Practical synthesis of optically active fluorine-substituted α-phenylethylamines by retardation of hydrogenolytic cleavage at benzylic position

Article abstract of DOI:10.1246/cl.2004.1424

High regioselectivity in hydrogenolysis of bis(α-methylbenzyl)amines having a fluorine atom on aromatic ring results from retardation of hydrogenolytic cleavage at benzylic position of fluorine-substituted aromatic ring.

Full text of DOI:10.1246/cl.2004.1424

1424
Chemistry Letters Vol.33, No.11 (2004)
Practical Synthesis of Optically Active Fluorine-substituted ꢀ-Phenylethylamines
by Retardation of Hydrogenolytic Cleavage at Benzylic Position
Masatomi Kanai,ꢀ Manabu Yasumoto, Yokusu Kuriyama, Kenjin Inomiya, Yutaka Katsuhara,
Kimio Higashiyama,y and Akihiro Ishiiꢀ
Chemical Research Center, Central Glass Co., Ltd., Kawagoe 350-1151
yFaculty of Pharmaceutical Science, Hoshi University, Shinagawa, Tokyo 142-8501
(Received July 29, 2004; CL-040897)
High regioselectivity in hydrogenolysis of bis(ꢀ-methylben-
Table 1. Regioselective hydrogenolysis of bis(ꢀ-methylben-
zyl)amines (1) affected by fluorine substituenta
zyl)amines having a fluorine atom on aromatic ring results from
retardation of hydrogenolytic cleavage at benzylic position of
fluorine-substituted aromatic ring.
CH3
CH3
S
NH2
+
2 wt% Pd/C
(0.05 wt% as Pd)
CH3 CH3
F
S
S
H
2 (0.5 MPa)
N
H
2
Recently we reported that highly regioselective hydrogenol-
ysis of bis(ꢀ-methylbenzyl)amines proceeded under influence of
trifluoromethyl group on aromatic ring. (Scheme 1).1 This regio-
selectivity was governed not by electronic effect but by steric ef-
fect of trifluoromethyl group.
CH3OH (1 M)
60 °C
CH3
CH3
F
S
1
12 h
H2N
+
F
Entry
Substrate (1)
Conversionb Regioselectivityc
CH3
CH3 CH3
Regioselective
hydrogenolysis
*
1
2
3
4
5
6
7
8
o-F
m-F
p-F
33%
39%
5%
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
*
*
NH2
N
a
b
H
a : b = >99 : 1
CF3
CF3
3,5-di-F
61%
99%
99%
99%
99%
o-F (phthalic acid salt)
m-F (phthalic acid salt)
p-Fd
Scheme 1. Regioselective hydrogenolysis of bis(ꢀ-methylben-
zyl)amines affected by trifluoromethyl group.
In synthetic application for optically active fluorine-substi-
tuted ꢀ-phenylethylamines,2–4 we were interested in regioselec-
tive hydrogenolysis of bis(ꢀ-methylbenzyl)amines affected by
fluorine substituent.5 In this communication, we disclose that a
fluorine atom at any position of aromatic ring plays an important
role to give a high regioselectivity of >99:1, and this high regio-
selectivity results from retardation of hydrogenolytic cleavage at
the benzylic position.
3,5-di-Fd
aRegioselective hydrogenolysis was carried out on a 10 mmol
scale.
bConversion was determined by GC analysis.
cRegioselectivity was determined by the ratio of ethylbenzene vs
fluorine-substituted ethylbenzene in GC analysis.
dAcetic acid (5.0 equiv.) was added.
Diastereomerically pure bis(ꢀ-methylbenzyl)amines (1)
having fluorine substituent at o-, m-, p-, and 3,5-di-position were
prepared by a similar method as described in previous re-
ports.1,5,6 First, we examined regioselective hydrogenolysis us-
ing free base of 1 (Table 1, Entries 1–4). Surprisingly, we found
that even at any fluorine substituted position high regioselectiv-
ities of >99:1 were observed under optimized reaction condi-
tions;1 2 wt % Pd/C (0.05 wt % as Pd),7 H2 0.5 MPa, CH3OH
(1 M), 60 ꢁC, 12 h. However, reaction rates were slow in all cas-
es, especially for p-F-1. They were dramatically increased using
organic acid salts of 1 without any decrease of regioselectivity
(Entries 5–8).
erned by steric effect of substituents were not observed
(Figure 1). Clearly methyl and ethyl groups were sterically more
hindered than fluorine atom. Therefore, high regioselectivity in
hydrogenolysis of fluorine-substituted 1 could not be rational-
ized only by the steric effect of fluorine atom.
The hydrogenolytic reaction rate affected by various sub-
stituents was examined using N-methyl secondary amines 5 as
a model substrate (Table 2). Results of Entries 1–4 seemed to
show the order of steric size. On the other hand, the reaction rate
was extremely retarded by incorporating a fluorine atom on the
CH3 CH3
*
*
This high regioselectivity might be governed mainly by ster-
ic effect of fluorine atom in a similar manner of trifluoromethyl
group.1 However, this consideration was not easily acceptable,
because fluorine atom would most closely resemble and mimic
hydrogen atom with respect to steric requirement.8 In fact, in
competitive hydrogenolytic cleavage of 4-fluoro-40-methyl-
and 4-fluoro-40-ethyl-disubstituted substrates (3 and 4)9 under
the same reaction conditions,10 expected regioselectivities gov-
N
a
b
H
F
R
3: R = CH3, a : b = >99 : 1, conversion 35%
4: R = C2H5, a : b = 84 : 16, conversion 9%
Figure 1. Competitive hydrogenolytic cleavage of 4-fluoro-40-
methyl- and 4-fluoro-40-ethyl-disubstituted substrates (3 and 4).
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.11 (2004)
1425
Soc., 118, 5142 (1996). b) F.-Y. Zhang, C.-C. Pai, and A. S. C.
Chan, J. Am. Chem. Soc., 120, 5808 (1998). c) W. Hu, M. Yan,
C.-P. Lau, S. M. Yang, and A. S. C. Chen, Tetrahedron Lett., 40,
973 (1999). d) Y.-Y. Yang and T. V. RajanBabu, Org. Lett., 2,
4137 (2000).
Table 2. Hydrogenolytic reaction rate of N-methyl secondary
amines (5) affected by various substituentsa
20 wt% Pd/C
CH3
CH3
(0.64 mol% as Pd)
2 0.5 MPa
CH3
H
N
H
CH3NH2
+
5
6
Only regioselective hydrogenolysis of ortho-fluorine-substitut-
ed bis(ꢀ-methylbenzyl)amine has been reported to give a mod-
erate regioselectivity of 89:11. However, its scope and limita-
tion and effect of fluorine atom were not discussed at all. G.
Bringmann and J.-P. Geisler, J. Fluorine Chem., 49, 67 (1990).
Diastereomeric mixtures of 1 were prepared through dehydra-
tion between corresponding fluorine-substituted acetophenones
(100 mmol) and commercially available (S)-ꢀ-phenylethyl-
amine (110 mmol), followed by reduction of resulting imines.
Dehydration was performed in the presence of a catalytic
amount of zinc chloride (1.00 mmol) in toluene (1 M) under re-
flux (15 h) with removal of produced water using a Dean–Stark
trap in quantitative yields. Three m-, p-, and 3,5-di-F-imines
were obtained solely as (E)-isomers, while o-F-imine contained
a small amount of (Z)-isomer (E:Z = 85:15). Reduction was
performed using sodium borohydride (100 mmol) in methanol
(1 M) at 0 ꢁC (7 h) in quantitative yields with moderate diaster-
eomeric excesses [ca. 60–70% de (S,S) for m-, p-, and 3,5-di-
F-1], except for o-F-1 [20% de (S,S)]. Diastereomeric excesses
of all bis(ꢀ-methylbenzyl)amines were easily improved to
>99.5% (S,S) by recrystallization of phthalic acid salts in ca.
70% recovery yields.
CH3OH (1 M)
60 °C
R
R
6
5
6 h
Substrate (5)
(R=)
Relative
Reaction Rate
Entry
Conversionb
1
2
3
4
5
6
7
p-H
77%
60%
49%
42%
9%
1
p-CH3
p-C2H5
p-CF3
p-F
m-F
3,5-di-F
0.78
0.64
0.55
0.12
0.09
<0.01
7%
0.2%
aRegioselective hydrogenolysis was carried out on a 2 mmol
scale.
bConversion was determined by GC analysis.
aromatic ring (Entries 5–7). These results could rationalize high
regioselectivities observed in Table 1 and unexpected regiose-
lectivities shown in Figure 1. The hydrogenolytic cleavage rate
at the benzylic position having a fluorine atom on the aromatic
ring was even slower than that at the benzylic position of unsub-
stituted benzene ring.
Finally, practical synthesis of optically active fluorine-sub-
stituted ꢀ-phenylethylamines (2) was examined on a 100 gram
scale.11 Above-mentioned o-, m-, p-, and 3,5-di-F-2 were ob-
tained in total yields of 40–60% and enantiomeric excesses of
>99.5% in all cases.
7
8
Pd/C (NX-type, 5 wt %, water content 50 wt %, N. E. CHEM-
CAT) was used.
R. Filler, in ‘‘Organofluorine Chemicals and Their Industrial
Applications,’’ ed. by R. E. Banks, Ellis Horwood, Ltd.,
Chichester, UK (1979), Chap. 6.
Diastereomeric excesses of 4-fluoro-40-methyl- and 4-fluoro-40-
ethyl-disubstituted substrates (3 and 4) were 67% (S,S) and 66%
(S,S), respectively.
9
10 Acetic acid (5.0 equiv.) was added.
In conclusion, we found that high regioselectivity in hydro-
genolysis of bis(ꢀ-methylbenzyl)amines having a fluorine atom
on the aromatic ring resulted from retardation of hydrogenolytic
cleavage at the benzylic position of fluorine-substituted aromatic
ring, and could be applied to practical synthesis of optically ac-
tive ꢀ-phenylethylamines having a fluorine atom at any position
on the aromatic ring.
11 Typical procedure for (S)-p-F-2. (A) A solution containing 138 g
(1.00 mol) of p-fluoroacetophenone, 133 g (1.10 mol) of (S)-ꢀ-
phenylethylamine, and 1.36 g (0.01 mol) of ZnCl2 in 500 mL
of toluene was refluxed with azeotropic removal of water for
15 h using a Dean-Stark trap. Reaction mixture was washed with
1 M NaOH, a saturated aqueous solution of NH4Cl (three times)
to remove residual (S)-ꢀ-phenylethylamine, and brine. After re-
moval of solvent under a reduced pressure, 241 g of p-F-imine
was obtained in a quantitative yield. (B) Sodium borohydride
(37.8 g, 1.00 mol) was added to a solution containing 241 g of
p-F-imine in 1.00 L of methanol at <10 ꢁC, and solution was
stirred for at 0 ꢁC (12 h). Reaction mixture was acidified with
1 M HCl and neutralized with 3 M NaOH. Extracted toluene so-
lution was washed with brine. After removal of solvent under a
reduced pressure, a diastereomeric mixture of p-F-1 was ob-
tained in a quantitative yield [243 g, 60% de (S,S)]. (C) To a so-
lution containing 243 g (1.00 mol) of p-F-1 in 360 mL of propan-
2-ol and 500 mL of heptane, 166 g (1.00 mol) of phthalic acid
was added and reaction mixture was heated until solid was dis-
solved. After temperature was lowered slowly to 20 ꢁC, 229 g of
phthalic acid salt of p-F-1 was obtained by filtration in 70% re-
covery yield [99.5% de (S,S)]. (D) Phthalic acid salt of p-F-1
was neutralized with 3 M NaOH. Extracted toluene solution
was washed with brine. After removal of solvent under a re-
duced pressure, 136 g (0.56 mol) of obtained free base p-F-1
in 600 mL of methanol was hydrogenolyzed in the presence of
2.72 g of Pd/C (0.05 wt % as Pd) under 0.5 MPa of H2 pressure
at 60 ꢁC for 12 h. Pd catalyst was filtered off through a Celite
pad, and after removal of solvent under a reduced pressure, res-
idue was distilled (69 ꢁC/7 mmHg) to give 76.4 g (0.55 mol) of
p-F-2 in 98% yield [GC purity = 99.9%, 99.7% ee, (S)].
We thank Prof. Kenji Uneyama (Okayama University) for
fruitful discussions.
References and Notes
1
2
M. Kanai, M. Yasumoto, Y. Kuriyama, K. Inomiya, Y.
Katsuhara, K. Higashiyama, and A. Ishii, Org. Lett., 5, 1007
(2003).
Regioselective hydrogenolysis of bis(ꢀ-methylbenzyl)amines
having electron-donating groups has been already reported.
a) G. Bringmann, J.-P. Geisler, T. Geuder, G. Kunkel, and L.
Kinzinger, Liebigs Ann. Chem., 1990, 795. b) G. Bringmann
and J.-P. Geisler, Tetrahedron Lett., 30, 317 (1989).
3
Optically active fluorine-substituted ꢀ-phenylethylamines have
been regarded as important intermediates in development of
medicines. a) H. Kurata, T. Kohama, K. Kono, and K. Kitayama,
WO 02051396 (2002). b) A. G. Taveras, C. J. Aki, R. W. Bond,
J. Chao, M. Dwyer, J. A. Ferreia, J. Chao, Y. Yu, J. J. Baldwin,
B. Kaiser, G. Li, J. R. Merritt, K. H. Nelson, and L. L. Rokosz,
WO 0208364 (2002). c) B. A. Mckittrick, G. Guo, Z. Zhu, and
Y. Ye, WO 02051808 (2002).
4
Recently enantioselective reductions of enamide have been re-
ported. a) M. J. Burk, Y. M. Wang, and J. R. Lee, J. Am. Chem.
Published on the web (Advance View) October 2, 2004; DOI 10.1246/cl.2004.1424