Superparamagnetic iron oxide as an efficient catalyst for the one-pot, solvent-free synthesis of α-aminonitriles

Article abstract of DOI:10.1016/j.tetlet.2009.02.199

Superparamagnetic Fe₃O₄ is shown to act as a very efficient catalyst for the one-pot, three-component synthesis of α-aminonitriles from aldehydes, amines, and TMSCN. The catalyst is easily recovered by the use of an external magnet and reused in several reactions without any noticeable loss of activity. The products are obtained rapidly at room temperature in good purity upon separation of the catalyst and evaporation of the volatiles of the reaction mixture.

Full text of DOI:10.1016/j.tetlet.2009.02.199

Tetrahedron Letters 50 (2009) 2322–2325
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Tetrahedron Letters
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Superparamagnetic iron oxide as an efficient catalyst for the one-pot,
solvent-free synthesis of
a-aminonitriles
*
*
Mohammad M. Mojtahedi , M. Saeed Abaee , Tooba Alishiri
Chemistry and Chemical Engineering Research Center of Iran, Pajouhesh Blvd, 17th Km Tehran-Karaj Highway, PO Box 14335-186, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Superparamagnetic Fe3O4 is shown to act as a very efficient catalyst for the one-pot, three-component
Received 29 December 2008
Revised 11 February 2009
Accepted 26 February 2009
Available online 4 March 2009
synthesis of
a-aminonitriles from aldehydes, amines, and TMSCN. The catalyst is easily recovered by
the use of an external magnet and reused in several reactions without any noticeable loss of activity.
The products are obtained rapidly at room temperature in good purity upon separation of the catalyst
and evaporation of the volatiles of the reaction mixture.
Ó 2009 Elsevier Ltd. All rights reserved.
Lewis acid-catalyzed reactions allow smooth transformation of
various functional groups in modern synthetic organic chemis-
try.1,2 However, there are limitations associated with the use of
conventional homogeneous Lewis acids. For example, work-up
usually results in complete decomposition of the catalyst and in
addition, the resulting inorganic salts are usually harmful to the
environment. To avoid these drawbacks, heterogeneous catalytic
systems have been used extensively in recent years in various syn-
thetic transformations.3–7 Mild reaction conditions, straightfor-
ward experimental procedures, minimal waste disposal, and
reusability of catalysts are advantages of heterogeneous systems.
In this context, magnetic particles have emerged as a useful group
of heterogeneous catalysts due to their numerous applications in
nanocatalysis,8,9 biotechnology,10,11 and medicine.12,13 Addition-
ally, the magnetic property of such particles provides the opportu-
nity for quantitative recovery of the catalyst by the use of an
external magnetic field.14–16
We recently presented an efficient protocol for the rapid room
temperature protection of alcohols and phenols with HMDS using
superparamagnetic Fe3O4 particles.17 After separation of the cata-
lyst using an external magnet, the silyl ether products were easily
obtained in good purity by evaporation of the volatiles. No additive
or co-catalyst, and no solvent during the reaction or work-up were
required. The ease of accessibility of the catalyst at low cost along
with its full recovery upon completion of the reactions and the che-
moselectivity of the process are advantages of this method. This
has encouraged us to study other organic functional group trans-
formations. In this Letter, we report the three-component Strecker
reaction of an aldehyde, an amine, and a ‘cyanide’ (Scheme 1).18,19
Although this important carbon–carbon bond forming reaction has
witnessed much recent progress,20–24 there are still demands for
the development of efficient procedures involving inexpensive,
recyclable catalytic systems under solvent-free conditions.
Table 1 summarizes the results of the Fe3O4-catalyzed reaction
of TMSCN with various aldehydes and amines. Initial experiments
were carried out under solvent-free conditions involving the reac-
tion of benzaldehyde, Et2NH, and TMSCN at room temperature cat-
alyzed by Fe3O4 (Table 1).25,26 Complete disappearance of the
aldehyde and rapid formation of the product were monitored by
TLC. The use of various amounts of the Lewis acid was investigated
to optimize the reaction conditions. A catalytic quantity of Fe3O4
(10 mol %) proved to be effective for complete conversion of the
starting materials to the desired product 3aa within 20 min (entry
1). The use of lower amounts of the catalyst (down to 2 mol %) pro-
longed the reaction time up to 2 h whilst still giving an almost
quantitative yield of 3aa. Omission of Fe3O4 from the reaction
medium led to formation of only trace quantities of 3aa after sev-
eral hours indicating the crucial role of the catalyst. Similar reac-
tions of benzaldehyde with other acyclic (entries 2 and 3), cyclic
(entries 4 and 5), and aromatic amines (entry 6) were conducted
under the same conditions affording high yields of the respective
CN
TMSCN
RCHO
+
R'R"NH
R
NR'R'
Fe3O4 (10 mol%)
3
1a: R=Ph
2a: Et2NH
1b: R=4-MeOC6H4
1c: R=4-ClC6H4
1d: R=4-FC6H4
2b: n-Bu2NH
2c: Me2NTMS
2d: morpholine
1e: R=4-MeO2CC6H4 2e:piperidine
1f: R=2-thienyl
2f: pyrrolidine
2g:aniline
1g: R=n-propyl
1h: R=C6H5CH2CH2
* Corresponding authors. Tel.: +98 21 44580720; fax: +98 21 44580762 (M.M.M.).
E-mail addresses: mojtahedi@ccerci.ac.ir (M.M. Mojtahedi), abaee@ccerci.ac.ir
(M. Saeed Abaee).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.199

M. M. Mojtahedi et al. / Tetrahedron Letters 50 (2009) 2322–2325
2323
Table 1
Strecker reaction of TMSCN and various aldehydes and amines catalyzed by Fe3O4
Entry
Amine
Aldehyde
Product
Yielda (%)
8920
CN
Ph
O
NH
1
3aa
3ab
N
Ph
CN
Ph
O
NH
2
9520
N
Ph
CN
N
O
NTMS
NH
3
4
3ac
3ad
9320
N
Ph
Ph
CN
Ph
O
9527
O
Ph
O
CN
Ph
O
NH
5
3ae
9028
N
Ph
CN
O
NH2
Ph
6
7
3ag
3be
3bf
3ce
3 cd
3de
9527
8920
9020
9320
8720
9420
HN
Ph
Ph
Ph
CN
C6H4(4-OMe)
O
NH
N
C6H4(4-OMe)
CN
C6H4(4-OMe)
O
O
O
O
NH
NH
8
N
N
C6H4(4-OMe)
C6H4(4-Cl)
C6H4(4-Cl)
C6H4(4-F)
CN
C6H4(4-Cl)
9
CN
C6H4 (4-Cl)
NH
NH
10
11
N
O
O
CN
C6H4 (4-F)
N
CN
C6H4(4-CO2Me)
O
O
9220
9021
8621
NH
NH
12
13
3ef
3fe
3ff
N
C6H4(4-CO2Me)
CN
S
S
S
N
O
CN
NH
14
S
N
a
Isolated yields.

2324
M. M. Mojtahedi et al. / Tetrahedron Letters 50 (2009) 2322–2325
Ph
Ph
Ph
TMSCN
PhCHO
1a
+
Fe3O4 (10 mol%)
NH
3ah
CN
NH2
88%
2h
de=60
Scheme 3.
Table 2
Fe3O4-catalyzed Strecker reaction of benzaldehyde, aniline, and TMSCN in compar-
ison with other methods
100
80
60
40
20
0
Catalyst
Solvent
Yield (%)
Reference
Fe3O4
RhI3
InI3
Montmorillonite
Silica sulfuric acid
NiCl2
—
CH3CN
Et2O
CH2Cl2
CH2Cl2
CH3CN
95
95
95
90
88
92
Present work
Majhi et al.30
Shen et al.27
Yadav et al.29
Chen et al.28
De et al.31
accessible catalyst is presented. After separation of the catalyst
with an external magnet, the reaction products are easily obtained
in good purity by evaporation of the volatiles. A comparison of the
performance of the present catalyst for the Strecker reaction with
some other recent reports27–31 on the condensation of benzalde-
hyde with aniline and TMSCN is shown in Table 2.
1
2
3
4
5
6
7
8
9
10
11
Number of cycles
Figure 1. A typical reaction mixture in the presence or absence of a magnetic field
(top). Efficient recovery of the catalyst (bottom).
Acknowledgment
products within the same time period. Other aromatic aldehydes
bearing electron-withdrawing groups and electron-releasing
groups reacted equally well with various amines under the same
conditions (entries 7–14).
Partial financial support of this work by the Ministry of Science,
Research, and Technology of Iran is gratefully appreciated.
Upon completion of the reactions, the catalyst was recovered
from the reaction mixture simply by applying an external perma-
nent magnet as shown in Figure 1 (top) and the products were iso-
lated in good purity by removing the volatiles under reduced
pressure. Further, the recovered Fe3O4 was reused successfully in
10 subsequent reactions without significant loss of catalytic per-
formance as illustrated in Figure 1 (bottom).
A flame atomic absorption spectroscopy (FAAS) experiment was
designed to study the stability of the Fe3O4 catalyst during the
reaction and the recycling process. Consequently, when a reaction
mixture filtrate was subjected to FAAS analysis, only 0.6 ppm Fe
was detected in the mixture which is equal to 0.1% of the starting
Fe3O4 used for catalysis. This illustrates that Fe3O4 initiates a het-
erogeneous catalytic cycle and does not undergo degradation dur-
ing the reactions allowing its successful reuse.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.199.
References and notes
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In the next step, the procedure was further explored by smooth
conversion of the aliphatic aldehydes butyraldehyde or 3-phenyl-
propionaldehyde into their corresponding
a
-aminonitriles 3ga,20
3gf,31 and 3he,20 respectively, in high yields (Scheme 2).
Finally, the diastereoselectivity of the process was examined for
the reaction between (S)-1-phenylethylamine 2h and benzalde-
hyde 1a. Under the above conditions, formation of 3ah24 was ob-
served in 83% yield within 20 min. The 1H NMR spectrum of the
reaction mixture revealed the formation of both possible products
with moderate 4:1 diastereoselectivity (Scheme 3).
17. Mojtahedi, M. M.; Abaee, M. S.; Eghtedari, M. Appl. Organomet. Chem. 2008, 22,
529–532.
In conclusion, an efficient protocol for the rapid room tempera-
ture Strecker reaction using Fe3O4 as an inexpensive and easily
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26. Typical procedure: Caution! TMSCN is very toxic and could produce hydrogen
cyanide in contact with water. All operations should be performed with special
care under a well-ventilated fume hood. A mixture of aldehyde (4 mmol),
amine (8 mmol), and Fe3O4 (10 mol % with respect to aldehyde) was stirred at
CN
CN
CN
N
N
N
Ph
3he
3ga
3gf
83%
80%
88%
Scheme 2.

M. M. Mojtahedi et al. / Tetrahedron Letters 50 (2009) 2322–2325
2325
room temperature for 1 min. TMSCN (4.8 mmol) was added to this mixture and
stirring was continued for another 15–20 min when TLC showed completion of
by comparison of their spectroscopic data with literature data. The isolated
yields of the products were 80–95%.
the
reaction.
A
conventional
permanent
magnet
(dimensions:
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30. Majhi, A.; Kim, S. S.; Kadam, S. T. Tetrahedron 2008, 64, 5509–5514.
31. De, S. K. J. Mol. Catal. A: Chem. 2005, 225, 169–171.
8 mm  25 mm  40 mm) was applied externally to the outside of the
reaction tube to separate the solid catalyst from the solution. The products
were obtained by evaporation of the volatiles under reduced pressure and
residues were purified by column chromatography, when necessary. All
products are known compounds. The identity of the products was confirmed