Lithium Perchlorate Mediated Three-Component Preparation of α-Aminonitriles under Solvent-Free Conditions

Article abstract of DOI:10.1081/SCC-120030307

A three-component reaction between aliphatic or aromatic aldehyde, an amine and trimethylsilyl cyanide mediated by solid LiClO₄, gave amino nitriles in good to excellent yields. The reaction proceeded smoothly under solvent-free conditions without any side products.

Full text of DOI:10.1081/SCC-120030307

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Lithium Perchlorate Mediated Three‐Component
Preparation of α‐Aminonitriles Under Solvent‐Free
Conditions
Najmedin Azizi a & Mohammad R. Saidi a
a Department of Chemistry, Sharif University of Technology, P.O. Box 11365‐9516, Tehran,
Iran
Published online: 21 Aug 2006.
To cite this article: Najmedin Azizi & Mohammad R. Saidi (2004): Lithium Perchlorate Mediated Three‐Component
Preparation of α‐Aminonitriles Under Solvent‐Free Conditions, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:7, 1207-1214
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 7, pp. 1207–1214, 2004
Lithium Perchlorate Mediated
Three-Component Preparation
of a-Aminonitriles Under
Solvent-Free Conditions
*
Najmedin Azizi and Mohammad R. Saidi
Department of Chemistry, Sharif University of Technology,
Tehran, Iran
ABSTRACT
A three-component reaction between aliphatic or aromatic aldehyde, an
amine and trimethylsilyl cyanide mediated by solid LiClO4, gave amino
nitriles in good to excellent yields. The reaction proceeded smoothly
under solvent-free conditions without any side products.
Key Words: Lithium perchlorate; a-Aminonitriles; Solvent-free
conditions; Three-component condensation.
*
Correspondence: Mohammad R. Saidi, Department of Chemistry, Sharif University
of Technology, P.O. Box 11365-9516, Tehran, Iran; Fax: þ98-21-601-2983; E-mail:
saidi@sharif.edu.
1207
DOI: 10.1081/SCC-120030307
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Azizi and Saidi
INTRODUCTION
Three-component condensations are interesting and important, not only
because three components are reacting together in one pot, but also because
this methodology would be useful for the preparation of a broad variety of
organic compounds. a-Aminonitriles are important intermediates in the syn-
thesis of amino acids, amides, and diamines.[1,2] Numerous methods describ-
ing the preparation of a-aminonitriles are reported in the literature using
different kind of catalysts including a variety of Lewis acids.[3] However, it
can be difficult to recover the Lewis acid catalyst in the three-component con-
densation for the synthesis of a-aminonitriles, because of the strong affinity of
the Lewis acids for the amino groups or because its reaction with water does
not allow regeneration of the Lewis acid. Also, in many cases, in Lewis acid-
catalyzed three-component synthesis of amino nitriles, a stoichiometric
amount of expensive Lewis acid is needed.[4]
RESULTS AND DISCUSSION
In continuation of our current work on the use of 5 M ethereal lithium per-
chlorate for three-component Mannich-type organic transformations,[5] and
the current challenge for developing solvent-free and environmentally benign
synthetic systems,[6] herein, we report a mild, convenient, and rapid method
for cyano amination of aldehydes with TMSCN using solid LiClO4 as a
promoter under solvent-free conditions.
Treatment of benzaldehyde with a secondary amine such as piperidine,
and trimethylsilyl cyanide in the presence of solid LiClO4 afforded the corres-
ponding a-aminonitriles in 90% yield without using any solvent at room
temperature. Similarly, several aromatic aldehydes and 2-methylpropanal
reacted under the same conditions to give the corresponding a-aminonitriles
in good to excellent yields, Sch. 1.
The reaction proceeded smoothly at room temperature and the prod-
ucts were isolated in good yields after a short reaction time. The generality
of this reaction is evident from the results summarized in Table 1, which
shows that a variety of aldehydes and secondary amines are converted into
Scheme 1.

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Table 1. Solid LiClO4-catalyzed aminocyanation of aldehydes by TMSCN.
Entry
1
Aldehyde
Amine
Product
Yieldsa (%)
90
2
3
4
5
76b
90
84c
92
6
7
93
90
8
9
94
90
76
10
11
12
84
92
(continued)

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Azizi and Saidi
Table 1. Continued.
Entry
13
Aldehyde
Amine
Product
Yieldsa (%)
91
14
74
aIsolated yields.
bBy using morpholine the aminocyanation reaction did not proceed, but with N-(tri-
methylsilyl)morpholine, the corresponding a-amino nitrile was formed.
cMe2NTMS was used, because dimethylamine is gas at r.t.
the corresponding a-aminonitriles. By using morpholine as a secondary amine
at the same reaction conditions, no product was formed. By using N-(tri-
methylsilyl)morpholine the corresponding a-aminonitriles was produced in
76% yield (Table 1, Entry 2). Since aqueous solution of dimethylamine
could not be used as an amine, instead, N-(trimethylsilyl)dimethylamine
was used (Table 1, Entry 4). LiClO4 is not an expensive reagent, it can be quan-
titatively recovered and reused after activation. The recovery procedure and
recycling are very simple. After the reaction is complete dichloromethane is
added with stirring; LiClO4 precipitates and can be quantitatively separated
by filtration. The recovered LiClO4 can be reactivated by heating in vacuum
at 1608C and reused. This is another feature of this reaction for developing
environmentally benign synthetic methods.
In conclusion, solid lithium perchlorate is found to be an efficient pro-
moter for the cyano amination of aldehydes. The reactions proceed smoothly
under solvent-free conditions with a very easy work up procedure.
EXPERIMENTAL
Typical Procedure for the Synthesis of a-Aminonitriles
The aldehydes (1 mmol), LiClO4 (2 mmol) were placed in a 5-mL flask
under argon and stirred for 1 min, then an amine (3 mmol) was added via syr-
inge. After 5 min, TMSCN (1.2 mmol) was added and the mixture was stirred
at r.t. for about 20 min. After the reaction is complete, the organic materials
separated by adding CH2Cl2 (10 mL). The precipitated LiClO4 was recovered
by filtration. Then the organic layer was washed with aqueous NaHCO3

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(2 Â 10 mL), water (2 Â 10 mL), and dried over Na2SO4. The reaction pro-
duct was recovered by simple removal of solvent and purified by column chro-
matography on silica gel eluting with petroleum ether/EtOAc, if necessary.
All compounds are known and were characterized on the basis of their spectro-
scopic data (IR, NMR) and by comparison with those reported in the literature.
2-(N-Pyrrolidino)-2-phenylacetonitrile (4a).[4] M.p. 84–868C (Lit.[4]
1
858C). H NMR (500 MHz, CDCl3): d (ppm) 1.80–1.81 (m, 4H), 2.66–2.72
(m, 4H), 5.30 (s, 1H), 7.25–7.35 (m, 5H); 13C NMR (125 MHz, CDCl3): d
(ppm) 50.1 (CH), 27.9 (CH2), 67.2 (CH2), 114.9 (CN), 124.0 (CH), 125.8
(CH), 130.8 (CH), 135.4 (CH), 140.4 (C); IR: (CH2Cl2), 2239 cm21
.
2-(N-Morpholino)-2-phenylacetonitrile (4b).[4] M.p. 92–938C (Lit.[4]
1
908C). H NMR (500 MHz, CDCl3): d (ppm) 2.57–2.58 (m, 4H), 3.70–3.75
(m, 4H), 4.80 (s, 1H), 7.37–7.54 (m, 5H); 13C NMR (125 MHz, CDCl3): d
(ppm) 50.3 (CH), 62.7 (CH2), 67.1 (CH2), 115.6 (CN), 127.5 (CH), 128.4
(CH), 130.3 (CH), 132.1 (C); IR: (CH2Cl2), 2230 (CN) cm21
.
2-(N-Piperidino)-2-phenylacetonitrile(4c). M.p.100–1028C(Lit.[4]1018C).
1H NMR (500 MHz, CDCl3): d (ppm) 1.45–1.60 (m, 6H), 2.49 (m, 4H), 4.81
(s, 1H), 7.33–7.38 (m, 3H), 7.52–7.54 (m, 2H); 13C NMR (125 MHz, CDCl3): d
(ppm) 24.3 (CH2), 26.2 (CH2), 51.3 (CH), 63.2 (CH2), 115.9 (CN), 128.2 (CH),
128.8 (CH), 129.3 (CH), 135.1 (C); IR: (CH2Cl2), 2232 (CN) cm21
.
2-(N,N-Dimethyl)-2-phenylacetonitrile (4d). Oil.[4] 1H NMR (500MHz,
CDCl3): d (ppm) 2.22 (s, 6H), 7.31–7.37 (m, 3H), 7.51–7.52 (m, 2H); 13C
NMR (125MHz, CDCl3), d 45.2 (CH3), 51.3 (CH), 115.9 (CN), 128.2 (CH),
128.8 (CH), 129.3 (CH), 135.1 (C); IR: (CH2Cl2), 2232 (CN) cm21
.
2-(N-Pyrrolidino)-2-( p-bromophenyl)acetonitrile (4e). M.p. 89–908C
(Lit.[1] 918C).1H NMR (500 MHz, CDCl3): d (ppm) 1.67–1.80 (m, 4H), 2.64–
2.71 (m, 4H), 5.31 (s, 1H), 7.25–7.28 (m, 2H), 7.30–7.33 (m, 2H); 13C NMR
(125 MHz, CDCl3): d (ppm) 25.2 (CH2), 50.1 (CH), 64.1 (CH2), 114.9 (CN),
124.0 (CH), 125.8 (CH), 132.8 (CH), 134.4 (CH), 146.4 (C); IR: (CH2Cl2),
2239 cm21
.
2-(N-Piperidino)-2-(p-bromophenyl)acetonitrile (4f). M.p. 106–1078C
1
(Lit.[1] 1088C). H NMR (500MHz, CDCl3): d (ppm) 1.45–1.60 (m, 6H),
2.49 (m, 4H), 4.81 (s, 1H), 7.33–7.40 (m, 2H), 7.52–7.56 (m, 2H); 13C
NMR (125MHz, CDCl3): d (ppm) 24.3 (CH2), 26.2 (CH2), 51.3 (CH), 63.2
(CH2), 115.9 (CN), 128.2 (CH), 128.8 (CH), 129.3 (C), 139.1 (C); IR:
(CH2Cl2), 2232 (CN) cm21
.
2-(N-Pyrrolidino)-2-( p-chlorophenyl)acetonitrile (4g). M.p. 85–868C
1
(Lit.[1] 848C). H NMR (500MHz, CDCl3): d (ppm) 1.80–1.81 (m, 4H),
2.66–2.72 (m, 4H), 5.30 (s, 1H), 7.25–7.35 (m, 5H); 13C NMR (125 MHz,
CDCl3): d (ppm) 50.1 (CH), 64.9 (CH2), 67.2 (CH2), 114.9 (CN), 124.0
(CH), 125.8 (CH), 130.8 (CH), 138.4 (C), 143.4 (C); IR: (CH2Cl2), 2239cm21
.

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Azizi and Saidi
2-(N-Piperidino)-2-(2-methoxyphenyl)acetonitrile (4h). Oil.[2] 1H NMR
(500 MHz, CDCl3): d (ppm) 1.45–1.60 (m, 6H), 2.49 (m, 4H), 3.84 (s, 3H),
5.15 (s, 1H), 6.91–7.10 (m, 2H), 7.34–7.45 (m, 2H); 13C NMR (125 MHz,
CDCl3): d (ppm) 24.2 (CH2), 26.6 (CH2), 51.8 (CH), 63.3 (CH2), 114.5
(CN), 112.4 (CH), 120.3 (CH), 124.1 (C), 129.1 (CH), 131.8 (CH), 157.1
(C); IR: (CH2Cl2), 2231 cm21
.
2-(N-Pyrrolidino)-2-(2-methoxyphenyl)acetonitrile (4i). Oil.[2] 1H NMR
(500 MHz, CDCl3): d (ppm) 1.80–1.81 (m, 4H), 2.66–2.75 (m, 4H), 3.82
(s, 3H), 5.35 (s, 1H), 6.90–6.99 (m, 2H), 7.31–7.50 (m, 2H); 13C NMR
(125 MHz, CDCl3): d (ppm) 26.4 (CH2), 51.4 (CH), 54.2 (CH2), 114.9 (CN),
113.4 (CH), 122.8 (CH), 125.1 (C), 129.1 (CH), 132.4, 158.4 (C); IR:
(CH2Cl2), 2235 cm21
.
2-(N-Pyrrolidino)-2-(4-methoxyphenyl)acetonitrile (4j). Oil.[2b] 1H NMR
(500 MHz, CDCl3): d (ppm) 1.79–1.81 (m, 4H), 2.65–2.77 (m, 4H), 3.81
(s, 3H), 5.30 (s, 1H), 6.70–6.80 (m, 2H), 7.21–7.24 (m, 2H); IR: (CH2Cl2),
2236 cm21
.
2-(N-Pyrrolidino)-2-(2,4-dichlorophenyl)acetonitrile (4k). M.p. 110–
1
1128C (Lit.[4b] 1108C). H NMR (500 MHz, CDCl3): d (ppm) 1.83–1.85
(m, 4H), 2.68–2.79 (m, 4H), 5.39 (s, 1H), 7.33–7.41 (m, 2H), 7.66–7.68
(m, 1H); IR: (CH2Cl2), 2235 cm21
.
2-(N-Pyrrolidino)-2-(o-nitrophenyl)acetonitrile (4l). M.p. 116–1188C
1
(Lit.[2d] 1168C). H NMR (500 MHz, CDCl3): d (ppm) 1.79–1.81 (m, 4H),
2.66–2.69 (m, 4H), 4.95 (s, 1H), 7.62 (m, 1H), 7.92 (m, 1H), 8.22 (m, 1H),
8.38 (m, 1H). 13C NMR (125 MHz, CDCl3): d (ppm) 50.1 (CH), 64.9
(CH2), 67.2 (CH2), 114.9 (CN), 123.2 (CH), 123.7 (C), 134.6 (CH), 135.4
(CH), 139.8 (CH), 148.4 (C); IR: (CH2Cl2), 1347, 1534, 2235 cm21
.
2-(N-Pyrrolidino)-2-(methyl 4-carboxylphenyl)acetonitrile (4m). M.p.
1
120–1228C (Lit.[1a] 1208C). H NMR (500 MHz, CDCl3): d (ppm) 1.80–
1.81 (m, 4H), 2.66–2.75 (m, 4H), 3.82 (s, 3H), 5.35 (s, 1H), 6.90–6.99
(m, 2H), 7.38–7.43 (m, 2H); IR: (CH2Cl2), 2240, 1730 cm21
.
2-(N-Pyrrolidino)-3-methylbutanonitrile (4n). Oil.[3b] 1H NMR
(500 MHz, CDCl3): d (ppm) 0.91 (d, J ¼ 6.6 Hz, 3H), 1.12 (d, J ¼ 6.6 Hz,
3H), 1.60 (m, 1H), 1.80–1.83 (m, 4H), 2.59–2.69 (m, 4H), 3.29
(d, J ¼ 10.1 Hz, 1H); IR: (CH2Cl2), 2225 (CN) cm21
.
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Received in Poland June 1, 2003

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