One-pot synthesis of β-amino esters by recyclable magnetic organocatalyst-catalysed Mannich-type reaction

Article abstract of DOI:10.3184/174751914X13968767247911

L-cysteine supported on an iron oxide magnetic nanoparticle was prepared by a facile and simple method. The catalyst was effectively applied to the one-pot synthesis of β-amino esters in moderate to good yield. Moreover, the magnetic organocatalyst could be readily recovered and reused up to five times without significant loss of its catalytic activity.

Full text of DOI:10.3184/174751914X13968767247911

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 MAY, 297–299
RESEARCH PAPER 297
One-pot synthesis of β-amino esters by recyclable magnetic
organocatalyst-catalysed Mannich-type reaction
Yibo Huanga, Dan Guanb and Liang Wangc*
aDepartment of Pharmacy, Changzhou Institute of Engineering and Technology, Changzhou, 213164, P.R. China
bDivision of Scientific Technology, Changzhou Institute of Engineering and Technology 213164, P.R. China
cSchool of Petrochemical Engineering, Changzhou University 213164, P.R. China
L-cysteine supported on an iron oxide magnetic nanoparticle was prepared by a facile and simple method. The catalyst was
effectively applied to the one-pot synthesis of β-amino esters in moderate to good yield. Moreover, the magnetic organocatalyst
could be readily recovered and reused up to five times without significant loss of its catalytic activity.
Keywords: magnetic nanoparticle, organocatalyst, one-pot synthesis, β-amino esters
β-Amino esters are important structural units in various
biologically-active compounds1 and are useful building blocks
in some drugs such as β-lactams and β-peptides.2,3 Hence, there
is interest in developing convenient method for preparing these
compounds. The classic multicomponent Mannich reaction
has been widely used for the synthesis of β-amino carbonyl
compounds, including the β-Amino esters.4,5 It has been
reported that some Lewis acids can effectively promote such
transformation.6–10 However, these methods suffer from some
disadvantages such as high catalyst loading, long reaction time,
reagents which are sensitive to the atmosphere as well as the
lack of recyclability of the catalysts.
Magnetic nanomaterials are envisaged to have a major
impact on many areas, including biotechnology, environmental
remediation, and especially catalysis.11,12 Since 2007, magnetic
nanoparticle immobilisation techniques have gradually been
developed to immobilise organocatalysts as shown by the
Connon13–15 and Varma groups.16–18 A magnetic nanoparticle
immobilised organocatalyst is a quasi-homogeneous system that
combines the advantages of high dispersion, high reactivity, and
easy magnetic separation. It has been developed as a powerful
tool for recycling organocatalyst.19 However, previous reports
suffer from the drawback due to complex synthetic procedures.
In continuation of our work on catalyst immobilisation and
recovery20,21, we now report the preparation of nano-Fe3O4
immobilised L-cysteine and its catalytic activity in the one-pot
synthesis of β-amino esters. The recovery and reusability of
such a catalyst were also investigated (Scheme 1).
Results and discussion
The nano-Fe3O4 immobilised L-cysteine was prepared
from Fe3O4 and L-cysteine by simple mechanical stirring
(Scheme 2).12 The interaction of nano-ferrites and L-cysteine
was due to weak hydrogen bonds and van der Waals forces. The
immobilised catalyst was then characterised by XRD, TEM
and FT-IR.
The crystalline structure of the catalyst 1 was determined
by power XRD (Fig. 1). The diffraction patterns and relative
intensities of all the peaks matched well with those of magnetite
standard spectra (JCPDS card no. 00-002-1035). No other oxide
or hydroxide phase was observed and the broad XRD peaks
clearly indicated the nanocrystalline nature of the catalyst. In
addition, TEM analysis (Fig. 2) showed that most of particles
were microspheres with an average size range of ~150 nm.
Furthermore, the size distribution of catalyst 1 was broad. The
minute tendency to form clusters was observed due to the weak
forces between the Fe3O4-L-cysteine molecules.
Then, the catalyst was examined by FT-IR. The characteristic
absorptions due to Vasym (asymmetric vibration) COO– of
carboxylic groups appeared at about 1620 cm–1. Moreover,
the S–H stretching peak at 2100 cm–1 disappeared. All these
changes indicated the successful attachment of L-cysteine on
the surface of nanoparticles.
EtOOC
COOEt
NH
NH2
CHO
+
COOEt
COOEt
Cat.
R1
R2
+
R1
Solvent
R2
Scheme 1 The synthesis of β-amino diethyl malonate.
O
HS
OH
O
EG, PEG, Urea
200 oC
NH2
.
Fe3O4
Fe3O4
S
OH
FeCl3 6H2O
NH2
1
r.t. Stirring
Scheme 2 Preparation of nano-Fe3O4 immobilised L-cysteine organocatalyst 1.
* Correspondent. E-mail: lwcczu@126.com

298 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 The optimisation of reaction conditiona
2000
1800
1600
1400
1200
1000
800
EtOOC
COOEt
NH
NH2
CHO
+
COOEt
COOEt
Cat.
+
Solvent
2a
3a
4
5a
Entry
Catalyst
Solvent
Yield/%b
1
2
3
4
5
6
7
8c
9d
No catalyst
Fe3O4
L-Cysteine
1
1
1
1
1
1
MeOH
MeOH
MeOH
MeOH
DCM
CH3CN
CHCl3
DCM
NR
18
83
81
87
72
78
83
88
600
400
200
0
0
10
20
30
40
50
60
70
80
90
DCM
2θ
Fig. 1 The XRD of catalyst 1.
aReaction condition: 2a (0.5 mmol), 3a (0.5 mmol), 4 (0.55 mmol), catalyst
loading (5 wt% with respect to the amount of 2a), reaction temperature
30 °C, solvent 3 mL, reaction time 12 h.
bIsolated yield.
Catalyst loading: c3 wt%; d10 wt%.
Table 2 Three-component reactions of aromatic aldehydes, amines and
diethyl malonatea
EtOOC
COOEt
CHO
+
NH2
COOEt
COOEt
NH
Cat. 1 (5 wt%)
CH2Cl2
R1
R2
+
R1
R2
Melting point/oC
Determined Reported
Entry
R1
R2
Product
Yields/%b
1
2
3
4
5
6
7
8
9
H
H
H
H
H
4-Cl
3-Cl
4-CH3O 5d
H
5a
5b
5c
92–93
81–82
110–112
70–72
118–120
88–89
74–75
98–100
106–108
105–107
92–9322
81–8223
111–11224
–
118–11923
88–8922
–
99–10022
107–10822
106–10722
88
76
78
21
82
82
88
90
80
81
4-Cl
4-Br
4-CN
3-NO2 3-Cl
4-Br
2-Cl
5e
5f
5g
5h
5i
4-Cl
H
Fig. 2 The TEM of catalyst 1.
The catalyst and solvent effects on the synthesis of β‑amino
malonic esters
4-Br
4-Br
10
5j
With the catalyst in hand, we began to explore its catalytic
activity for the one-pot synthesis of β-amino esters. Initially, the
reaction conditions were optimised using the model reaction of
benzaldehyde 2a, aniline 3a, and diethyl malonate in different
conditions. As shown in Table 1, the model reaction did not
work without any catalyst, with only aryl aldimines were
observed as by-products. In the presence of Fe3O4, the yield
that was obtained was very low (18% yield, entry 2). However,
an 83% yield was obtained using L-cysteine as catalyst. By
comparison, our nano-organocatalyst 1 also showed good
catalytic activity for the model reaction, affording the product
in 81% yield (entry 4). In addition, different solvents were
evaluated and dichloromethane was the best choice (87% yield,
entry 5). When the catalyst loading varied from 3 wt% to
10 wt%, the yield increased from 83% to 88% (entries 5, 8 and
9) and 5 wt% amount of catalyst was sufficient.
aReaction conditions: aldehyde (0.5 mmol), amine (0.5 mmol), diethyl
malonate (0.55 mmol), CH2Cl2 (3 mL), catalyst loading (5 wt% with respect
to the amount of aldehyde), reaction temperature 30 °C, reaction time 12 h.
bIsolated yield.
and some electron-deficient aromatic aldehydes were easily
transformed to the corresponding products (entries 1, 7 and
8). Halogenated aromatic aldehydes and aromatic amines also
could obtain good yields (entries 6 and 9). But for electron-rich
aromatic amines, the yield is too low to be detected by LC-MS
(entry 4).
Recovery of nano‑organocatalyst
The most important feature is the ease of separation and
reusability for a heterogeneous catalyst. The recyclability of
our magnetic organocatalyst 1 was investigated. After finishing
the reaction, the catalyst was separated by simple filtration
with an exterior magnetic field. The catalyst was then washed
with water, dried under vacuum and reused for next run. The
results clearly indicated that the catalyst could be reused for
five consecutive cycles without obvious changes in its activity
(Fig. 3).
Synthesis of different β‑amino diethyl malonate
Using the optimised reaction condition, we investigated the
reactions of various aldehydes and amines using nano-Fe3O4-
L-cysteine as catalyst. The results are summarised in Table 2.
Generally, most of reactions proceeded smoothly. Benzaldehyde

JOURNAL OF CHEMICAL RESEARCH 2014 299
Diethyl 2‑(phenyl(4‑methoxyphenylamino)methyl)malonate (5d):
Yellow solid, m.p. 70–72°C. 1H NMR (300 MHz, CDCl3): δ 7.35–7.26
(m, 5 H), 6.69–6.67 (d, J=7.2 Hz, 2H), 6.58–6.55 (d, J=7.2 Hz, 2
H), 5.10 (d, J=5.8 Hz, 1 H), 4.14–4.10 (m, 4 H), 3.68 (s, 3H), 3.38 (d,
J=5.8 Hz, 1 H), 1.20 (t, J=7.2 Hz, 3 H), 1.12 (t, J=7.2 Hz, 3 H) ppm;
13C NMR (75 MHz, CDCl3): δ 167.7, 166.9, 146.1, 141.6, 131.6, 129.5,
128.0, 118.8, 118.6, 62.4, 62.0, 57.5, 56.4, 55.2, 14.1, 13.8 ppm. HR-Mass
C21H25NO5 for M+, calcd 371.1727, found 371.1728.
Diethyl 2‑(4‑bromophenyl(4‑chlorophenylamino)methyl)malonate
(5f):22 White solid, m.p. 88–89°C. 1H NMR (300 MHz, CDCl3): δ
7.40–7.34 (m, 2 H), 7.16–7.12 (m, 2 H), 6.97–6.34 (m, 2 H), 6.41–6.38
(m, 2 H), 5.04 (d, J=5.5 Hz, 1 H), 3.83 (d, J=5.5 Hz, 1H), 4.16–4.02
(m, 4 H), 1.10–1.04 (m, 6 H) ppm; 13C NMR (75 MHz, CDCl3): δ 167.9,
167.1, 145.0, 138.5, 132.0, 129.2, 128.9, 121.9, 114.9, 62.1, 61.9, 57.8,
56.8, 14.1, 14.0 ppm; MS (ESI) m/z ([M+1]+) 454.
Fig. 3 The recovery of magnetic organocatalyst 1.
Diethyl 2‑(4‑cyano‑phenyl(phenylamino)methyl)malonate (5g):
1
White solid, m.p. 74–75°C. H NMR (300 MHz, CDCl3): δ 7.60–7.54
(m, 2 H), 7.50–7.45 (m, 2 H), 7.18–7.04 (m, 2 H), 6.78–6.62 (m, 1 H),
6.58–5.52 (m, 2 H), 5.26 (d, J=7.2 Hz, 1 H), 4.18–4.08 (m, 4 H), 3.88 (d,
J=7.2 Hz, 1 H), 1.20–1.14 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ 167.8, 167.0, 146.1, 145.6, 132.6, 129.5, 128.0, 118.8, 118.6, 62.3, 62.1,
57.7, 56.9, 14.1, 14.0 ppm. HR-Mass C21H22N2O4 for M+, calcd 371.1727,
found 371.1728.
Conclusion
In summary, the nano-ferrite immobilised L-cysteine
organocatalyst was easily prepared and successfully applied in
the one-pot synthesis of β-amino malonic esters. The magnetic
organocatalyst was stable and could be recovered by simple
magnetic decantation. The simple procedure for catalyst
preparation, easy recovery and reusability of the catalyst can be
expected to contribute to its utilisation for the development of
benign chemical process and products.
We thank National Natural Science Foundation of China
(21302014), the Natural Science Foundation for Colleges and
Universities of Jiangsu Province (13KJB150002), Jiangsu
Overseas Research & Training Program for University
Prominent Young and Middle-aged Teachers in 2011, and
Changzhou Scientific Application Program on Basic Research
(CJ20130003) for financial support.
Experimental
1H NMR and 13C NMR spectra were recorded with Bruker AM
300 spectrometer using CDCl3 as a solvent and TMS as an internal
standard. FT-IR spectra were recorded on a Perkin-Elmer FT-IR
X 1760 instrument. Mass spectra were obtained on TSQ Quantum
LC-MS. HR-Mass were recorded on Bruker ultrafine MALDI-
TOF-TOF. TEM were recorded on JEM-2000 transmission electron
microscope with an acceleration voltage of 200 kV. X-ray diffraction
(XRD) patterns of samples were recorded on a Bruker AXS D8
ADVANCE X-ray diffractometer.
Received 16 December 2013; accepted 13 March 2014
Paper 1302347 doi: 10.3184/174751914X13968767247911
Published online: 6 May 2014
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