Heterogeneous raney nickel and cobalt catalysts for racemization and dynamic kinetic resolution of amines

Article abstract of DOI:10.1002/adsc.200700336

Raney metals were studied as heterogeneous catalysts for racemization and dynamic kinetic resolution (DKR) of chiral amines, as an alternative to metals like palladium or ruthenium. Both Raney nickel and cobalt were able to selectively racemize various chiral amines with high selectivity. In the racemization of benzylic primary amines, the minor formation of side products, e.g., secondary amines, can be suppressed by varying the hydrogen pressure. In the racemization of aliphatic amines over Raney catalysts, the selectivity is very high, with the enantiomeric amine as the sole product. DKR of racemic aliphatic amines can be performed with immobilized Candida antarctica lipase B and Raney nickel in one pot; for 2-hexylamine, a yield of 95% of the acetylated amide was achieved, with 97% ee. Attention is devoted to the compatibility of the enzyme and the metal catalyst during the DKR. For benzylic primary amines, a two-pot process is proposed in which the liquid is alternatingly shuttled between two vessels containing the solid racemization catalyst and the biocatalyst. After 4 such cycles, the amide of (R)-1-phenylethylamine was obtained with 94% yield and more than 90% ee.

Full text of DOI:10.1002/adsc.200700336

FULL PAPERS
DOI: 10.1002/adsc.200700336
Heterogeneous Raney Nickel and Cobalt Catalysts for
Racemization and Dynamic Kinetic Resolution of Amines
Andrei N. Parvulescu,a Pierre A. Jacobs,a and Dirk E. De Vosa,*
a
Centre for Surface Chemistry and Catalysis, K.U.Leuven, Kasteelpark Arenberg 23, 3001 Leuven, Belgium
Fax : (+32)-16-32-1998; e-mail: dirk.devos@biw.kuleuven.be
Received: July 10, 2007; Revised: October 10, 2007; Published online: December 20, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Raney metals were studied as heterogene- pot; for 2-hexylamine, a yield of 95% of the acetylat-
ous catalysts for racemization and dynamic kinetic ed amide was achieved, with 97% ee. Attention is
resolution (DKR) of chiral amines, as an alternative devoted to the compatibility of the enzyme and the
to metals like palladium or ruthenium. Both Raney metal catalyst during the DKR. For benzylic primary
nickel and cobalt were able to selectively racemize amines, a two-pot process is proposed in which the
various chiral amines with high selectivity. In the rac- liquid is alternatingly shuttled between two vessels
emization of benzylic primary amines, the minor for- containing the solid racemization catalyst and the
mation of side products, e.g., secondary amines, can biocatalyst. After 4 such cycles, the amide of (R)-1-
be suppressed by varying the hydrogen pressure. In phenylethylamine was obtained with 94% yield and
the racemization of aliphatic amines over Raney cat- more than 90% ee.
alysts, the selectivity is very high, with the enantio-
meric amine as the sole product. DKR of racemic Keywords: chiral amides; chiral amines; dynamic ki-
aliphatic amines can be performed with immobilized netic resolution; kinetic resolution; Raney cobalt;
Candida antarctica lipase B and Raney nickel in one Raney nickel
Introduction
neous Ru complexes, supported metal catalysts or
solid acids can be used as racemization catalysts.[4] For
Enantiomerically pure amines are an important prod- amines, on the other hand, racemization catalysts are
uct class in the pharmaceutical and agrochemical in- scarce. Pd on C or on alkaline earth supports can rac-
dustry. They are used as resolving agents, as chemical emize benzylic amines, but is not effective for aliphat-
building blocks for active compounds or as chiral aux- ic amines.[5,6] Only Parkꢀs group has succeeded in ap-
iliaries.[1] Kinetic resolution, usually with enzymatic plying Pd for the racemization of aliphatic amines, by
catalysts, is a widely used method for production of designing a highly specific nanoparticulate catalyst.[5c]
chiral amines, as it is usually more favorable regard- Even then, reactions with aliphatic amines require
ing price, chemoselectivity and ee than alternative strongly increased concentrations of Pd and enzyme,
methods such as diastereomeric crystallization or and operation at 1008C. Bäckvall and co-workers
asymmetric hydrogenation of imines, enamines or have described the use of the Shvo Ru complex for
oximes.[1,2] Kinetic resolution uses relatively cheap the racemization of aliphatic amines,[7] but the com-
racemic amines and enzymes,[3] but faces the limita- plex is expensive and still requires long reaction
tion that the yield per run cannot exceed 50%.
times, e.g., 3 days. An alternative approach to metal-
In order to increase the yield, the kinetic resolution catalyzed racemization via imine formation is the rac-
can be combined with an in situ continuous racemiza- emization catalyzed by alkylsulfanyl radicals.[8] This
tion of the unwanted enantiomer. The resulting pro- method seems to work well for aliphatic amines but
cess is termed dynamic kinetic resolution (DKR) and the question of the recovery and reuse of these orga-
provides the desired product in theoretical yields up nocatalysts is still open.
to 100%. In chosing a racemization catalyst, compati-
In the search for new heterogeneous racemization
bility with the enzyme, usually a lipase, and the other catalysts, the use of less expensive transition metals
reagents is a crucial issue. Most reports on successful would be a great advantage. A ꢁdirt-cheapꢀ catalyst
DKR focus on secondary alcohols, for which homoge- like Ni on charcoal has in recent years proven to be a
Adv. Synth. Catal. 2008, 350, 113 – 121
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113

Andrei N. Parvulescu et al.
Table 1. Racemization of (S)-1-phenylethylamine over Raney catalysts in various reaction conditions.[a]
FULL PAPERS
Catalyst [mg]
pH [MPa]
X [%]
SR-amine [%]
ee [%]
S
sec-amine [%]
Shyd [%]
2
Ideal
-
0
50
62
62
53
14
21
46
100
62
61
0
0
0
0
71
59
7
-
-
-
11
-
-
-
-
Raney Ni, 40
Raney Ni, 70
Raney Ni, 40
Raney Co, 80
Raney Co, 45[b]
Raney Co, 80[b]
38
25
10
-
-
2
0.01
0.01
0.01
0.02
0.02
90
100
100
98
[a]
Reaction conditions: 0.33 mmoles (S)-1-phenylethylamine, 4 mL toluene, 708C, 24 h. X, conversion of the (S)-amine;
R-amine, selectivity for the (R)-amine; Ssec-amine, selectivity for the secondary amine; Shyd =selectivity for hydrogenation of
S
the aromatic ring.
72 h.
[b]
worthwhile alternative to Pd catalysts in various cou- and Co catalysts in various reaction conditions. After
pling reactions;[9] in some enantioselective hydrogena- short optimization of the conditions, the performance
tions, Ni, modified with tartrate, is as well an alterna- of both catalysts became close to the ideal behavior
tive to the use of noble metals.[10] Similarly, one may (Table 1). Raney Ni is the more active catalyst: after
therefore explore Ni or Co metals as catalysts in race- 24 h, 50% conversion is reached using a lower cata-
mization or dynamic kinetic resolution. In the patent lyst loading than with Co.
literature, the use of Ni and Co as metal oxides or
Raney catalysts has been described for racemization
of chiral amines; but as the process is conducted at Effects of Hydrogen Pressure
high temperature and with a mixture of hydrogen,
ammonia and the corresponding ketone, it rather re- The racemization reaction likely occurs via the dehy-
sembles the industrial reductive amination route for drogenation-hydrogenation
route
depicted
in
the synthesis of amines than a selective low-tempera- Scheme 1. Even if the racemization process does not
ture process that could become compatible with enzy- consume H2, the hydrogen pressure may affect the
matic resolution.[11] Raney Co has been used in the position of the equilibrium between amine and imine,
racemization of 2-aminobutanol[12] and in the racemi- and therefore the rates of the dehydrogenation, hy-
zation of (S)-3-quinuclidinol as a key step in the syn- drogenation and possible side reactions. Consequent-
thesis of (R)-3-tert-butoxycarbonyl-5,5-dimethyl-1,3- ly, the overall racemization process is expected to
thiazolidine-4-carboxylic acid from (R)-l-penicill- depend on the hydrogen pressure. Table 1 shows that
amine.[13] However, it is at present unclear whether hydrogen pressure affects the selectivity: besides the
Raney catalysts are generally useful as racemization desired (R)-amine, by-products are the secondary
catalysts. The aim of the present paper is therefore to amine bis(1-phenylethyl)amine (Scheme 2, 4), as a
explore the substrate scope of Raney catalysts in mixture of diastereomers, and, in some cases, the hy-
amine racemization, and to investigate the coupling drogenation
product
1-cyclohexylethylamine
with an enzymatic resolution in a DKR process.
(Scheme 2, 5). In line with our previous observations
using Pd racemization catalysts, formation of bis(1-
phenylethyl)amine may proceed as depicted in
Scheme 2.[6] Attack of the amine (1) on the imine (2)
results in an aminal intermediate, from which NH3 is
readily eliminated to form imine (3). Reduction of 3
results in the secondary amine bis(1-phenylethyl-
amine) (4). The latter compound seems to be stable
in the presence of hydrogen and Ni or Co catalysts;
Results and Discussion
Racemization
Initial Screening of Catalysts and Conditions
Starting from a pure enantiomer with 100% ee, race-
mization should ideally yield 50% conversion of the
initial enantiomer with 100% selectivity for the enan-
tiomer, leading to an ee of 0%. Moreover, the racemi-
zation catalyst should operate in relatively mild condi-
tions in order to be compatible with an enzymatic res-
olution. (S)-1-Phenylethylamine, chosen as the initial
substrate, was converted with commercial Raney Ni Scheme 1. Racemization of (S)-1-phenylethylamine.
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Heterogeneous Raney Nickel and Cobalt Catalysts
FULL PAPERS
Scheme 2. Reaction mechanism for racemization of (S)-1-phenylethylamine over Raney metal catalysts.
hydrogenolysis to ethylbenzene and racemic phenyl- H2, and its activity decreases upon hydrogen addition,
ethylamine, which is a major reaction on Pd cata- suggesting that an excess of H2 suppresses the dehy-
lysts,[6] is not observed with the base metals Ni or Co. drogenation step. In the absence of external hydro-
Ring hydrogenation with formation of 1-cyclohexyl- gen, racemization on the Raney Ni catalyst is almost
ethylamine (5) was observed when a large amount of complete after 200 min, and only traces of secondary
the catalyst was used (Table 1) combined with a suffi- amine (ꢀ2%) were found together with the amines.
cient availability of hydrogen.
At 0.01MPa H2 the racemization was slightly slower,
In discussing the effect of hydrogen pressure on the but selectivity was still 100%. At higher hydrogen
reaction, it should be considered that commercial pressures ring hydrogenation became the dominant
Raney Ni catalysts contain a considerable amount of reaction, with a selectivity over 50% at 0.2MPa of
hydrogen, either as chemisorbed or as interstitial H2. In further experiments with Raney Ni, the H2
H.[14] This is not the case for Raney Co catalysts, and pressure was set at 0.01MPa.
explains that the effects of hydrogen pressure on the
activity of the two catalyst types are different, as
shown in Figure 1. In absence of hydrogen no reaction Substrate Scope and Catalyst Stability
takes place for Co Raney. Increasing the hydrogen
pressure results in activity increase and ee decrease. The catalytic activity of the two Raney catalysts was
At pressures above 0.02MPa, the selectivity decreas- tested for 14 other substrates comprising benzylic and
es. Whereas after 24 h at 0.2MPa H2, the ee is almost aliphatic amines. The nature of the amine, and in par-
zero, ring-hydrogenated compounds have been ticular its aliphatic or benzylic character, plays a very
formed with a selectivity of 18%. Hence, 0.02MPa H2 important role. For the benzylic amines (Table 2, en-
seems to be the optimum for Raney Co. Contrarily, tries 1–9) the Raney catalysts present satisfactory ac-
Raney Ni even performs racemization without added tivity, even if side product formation may decrease
Figure 1. Hydrogen pressure influence on the racemization of (S)-1-phenylethylamine over: (left) Raney Co, 24 h in standard
*
racemization conditions; (right) Raney Ni, 200 min in standard racemization conditions;
mer; enantiomeric excess.
selectivity toward (R)-enantio-
~
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Andrei N. Parvulescu et al.
FULL PAPERS
Table 2. Racemization activity of Raney catalysts for optically active amines.[a]
Entry
1
R1
Ph
R2
R3
H
Catalyst
t [h]
X [%]
SR-amine [%]
ee [%]
CH3
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
Ni
Co
24
72
48
72
24
72
24
72
48
72
48
72
48
72
72
72
24
72
24
72
24
72
24
72
24
72
48
72
24
72
53
46
33
49
50
28
13
21
19
11
9
22
36
43
49
48
16
-
42
47
46
31
47
50
46
17
50
22
20
-
90
98
77
100
84
90
0
64
100
80
0
9
44
2
8
48
100
71
61
83
82
61
33
22
2
2
4-MeO-C6H4
4-Me-C6H4
4-F-C6H4
Ph
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
CH3
H
H
H
H
H
H
H
H
H
3
4
5
6
1-naphthyl
2-naphthyl
100
86
91
7
86
8
-(o-C6H4)-(CH2)3-
100
100
100
-
3
9
Ph
CH2OH
CH3
68
100
16
6
8
38
7
10
11
12
13
14
15
c-C6H11
100
100
100
100
100
100
100
100
100
100
100
-
n-C4H9
CH3
n-C5H11
CH3
0
9
n-C6H13
CH3
67
0
57
59
100
Ph-CH2CH2
2-methylpiperidine
CH3
[a]
Standard racemization conditions: H2 pressure 0.01MPa for Raney Ni, 0.02MPa for Raney Co. Symbols as in Table 1.
the selectivity of the process. The substitution pattern Raney Co was totally inactive. For benzylic amines
on the benzylic amines has marked effects as well. the selectivities were sometimes lower because of the
Raney Ni was very active in the racemization of (S)- formation of side products. Secondary amines were
1-phenylethylamine (entry 1) and (S)-p-tolylethyl- the side products for Raney Ni; hydrogenolysis prod-
amine (entry 3), but the activity was lower toward ucts were only identified in the case of Raney Co, in
(S)-p-methoxyphenylethylamine (entry 2). On the very small amounts of less than 5% yield (entries 5–
contrary, with the Co catalyst, the methoxy-substitut- 7).
ed amine reacted faster than the methyl-substituted
For both Raney catalysts, the racemization selectiv-
amine. A challenging substrate is (S)-p-fluorophenyl- ity was much higher for aliphatic amine substrates
ethylamine, in which the carbon-fluorine bond is sus- (entries 10–15): no side products were identified at
ceptible to hydrogenolysis (entry 4). For Raney Ni the all. The substrate scope comprises various 2-alkyl-
latter reaction was the only one observed, but the amines, optionally substituted with cycloalkyl or
cobalt catalyst showed a much higher selectivity for phenyl groups. Generally, Raney Ni was able to com-
racemization compared to dehalogenation. Both cata- pletely racemize these compounds after 24 h with
lysts presented limited activity towards a secondary 100% selectivity, while Raney Co needed longer reac-
benzylic amine (entry 5) and to (S)-1-naphthylethyl- tion times. As in the case of the benzylic amines
amine (entry 6). By contrast, (S)-2-naphthylethyl- (entry 5), racemization of secondary amines is slower
amine was well racemized on both catalysts, showing but still highly selective, as illustrated by the case of
that reactant structure has a subtle effect on reactivity 2-methylpiperidine (entry 15).
(entry 7). Excellent results are also obtained with 1-
It has been reported that Raney catalysts such as
aminotetralin (entry 8). Raney Ni was active towards Raney Ni loose some of their activity in alkene hy-
racemization of (S)-2-phenylglycinol (entry 9) while drogenation because of agglomeration of the Ni parti-
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Heterogeneous Raney Nickel and Cobalt Catalysts
FULL PAPERS
cles in the porous structure.[15] Therefore, the re-use
of the Raney Ni catalyst has been attempted in the
racemization of (S)-1-phenylethylamine. After four
reaction cycles of 24 h, an overall activity decrease of
38% was indeed observed, but the racemization se-
lectivity remained constant. No leaching of the Ni
was observed during the process.
Dynamic Kinetic Resolution
Choice of Enzyme and Acylating Agent
Apart from the racemization, the kinetic resolution
(KR) is the other essential event in dynamic kinetic
resolution (DKR). Success in KR depends on the
choice of appropriate resolving enzymes and reagents.
As a biocatalyst, Candida antarctica lipase B (CALB)
immobilized in acrylic resin was selected. This immo-
Scheme 3. Combined kinetic resolution and racemization of
amines in one-pot or two-pot configuration.
bilized enzyme has a broad substrate tolerance, com- In our experiments, kinetic resolutions using CALB
prising primary amines and secondary alcohols, and and ethyl methoxyacetate indeed resulted in very
has a high thermal stability. Previously, it has been re- strong enantiodifferentiation. From the experiments
ported that this enzyme allows one to resolve 1-phe- shown in Figure 2, an E value of ~1200 could be cal-
nylethylamine with an E value higher than 2000.[6] culated for resolution of 1-phenylethylamine, based
Additionally, the acrylic matrix of the immobilized on the formula proposed by Rakels et al.[18] In agree-
enzyme is sufficiently inert to avoid unwanted effects ment with literature,[3] the value is somewhat lower
on the enzyme or side reactions.[16] A second crucial for 2-heptylamine, with E ~600.
element is the choice of the acylating agent, as it
In the present work, racemization and kinetic reso-
should fit well in the enzymeꢀs active site and give a lution were either combined in one pot in a true
high E value. On the other hand, spontaneous reac- DKR; or a two-pot procedure was applied in which
tion of the acylating agent with formation of racemic the solid biocatalyst and the solid chemocatalyst were
amide is to be avoided. Besides simple esters, e.g., separated and the liquid reaction mixture was alter-
isopropyl acetate, ethyl methoxyacetate is an excel- natingly allowed to contact one or the other catalyst
lent reagent for enantioselective acylation of aliphatic (Scheme 3).
amines in the presence of CALB.[17] Acylating agents
bearing C=C double bonds must be avoided, as hy-
drogenation catalysts are used for the racemization. One-Pot Dynamic Kinetic Resolution of Aliphatic
Amines
In the one-pot system, the enzyme and the acyl donor
were added to the reaction suspension containing the
racemization catalyst. Results of DKR with CALB
and the Raney catalysts are presented in Table 3. The
conversion strongly depends on the nature of the cat-
alyst and the nature of the substrate. Raney Co
showed little activity in DKR of 1-phenylethylamine
(entry 1) and was even completely inactive in DKR of
aliphatic amines (entry 7). Raney Ni was more active
in the DKR of chiral amines, with yields well over
50%, even if the reaction times were considerably
longer than for the racemization of the corresponding
amines (Table 2). Moderate results were obtained in
DKR of benzylic amines: after 120 h, 63% of the 1-
phenylethylamine was converted by CALB and the
Raney Ni catalyst (entry 2). For some of the benzylic
*
Figure 2. Kinetic resolution of 2-heptylamine ( ) and 1-phe-
~
amines, the ee of the amide product was somewhat
nylethylamine ( ) with 100 mg immobilized enzyme and
0.35 mmol ethyl methoxyacetate at 708C.
lower than expected (entries 3 and 4).
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Andrei N. Parvulescu et al.
Table 3. One-pot dynamic kinetic resolution of optically active amines using Raney metal catalysts and lipases.[a]
FULL PAPERS
Entry
Substrate
Cat.
t [h]
T [8C]
X [%]
SR-amide [%]
eeR-amide [%]
1
2
3
4
5
6
7
8
1-phenylethylamine[b]
1-phenylethylamine[c]
1-p-tolylethylamine[d]
1-aminotetralin[d]
Co
Ni
Ni
Ni
Ni
Ni
Co
Ni
Ni
Ni
Ni
Ni
Ni
72
120
72
72
48
96
96
96
48
96
96
96
96
70
80
70
70
70
70
80
70
80
80
80
80
80
63
62
72
65
64
98
50
74
78
87
75
70
79
100
98
90
94
99
97
100
99
97
96
100
94
80
87
98
97
100
98
94
94
82
96
98
2-hexylamine[d]
2-hexylamine[d]
2-heptylamine[e]
2-heptylamine[d]
9
2-heptylamine[d]
10
11
12
13
2-heptylamine[d]
2-octylamine[d]
92
98
100
1-cyclohexylethylamine[d]
1-methyl-3-phenylpropylamine[d]
[a]
Standard DKR conditions. Symbols as in Table 1.
80 mg Raney Co, 0.35 mmoles isopropyl acetate and 0.02MPa H2.
40 mg Raney Ni, 0.35 mmoles methyl decanoate and 0.01MPa H2.
40 mg Raney Ni, 0.35 mmoles ethyl methoxyacetate and 0.01MPa H2.
80 mg Raney Co, 0.35 mmoles ethyl methoxyacetate and 0.02MPa H2.
[b]
[c]
[d]
[e]
In the case of aliphatic amines (entries 5–13), the Compatibility of Enzyme and Raney Catalysts in
high chemoselectivity observed in the racemization One-Pot DKR
using Raney Ni was preserved in the DKR experi-
ments, even if the reaction times were again longer. For the Co Raney catalyst, oxidative corrosion was
Results were excellent for the 2-alkylamines (en- pinpointed as the reason for the catalyst deactivation
tries 6, 10 and 13). The yields in this series decreased in the DKR. The oxidation was evidenced by the ap-
with the length of the alkyl chain, 2-hexylamine pearance of a pink hue in the solution, as well as by a
giving the best result, viz. 95% yield combined with colour change of the catalyst from dark brown to
97% ee (entry 6). Increasing the reaction time or the pink. UV/Vis spectra of the solution recovered from
temperature raised the conversion without affecting DKR of 1-phenylethylamine with Raney Co
the selectivity (entries 5, 6 and 8–10). A good yield of (Figure 3) confirmed the presence of a mixture of oc-
79% (R)-amide at 98% ee was obtained for 1-methyl- tahedral and tetrahedral divalent Co species, with ab-
3-phenylpropylamine (entry 13).
sorption maxima at 520 nm and 580 nm.[19] Based on
the extinction coefficients for such species, it could be
estimated that ~5% of the total Co is dissolved. In
the presence of one equivalent of acetic acid, the
leaching is even much more pronounced, with dissolu-
tion of ~13% of the total Co. Note that background
hydrolysis of the acylating agent, caused by, e.g., the
enzymeꢀs hydration water, could maximally produce
one equivalent of acid.
In contrast, leaching to the solution was not ob-
served for the Raney Ni catalyst. This enhanced sta-
bility may be due to the high hydrogen content of the
framework which helps to keep the Ni in a zerovalent
state. Moreover, Raney Ni catalysts are frequently
doped with acids such as tartaric acid, proving the rel-
ative stability of this metal catalyst towards acids.[10]
Even then, the conversion rates in the one-pot DKR
are considerably lower than could be expected based
on the rates of the separate racemization or kinetic
resolutions, especially for the benzylic amines. In
order to assess whether a decreased racemization rate
is at the origin of the decreased DKR rate, the effect
of various compounds on the racemization activity of
Figure 3. UV/Vis spectra of supernatants of: a) DKR of 1-
phenylethylamine in one-pot procedure with Raney Co and
i-PrOAc as acylating agent, 24 h; b) racemization of (S)-1-
phenylethylamine with Raney Co and 1 equivalent of
AcOH, 24 h.
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Heterogeneous Raney Nickel and Cobalt Catalysts
Table 4. Influence of various molecules on the racemization of (S)-1-phenylethylamine using a Raney Ni catalyst.[a]
FULL PAPERS
Additive
Mole additive/mole amine
X [%]
SR-amine [%]
ee [%]
1
2
3
4
5
6
7
8
9
-
-
53
60
45
29
62
19
13
2
90
68
93
100
67
0
0
N-(1-phenylethyl)acetamide
methyl alcohol
enzyme[b]
methyl decanoate
isopropyl acetate
octanoic acid
octanoic acid
acetic acid
0.37
1.4
-
1.4
1.4
0.08
1.4
0.2
1.4
15
43
3
70
74
96
87
95
80
100
100
100
100
7
3
10
acetic acid
[a]
[b]
Standard racemization conditions: 40 mg Raney Ni, 24 h. Symbols as in Table 1.
100 mg immobilized CALB (Novozyme 435).
Raney Ni was tested (Table 4). The compounds used the racemization is sufficiently fast, and the decreased
are either added in a typical DKR experiment, or DKR rate is to be ascribed to slow resolution. Rele-
they are formed as products or by-products. The vant data are gathered in Figure 4 and Figure 5, for a
amide product or an alcohol like methanol hardly benzylic and a linear aliphatic amine during KR or
have an effect on the racemization (entries 2 and 3). DKR with CALB and Raney Ni. Clearly, the amineꢀs
The enzyme itself, and an ester like isopropyl acetate ee remains low during the DKR of 1-phenylethyl-
slightly decrease the activity of the Ni catalyst (en- amine (Figure 4). This proves that low enzyme activi-
tries 4, 5 and 6). However, a strong activity decrease ty in this case is the bottleneck. Rates are somewhat
is observed with acetic and octanoic acid, even at a better matched in the DKR of 2-heptylamine
molar ratio of 0.08–0.2 with respect to the amine (en- (Figure 5), in which a high yield of enantiopure amide
tries 7 and 9). This shows that even minor hydrolysis is eventually reached (Table 3, entry 10). At first
of the acyl donor could strongly slow down the race- sight, it might seem surprising that reduced enzyme
mization. However, Ni is not susceptible to dissolu- activity is yield-limiting for the benzylic amine, but
tion, not even when an excess of the acids is added not for the linear aliphatic amine. However, one
(entries 8 and 10).
should consider that linear aliphatic amines react
The most appropriate way to identify the rate-de- much faster with the enzyme than the benzylic ones,
termining step in a DKR is to follow the ee of the re- as proven by Figure 2. Hence, if the enzyme loses part
sidual amine. Indeed, if this ee is high, the racemiza- of its activity when it is mixed with the Raney cata-
tion is too slow; if, on the contrary, the ee stays low,
Figure 4. The ee of the remaining amine in DKR and in KR
Figure 5. The ee of the remaining amine in DKR and in KR
~
~
*
*
of 1-phenylethylamine vs. conversion: ee in DKR; ee in
KR. The full line represents the theoretical course of the ee
vs. conversion for a KR with E=1200. DKR was performed
at 708C in toluene with Raney Ni, 100 mg immobilized
enzyme and 0.35 mmol ethyl methoxyacetate.
of 2-heptylamine vs. conversion: ee in DKR; ee in KR.
The full line represents the theoretical course of the ee vs.
conversion for a KR with E=600. DKR was performed at
708C in toluene with Raney Ni, 100 mg immobilized
enzyme and 0.35 mmol ethyl methoxyacetate.
Adv. Synth. Catal. 2008, 350, 113 – 121
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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119

Andrei N. Parvulescu et al.
FULL PAPERS
Table 5. Two-pot dynamic kinetic resolution of 1-phenyle-
Conclusions
thylamine over Raney/lipase catalysts.[a]
Raney metals are efficient heterogeneous catalysts for
liquid-phase racemization of optically active amines.
Noteworthily, Raney Ni is one of the few compounds
known to racemize even aliphatic primary amines
with high selectivity. Raney Ni generally presented a
higher racemization activity and a better stability
than Raney Co. Hydrogen pressure was shown to be
the critical parameter in controlling the chemoselec-
tivity of the racemization on both catalysts. For ali-
phatic amines, racemization and enzymatic resolution
Entry Catalyst
Runs X [%] SR-amide [%] eeR-amide [%]
1
2
Raney Co
Raney Ni
2
4
70
100
100
94
99
91
[a]
Standard DKR conditions: (i) 80 mg Raney Co, 0.6
mmoles i-PrOAc, 0.02MPa H2; (ii) 40 mg Raney Ni, 0.5
mmoles ethyl methoxyacetate, 0.01mPa H2. Symbols as in
Table 1.
lyst, this will be particularly felt in the reaction of the could be combined in one pot, resulting in an efficient
benzylic amine, while there still remains sufficient ac- DKR. For the benzylic amines, which react less fast
tivity for the DKR of the linear aliphatic amine.[20]
with the enzyme, it could be demonstrated that the
A final concern are the amide ees in the one-pot slow enzymatic conversion of the amine in the pres-
DKR. While these ees are generally very good, they ence of the Ni catalyst is the main effect impeding ef-
are substantially lower than expected in a few cases ficient one-pot DKR. However, benzylic amines
(Table 3, entries 3, 4 and 11). There are several possi- could be efficiently converted to the enantiopure
ble causes for such an ee deterioration. First, the amide by alternating reaction with the lipase and with
amine and the acylating agent may react in a non- the racemization catalyst.
enantioselective way, either in an uncatalyzed reac-
tion, or under the influence of the base-leached
Raney catalysts. Control experiments have, however,
Experimental Section
shown that amides are not at all produced in the ab-
sence of the enzyme. Secondly, the amide product
itself might be susceptible to racemization. Tests in
the presence of the Raney catalysts have shown, how-
ever, that this effect can be neglected as well. Finally,
it can be speculated that, if the enzyme loses part of
its activity in the mixture with the Raney catalyst, it
might also loose some of its enantiospecificity.
All reagents were obtained from commercial sources and
were used as received. Raney Ni was from Strem Chemicals;
Raney Co was a gift from Degussa. The catalysts were kept
under solvent and were carefully washed with ethanol and
toluene for total removal of the initial solvent water. Candi-
da antarctica lipase B, immobilized in acrylic resin (Novo-
zyme 435) was purchased from Aldrich.
Racemization reactions were performed in 10-mL stain-
less steel autoclaves at 708C under a hydrogen pressure of
0–0.2MPa. In order to obtain a pressure below 0.1MPa, a
5% H2 dilution in N2 was used as the reactive gas. A stan-
dard racemization reaction contained chiral amine (0.33
mmoles), toluene (4 mL) and Raney Ni (40 mg) or Raney
Co (80 mg). Catalyst weights are expressed as dry solid
powder mass.
Two-Pot Resolution and Racemization of Benzylic
Amines
In a two-pot system, deactivating effects of one cata-
lyst on the other, e.g., poisoning of the enzyme by Ni
ions can be largely avoided. The liquid reaction mix-
ture is then shuttled between the two reaction vessels.
In order to better control the undesired hydrolysis of
the acylating agent, it is added in small portions
before each resolution step, in quantities that are suf-
ficient to acylate half of the residual amine. The
method was tested in the DKR of 1-phenylethyl-
Dynamic kinetic resolution was performed using either a
one-pot or a two-pot reaction system. One-pot reactions
were performed in conditions similar to those of the racemi-
zation, using the same amount of racemization catalyst, rac-
emic amine (0.33 mmoles) and toluene (4 mL). Immobilized
Candida Antarctica Lipase B (Novozym 435) (100 mg) was
added as the resolution catalyst, together with 0.35 mmoles
amine, for which DKR in a one-pot system was not of the acylating agent. The reaction in the two-pot system
was started with the racemic amine (0.33 mmoles), the re-
solving enzyme (100 mg) and the acylating agent (0.17
mmoles) in 4 mL toluene. Upon depletion of the (R)-enan-
tiomer, the mixture was centrifuged, the Raney catalyst was
added to the supernatant and the racemization was started.
When the amine was close to racemic, the Raney catalyst
was removed by centrifugation, and the supernatant was
mixed again with the enzyme of the first racemization step,
together with 0.17 mmoles fresh acylating agent. Throughout
the experiment, the initial batches of biocatalyst and Raney
catalyst were employed, without addition of fresh catalyst.
successful. As shown in Table 5, two runs with Raney
Co lead to an amide yield of 70% with an ee of 99%,
vs. a theoretical yield of 75%. With Raney Ni, the
amide yield after 4 runs (52 h) was 94% with an ee of
91%, vs. a theoretical yield of 93.75%. The major ad-
vantage in comparison with the transformation of 1-
phenylethylamine in the one-pot system is that yields
are much higher after shorter reaction times (com-
pare Table 5, entry 2 with Table 3, entries 1 and 2).
120
asc.wiley-vch.de
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 113 – 121

Heterogeneous Raney Nickel and Cobalt Catalysts
FULL PAPERS
Between the successive uses, the catalysts were kept under a
dry N2 atmosphere.
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At the end of the reaction according to the one-pot proce-
dure, the autoclave was cooled to room temperature and a
sample was taken from the supernatant. In the two-pot pro-
cedure samples were taken after each reaction step.
Yields and enantiomeric purities of reactants and products
were determined with GC (HP 6890) on a CP-CHIRASIL-
DEX CB chiral column (25 m) with FID detector using tet-
radecane as internal standard. In the analysis of the racemi-
zation reactions, the aliphatic amines were transformed to
the corresponding amides by adding two drops of acetic an-
hydride and two drops of triethylamine to the GC vial
(2 mL). The secondary amines and the ring-hydrogenated
products were identified with a Agilent 6890-N GC-MS and
an Agilent 5973 mass spectrometer on a 30 m HP-5MS
column.
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Acknowledgements
We are grateful to the Bilateral program Flanders-Romania
BIL 04/42, to the IAP program Supramolecular Chemistry
and Catalysis of the Belgian Federal Government, to a
G.O.A. action of the Research Council of K. U. Leuven, and
to Cost action D24.
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