a Rigaku AFC7R diffractometer with filtered
Cu Ka radiation (l = 154178 A) and a rotating anode
generator. Crystal data of S,S-F1-3Á p-TsOH; M = 1662.09;
monoclinic space group P21(#4), Z = 2 with a = 21.630(1)A,
b = 9.5087(7)A, c = 21.567(2)A, b = 100.439(5)o, V =
4362.3(5) A3, and Dcalc = 1.265 g/cm3. All calculations
were performed using the CrystalStructure crystallographic
software package. The structure was solved by direct
methods and expanded using Fourier techniques. The non-
hydrogen atoms were refined anisotropically. Hydrogen
atoms were refined using the riding model. The final R- and
Rw-factors after full-matrix least squares refinement were
0.077 and 0.072, respectively, based on 5909 observed
reflections (I > 3.00 s(I)). Crystallographic data have been
deposited with Cambridge Crystallographic Data Center as
supplementary publication no. CCDC 258053.
3.2.8. (aS)-a-(trifluoromethyl)-N-[(s)-1-phenylethyl]-
benzenemethanamine (S,S-F3-3)
Total yield 89%. S,S:R,S = 77:23.
Major isomer (S,S-F3-3): 1H NMR, d 1.37 (d, 6.7 Hz, 3H),
1.89 (br, 1H), 3.97 (q, 6.7 Hz, 1H), 4.04 (q, 6.8 Hz, 1H),
7.15–7.40 (Ar–H, 10H). 13C NMR, d 23.50, 56.00, 61.63 (q,
28.7 Hz), 126.01 (q, 281.9 Hz), 126.64, 127.29, 128.14,
128.55, 128.66, 128.71, 135.37, 144.52. 19F NMR, d +88.72
(d, 6.8 Hz, 3F). HRMS (EI), calculated for C16H16F3N (Mꢀ+)
279.1233, found 279.1223.
3.2.9. (aS)-a-(trifluoromethyl)-N-[(S)-1-phenylethyl]-
benzenemethanamine (p-toluenesulfonic acid salt)
(S,S-F3-3Áp-TsOH)
Recrystallization of organic acid salt was carried out from
a solution containing crude diastereomeric mixture of S-F3-3
(1.0 equiv.) and p-TsOH (1.0 equiv.) in i-propanol/n-hexane
mixed solvent (50/50, 4 mL/mmol).
3.2.6. (aS)-a-(difluoromethyl)-N-[1-phenylethyl]-
benzenemethanamine (S,S-F2-3)
Total yield 84%. S,S:R,S = 79:21.
Major isomer (S,S-F2-3): 1H NMR, d 1.36 (d, 6.5 Hz, 3H),
1.80 (br, 1H), 3.88 (q, 6.5 Hz, 1H), 3.94 (dt, 4.4 Hz, 12.2 Hz,
1H), 5.88 (dt, 4.4 Hz, 57.2 Hz, 1H), 7.10–7.45 (Ar–H, 10H).
13C NMR, d 22.73, 55.18, 61.83 (t, 21.9 Hz), 117.27 (t,
245.1 Hz), 126.43, 126.96, 128.05, 128.16, 128.31, 128.47,
136.13, 144.74. 19F NMR, d +37.61 (ddd, 280.7 Hz, 57.2 Hz,
12.2 Hz, 1F), +38.46 (ddd, 280.7 Hz, 57.2 Hz, 12.2 Hz, 1F).
HRMS (EI), calculated for C16H17F2N (Mꢀ+) 261.1328,
found 261.1345.
mp, 185–187 8C.
X-ray, a colorless prismatic crystal of C92H96F12N4O12S4
having approximate dimensions of 0.20 mm  0.10 mm Â
0.20 mm was mounted on a glass fiber. All measurements
were made on a Rigaku AFC7R diffractometer with filtered
Cu Ka radiation (l = 154178 A) and a rotating anode
generator. Crystal data of S,S-F3-3Á p-TsOH: M = 1896.01;
monoclinic space group P21(#4), Z = 2 with a = 22.022(4)A,
b = 9.561(3)A, c = 21.930(4)A, b = 99.48(1)o, V = 4554.4(2)

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M. Kanai et al. / Journal of Fluorine Chemistry 126 (2005) 377–383
A3, and Dcalc = 1.317 g/cm3. All calculations were per-
formed using the CrystalStructure crystallographic software
package. The structure was solved by direct methods and
expanded using Fourier techniques. The non-hydrogen
atoms were refined anisotropically. Hydrogen atoms were
refined using the riding model. The final R- and Rw-factors
after full-matrix least squares refinement were 0.074 and
0.069, respectively, based on 4489 observed reflections
(I > 3.00 s(I)). Crystallographic data have been deposited
with Cambridge Crystallographic Data Center as supple-
mentary publication no. CCDC 258055.
Enantiomer excess >99.0% ee (chiral HPLC; acetamide
of S-F2-4, S isomer 8.0 min, R isomer 12.0 min, n-hexane/
i-propanol = 75/25, 25 8C, 240 nm, 1.0 mL/min).
3.3.3. (S)-a-trifluoromethylbenzylamine (S-F3-4)
1H NMR, d 1.77 (br, 2H), 4.39 (q, 7.5 Hz, 1H), 7.30–7.50
(Ar–H, 5H). 19F NMR, d +85.06 (d, 7.5 Hz, 3F).
Enantiomer excess >99.0% ee (chiral GC; acetamide of
S-F3-4, R isomer 15.4 min, S isomer 15.6 min).
Acknowledgement
3.3. Regioselective hydrogenolysis of diastereomerically
pure bis(a-methylbenzyl)amine derivatives (S-4)
We thank Prof. Kenji Uneyama (Okayama University) for
fruitful discussions.
A solution containing organic acid salt of diastereomeri-
cally pure bis(a-methylbenzyl)amine derivative (S,S-3,
>99.0% de) 1 mmol (1.0 equiv.) in methanol 5 mL was
hydrogenolyzed in the presence of 5% palladium/carbon
(NX-type, water content 50%, N.E. CHEMCAT) 8.5 mg
under 0.5 MPa of H2 at 60 8C for 12 h. Palladium catalyst
was filtered off through a Celite pad. Regioselectivity was
determined by GC (DB-5; length 30 M, i.d. 0.25 mm, film
0.25 mm). After removal of solvent under a reduced
pressure, crude product of partially fluorinated a-methyl-
benzylamine (S-4) was obtained in the following yield. Yield
was determined by internal reference method (internal
standard; C6F6) in 19F NMR. Enantiomer excess was
determined by chiral HPLC (CHIRALPAK AS; length
25 cm, i.d. 0.46 cm) or GC (Chirasil-DEX CB; length 25 M,
i.d. 0.25 mm, film 0.25 mm). Trifluorinated a-methylben-
zylamine (S-F3-4) was prepared according to Ref. [2].
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WO 02/50056.
[4] Only novel synthesis of racemic a-difluoromethylbenzylamine deri-
vatives has been reported, B. Greedy, V. Gouverneur, Chem. Com-
mun., (2001) 233–234.
[5] G.K.S. Prakash, J. Hu, G.A. Olah, J. Fluorine Chem. 112 (2001) 357–
362.
[6] Rotation frame nuclear Overhauser Effect.
[7] S-F0-2 was synthesized as sole E isomer in a similar manner with
Table 1. Total yield 96%, E:Z = >99:1. S-E-F0-2, 1H NMR [CDCl3,
(CH3)4Si], d 1.54 (d, 6.4 Hz, 3H), 2.26 (s, 3H), 4.84 (q, 6.4 Hz, 1H),
7.10–7.90 (Ar–H, 10H).
3.3.1. (S)-a-fluoromethylbenzylamine (S-F1-4)
This compound was unstable on GC analysis. Therefore,
S-F1-4 was characterized as its corresponding acetamide.
Acetamide of S-F1-4: 1H NMR, d 2.06 (s, 3H), 4.66 (ddd,
47.3 Hz, 14.0 Hz, 4.0 Hz, 1H), 4.72 (ddd, 47.3 Hz, 14.0 Hz,
4.0 Hz, 1H), 5.28 (ddt, 25.3 Hz, 8.0 Hz, 4.0 Hz, 1H), 6.06
(br, 1H), 7.30–7.40 (Ar–H, 5H). 13C NMR, d 23.36, 53.03 (d,
19.1 Hz), 84.83 (d, 174.4 Hz), 127.03, 128.13, 128.88,
137.90, 169.57. 19F NMR, d À61.5 (dt, 25.3 Hz, 47.3 Hz).
HRMS (EI), calculated for C10H13FNO (MH+) 182.0980,
found 182.0993.
[8] A. Ishii, F. Miyamoto, K. Higashiyama, K. Mikami, Tetrahedron Lett.
39 (1998) 1199–1202.
[9] Recently geometry of F3-2 has been reported to be Z configuration,
which is inconsistent with our result (E configuration), B. Torok,
G.K.S. Prakash, Adv. Synth. Catal., 345 (2003) 165–168.
[10] Asymmetric induction by chiral auxiliary itself, which meant hydride
attack from CH3 side vs. from Ph side in following Fig. 3, was
estimated to be 78:22 (average of entries 2 and 3 in Table 1).
Considering geometry of S-F1-2 (E:Z = 75:25) as an additional factor,
diastereomeric ratio of S-F1-3 was calculated to be S,S:R,S = 64:36
(found 67:33).
Enantiomer excess >99.0% ee (chiral HPLC; S isomer
10.0 min, R isomer 14.0 min, n-hexane/i-propanol = 75/25,
25 8C, 240 nm, 1.0 mL/min).
[11] Asymmetric reduction of S-F0-2 (E:Z = >99:1) was carried out using
sodium borohydride in a similar manner with Table 1. Yield 96%, S,S
(anti):R,S (syn) = 86:14. S,S-F0-3. 1H NMR [CDCl3, (CH3)4Si], d 1.27
(d, 6.6 Hz, 6H), 1.60 (br, 1H), 3.50 (q, 6.6 Hz, 2H), 7.18–7.35 (Ar–H,
10H).
3.3.2. (S)-a-difluoroluoromethylbenzylamine (S-F2-4)
1H NMR, d 1.71 (br, 2H), 4.15 (ddd, 12.9 Hz, 9.6 Hz,
4.5 Hz, 1H), 5.74 (dt, 4.5 Hz, 56.5 Hz, 1H), 7.25–7.45 (Ar–
H, 5H). 13C NMR, d 57.92 (dd, 24.0 Hz, 21.5 Hz), 117.17 (t,
243.8 Hz), 127.48, 128.38, 128.64, 137.42. 19F NMR, d
+34.52 (ddd, 277.6 Hz, 56.5 Hz, 12.9 Hz, 1F), 37.68 (ddd,
277.6 Hz, 56.5 Hz, 9.6 Hz, 1F). HRMS (EI), calculated for
C8H8F2N (M À H) 156.0624, found 156.0614.
[12] J.-P. Charles, H. Christol, G. Solladie, Bull. Soc. Chim. Fr. (1970)
4439–4446.
[13] By-product was completely in accordance with authentic sample in
analysis of GC and 1H NMR. Racemic linear secondary amine was
synthesized from 2-phenylethylamine and acetophenone through a
similar dehydration and following hydride reduction using sodium
borohydride in a total yield of 85%. 1H NMR [CDCl3, (CH3)4Si], d
1.32 (d, 6.6 Hz, 3H), 1.50 (br, 1H), 2.65–2.85 (m, 4H), 3.77 (q, 6.6 Hz,

M. Kanai et al. / Journal of Fluorine Chemistry 126 (2005) 377–383
383
1H), 7.13–7.39 (Ar–H, 10H). 13C NMR [CDCl3, (CH3)4Si], d 24.18,
36.31, 48.77, 58.06, 125.95, 126.40, 126.73, 128.27, 128.55, 139.94,
145.48.
Shin, C.S. Park, D. Choi, W.K. Lee, Tetrahedron Lett., 39 (1998)
9193–9196.
[15] R. Baltzly, P.B. Russell, J. Am. Chem. Soc. 75 (1953) 5598–5602.
[16] Fluorine would most closely resemble and mimic hydrogen with
respect to steric requirement, R. Filler, in: R.E. Banks (Ed.), Organo-
fluorine Chemicals and Their Industrial Applications, Ellis Horwood
Ltd., Chichester, UK, 1979 (Chapter 6).
[14] (D)-phenylalanine derivatives were prepared through cis-2,3-disub-
stituted aziridines, which was synthesized from N-a-hydroxymethyl-
benzyl-a-methylbenzylamines via intramolecular cyclization, by the
same regioselective manner as our case, J.-W. Chang, J.H. Bae, S.-H.