FeCl3: Highly efficient catalyst for synthesis of α-amino nitriles

Article abstract of DOI:10.1002/cjoc.201090100

α-Amino nitriles are synthesized by the three-component coupling reaction of aldehydes, amines and trimethylsilyl cyanide using FeCl₃ as a solid acid catalyst, under solvent-free conditions in good yields. The catalyst was recovered by simple f

Full text of DOI:10.1002/cjoc.201090100

NOTE
FeCl3: Highly Efficient Catalyst for Synthesis of
α-Amino Nitriles
Heravi, Majid M.*
Ebrahimzadeh, Mojgan
Oskooie, Hossein A.
Baghernejad, Bita
Department of Chemistry, School of Science, Azzahra University, Vanak, Tehran, Iran
α-Amino nitriles are synthesized by the three-component coupling reaction of aldehydes, amines and trimethyl-
silyl cyanide using FeCl3 as a solid acid catalyst, under solvent-free conditions in good yields. The catalyst was re-
covered by simple filtration and was recycled in subsequent reactions.
Keywords one-pot, FeCl3, trimethyl silyl cyanide, α-aminonitriles
Introduction
Scheme 1
α-Amino nitriles, are important precursors in the
synthesis of natural and unnatural α-amino acids, vari-
ous nitrogen-containing heterocycles1 and other bio-
logically useful molecules such as saframycin A.2 The
Strecker reaction, discovered in 1850,3 has been recog-
nized as the first multicomponent reaction4 published
ever and has a central importance to the life sciences.5
The three-component coupling of an amine, a carbonyl
compound (generally an aldehyde) and either hydrogen
cyanide or its alkaline metal cyanides to give
α-aminonitriles6 constitutes an important indirect route
in the synthesis of α-amino acids.7 Some of the Strecker
methodologies rely on the use of toxic cyanide deriva-
tives involving harsh reaction conditions, which poses
problems to be addressed, particularly when large-scale
applications are considered. In order to avoid partially
this inconvenience, acetone cyanohydrin, diethylalu-
minium cyanide, TMSCN, etc. have been introduced as
cyanide sources in the Strecker reaction, wherein
TMSCN is a promising alternative, simplest, safe, easy
to handle, most soluble and more effective cyanide ion
source for the nucleophilic addition reactions. Many of
the Strecker reactions involve the use of expensive re-
agents, harsh conditions, extended reaction time, and
also require tedious workup leading to the generation of
a large amount of toxic waste. In order to overcome
these problems recently one-pot procedures have been
developed for this transformation.8 In continuation of
our work to develop new catalysts for organic transfor-
mations,9 here we report a mild, efficient and environ-
mentally benign method for the preparation of
α-aminonitriles from aldehydes, amines and trimethyl-
silyl cyanide in the presence of FeCl3 as a safe catalyst
under solvent-free condition at room temperature
(Scheme 1).
Results and discussion
FeCl3 is an efficient catalyst in modern organic syn-
thesis.10 It has become the focus of attention in several
environmentally friendly and atom-economical organic
transformations. Recent reports on FeCl3 catalyzed ary-
lation of benzyl alcohols and benzyl carboxylates,11 and
hydroarylation of styrenes,12 have highlighted the ap-
plications of FeCl3 in organic synthesis. In this contri-
bution, we disclose a simple and practical synthesis of
α-aminonitriles catalyzed by FeCl3. Mild reaction con-
ditions and environmentally friendly catalyst make this
transformation an attractive option for the straightfor-
ward preparation of these compounds. The reaction of
aldehydes and amines with TMSCN in the presence of a
catalytic amount of FeCl3 (5 mmol%) afforded the cor-
responding α-aminonitriles under solvent free condition
in good yields (Scheme 1, Table 1). The reaction is suc-
cessful using amines with a variety of aldehydes but not
ketones. These three-component coupling reactions
proceeded efficiently at room temperature with high
selectivity. No cyanohydrin trimethylsilyl ethers (an
adduct between an aldehyde and trimethylsilyl cynide)
were obtained under these reaction conditions. This is
because of the rapid formation and activation of the im-
ines by FeCl3. The reactions are clean and highly selec-
tive affording exclusively α-aminonitriles in high yields
in a relatively short reaction time. This method is
equally effective with aldehydes bearing electron with-
drawing substituents in the aromatic ring. However, we
found that the reaction did not proceed with aliphatic
aldehydes.
*
E-mail: mmh1331@yahoo.com; Fax: 00982188047861
Received April 14, 2009; revised August 24, 2009; accepted September 14, 2009.
480
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Chin. J. Chem. 2010, 28, 480— 482

Catalyst for Synthesis of α-Amino Nitriles
Table 1 Synthesis of α-amino nitriles in the presence of FeCl3 as a catalyst
m.p./℃
Entry
1
2
Product
Time/min
Yielda/%
Observed
Found
73—7413
oil14
1
2
3
4
5
6
7
8
Benzaldehyde
Aniline
4a
4b
4c
4d
4e
4f
75
Oil
15
15
15
15
15
15
10
10
78
75
75
74
74
74
80
81
Benzaldehyde
Benzyl amine
Aniline
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
4-Methylbenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
92—93
94—9513
76—7813
Oil15
109—11213
Benzyl amine
Aniline
Oil
Oil15
74—76
Oil
Benzyl amine
Aniline
4g
4h
110
Benzyl amine
Oil
Oil15
a Yields of isolated products.
The amount of catalyst has been optimized to 5
mmol%; however, lesser amount (3 mmol%) would also
work with longer reaction time. This method does not
require any additives or stringent reaction conditions to
proceed.
The synthesis of α-amino nitriles was carried out
using various common solvents such as CCl4, acetoni-
trile, methanol, ethylacetate and THF. With using FeCl3
as a catalyst, the highest yield of products was obtained
under solvent-free condition. In addition, the time re-
quired for completion of the reaction was found to be
less in this condition (Table 2).
Table 3 Reuse of the FeCl3 for synthesis of 4aa
Entry
Time/h
1.5
Yielda/%
1
78
73
70
68
68
2
2.0
3
3.0
4
4.0
5
4.5
a Isolated yields.
this new approach. Some highly toxic and expensive
reagents can be avoided. We expected that this green
complimentary method would provide a general appli-
cation in organic synthesis.
Table 2 Synthesis of 4a with FeCl3 in the presence of different
solvent
Entry
Solvent
CCl4
Time/min
Yielda/%
Experimental
1
2
3
4
5
6
25
20
20
20
20
15
60
67
65
66
71
78
All products are known compounds and were char-
acterized by m.p., IR, H NMR and GC/MS. Melting
points were measured by using the capillary tube
method with an electro thermal 9200 apparatus. H
1
Acetonitrile
Methanol
Ethylacetate
THF
1
NMR spectra were recorded on a Bruker AQS
AVANCE-500 MHz spectrometer using TMS as an in-
ternal standard (CDCl3 solution). IR spectra were re-
corded from KBr disk on the FT-IR Bruker Tensor 27.
GC/MS spectra were recorded on an Agilent Technolo-
gies 6890 network GC system and an Agilent 5973
network Mass selective detector. Thin layer chromatog-
raphy (TLC) on commercial aluminum-backed plates of
silica gel, 60 F254 was used to monitor the progress of
reactions.
Solvent-free
a Yield of isolated products.
Next, we investigated the reusability of FeCl3. At the
end of the reaction, the catalyst could be recovered by a
simple filtration, washed with methanol and subjected to
a second run of the reaction process. To assure that the
catalysts were not dissolved in dichloromethane, they
were weighed after filteration and before use and reused
for the next reaction. The results show that these cata-
lysts are not soluble in dichloromethane.
General procedure for the synthesis of α-amino ni-
triles
In Table 3, the comparison of efficiency of FeCl3 in
synthesis of 4a after five times is reported. As shown in
Table 3 the first reaction using recovered FeCl3 afforded
a similar yield to that obtained in the first run. In the
second, third, fourth and fifth runs, the yields were
gradually decreased.
In summary, the mild reaction conditions, experi-
mental simplicity, low cost, excellent yield, and the en-
vironmentally benign nature are major advantages of
A mixture of aldehyde (1 mmol), amine (1 mmol),
trimethylsilyl cyanide (1 mmol) and FeCl3 (5 mmol%)
was stirred vigorously at room temperature for the indi-
cated time (Table 1). After completion of the reaction, as
indicated by TLC, the reaction mixture was extracted
with dichloromethane (10 mL×3), then the solvent was
evaporated. The residue was recrystallized from ethanol
to give the pure product.
Chin. J. Chem. 2010, 28, 480— 482
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
481

Heravi et al.
FULL PAPER
Selected physical data
2529.
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4a: m.p. 75 ℃; IR (KBr) ν: 3360, 3025,－2950, 2230,
1
1600, 1500, 1460, 1315, 1140, 995, 750 cm ; 1H NMR
(CDCl3, 500 MHz) δ: 4.1 (s, 1H, NH), 5.4 (s, 1H), 6.5—
6.8 (m, 5H), 7.1—7.8 (m, 5H); GC/MS (m/z): 208 (M＋).
4b: Colorless oil; IR (KBr) ν: 3400, 2930, －2230,
9
1
1
1650, 1514, 1400, 1108, 1028, 920, 825, 751 cm ; H
NMR (CDCl3, 500 MHz) δ: 1.80 (s, 1H, NH), 3.90 (q,
J＝13.0 Hz, 2H), 4.85 (s, 1H), 6.85 (d, J＝8.0 Hz, 1H),
7.15 (t, J＝7.8 Hz, 1H), 7.25—7.40 (m, 6H), 7.45—
7.51 (m, 2H); GC/MS (m/z): 222 (M＋).
4c: m.p. 92—93 ℃; IR (KBr) ν: 3380, 3060, 2930,
1
2240, 1600, 1500, 1455, 1290, 1116,1040, 929, 760; H
NMR (CDCl3, 500 MHz) δ: 3.80 (s, 3H), 4.1 (d, J＝8.1
Hz, 1H), 5.30 (d, J＝8.1 Hz, 1H), 6.50 (d, J＝8.1 Hz,
2H), 6.80 (t, J＝7.9 Hz, 1H), 7.05 (d, J＝8.0 Hz, 2H),
7.25 (t, J＝7.9 Hz, 2H), 7.50 (d, J＝8.0 Hz, 2H);
GC/MS (m/z): 238 (M＋).
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10 (a) Diaz, D. D.; Miranda, P. O.; Padron, J. I.; Martin, V. S.
Curr. Org. Chem. 2006, 10, 457.
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Chin. J. Chem. 2010, 28, 480— 482