Microwave-promoted racemization and dynamic kinetic resolution of chiral amines over Pd on alkaline earth supports and lipases

Article abstract of DOI:10.1016/j.jcat.2008.02.005

Microwave irradiation was applied in the racemization and dynamic kinetic resolution of primary benzylic amines. Racemization reactions catalyzed by 5% Pd/BaSO₄ and 5% Pd/CaCO₃ were faster and more selective when performed under microwave conditions. The use of microwave irradiation stopped the formation of side products, such as secondary amines and ethylbenzene. This was correlated with the selective heating of the metal sites under microwave heating. The influence of the microwave irradiation also was checked in the kinetic resolution; no influence on the activity and enantioselectivity of the immobilized Candida Antarctica Lipase B (Novozym 435) was observed when both conventional and microwave heating were compared. The racemization catalysts were combined in one pot with the biocatalyst Novozym 435 to perform the dynamic kinetic resolution of benzylic amines under microwave irradiation. High yields (up to 88%) of enantiopure amides were obtained in less than 1 h when microwave irradiation was applied.

Full text of DOI:10.1016/j.jcat.2008.02.005

Journal of Catalysis 255 (2008) 206–212
www.elsevier.com/locate/jcat
Microwave-promoted racemization and dynamic kinetic resolution
of chiral amines over Pd on alkaline earth supports and lipases
Andrei N. Parvulescu a, Erik Van der Eycken b, Pierre A. Jacobs a, Dirk E. De Vos a,∗
a
Katholieke Universiteit Leuven, Centre for Surface Chemistry and Catalysis, Kasteelpark Arenberg 23, B-3001 Leuven, Belgium
b
Katholieke Universiteit Leuven, Laboratory of Organic and Microwave-Assisted Chemistry, Department of Chemistry, Celestijnenlaan 200f/02404,
B-3001 Leuven, Belgium
Received 20 December 2007; revised 6 February 2008; accepted 7 February 2008
Available online 14 March 2008
Abstract
Microwave irradiation was applied in the racemization and dynamic kinetic resolution of primary benzylic amines. Racemization reactions
catalyzed by 5% Pd/BaSO and 5% Pd/CaCO were faster and more selective when performed under microwave conditions. The use of microwave
4
3
irradiation stopped the formation of side products, such as secondary amines and ethylbenzene. This was correlated with the selective heating
of the metal sites under microwave heating. The influence of the microwave irradiation also was checked in the kinetic resolution; no influence
on the activity and enantioselectivity of the immobilized Candida Antarctica Lipase B (Novozym 435) was observed when both conventional
and microwave heating were compared. The racemization catalysts were combined in one pot with the biocatalyst Novozym 435 to perform the
dynamic kinetic resolution of benzylic amines under microwave irradiation. High yields (up to 88%) of enantiopure amides were obtained in less
than 1 h when microwave irradiation was applied.
© 2008 Elsevier Inc. All rights reserved.
Keywords: Pd catalyst; Chiral amines; Dynamic kinetic resolution; Kinetic resolution; Microwave irradiation
1. Introduction
racemization requires a chemocatalyst. To have a good DKR
process, the two catalysts should be able to work together, and
as a further condition, the reaction rates of the two processes
should be of similar orders of magnitude [4]. There are few re-
ports on successful catalysts for racemization of chiral amines
[5,6] compared with the numerous studies on alcohol racem-
ization [7]. Most of the racemization catalysts are metal-based,
and the reactions occur through a redox mechanism. Recently,
some of us proposed Pd on alkaline earth supports as racem-
ization catalysts for benzylic amines [6]. Although the catalysts
were highly active and selective for racemization of benzylic
amines, the reaction times for dynamic kinetic resolution were
still longer than 24 h in some cases, and small amounts of side
products were formed (4–19 mol% of the total substrate con-
verted).
Enantiomerically pure amines are valuable optically active
compounds that have great importance as chemical interme-
diates in the pharmaceutical and agrochemical industries. Be-
sides such classic methods as diastereomeric crystallization and
asymmetric hydrogenation of imines, enamines, and oximes
[1,2], chiral amines can be separated by kinetic resolution. Al-
though this is a highly enantioselective process that starts from
relatively cheap racemic mixtures, kinetic resolution has a ma-
jor drawback—the yield is limited to 50%. To increase the
yield, the unwanted enantiomer should be transformed to the
racemic mixture and then submitted to a new resolution. Com-
bination of continuous racemization of the remaining enan-
tiomer with kinetic resolution, called dynamic kinetic resolu-
tion (DKR), provides the desired enantiomer in yields theoreti-
cally close to 100%. Whereas lipases are used for resolution [3],
To improve the performance of these Pd catalysts, we chose
to test microwave irradiation as a heating source. Microwave ir-
radiation has been reported to be a very attractive tool for chem-
ical applications in both organic and materials synthesis [8].
The unconventional nature of the heating occurs at a molec-
*
Corresponding author. Fax: +32 16321998.
E-mail address: dirk.devos@biw.kuleuven.be (D.E. De Vos).
0021-9517/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2008.02.005

A.N. Parvulescu et al. / Journal of Catalysis 255 (2008) 206–212
207
ular level by direct excitation of molecules, which induces a
rapid and simultaneous heating of the whole reaction mixture.
The thermal effects caused by microwave irradiation are a con-
sequence of the inhomogeneity of the microwave field within
the sample due to selective absorption of the radiation by po-
lar compounds. These thermal effects can be used to efficiently
improve processes or modify selectivities [8]. Although there
are increasing reports on the application of microwave irradia-
tion in various organic syntheses, its application in asymmetric
synthesis is limited, particularly in heterogeneously catalyzed
asymmetric synthesis [9–11]. Most of the reports on asymmet-
ric transformations deal with the use of microwave irradiation
in the enzymatic resolution of chiral alcohols [10,11,13]. Al-
though microwave irradiation seems to improve the thermal
stability of the enzymes [10–12], there are conflicting reports
regarding the effect on enzyme activity and enantioselectivity
[10,11,13]. To the best of our knowledge, no reports exist on
the use of microwave irradiation for the enzymatic resolution
or dynamic kinetic resolution of chiral amines. In this paper,
we investigate the use of microwave irradiation in the DKR of
benzylic amines with Pd on alkaline earth supports and lipases
and compare the results with those obtained under normal heat-
ing conditions.
lysts were separated by centrifugation, and a sample was
obtained for further analysis.
Microwave reactions were performed in a commercially
available single-mode microwave unit (CEM Discover) consist-
ing of a continuous focused microwave power delivery system
with operator-selectable power from 0–300 W and a microwave
frequency source of 2.45 GHz. The reactions were performed
in closed glass tubes. In the racemization and DKR condi-
tions, reaction mixtures were flushed with hydrogen before
vials were closed; the H2 partial pressure inside each vial was
0.005 MPa. The reactions were magnetically stirred. Tempera-
ture control was ensured with a vertically focused infrared tem-
perature sensor. Temperature, pressure, and power profiles were
monitored using commercially available software provided by
the microwave manufacturer. Reactions were conducted at 70–
120 ◦C.
Yields and enantiomeric purities of the substrate and re-
action products were determined with GC (HP 6890) on a
CP-CHIRASIL-DEX CB chiral column (25 m) with a flame
ionization detector using tetradecane as an internal standard.
Reaction products also were identified by GC-MS, using an Ag-
ilent 6890-N unit with an Agilent 5973-MSD on a silica column
HP-5MS (30 m).
2. Experimental
3. Results and discussion
All reagents were obtained from commercial sources and
used as received. The 5% Pd/BaSO4 was prepared as reported
previously [6a]; the 5% Pd/CaCO3 was a gift from Johnson
Matthey. The catalysts were used further with no other pretreat-
ment. Candida antarctica lipase B immobilized in acrylic resin
(Novozym 435) was purchased from Aldrich.
3.1. Racemization
Dynamic kinetic resolution consists of two simultaneous
processes: racemization and kinetic resolution. To evaluate the
effect of microwaves on the overall process, we first investi-
gated how each individual process is affected by the microwave
irradiation. As heterogeneous catalysts, Pd on alkaline metal
supports are active in the racemization of benzylic amines [6].
Table 1 presents the racemization of (S)-1-phenylethylamine
(1) under both normal and microwave conditions over Pd on al-
kaline earth supports. Because it is known that reactions under
microwaves work very well at unusually high temperatures, we
performed the experiments between 70 and 120 ◦C, a broader
temperature range than used in previous work with conven-
tional heating. Table 1 reports amine conversion and the en-
suing e.e. decrease, along with selectivity. Indeed, Scheme 1,
for which kinetic evidence has been gathered previously, shows
that the main racemization reaction follows a metal-catalyzed,
H2-dependent dehydrogenation–hydrogenation route, with for-
mation of an intermediate prochiral imine (2). However, the
selectivity of the reaction may be decreased by acid- and metal-
catalyzed secondary reactions to the putative aminal and imine
(3) intermediates, and eventually to the secondary amine bis-
(1-phenyl)ethylamine (4), or the hydrogenolysis products race-
mic amine (1) and ethylbenzene (5). In particular, compounds
(4) and (5) account for the selectivity deficiency displayed in
Table 1.
The following reactions were conducted under conventional
heating conditions:
• Racemization reactions. Reactions were performed in
10-ml stainless steel autoclaves that were heated at 70–
120 ◦C by inserting them in a copper block, placed on top
of a heating plate equipped with magnetic stirring and a
thermocouple temperature controller. The hydrogen par-
tial pressure was set at 0.005–0.01 MPa. To easily obtain
H2 partial pressures <0.1 MPa, a 5% H2 dilution in N2
was used as the reactive gas. For the standard racemization,
0.33 mmol of (S)-1-phenylethylamine, 4 ml of toluene, and
40 mg of catalyst were used.
• Kinetic resolution. Reactions were performed in 10-ml
closed glass vials at 70–100 ◦C on a heated copper block.
For the standard resolution, 0.33 mmol of (R, S)-1-phenyl-
ethylamine, 0.35 mmol of acylating agent, 4 ml of toluene,
and 100 mg of biocatalyst were used.
• Dynamic kinetic resolution. Reactions were performed un-
der similar conditions as for racemization, using 0.33 mmol
of racemic 1-phenylethylamine, 4 ml of toluene, 100 mg of
immobilized Candida antarctica lipase B (Novozym 435)
as a resolution catalyst, 40 mg of racemization catalyst, and
0.35 mmol of acylating agent. At the end of the reaction,
the autoclave was cooled to room temperature, the cata-
Hydrogen pressure is a key parameter for this racemization
reaction, and it strongly affects catalyst activity. Even if hydro-
gen does not appear in the net racemization equation, it influ-

208
A.N. Parvulescu et al. / Journal of Catalysis 255 (2008) 206–212
Table 1
a
Normal vs. microwave heating in racemization of (S)-1-phenylethylamine over Pd/alkaline earth supports
Entry
Catalyst
Heating
Time
(min)
Press. H
(MPa)
T
Conversion
(%)
Sel.
(%)
e.e.
S-amine
(%)
2
R-amine
◦
( C)
1
2
3
4
5
6
7
8
9
5% Pd/BaSO
Normal
Normal
150
40
15
13
90
15
15
15
15
15
0.01
0.01
70
80
80
100
70
80
100
100
100
120
24
21
21
38
30
22
37
36
11
45
97
98
100
100
96
100
100
99
52
59
58
25
42
66
25
28
78
11
4
Microwave
Microwave
Normal
Microwave
Microwave
Normal
0.005
0.005
0.01
0.005
0.005
0.01
5% Pd/CaCO
3
Normal
Microwave
0.005
0.005
99
100
10
a
Standard racemization conditions.
Scheme 1. Racemization mechanism of (S)-1-phenylethylamine over Pd/alkaline earth supports.
ences the equilibrium between the amine and imine (Scheme 1).
In conventional conditions, the activity of Pd on alkaline earth
for (S)-1-phenylethylamine racemization is highest in a hydro-
gen pressure range of 0.01–0.02 MPa [6]. At lower pressure,
the racemization rate sharply decreases. The data in Table 1
show that under microwave irradiation, the racemization cat-
alysts work very well even at a lower hydrogen pressure of
0.005 MPa. For both 5% Pd/BaSO4 and 5% Pd/CaCO3, better
results were obtained with 0.005 MPa H2 under microwave than
with 0.01 MPa H2 under normal conditions. Under microwave
conditions at 80 ◦C and 0.005 MPa H2 (entry 3), 5% Pd/BaSO4
gave similar conversion and better selectivity after 15 min com-
pared with the results obtained under normal heating conditions
at 0.01 MPa H2 after 40 min (entry 2). For 5% Pd/CaCO3 as
well, a lower hydrogen pressure of 0.005 MPa suffices for mi-
crowave conditions (entries 7 vs. 8), whereas this pressure gave
low conversion under normal heating conditions (entry 9).
Switching to the microwave conditions not only was bene-
ficial for the conversion, but also ensured 100% selectivity. At
a reaction temperature of 120 ◦C, a 45% conversion with 100%
selectivity was reached within 15 min, corresponding to vir-
tually complete racemization (entry 10). The data of Table 1
suggest that microwave irradiation promotes the redox racem-
ization process while suppressing formation of the secondary
products. Such a promotion of redox processes on metallic
catalysts also was observed previously when microwave radi-
ation was used instead of classical heating [9b,13,14]. When
microwave irradiation is used as an energy source for hetero-
geneous catalytic systems, the microwaves can interact directly
with the metal sites on the catalysts’ surface, creating hot spots.
Meanwhile, the adsorbed organic layers do not heat up substan-
tially, resulting in significant temperature gradients between the
catalyst and the bulk liquid [8d,9c,16]. Thus, the desired metal-
catalyzed reactions from (S)-(1) to (2), and back to (R, S)-(1),
are promoted while the decisive step in the side-product for-
mation, viz. the reaction to (3), is occurring on acid–base sites
and is not accelerated (Scheme 1). This explains why the se-
lectivities are systematically improved when microwaves are
used. Together with the use of an optimized basic support, this
results in the 100% selectivity during racemization. Similar se-
lectivity promoting the effects of microwaves were reported by
Roussy et al. for Pt/Al2O3 reforming catalysts; along besides
thermal effects, they claimed that the microwaves may also
modify the geometric and/or electronic properties of the metal-
lic particles [15].
All previous reactions were performed in toluene, which is
known to be almost transparent to the microwave energy. The
degree of interaction between an organic molecule and the mi-
crowave field is measured by the loss factor, tanδ [8]. The
loss factor is dependent on the dielectric constant, and on the

A.N. Parvulescu et al. / Journal of Catalysis 255 (2008) 206–212
209
Table 2
Solvent effect on racemization of (S)-1-phenylethylamine over 5% Pd/CaCO in microwave and normal heating conditions
a
3
Solvent
tanδ
Heating
Time
(min)
Conversion
(%)
Sel.
(%)
e.e.
S-amine
(%)
R-amine
Toluene
Toluene
0.04
0.047
na
Microwave
Normal
Microwave
Normal
Microwave
Normal
Microwave
Normal
15
15
5
37
11
32
5
21
9
100
99
100
99
100
75
100
78
25
78
37
91
58
87
23
35
Tetrahydrofuran
Tetrahydrofuran
Isopropyl acetate
Isopropyl acetate
Dimethylformamide
Dimethylformamide
5
10
15
12
12
0.161
39
38
a
◦
Standard racemization conditions, 0.005 MPa H , 4 ml solvent, 100 C. na = not available.
2
Table 3
We also explored microwave promotion for the racemiza-
tion of other benzylic amines. Table 3 provides compara-
tive data for microwave and conventional heating. In most
cases, the reactions were very fast when microwave irradia-
tion was used. For (S)-1-(p-tolyl)ethylamine, the conversion
under microwave irradiation was 28% after 15 min, whereas
under classical conditions, it was only 8%. In addition, for
bulkier amines, such as (S)-2-naphthylethylamine and (S)-
1-aminotetraline, reactions performed under microwave were
faster than those under normal heating conditions. Only for
(S)-2-naphthylethylamine was the racemization reaction under
microwave rather slow compared with the reactions of the other
substrates, with only 6% conversion obtained after 15 min. The
selectivity remained 100% for all reactions performed under
microwaves. (S)-1-Methyl-3-phenylpropylamine is a particular
substrate, a pseudo-aliphatic amine. When using toluene as the
solvent, the conversion was low (3%) after 50 min under mi-
crowave, but changing to isopropanol increased the conversion
to 36% after just 15 min. In isopropanol and with classical heat-
ing, the conversion was only 4% after the same period. Unfor-
tunately, however, this result cannot be used in a DKR process,
because lower-alcohol solvents often deactivate lipases. Pd on
alkaline earth supports was not able to racemize any other chi-
ral aliphatic amines, even when the reactions were performed
under microwave conditions.
a
Microwave-promoted racemization of chiral amines over 5% Pd/CaCO
3
Substrate
Heating
Conver- Sel.
sion (%) (%)
e.e.
R-amine S-amine
(%)
(S)-1-Phenylethylamine
Microwave 45
Normal 34
100
99
11
31
(S)-1-(p-methoxyphenyl)- Microwave 35
ethylamine Normal 13
100
100
30
74
(S)-1-p-Tolylethylamine Microwave 28
100
100
45
83
Normal
8
(S)-2-Naphthylethylamine Microwave
6
1
100
100
89
98
Normal
(S)-1-Aminotetraline
Microwave 28
Normal 20
100
98
44
61
(S)-N-Methyl-1-phenyl-
ethylamine
Microwave 28
Normal 15
100
100
45
70
b
(S)-1-Methyl-3-phenyl-
propylamine
Microwave 36
100
100
100
28
94
91
c
Microwave
3
4
b
Normal
a
Reaction conditions: 0.33 mmol substrate, 40 mg 5% Pd/CaCO , 4 ml sol-
3
◦
vent, 0.005 MPa H , 15 min, 120 C.
2
b
4 ml isopropanol.
4 ml toluene, 50 min.
c
ability of a molecule to be polarized by an electric field. To
detect any relationship between the loss factor of the solvent
and the racemization activity of Pd catalysts, we chose sol-
vents with different polarities for testing. Our results (Table 2)
suggest no evident relationship between a solvent’s microwave-
absorbing capacity of a racemization activity. The activity of
5% Pd/CaCO3 was almost the same when toluene (tanδ =
0.04) or DMF (tan δ = 0.161) were used, even if there was a
significant difference in their loss factors. The best results under
microwave conditions were obtained in THF (tanδ = 0.047),
which had a loss factor comparable to that of toluene.
In these different solvents, the beneficial effects of the mi-
crowaves on the selectivity are again apparent. Clear examples
are the reactions performed in isopropyl acetate and DMF. For
the microwave reaction, the selectivity to the corresponding
(R)-enantiomer was 100%. When classical heating was used,
selectivity decreased significantly, with 75% selectivity to the
(R)-amine obtained in isopropyl acetate and 78% in DMF. In
these cases, ethylbenzene was the main side product.
3.2. Kinetic resolution
The other component of a dynamic kinetic resolution is the
enzymatic resolution. Microwave-mediated kinetic resolutions
of alcohols using lipases have been reported previously [10,11].
For both alcohols and amines, Candida antarctica lipase B im-
mobilized on an acrylic resin (CALB; commercially known as
Novozym 435) is a potential catalyst. This immobilized enzyme
has a broad substrate tolerance comprising primary amines and
secondary alcohols. It is generally (R)-selective and has a high
thermal stability, up to at least 90 ◦C. Besides the enzyme used,
a proper choice of acylating agent is also critical to obtain a
good kinetic resolution. It was previously observed that iso-
propyl acetate and ethyl methoxyacetate are excellent reagents
for the enantioselective acylation of chiral amines in the pres-
ence of CALB [6,17]. Microwave irradiation has not yet been
applied for the kinetic resolution of amines. Based on the re-

210
A.N. Parvulescu et al. / Journal of Catalysis 255 (2008) 206–212
sults obtained in the kinetic resolution of alcohols over CALB,
no clear conclusion can be established regarding the effect of
the microwaves on enzyme activity [10,11]; therefore, we stud-
ied the activity of Novozym 435 in amine resolution using
our monomodal microwave reactor (Table 4). For the kinetic
resolution of 1-phenylethylamine, the results obtained under
microwave conditions were very similar to those of reactions
performed under normal conditions, both with isopropyl ac-
etate and ethyl methoxyacetate. No differences in activity or
enantioselectivity were seen between the two different heat-
ing systems. The enzymatic kinetic resolution was fastest when
ethyl methoxyacetate was used as the acylating agent; toluene
seemed to be the best solvent for application of Novozym 435.
When isopropyl acetate was used both as the acylating agent
and the solvent, the activity was doubled, but the enantioselec-
tivity for the (R)-amide decreased.
3.3. Dynamic kinetic resolution
After evaluating the effect of microwaves on racemization
and kinetic resolution, we performed microwave-promoted dy-
namic kinetic resolution. The reactions were performed in one
pot, by adding the immobilized enzyme and the acylating agent
to the racemization mixture (Scheme 2). To achieve a good
DKR, the rate of racemization should be at least of a simi-
lar order of magnitude as the kinetic resolution. This means
that not only both catalysts should be operational in each oth-
er’s presence, but also their relative amounts should be properly
balanced. Insufficient racemization catalyst results in slow over-
all conversion and decreased product enantiopurity, because the
enzyme encounters an excess of the (S)-enantiomer. In princi-
ple, excessive racemization catalyst does not harm the reaction,
but an excess of the chemocatalyst is known to decrease the
enzyme’s activity [18]. Table 5 compares microwave and con-
ventional conditions, keeping the amounts of racemization and
resolution catalysts identical. Based on the results obtained in
the kinetic resolution experiments, ethyl methoxyacetate is the
preferred acylating agent. The strongly beneficial effect of mi-
crowaves on the DKR can be rationalized by assuming that the
racemization is selectively promoted while the resolution is un-
affected. This means that higher yields are reached after shorter
reaction times. Concurrently, because the residual amine is
racemized more efficiently, a sufficient concentration of the
Table 4
a
Kinetic resolution of 1-phenylethylamine with Novozym 435
Acylating agent
(mmol)
Solvent
Heating
Conver- e.e.
sion (%) (%)
R-amide
b
b
c
c
d
Isopropyl acetate, 0.35
Isopropyl acetate, 0.35
Isopropyl acetate, 0.35
Isopropyl acetate, 0.35
Isopropyl acetate, 0.35
Toluene
Toluene
Toluene
Toluene
Isopropyl Microwave 24
acetate
Microwave 14
Normal 14
Microwave 11
Normal 10
100
100
100
100
96
d
Isopropyl acetate, 0.35
Isopropyl Normal
acetate
23
97
c
Ethyl methoxyacetate, 0.35 Toluene
Ethyl methoxyacetate, 0.35 Toluene
Ethyl methoxyacetate, 0.35 THF
Ethyl methoxyacetate, 0.35 THF
Microwave 40
99
99
100
99
c
Normal
Microwave 13
Normal 12
41
d
d
a
Reaction conditions: 0.33 mmol 1-phenylethylamine, 100 mg Novozym
◦
435, 4 ml solvent, 100 C.
b
c
d
◦
20 min, 80 C.
15 min.
10 min.
Scheme 2. DKR of 1-phenylethylamine.
a
Table 5
Microwave vs. classical heating in the DKR of chiral benzylic amines over Pd/ alkaline earth supports
Substrate
Catalyst
Heating
Conversion
(%)
Sel.
(%)
e.e.
R-amide
(%)
R-amide
b
1-Phenylethylamine
5% Pd/BaSO
Microwave
Normal
89
75
99
99
97
99
4
5% Pd/CaCO
5% Pd/CaCO
5% Pd/CaCO
Microwave
Normal
88
73
99
81
97
99
3
3
3
3
c
1-p-Tolylethylamine
Microwave
Normal
97
60
91
99
98
97
d
2-Naphthylethylamine
Microwave
Normal
84
70
92
98
95
95
e
1-Aminotetraline
5% Pd/CaCO
Microwave
Normal
64
54
95
94
95
95
a
◦
Standard DKR reaction conditions: 100 C, 100 mg Novozym 435, 0.35 mmol ethyl methoxyacetate, 40 mg racemization catalyst, 0.005 MPa H .
2
50 min.
75 min.
85 min.
b
c
d
e
75 min and 0.70 mmol ethyl methoxyacetate.

A.N. Parvulescu et al. / Journal of Catalysis 255 (2008) 206–212
211
(R)-amine is available to the enzyme at any time, resulting in
good enantiodiscrimination even at high conversion levels. The
(R)-N-(1-phenylethyl)-2-methoxyacetamide was obtained at a
88% yield after just 50 min at 100 ◦C over 5% Pd/BaSO4, with a
good e.e. of 97% (Table 5). The slightly lower e.e.’s in some re-
actions may be caused by the uncatalyzed reaction of the amine
with the acylating agent. For the DKR of 1-(p-tolyl)ethylamine,
a slightly longer reaction time of 75 min was necessary. Using
classical heating, the conversion of this substrate was just 60%
after 75 min, whereas it attained 97% under microwave condi-
tions in this same period. The same trends are apparent in the
DKRs of 2-naphthylethylamine and 1-aminotetraline; for ex-
ample, for 2-naphthylethylamine, 84% conversion with a 77%
yield of the desired (R)-amide was obtained after 85 min under
microwave conditions.
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The stability of the catalytic system under microwave radi-
ation was proven by recovering the catalysts and reusing them
for two DKR cycles. No loss of activity or selectivity was ob-
served.
4. Conclusion
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Microwave irradiation proved to be an efficient tool for the
racemization and DKR of chiral benzylic amines over Pd on al-
kaline earth metals and lipases. The nature of the heating seems
to have the greatest impact on the racemization step. Under
microwave irradiation, the racemization rate increased, as did
the selectivity. It is thought that microwave heating selectively
affects the temperature of the metal clusters, whereas protons
responsible for side reactions are not influenced. The enzymatic
kinetic resolution of chiral amines seems not to be influenced by
the source of heating; identical results were obtained under mi-
crowave or classical heating conditions when CALB was used.
The DKR of benzylic amines under microwave conditions gave
the desired (R)-amides in high yields (often >80%) and with
e.e.’s between 95% and 98% in 90 min or less, whereas longer
times were needed to achieve similar conversion levels under
conventional heating.
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Acknowledgments
This work was supported by the Bilaterial Flanders–Roma-
nia cooperation of the Flemish government.and the IAP, GOA,
CECAT, and VIRKAT programmes.
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