Heterogeneous Catalytic Hydrogenation of Chiral Amino Acid Methyl Esters to Amino Alcohols with Retention of Configuration Over Mg-Modified Cu/ZnO/Al2O3 Catalyst

Article abstract of DOI:10.1007/s10562-017-2116-3

Selective hydrogenation of amino acid methyl esters to chiral amino alcohols is an important and fascinating process. The CuZn_0.3Mg_0.1AlO_x catalyst for the synthesis of chiral amino alcohols was prepared by the fractional

Full text of DOI:10.1007/s10562-017-2116-3

Catal Lett (2017) 147:2160–2166
DOI 10.1007/s10562-017-2116-3
Heterogeneous Catalytic Hydrogenation of Chiral Amino Acid
Methyl Esters to Amino Alcohols with Retention of Configuration
Over Mg-Modified Cu/ZnO/Al2O3 Catalyst
Bing Zhan1 · Shuangshuang Zhang1 · Jun Yu1 · Xiuzheng Xiao1 · Xiaoming Guo1 ·
Dongsen Mao1 · Guanzhong Lu1,2
Received: 7 April 2017 / Accepted: 12 June 2017 / Published online: 19 June 2017
© Springer Science+Business Media, LLC 2017
Abstract Selective hydrogenation of amino acid methyl
esters to chiral amino alcohols is an important and fascinat-
ing process. The CuZn0.3Mg0.1AlOx catalyst for the synthe-
sis of chiral amino alcohols was prepared by the fractional
co-precipitation method in the 50–100 g scale. The effect of
the reduction gas on the catalytic activity, and the effects of
the reaction conditions (R-p-m/Cat, temperature, reaction
time, H2 pressure and solvent) on the catalytic hydrogena-
tion of R-phenylglycine methyl ester (marked as R-p-m)
were investigated. When R-p-m in the ethanol solvent was
hydrogenated at 5 MPa of H2 and 80°C for 10 h over this
catalyst reduced by H2, 87.7% yield of R-phenylglycinol
with ~100% ee value was obtained, and its reaction acti-
vation energy (Ea) was 36.7 kJ/mol. After repeated usage
16 times, its catalytic activity was hardly varied. Using this
catalyst to catalyze the preparation of other amino alco-
hols, the high yield of product with ~100% ee value was
obtained also.
* Guanzhong Lu
gzhlu@ecust.edu.cn
1
Research Institute of Applied Catalysis, School of Chemical
and Environmental Engineering, Shanghai Institute
of Technology, Shanghai 201418, China
2
Key Laboratory for Advanced Materials and Research
Institute of Industrial catalysis, East China University
of Science and Technology, Shanghai 200237, China
Vol:.(1234567890)
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Heterogeneous Catalytic Hydrogenation of Chiral Amino Acid Methyl Esters to Amino Alcohols…
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Graphical Abstract
not only extremely expensive to mass production, but
also its reactant conversion was relatively low [12]. But
these catalytic systems are not commercially available.
To overcome these problems, a high efficient, inexpen-
sive and stable catalyst for the hydrogenation of chiral
amino acids or esters is desperately needed. Therefore,
we have developed the special structure Cu/ZnO/Al2O3
catalyst for the selective hydrogenation of L-phenylala-
nine methyl esters to l-phenylalaninol with high ee value
[16–19], which will provide a new and green synthetic
approach for the manufacture of chiral amino alcohols.
Compared with the Pt catalyst, the CuZn0.3Mg0.1AlOx is
not only very cheap, but also much higher reactant con-
version and product yield with ~100% ee value can be
obtained, although they need to be reduced before being
used.
Keywords Amino acid esters · Chiral amino alcohols ·
Mg-modified Cu/ZnO/Al2O3 catalyst · Catalytic
hydrogenation · High ee value
1 Introduction
Chiral amino alcohols are widely used chiral compounds
and contained in many synthetic and natural products [1,
2], and often used as the intermediates in pharmaceutical
industries, synthesis of insecticidal compounds and chi-
ral auxiliaries [3–5]. And they are also popularly applied
as chiral ligands in asymmetric catalysis and resolving
agents in asymmetric synthesis [6–8]. Therefore, devel-
oping valid methods to synthesize chiral amino alcohols
has extremely vital significance for chemists. Convention-
ally, chiral amino alcohols can be achieved by hydrogena-
tion of amino acids or esters with metal hydrides [9–11],
which can occur at low temperatures thereby retaining
the integrity of the stereogenic center. However, most of
the metal hydrides are only used for the preparation of
amino alcohols in a scale of 100–150 g, and these routes
suffer from the production of a large amount of salts, and
using expensive or excessive reagents. In recent years,
the precious metal catalysts were used to prepare chiral
amino alcohols under relatively mild reaction conditions,
such as Pt, Ru, Os oxide and their complexes [12–15].
Although the Pt catalyst was employed at lower tempera-
ture and not required to be reduced, these catalysts are
As a kind of chiral amino alcohols, chiral phenylgly-
cinol has the extremely widespread application, and it
and its derivatives can be used as the starting materials,
chiral auxiliaries, protection reagents and ligands in the
pharmaceutical, fine chemical industries and other fields
[20–25]. For example, it can be used to prepare morpho-
line compounds to treat asthma and alleviate pain, indole
compounds to resist atherosclerosis, isoquinoline drugs
and so on [26]. Chiral phenylglycinol itself is a kind of
high value-added fine chemical products.
In this paper, we used the inexpensive
CuZn0.3Mg0.1AlOx heterogeneous catalyst prepared in
a relatively big scale to catalyze the hydrogenation of
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2162
B. Zhan et al.
R-phenylglycine methyl ester to R-phenylglycinol, its
reaction formula was described as follows and the effects
of different reaction conditions on this catalytic hydro-
genation were investigated. We also expanded the appli-
cation of this catalyst for producing a series of other
amino alcohols.
of this catalyst prepared was hardly decreased compared
with the results reported [18]. In detail, the mixed solution
(A) of 1.0 M Cu(NO3)2 and 1.0 M Zn(NO3)2, and 0.5 M
Na2CO3 solution were co-precipitated at 70°C under strong
stirring by adjusting the flow rates of two solutions to keep
pH=7.5. The mixed solution (B) of 1.0 M Al(NO3)3 and
1.0 M Mg(NO3)2, and 0.5 M Na2CO3 solution were co-
precipitated under the same conditions above. Then (A)
and (B) was mixed at 70°C under strong stirring. After this
synthesis solution was stirred for 2 h and cooled statically
for 1 h, the catalyst precursor was filtrated and washed with
deionized water until the filtrate was neutral, followed by
dry at room temperature for 12 h and at 120°C for 24 h.
Finally, it was heated to 450°C at 5°C/min and calcined
at 450°C for 4 h. The calcined sample was pressed and
crushed to 20–40 mesh.
where R represents
,
,
, -CH3,
,
,
,
.
2.2 Raw Material Preparation
2 Experimental Section
2.1 Catalyst Preparation
3 g amino acid methyl ester hydrochloride was dissolved in
deionized water, and pH of mixed solutions was controlled
to 8 by adding 0.5 M Na2CO3 aqueous solution. After this
mixed solution was extracted with ethyl acetate, the upper
liquid was obtained. Then ethyl acetate was removed
by rotary evaporation, and amino acid methyl ester was
obtained as the raw material. All the chemicals were com-
mercially available and used without further purification.
The CuZn0.3Mg0.1AlOx catalyst was prepared by the co-
precipitation method [18], but we have enlarged the scale
of preparing catalyst more than ten times, and the activity
88
86
84
82
80
78
2.3 Testing of the Catalyst Activity
The activity of catalyst for hydrogenation of R-phenyl-
glycine methyl ester was tested in a 0.5 L stainless steel
autoclave under stirring at a speed of 500 rpm. After 1 g
catalyst (20–40 mesh) was put in the reactor, the reac-
tor was swept with H2 five times to flush out air. Then
the catalyst was reduced at 1 MPa H2 and 250°C for 4 h.
After the autoclave was cooled in H2 atmosphere to room
temperature, 1.5 g R-phenylglycine methyl esters (R-p-m)
diluted in 150 mL ethanol was added (R-p-m/Cat=1.5,
wt.). The typical reaction conditions were at 5 MPa of
H2 and 80°C for 10 h. After the reaction was ended, the
autoclave was cooled in H2 atmosphere to room tempera-
ture. Then solid catalyst was separated by centrifugation.
The product was purified by column chromatography on
350
400
450
500
550
Calcination temperature(oC)
Fig. 1 Effect of the calcination temperature on the catalyst perfor-
mance. (Reaction conditions: 5 MPa H2, 1.0 g catalyst, 1.5 g reactant,
at 80°C for 10 h)
Table 1 The effect of reduction
Entry
Reduction gas (mol)
Conv. (%)
Sel. (%)
Yield (%)
ee (%)
gas on the catalytic activity of
the CuZn0.3Mg0.1AlOx catalyst
1
2
3
4
H2 (10%)+N2 (90%)
CO (29.7%)+N2 (10.1%)+H2 (60.2%)
CO (1.51%)+N2 (98.49%)
H2
>99.9
>99.9
>99.9
>99.9
45.9
71.9
62.8
80.4
45.9
71.9
62.8
80.4
>99.9
>99.9
>99.9
>99.9
Reaction conditions: 4 MPa H2, 1.0 g catalyst, 1.5 g reactant, at 80°C for 10 h
1 3

Heterogeneous Catalytic Hydrogenation of Chiral Amino Acid Methyl Esters to Amino Alcohols…
2163
90
85
80
75
70
65
60
55
50
45
90
80
70
60
50
40
30
20
10
0
a
b
60
80
100
120
140
1.0
1.5
2.0
2.5
3.0
Temperature (oC)
R-p-m/Cat (wt.)
90
90
c
d
85
80
75
70
65
60
55
50
45
85
80
75
70
65
60
55
50
45
2
3
4
5
6
2
4
6
8
10
12
H2 pressure (MPa)
Reaction time (h)
Fig. 2 Effect of the reaction condition on the yield of R-phenylgly-
cinol over the CuZn0.3Mg0.1AlOx catalyst: a R-p-m/Cat, b tempera-
ture, c reaction time, and d H2 pressure. (Reaction conditions: a at
80°C and 5 MPa of H2 for 10 h; b R-p-m/Cat=1.5, at 4 MPa of H2
for 5 h; c R-p-m/Cat=1.5, at 80°C and 4 MPa of H2; and d R-p-m/
Cat=1.5, at 80°C for 10 h)
Table 2 Solvent effect on the yield of R-phenylglycinol over the
2.2
2.0
1.8
1.6
1.4
1.2
CuZn0.3Mg0.1AlOx catalyst
Solvent
Methanol
83.3
Ethanol
87.7
Isopropanol
63.2
THF
56.8
Yield (%)
silica gel with ethyl acetate/methanol (3/2, v/v) as the elu-
ent. Thus we obtained the light yellow powder product by
rotary evaporation. Reactants and products were analyzed
by High Performance Liquid Chromatograph (HPLC, Agi-
lent 1260 Infinity) equipped with an ultraviolet detector and
a column (Eclipse XDB-C18, 150×4.6 mm, 5 mm particle
size), then the conversion of R-phenylglycine methyl ester
(X), yield (Y) and chemoselectivity to R-phenylglycinol (S)
were calculated [18, 19], in which the yield is the LC yield.
And the ee value of products was determined by HPLC
equipped with an ultraviolet detector (wavelength 258 nm)
and a chiral column (CHIRALPAK AY-H, 250×4.6 mm,
5 μm particle size) [19].
1.0
Ea= 36.7 kJ/mol
0.8
0.6
2.65 2.70 2.75 2.80 2.85 2.90 2.95 3.00 3.05
1000/T /K-1
Fig. 3 Arrhenius plots of ln r against to 1/T for hydrogena-
tion of R-phenylglycine methyl ester to R-phenylglycinol over the
CuZn0.3Mg0.1AlOx catalyst
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B. Zhan et al.
Table 3 Hydrogenation of
R-phenylglycine methyl ester
to R-phenylglycinol over the
CuZn0.3Mg0.1AlOx catalyst
Entry Temp. (K) WCatal. (mg) Time (h) Conv. (%) Yield (%) Sel. (%) ee (%)
r
(mmol g−1 h−1
)
1
2
3
4
5
333
343
353
363
373
1000
1000
1000
1000
1000
0.5
0.33
0.5
0.17
0.33
21.9
13.2
29.8
12.2
29.9
10.2
10.1
18.4
10.8
28.4
46.5
76.5
61.7
88.5
94.9
>99.9 1.85
>99.9 2.76
>99.9 3.34
>99.9 5.91
>99.9 7.74
120
100
80
60
40
20
0
H2 as the reduction gas for the CuZn0.3Mg0.1AlOx catalyst.
The effect of the calcination temperature of the catalyst
on its activity was tested also and the results are shown in
Fig. 1, which shows that the appropriate calcination tem-
perature is 450°C.
Conversion
Yield
We have compared the catalytic performance of the
CuZn0.3Mg0.1AlOx catalyst with industrial Copper cata-
lyst used in the manufacture of hydrogen (HTCB-7),
ammonia (HT-CB5/9) and methanol (MS-2) from Liaon-
ing Haitai Sci-Tech Development Co., Ltd. (China). The
results showed that they exhibited poor performances with
very low yield (<10%) of amino alcohols, which should
be ascribed to the different compositions and preparation
methods [16–18].
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
Recycling times
3.2 Effect of the Reaction Condition
Fig. 4 Repeated usage of the CuZn0.3Mg0.1AlOx catalyst in the
hydrogenation of R-phenylglycine methyl ester at 80°C and 5 MPa
H2 for 10 h (R-p-m/Cat=1.5, wt.). Experimental errors of the conver-
sion and yield are within 2%
Figure 2a shows the effect of the catalyst amount (R-p-m/
Cat) on the yield of R-phenylglycinol at 80°C and 5 MPa
of H2 for 10 h. The results show that with the increase in
the catalyst amount from R-p-m/Cat=1.15 to 1.5, the yield
of R-phenylglycinol was increased, and when R-p-m/Cat
was >1.5, the product yield was obviously reduced with
increasing the catalyst amount. The optimized catalyst
amount should be R-p-m/Cat=1.5, which was adopted in
the following experiments.
R-phenylglycinol (product): 1H NMR (Bruker
AVANCE-III 500, CDCl3) δ 7.43–7.22 (m, 5H), 4.07 (dd,
J=8.4, 4.4 Hz, 1H), 3.77 (dd, J=10.7, 4.4 Hz, 1H), 3.58
(dd, J=10.7, 8.4 Hz, 1H), 2.16 (s, 3H). FT-IR (Nicolet
iN10 FT-IR spectrometer, KBr): 3330, 3275, 1604, 1497,
1453, 1361, 1198, 1080, 1050, 759, 702, 532 cm−1. (3S,
6R)-3,6-diphenylpiperazine-2,5-dione (byproduct): 1H
NMR (CDCl3) δ 7.58 (s, 2H), 7.45 (d, J=10.0 Hz, 4H),
7.36 (d, J=10.0 Hz, 4H), 7.33 (d, J=5.0 Hz, 2H), 6.74 (s,
2H). FT-IR (KBr): 3342, 3203, 1705, 1679, 1610, 1490,
1206, 1043, 795, 760, 705, 564 cm−1.
The influence of the reaction temperature on the yield
of R-phenylglycinol was tested in 4 MPa of H2 for 5 h.
As shown in Fig. 2b, the yield of R-phenylglycinol was
increased with the increase in the reaction temperature
from 60 to 80°C. When the reaction temperature was
>80°C, the yield of the target product decreased. There-
fore, the appropriate reaction temperature is 80°C. The
effect of the reaction time on the R-phenylglycinol yield
is shown in Fig. 2c at 80°C and 4 MPa of H2. With the
increase in the reaction time from 2 to 10 h, the product
yield was obviously increased, and after the reaction time
was >10 h, the increase of yield tended to be gentle. Thus
the appropriate reaction time should be 10 h when the reac-
tion was operated at 80°C. The effect of the hydrogen pres-
sure was tested at 80°C for 10 h, and the results (Fig. 2d)
show that the product yield was increased with increasing
H2 pressure, and when H2 pressure was 5 MPa, the highest
3 Results and Discussion
3.1 Pretreatment of the Catalyst
Prior to reaction, the catalyst was treated by different
reduction gases under the same reaction condition, and
their effects on the activity of the CuZn0.3Mg0.1AlOx cata-
lyst are shown in Table 1. The results show that the cata-
lyst reduced by pure H2 exhibited the best catalytic activity
with 80.4% selectivity to product. Thus we selected pure
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Heterogeneous Catalytic Hydrogenation of Chiral Amino Acid Methyl Esters to Amino Alcohols…
2165
Table 4 Hydrogenation of various amino acid methyl esters over the CuZn0.3Mg0.1AlOx under optimal reaction conditions
Amino acid
methyl ester
Conv.
(%)
Sel.
(%)
Yield
(%)
ee
(%)
Entry
Amino alcohol
Main byproduct
1
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
59.3
57.4
60.6
63.2
67.2
87.7
80.1
22.7
59.3
57.4
60.6
63.2
67.2
87.7
80.1
22.7
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
2
3
4
5
6
7
8
Reaction conditions: 5 MPa H2, 1.0 g catalyst, 1.5 g reactant, at 80°C for 10 h
yield was obtained. Hence 5 MPa of H2 pressure should be
most appropriate.
result indicates that CuZn0.3Mg0.1AlOx is an excellent cata-
lyst for hydrogenation of R-phenylglycine methyl ester, due
to its relatively low activation energy.
Based on the results mentioned above, the appropri-
ate reaction conditions can be determined to be R-p-m/
Cat=1.5 at 5 MPa of H2 and 80°C for 10 h. Under these
reaction conditions, the yield of R-phenylglycinol can reach
87.7% and its ee value is ~100% obtained by HPLC.
The solvent effect on this catalytic reaction was also
examined and results are shown in Table 2. In compari-
son with other solvents (methanol, isopropanol and THF),
when ethanol was used as a solvent, the highest product
yield (87.7%) could be obtained.
3.4 Repeated Usage of the Catalyst
The stability of the CuZn0.3Mg0.1AlOx catalyst was tested
by repeated usage. The results in Fig. 4 show that the cata-
lyst has the good operation stability, and after repeated
usage 16 times, the performance of the catalyst was hardly
changed and the product yield was kept at 85.6–87.7%.
3.5 Hydrogenation of Different Amino Alcohols
3.3 The Calculation of Activation Energy (Ea)
To know the applicability of the CuZn0.3Mg0.1AlOx cata-
lyst for the hydrogenation of other amino acid methyl
esters to prepare amino alcohols, eight kinds of amino
acid methyl esters were used as the reactants (Table 4).
The concentrations of the reactants and products were
analyzed by GC (FULI GC-7970) equipped with FID and
a polar capillary chromatographic column (AE PEG-20
30 m×0.32 mm×0.5 μm). As shown in Table 4, when
The activation energy (Ea) for hydrogenation of R-phe-
nylglycine methyl ester to R-phenylglycinol over the
CuZn0.3Mg0.1AlOx catalyst was calculated based on the
data of the temperature effect in Table 3, in which the for-
mation rate (r) of product and reactant conversion were
below 30%. Based on Arrhenius plots of ln r against to 1/T
(Fig. 3), the Ea value was calculated to be 36.7 kJ/mol. This
1 3

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B. Zhan et al.
2. Corey EJ, Bakshi RK, Shibata S (1987) J Am Chem Soc
109:5551
eight kinds of reactants were catalytically hydrogenated, the
corresponding eight kinds of amino alcohols (l-leucinol,
d-valinol, l-isoleucinol l-alaninol, l-threoninol, R-phenyl-
glycinol and l-phenylalaninol) can be obtained with rela-
tive high yields without racemization, which shows that the
CuZn0.3Mg0.1AlOx catalyst exhibited also the high catalytic
activity for other seven reactants besides l-tyrosinol hydro-
chloride (Table 4, entry 8), because the chloride ion may
lead to a deactivation of the catalyst [27] and a low yield
of l-tyrosinol hydrochloride. The byproducts of these reac-
tions are show in Table 4. The products of the eight kinds
of amino alcohols were all kept their own original configu-
ration with high ee value. The main reason is that the coor-
dination adsorption of amino acid methyl esters onto the
catalyst active sites in the whole reaction process did not
vary their configurations [19].
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4 Conclusions
16. Gao CY, Xiao XZ, Mao DS, Lu GZ (2013) Catal Sci Technol
3:1056
17. Shi ZP, Xiao XZ, Mao DS, Lu GZ (2014) Catal Sci Technol
4:1132
In summary, the CuZn0.3Mg0.1AlOx catalyst was prepared
in a relatively large scale by the fractional co-precipitation
method under the conditions of aging at 70°C for 2 h and
calcination at 450°C for 4 h. Using this catalyst reduced
by H2, 87.7% yield of R-phenylglycinol with ~100% ee
value could be obtained by the hydrogenation of R-phe-
nylglycine methyl ester (R-p-m) at 80°C and 5 MPa of H2
for 10 h with R-p-m/Cat=1.5(wt.). The reaction activation
energy (Ea) is 36.7 kJ/mol. After repeated usage 16 times,
its catalytic activity was hardly varied. When this catalyst
was used to catalyze the preparation of other seven kinds
of amino alcohols, the high yield of product with ~100%
ee value can be obtained also. The CuZn0.3Mg0.1AlOx is an
efficient heterogeneous catalyst for hydrogenation of amino
acid methyl esters to amino alcohols in ethanol.
18. Shi ZP, Zhang SS, Xiao XZ, Mao DS, Lu GZ (2016) Catal Sci
Technol 6:3457
19. Zhang SS, Yu J, Li HY, Mao DS, Lu GZ (2016) Sci Rep 6:33196
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Eur J Org Chem 2012:1835
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Acknowledgements We would like to acknowledge the financial
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support from the School to Introduce Talents Project (YJ2011-46).
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