In this communication, we disclose that the hydrogenolysis
of bis(R-methylbenzyl)amine derivatives having a trifluoro-
methyl substituent, a strong electron-withdrawing group, also
proceeds similarly in a highly regioselective manner and that
these regioselectivities are governed not by the electronic
effect but by the steric effect of the substituent. Moreover,
we can provide a practical asymmetric synthesis of trifluoro-
methyl substituted R-phenylethylamines through the highly
regioselective hydrogenolysis affected by a trifluoromethyl
group.4
First, we examined the regioselective hydrogenolysis of
the free base of 3 under standard debenzylation conditions:
Pd/C 2 wt % (0.05 wt % as Pd metal), H2 0.5 MPa, methanol,
60 °C, 12 h. In all cases (Table 2, entries 1-4), the high
Table 2. Regioselective Hydrogenolysis of Diastereomerically
Pure Bis(R-methylbenzyl)amine Derivatives (3)a
The diastereomeric mixtures of bis(R-methylbenzyl)amine
derivatives (3) were prepared through the dehydration be-
tween the corresponding trifluoromethyl substituted aceto-
phenones (1) and the commercially available (S)-R-phenyl-
ethylamine. The reaction was performed in the presence of
a catalytic amount of zinc chloride in toluene under reflux
with the removal of the produced water using a Dean-Stark
trap, followed by the hydride reduction of the resulting imines
(2) using sodium borohydride in methanol at 0 °C in
quantitative yields and moderate diastereomeric excesses (ca.
70% de), except for o-CF3-3 (Table 1). During the prepara-
conversion
regio-
b
c
entry
substrate (3)
of 3
selectivity
1
2
3
4
5
6
7
o-CF3
m-CF3
p-CF3
25%
76%
58%
>99%
>99%
>99%
>99%
99/1
96/4
97/3
>99/1
>99/1
>99/1
>99/1
3,5-bis-CF3
d
o-CF3
m-CF3 (phthalic acid salt)
p-CF3 (phthalic acid salt)
Table 1. Preparation of Diastereomeric Mixtures of
Bis(R-methylbenzyl)amine Derivatives (3)a
a Regioselective hydrogenolysis was carried out on a 10 mmol scale.
b Conversion of 3 was determined by GC analysis. c Regioselectivity was
determined by the ratio of ethylbenzene vs trifluoromethyl-substituted
ethylbenzene in GC analysis. d Acetic acid (5.00 equiv) was added.
regioselectivities of >96:4 were observed without any
racemization of the expected products 4;6 however, the
reaction rates of the monosubstituted o-, m-, and p-CF3-3
were slow, except for 3,5-bis-CF3-3. The order of the rates
(3,5-bis- > m- > p- > o-CF3-3) was reasonable, considering
the inductive effect (-I) and the steric hindrance of the
substrate
total yield
diastereomeric
entry
(1)
of 3
ratio of 3
1b
2
3
o-CF3
m-CF3
p-CF3
3,5-bis-CF3
40%c
(S,S)/(R,S) ) 59/41
(S,S)/(R,S) ) 86/14
(S,S)/(R,S) ) 85/15
(S,S)/(R,S) ) 84/16
quantitative
quantitative
quantitative
4
(4) Trifluoromethyl-substituted R-phenylethylamines have been regarded
as important intermediates in the development of medicines. (a) Alvaro,
G.; Di Fabio, R.; Giovannini, R.; Guercio, G.; St-Denis, Y.; Ursini, A. WO
0125219, 2001. (b) Armstrong, H. M.; Beresis, R.; Goulet, J. L.; Holmes,
M. A.; Hong, X.; Mills, S. G.; Parsons, W. H.; Sinclair, P. J.; Steiner, M.
G.; Wong, F.; Zaller, D. M. WO 0100213, 2001. (c) Bloom, J. D.; Digrandi,
M. J.; Dushin, R. G.; Lang, S. A.; O’Hara, B. M. WO 0034269, 2000.
From an industrial point of view, our synthetic method is very practical,
because enantiomerically pure (>99.5% ee) trifluoromethyl-substituted
R-phenylethylamines are easily prepared in an acceptable yield. Recently,
the enantioselective hydrogenation of enamides or phosphinylimines using
a catalytic amount of Rh catalysts containing various chiral phosphine
ligands has been studied. However, the optical purity of the obtained
acetamides or phosphinamides was insufficient, and a sequential tedious
hydrolysis of the resulting hydrogenated products followed. (a) Spindler,
F.; Blaser H.-U. AdV. Synth. Catal. 2001, 343, 68. (b) Hu, W.; Yan. M.;
Lau, C.-P.; Yang, S. M.; Chan, A. S. C.; Jiang, Y.; Mi, A. Tetrahedron
Lett. 1999, 40, 973. (c) Zhang, F.-Y.; Pai, C.-C.; Chan, A. S. C. J. Am.
Chem. Soc. 1998, 120, 5808. (d) Burk, M. J.; Wang, Y. M.; Lee, J. R. J.
Am. Chem. Soc. 1996, 118, 5142.
a Preparation was carried out on a 100 mmol scale. b Dehydration was
carried out in the presence of 15 mol % zinc chloride for 44 h, and then
the hydride reduction was carried out using 2.30 equiv of sodium
borohydride. c Isolated yield of o-CF3-2, which contained three isomers (ratio
) 19:40:41), was 76%. Reaction conversion of o-CF3-2 to o-CF3-3 was
55%.
tion of o-CF3-2, even when the dehydration was carried out
in the presence of 15 mol % zinc chloride for 44 h, the
isolated yield of o-CF3-2 was only 76% because of the steric
hindrance of the ortho-trifluoromethyl substituent. The m-,
p-, and 3,5-bis-CF3-2 were obtained solely as (E)-isomers,
while o-CF3-2 contained three isomers (ratio ) 19:40:41)
consisting of atropisomers or geometric isomers.5 Also, for
the hydride reduction of the resulting o-CF3-2 even using
2.30 equiv of sodium borohydride, the reaction conversion
was only 55%. The diastereomeric excesses of m-, p-, and
3,5- bis-CF3-3 were easily improved to >99.5% by the
recrystallization of the phthalic acid salts for m- and p-CF3-3
or the p-toluenesulfonic acid (p-TsOH) salt for 3,5-bis-CF3-3
in ca. 70% recovery yields.
(5) Ratio of the three isomers was determined by 19F NMR. The chemical
shifts in the 19F NMR were δ 101.9, 102.0, and 103.7 ppm (C6F6, CDCl3)
for the ratio of 19:40:41, respectively. The structures of each isomer were
unclear, but they were likely stereoisomers since hydrogenolysis of each
provided a mixture of o-CF3-3. The ratio of 19:40:41 in three isomers
changed to that of 25:48:27 after 2 h at 120 °C.
(6) We used 5% Pd/C (NX-type, water content 50%) purchased from
N. E. CHEMCAT. The racemization and overhydrogenolysis of the expected
products 4 were observed using Pd(OH)2/C as a Pd catalyst for a longer
reaction time.
1008
Org. Lett., Vol. 5, No. 7, 2003