Efficient dynamic kinetic resolution of arylamines with Pd/layered double-hydroxide-dodecyl sulfate anion for racemization

Article abstract of DOI:10.1016/j.tetlet.2013.11.041

A novel and efficient racemization catalyst, Pd/layered double-hydroxide-dodecyl sulfate anion, was prepared and used in the dynamic kinetic resolution (DKR) of arylamines. The undesired enantiomer was completely racemized at 55 C, allowing the catalyst to be compatible with biocatalysts. DKR proceeded smoothly and showed a broad substrate scope, with good conversion and high product enantiomeric excesses (ee_p). The system could be reused more than 30 times without loss of conversion and ee_p value.

Full text of DOI:10.1016/j.tetlet.2013.11.041

Tetrahedron Letters 55 (2014) 397–402
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Tetrahedron Letters
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Efficient dynamic kinetic resolution of arylamines with Pd/layered
double-hydroxide-dodecyl sulfate anion for racemization
⇑
⇑
Gang Xu, Xiaoting Dai, Simin Fu, Jianping Wu , Lirong Yang
Institute of Bioengineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient racemization catalyst, Pd/layered double-hydroxide-dodecyl sulfate anion, was pre-
pared and used in the dynamic kinetic resolution (DKR) of arylamines. The undesired enantiomer was
completely racemized at 55 °C, allowing the catalyst to be compatible with biocatalysts. DKR proceeded
smoothly and showed a broad substrate scope, with good conversion and high product enantiomeric
excesses (eep). The system could be reused more than 30 times without loss of conversion and eep value.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 12 September 2013
Revised 3 November 2013
Accepted 11 November 2013
Available online 19 November 2013
Keywords:
Racemization catalyst
Dynamic kinetic resolution
Arylamines
Lipase
Introduction
catalysts with enzymes are also not ideal and the substrate scope
of some catalysts is narrow.
Enantiomerically pure arylamines are important intermediates
in the synthesis of pharmaceuticals, fragrances, and agrochemicals.
Of the conventional preparative methods, kinetic resolution (KR) is
one of the most practical1 because of its high selectivity, mild reac-
tion conditions, and low waste. Its main drawback is that the max-
imum theoretical conversion of the method is only 50%. Dynamic
kinetic resolution (DKR)2,3 which combines KR with in situ racemi-
zation of the undesired enantiomer, has potential to overcome this
problem and increase conversion to 100%. In a typical process
involving amines, a highly selective KR catalyst, an efficient race-
mization catalyst, and compatibility between these catalysts are
the basic requirements.4,5 Many efficient KR catalysts have been
developed, such as Novozym 435, which has been widely used in
KR reactions of alcohols and amines; however, there is a need for
further research into the preparation of efficient racemization
catalysts. In recent years, there has been increased investigation
into catalysts for DKR of chiral amines, including Ru complexes,6
Raney Ni,7 Pd nanoparticles,8 and Pt microcapsules.9 However, high
yields and enantioselectivity generally require long reaction times
at high reaction temperatures, and the results can be affected by
the formation of ethylbenzene (ETB) as a by-product. DKR catalysts
Among these racemization catalysts, Pd nanoparticles are
preferred. Although many Pd catalysts have been developed for
DKR of amines, most of these suffer from the drawbacks mentioned
above. Parvulescu et al.8e showed that a basic Pd/layered double-
hydroxide (LDH) catalyst could be used to racemize arylamines.
Recently, LDHs have received increasing attention because of their
potential applications as basic supports for transition metals in
various organic transformations. In this study, based on Parvule-
scu’s work, we developed a new efficient catalyst, namely a
dodecyl-sulfate anion (DS)-embedded-LDH-supported Pd (Pd/
LDH-DS),10 to build a successful DKR system for arylamines.
Parvulescu et al.8d suggested that in the DKR process, racemiza-
tion occurs by dehydrogenation and hydrogenation, with ETB and
amine or imine condensation products as potential side products
(Fig. 1).
Results and discussion
From previous research, we know that the surface acidity or
alkalinity8e and specific surface area of the catalyst can affect the
racemization of the amines. We therefore designed various cata-
lysts to study these properties. Compared with other Pd catalysts,
Pd/LDH-DS showed much better results in the racemization of (S)-
1-phenylethylamine (Table 1). After reaction for 15 h, the amine
enantiomeric excess (eeamine) reached 3% when Pd/LDH-DS was
used as the racemization catalyst. The efficiency of Pd/LDH-DS
was higher than those of other Pd catalysts, and less ETB was
such as Pd/C8a,b and Pd/BaSO4 are only suitable for the prepara-
8d
tion of a few optically active amines. These racemization catalysts
also still have some drawbacks such as low catalytic efficiencies
and poor selectivity. The compatibilities of the racemization
⇑
Corresponding authors. Tel./fax: +86 571 87952363.
E-mail addresses: wjp@zju.edu.cn (J. Wu), lryang@zju.edu.cn (L. Yang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.041

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G. Xu et al. / Tetrahedron Letters 55 (2014) 397–402
NH2
NH
NH2
-H2
+H2
(S)-1a
(R)-1a
-NH3
+H2
+H2
N
Figure 1. Mechanism of Pd/LDH-DS catalyzed racemization of (S)-1-
phenylethylamine.
Figure 3. XRD pattern of Pd/LDH-DS.
(2h = 40.1°, 2h = 46.6°, 2h = 68.0°), which do not exist in the curve
of LDH-DS, indicating that Pd was successfully loaded on the
LDH-DS surface.
Table 1
Racemization of (S)-1-phenylethylamine over Pd catalysts
In this study, a model reaction using Novozym 435 as the cata-
lyst for enantioselective acylation, 1-phenylethylamine as the
model substrate, 4-chlorophenyl valerate as an acyl donor for
amine acylation, and toluene as the solvent was combined with
the racemization catalyst Pd/LDH-DS to build a successful DKR sys-
tem for 1-phenylethylamine.
Entry Catalyst
Specific surface area (m2/g) eeamine (%) Sel.ETB (%)
1
2
3
4
5
6
7
Pd/C
Pd/BaSO4
Pd/CaCO3
55
2.967
0.945
60
8
10
44
31
8
15
11
12
12
2
Pd/AlO(OH) 9.872
Pd/BaCO3
Pd/LDH8e
Pd/LDH-DS
2.353
73
13
2
As a lipase, the optimum temperature of Novozym 435 is low,
such that high reaction temperatures may reduce its efficiency.
However, the high catalytic efficiency of Pd/LDH-DS allows the
reaction to be performed at low temperature. The optimal reaction
temperatures for racemization using catalysts such as Ru
69.389
3
Reaction conditions: 0.33 mmol of (S)-1-phenylethylamine, 4 ml of toluene, 40 mg
of Pd catalysts, 55 °C, 15 h, 0.03 MPa H2, catalyst loading 5 wt % Pd on support.
8d
complexes6, Pd/BaSO4,8d and Pd/CaCO3 are as high as 90 °C, and
racemization using Pd/AlO(OH) requires a temperature of 70 °C.
However, we achieved nearly 100% product ee (eep) at 100% con-
version (Table 2, entry 1) at a lower temperature (55 °C), shows
that the new racemization catalyst had better compatibility with
the enzyme.
We then expanded the substrate scope to build successful DKR
systems for other arylamines. The results are shown in Table 2.
The results in Table 2 show that DKR was successful with most
arylamines using Pd/LDH-DS as the racemization catalyst. Quite a
few of the reactions achieved nearly 100% eep at 100% conversion.
From the results, we can also conclude that the reaction proceeded
more efficiently when electron-donating groups were substituted
on the benzene ring. When the substituents were electron-with-
drawing groups, the conversion and eep values of the reaction were
low (Table 2, entries 7–11).
The eep values of some arylamines did not reach 100% during
the DKR process. Decreased selectivity of the enzyme may be the
reason for the reduced eep. The KR of the arylamines with 4-chlo-
rophenyl valerate as an acyl donor was then investigated. The re-
sults in Table 3 show that eep values cannot reach 100% after
reaction under the same condition, suggesting that the catalyst
for the enantioselective acylation reaction, that is the lipase, was
the reason for the decrease in eep values in DKR.
Figure 2. SEM image of Pd/LDH-DS.
detected after racemization, showing that the side reaction was
effectively suppressed.
As a heterogeneous catalyst, Pd/LDH-DS can be easily separated
from the system, and the reaction system showed good operational
stability. The catalyst can be reused more than 30 times without
any loss of conversion and eep value (Fig. 4). This reusability makes
the catalyst suitable for the preparation of optically active amines.
These results show that the new catalyst features several signif-
icant improvements. First, the alkaline environment prevents
hydrogenolysis of C–N bonds on Pd,11 so that side reactions are
suppressed. Second, the intercalation of DS improves the lipophil-
icity of the catalyst,10 making it easier for the substrate to react on
the catalyst surface. Third, the intercalation of DS enlarges the
surface area, and this improves the efficiency by adding more reac-
tion sites. The SEM image (Fig. 2) shows that the catalyst has
layered structure which increases its surface area. And in Figure 3,
the curve of Pd/LDH-DS has three Pd crystal characteristic peaks
Conclusions
In summary, an efficient heterogeneous catalyst, Pd/LDH-DS,
was designed for racemization of arylamines, giving high eep

G. Xu et al. / Tetrahedron Letters 55 (2014) 397–402
399
Table 2
The DKR of arylamines with long carbon-chain esters as acyl donor
Entry
Substrate
Product
eeP (%)
Conv. (%)
NH2
O
HN
(CH2)3CH3
1
>99
>99
>99
94
R
1a
2a
NH2
O
HN
(CH2)3CH3
2
>99
R
1b
2b
NH2
O
HN
(CH2)3CH3
3
>99
R
1c
2c
NH2
H
N
(CH2)3CH3
R
O
4
>99
89
1d
2d
NH2
O
HN
(CH2)3CH3
R
5
>99
>99
1e
2e
NH2
O
HN
(CH2)3CH3
R
6
>99
>99
1f
2f
NH2
O
HN
(CH2)3CH3
7
88.2
98
F
R
1g
F
2g
(continued on next page)

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G. Xu et al. / Tetrahedron Letters 55 (2014) 397–402
Table 2 (continued)
Entry
Substrate
Product
eeP (%)
Conv. (%)
NH2
O
HN
(CH2)3CH3
8
92.7
95
R
Cl
1h
1i
Cl
2h
NH2
O
HN
(CH2)3CH3
9
93
>99
R
Br
Br
2i
NH2
O
HN
(CH2)3CH3
10
95
>99
R
O
1j
O
2j
NH2
O
HN
(CH2)3CH3
11
>99
>99
R
1k
2k
NH2
O
Cl
HN
Cl
(CH2)3CH3
12
94.3
92.9
R
1l
2l
NH2
O
Cl
HN
(CH2)3CH3
13
93.4
93
Cl
R
1m
2m
NH2
O
F3
C
HN
(CH2)3CH3
14
F3C
>99
>99
R
1n
2n

G. Xu et al. / Tetrahedron Letters 55 (2014) 397–402
401
Table 2 (continued)
Entry
Substrate
Product
eeP (%)
Conv. (%)
NH2
O
Cl
HN
Cl
(CH2)3CH3
15
90.2
>99
R
Cl
1o
Cl
2o
Reaction condition: 4 ml of toluene, 0.33 mmol of 1-phenylethylamine, 0.35 mmol of 4-chlorophenyl valerate, 40 mg of Pd/LDH-DS, 100 mg of Novozym 435, 0.03 MPa H2,
55 °C, rotation speed 200 r/min, 15 h for each reaction run.
Table 3
The KR of arylamines with 4-chlorophenyl valerate as acyl donor
Entry
Substrate
eep (%)
Yield (%)
50
NH2
NH2
NH2
1
>99
F
2
3
>99
50
Cl
92.7
53.5
Br
Cl
NH2
4
5
94
92
51.2
53.5
Figure 4. Catalyst reuse with 4-chlorophenyl valerate as acyl donor (N conversion,
j eep).
NH2
Cl
NH2
Cl
Acknowledgments
The authors thank the National Basic Research Program of
China (973 Program, No. 2011CB710800), Hi-Tech Research and
Development Program of China (863 Program, 2011AA02A209),
National Natural Science Foundation of China (No. 20936002) for
the financial supports, Research on Public Welfare Technology
Application Projects of Zhejiang Province, China (No. 2010C31127).
6
88
54.1
Cl
KR reaction conditions: 4 ml of toluene, 0.33 mmol of 1-phenylethylamine,
0.35 mmol of 4-chlorophenyl valerate, 100 mg of Novozyym 435, 0.03 MPa H2,
55 °C, rotation speed 200 r/min.
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