An efficient and mild ruthenium-catalyzed racemization of amines: Application to the synthesis of enantiomerically pure amines

Article abstract of DOI:10.1016/S0040-4039(02)00817-1

An efficient and mild Ru-catalyzed racemization of amines under transfer hydrogenation conditions is reported. A significant advantage of this new procedure is that the ruthenium hydrogen transfer catalysts allow high functional group tolerance. Interestingly, both primary and secondary amines were efficiently racemized under these conditions. We also report on the combination of this new amine racemization with an enzymatic kinetic resolution of primary amines.

Full text of DOI:10.1016/S0040-4039(02)00817-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4699–4702
An efficient and mild ruthenium-catalyzed racemization of
amines: application to the synthesis of enantiomerically pure
amines
´
Oscar Pa`mies, Alida H. Ell, Joseph S. M. Samec, Nina Hermanns and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden
Received 4 March 2002; revised 17 April 2002; accepted 25 April 2002
Abstract—An efficient and mild Ru-catalyzed racemization of amines under transfer hydrogenation conditions is reported. A
significant advantage of this new procedure is that the ruthenium hydrogen transfer catalysts allow high functional group
tolerance. Interestingly, both primary and secondary amines were efficiently racemized under these conditions. We also report on
the combination of this new amine racemization with an enzymatic kinetic resolution of primary amines. © 2002 Published by
Elsevier Science Ltd.
The value of enantiopure amines lies mainly in their
utility as building blocks for the synthesis of agrochem-
icals and pharmaceuticals. In recent years, many
approaches for the preparation of enantiomerically
pure amines have been developed.1 Among these meth-
ods, the enzymatic kinetic resolution (KR) of the race-
mate still has a dominant role.2 However, a major
drawback with KR is that the yield is limited to a
maximum of 50%.3 Racemization is therefore an impor-
tant tool that in combination with the KR can provide
an efficient use of all racemate (after several racemiza-
tion/KR repetitions the yield of the product can
approach 100%).4 However, only a few methods for
racemization of amines are known in the literature.4,5
Moreover, their potential utility is hampered by the
harsh reaction conditions (high temperatures, and
strong basic and/or reductive media) usually required,
making these procedures incompatible with several
functional groups. Therefore, it is important to develop
new methods to racemize amines under conditions that
can tolerate a wide number of different functional
groups.
nium-catalyzed racemization of amines under transfer
hydrogenation conditions (Eq. (1)). An important
advantage of this new procedure is that the ruthenium
hydrogen transfer catalysts allow high functional group
tolerance.8 We also report on the combination of this
new amine racemization with an enzymatic KR of
primary amines.5d,5e,9
(1)
In a first set of experiments the racemization of (S)-1-
phenylethylamine (S)-2a using Ru-catalyst precursor
110 was studied under different reaction conditions. The
results are summarized in Table 1. Despite the complete
racemization of (S)-2a (entry 1), the efficiency of the
process was poor, since considerable amounts of imine
4a and the corresponding amine 5a were formed. The
latter two compounds are formed via attack by 2a on
imine 3a followed by elimination of ammonia (Scheme
1).5a
We have previously shown that low valent ruthenium
complexes catalyze transfer hydrogenation of imines to
amines6 and transfer dehydrogenation of amines to
imines.7 These transformations are key steps in the
racemization of amines. We now report on a ruthe-
To increase the efficiency of the process it is necessary
to decrease the amount of the side products. Three
* Corresponding author. Tel.: +46-8-674-7178; fax: +46-8-154908;
e-mail: jeb@organ.su.se
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00817-1

4700
O. Pa`mies et al. / Tetrahedron Letters 43 (2002) 4699–4702
different approaches were tried: (a) dilution of the
reaction mixture; (b) addition of ammonia and (c)
addition of a hydrogen source to increase the concen-
tration of 1a.
tion of 0.5 or 1 equiv. of 2,4-dimethyl-3-pentanol 6 as a
mild hydrogen donor successfully inhibited the forma-
tion of side products (entries 6 and 7).
The results show that the concentration greatly affects
the formation of side products 4 and 5 (entries 1–4).
Thus, at low concentration the efficiency of the racem-
ization was higher, but the side product formation was
not completely inhibited. The addition of ammonia led
to a significant improvement and the formation of side
products 4 and 5 was effectively inhibited (entry 5).
However, the scope of this procedure is limited since
the use of highly basic ammonia reduces the functional
group tolerance. Interestingly, we found that the addi-
Figure 1. Temperature effect on the racemization of (S)-2a.
Scheme 1. Proposed mechanism for the formation of imine 4a and amine 5a (phenyl groups on cyclopentadien(yl) rings are
omitted for clarity).
Table 1. Racemization of (S)-2a using catalyst precursor 1a
OH
6
Entry
t (h)
Additive
Conc. 2ab
% 2ac (% eed)
% 4c
% 5c
1
2
3
4
5
6
7
48
48
48
48
48
48
48
–
–
–
–
1
0.5
5 (0)
21 (3)
84 (6)
91 (3)
98 (2)
98 (2)
98 (2)
12
8
5
29
15
11
0.25
0.125
0.25
0.25
0.25
3
6
1 equiv. NH3
0.5 equiv. 6
1 equiv. 6
B1
B1
B1
B1
B1
B1
a Reaction conditions: (S)-2a (0.25 mmol), 1 (5 mol%) in toluene at 100°C.
b Concentration in M.
c Yield measured by GC on a CP-Chirasil-Dex CB column using pentadecane as internal standard based on the corresponding acetates after 24
h.
d Enantiomeric excess measured by GC on a CP-Chirasil-Dex CB column based on the corresponding acetates.

O. Pa`mies et al. / Tetrahedron Letters 43 (2002) 4699–4702
Table 2. Ru-catalyzed racemization of amines 2a–ka
4701
NHR'
NHR'
Toluene / 110 oC
R
R''
R
R''
6 (0.5 equiv.) / cat. 1
Entry
Amine
R
R%
R%%
% Racemization after 1 hb
t (h)
% 2c (% eed)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
24
43
21
30
11
100e
18
44
28
–
24
9
24
9
36
1
24
12
12
48
48
98 (3)
98 (3)
95 (2)
4-OMe-Ph
4-F-Ph
4-Me-Ph
2-Naphthyl
Ph
Ph
4-OMe-Ph
Ph
92 (2)
H
99 (5)
Me
Ph
Ph
H
H
H
\99 (0f)
98 (1)
\99 (3)
CO2Me
CH2OTBDPS
CH2OTBDMS
98 (1g)
10
11
2j
2k
Ph
Ph
\95h (57g)
\95h (32g)
–
a Reaction conditions: (S)-2 (0.25 mmol), 1 (5 mol%), 6 (0.12 mmol), toluene (2 mL).
b % Racemization defined as 100-% ee, measured after 1 h.
c Yield measured by GC on a CP-Chirasil-Dex CB column using pentadecane as internal standard.
d Enantiomeric excess measured by GC on a CP-Chirasil-Dex CB column based on the corresponding acetates.
e After 10 min, 70% racemization had occurred.
f Measured by GC based on the amine.
g Measured by HPLC on a Daicel, Chiracel OD-H column based on the amine.
h Yield measured by NMR.
An important temperature effect was also observed
(Fig. 1). Thus, as expected, the racemization efficiency
is better at higher temperature.
This new procedure was then applied to the practical
synthesis of enantiomerically pure (R)-N-(1-
phenylethyl) acetamide (R)-7a and (R)-N-((4-
methoxyphenyl)ethyl) acetamide (R)-7b from the
corresponding (rac)-amines 2a and 2b. For this pur-
pose, the racemization procedure was combined with
the enzymatic KR of primary amines in a two step
manner (Scheme 2).
A number of different amines 2a–k were racemized
employing this new procedure (Table 2).11 Interestingly,
both primary and secondary amines were efficiently
racemized under these conditions. We also found that
electronic variations of para-substituted 1-phenylethyl-
amines have an effect on the efficiency of the racemiza-
tion. Thus, the presence of electron-donating sub-
stituents increases the rate of racemization (entries 2
and 4) while electron-withdrawing substituents led to a
lower reaction rate (entry 3). A similar behavior was
observed in the series of secondary amines (entries 6–8).
Thus, the fastest racemization was observed for the
electron-rich N-methyl-1-phenylethylamine (entry 6).
Interestingly, the a-amino ester 2i was also efficiently
racemized under these conditions (entry 9). This
method can also be applied to sterically hindered pro-
tected a-amino alcohols 2j and 2k. However the
efficiency of the process is lower. A possible explana-
tion can be found in the high steric bulk of the silyl
groups. This seems to be corroborated by the higher
efficiency when the phenyl groups of the TBDPS is
replaced by the less hindered methyl groups (entry 10
versus 11).
The enantiomerically pure acetamides (R)-7a and (R)-
7b were efficiently prepared by enzymatic KR of (rac)-2
using Candida antarctica lipase (N-435) and ethyl ace-
tate as acyl donor at 40°C.2b After separation of (S)-2
and (R)-7 by standard extraction, (R)-7 were collected
and the recovered amines (S)-2 were racemized at
110°C using the procedure described in Table 2. After
the racemization, ethyl acetate and the recovered
enzyme from the previous KR were added to the solu-
tion. After this second KR run, the corresponding
acetamides 7 were isolated in good combined yield
NHAc
NH2
(R)-7
R
N-435 / AcOEt
Toluene
+
NH2
R
Application of catalyst 1 in a repetitive process was
probed with 1-(4-methoxyphenyl)ethyl amine 2b. Thus,
after completion of the reaction from entry 2 in Table
2, the mixture was cooled and concentrated to dryness,
additional aliquots of substrate, alcohol 6 and solvent
were added, and racemization was continued without
appreciable loss of activity. Up to three cycles were
carried out without addition of more catalyst.
(rac)-2 a R= H
b R= OMe
(S)-2
R
cat 1 / 6
Toluene
Scheme 2.

4702
O. Pa`mies et al. / Tetrahedron Letters 43 (2002) 4699–4702
(69% for (R)-7a and 66% for (R)-7b) in almost enan-
tiomerically pure form (ee >98%).
Chimia 1996, 50, 668; (e) Choi, Y. K.; Kim, M. J.; Ahn,
Y.; Kim, M. J. Org. Lett. 2001, 3, 4099. For amino acid
derivatives, see: (f) Hateley, M. J.; Schichl, D. A.; Fis-
cher, C.; Beller, M. Synlett 2001, 1, 25; (g) Sheldon, R.
A.; Wegman, M. A.; Hacking, M. A. P. J.; Rops, J.;
Pereira, P.; van Rantwijk, F. Tetrahedron: Asymmetry
1999, 10, 1739.
In summary, we have developed a new procedure for
the racemization of primary and secondary amines. The
efficiency of the process together with the mild reaction
conditions make the present method an attractive alter-
native to existing methods for racemizing amines. Fur-
ther studies to investigate the scope and limitations of
this procedure and to study the possibility to perform
in situ DKR are under way.
6. (a) Wang, G.-Z.; Ba¨ckvall, J. E. J. Chem. Soc., Chem.
Commun. 1992, 980; (b) Samec, J. S. M.; Ba¨ckvall, J. E.
Chem. Eur. J., in press.
´
7. Ell, A. H.; Samec, J. S. M.; Brasse, C.; Ba¨ckvall, J. E.
Chem. Commun. 2002, 1144.
8. (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev.
1992, 92, 1051; (b) Gladiali, S.; Mestroni, G. In Transi-
tion Metals for Organic Synthesis; Beller, M.; Bolm, C.,
Eds.; Wiley VCH: Weinheim, 1998; pp. 97–119; (c)
Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999,
10, 2045.
Acknowledgements
Financial support from the Swedish Foundation for
Strategic Research and the Swedish Research Council is
gratefully acknowledged.
9. A similar coupled system has been used by us and others
to perform DKR on alcohols. See for instance: (a)
Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J. E. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1211; (b) Persson, B. A.;
Larsson, A. L. E.; LeRay, M.; Ba¨ckvall, J. E. J. Am.
Chem. Soc. 1999, 121, 1645; (c) Persson, B. A.; Huerta, F.
F.; Ba¨ckvall, J. E. J. Org. Chem. 1999, 64, 5237; (d) Lee,
D.; Huh, E. A.; Kim, M. J.; Jung, H. M.; Koh, J. H.;
Park, J. Org. Lett. 2000, 2, 2377; (e) Huerta, F. F.;
Laxmi, Y. R. S.; Ba¨ckvall, J. E. Org. Lett. 2000, 2, 1037;
(e) Huerta, F. F.; Ba¨ckvall, J. E. Org. Lett. 2001, 3, 1209;
(f) Pa`mies, O.; Ba¨ckvall, J. E. J. Org. Chem. 2001, 66,
4022; correction J. Org. Chem. 2002, 67, 1418; (g) Kim,
M. J.; Choi, Y. K.; Choi, M. Y.; Kim, M. J.; Park, J.
J. Org. Chem. 2001, 66, 4736; (h) Pa`mies, O.; Ba¨ckvall,
J. E. Adv. Synth. Catal. 2001, 343, 726; (i) Pa`mies, O.;
Ba¨ckvall, J. E. J. Org. Chem. 2002, 67, 1261.
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10. Ru-complex 1 was prepared according to Ref. 9e and
recrystallized from CH2Cl2/pentane prior to use.
11. In a typical experiment: To a solution of (S)-2a (32 mL,
0.25 mmol), 6 (18 mL, 0.125 mmol) and pentadecane (69
mL) in dry toluene (2 mL) under argon ruthenium cata-
lyst 1 (13.6 mg, 0.0125 mmol) was added. The resulting
reaction mixture was stirred at 110°C for 24 h under
argon. To determine the yield and ee by GC, a sample
(0.25 mL) was quenched with acetic anhydride (0.25 mL)
and triethylamine (0.25 mL). After 5 min the sample was
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