LiBr: A mild Lewis acid catalyst for efficient one-pot synthesis of α-amino nitriles

Article abstract of DOI:10.1080/00397910802213729

α-Amino nitriles are synthesized in a one-pot, three-component coupling of aldehydes, amines, and trimethylsilyl cyanide using a catalytic amount of LiBr at ambient temperature. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802213729

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LiBr: A Mild Lewis Acid Catalyst
for Efficient One-Pot Synthesis
of α-Amino Nitriles
Anil Saini Suresh a & Jagir S. Sandhu a
a Department of Chemistry , Punjabi University ,
Patiala, Punjab, India
Published online: 14 Oct 2008.
To cite this article: Anil Saini Suresh & Jagir S. Sandhu (2008) LiBr: A Mild Lewis
Acid Catalyst for Efficient One-Pot Synthesis of α-Amino Nitriles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:21, 3655-3661, DOI: 10.1080/00397910802213729
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Synthetic Communications1, 38: 3655–3661, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802213729
LiBr: A Mild Lewis Acid Catalyst for Efficient
One-Pot Synthesis of a-Amino Nitriles
Anil Saini Suresh and Jagir S. Sandhu
Department of Chemistry, Punjabi University, Patiala, Punjab, India
Abstract: a-Amino nitriles are synthesized in a one-pot, three-component cou-
pling of aldehydes, amines, and trimethylsilyl cyanide using a catalytic amount
of LiBr at ambient temperature.
Keywords: LiBr, Strecker nitriles, trimethylsilyl cyanide
The addition of cyanide to imine is the most common strategy to prepare
a-amino nitriles, which serve as important synthons in synthetic organic
chemistry. Because of their wide range of applications, these compounds
have received a great deal of attention in recent years in connection with
their synthesis. Because alkali cyanides are well-known poisons and they
also produce highly alkaline reaction conditions that are not tolerated in
many cases, particularly when conjugated aldehydes are used,[1] and
instead solvolyzed by-products are produced, clearly some improvements
were necessary. Therefore, to overcome these problems, some alternative
cyanide transferring agents have been used such as diethyl phosphoro-
cyanidate,[2] a-trimethylsiloxy nitriles,[3] acetone cyanohydrin,[4] and tri-
methylsilyl cyanide (TMSCN).[5] Out of these nonalkali metal cyanide
variants, trimethylsilyl cyanide has emerged as the most useful, safest,
and more effective cyanide source for nucleophilic addition to carbon-
oxygen or carbon–nitrogen double bonds. It is worth mentioning here
that in aprotic solvents, it almost produces neutral conditions. Invariably
on mixing aldehyde and amine, Schiff’s bases are produced, which are
Received February 7, 2008.
Address correspondence to Jagir S. Sandhu, Department of Chemistry,
Punjabi University, Patiala, Punjab, India. E-mail: j_sandhu2002@yahoo.com
3655

3656
A. S. Suresh and J. S. Sandhu
Scheme 1.
used in situ, and TMSCN addition occurs. Evidently this process requires
polarization of the C ¼ N bond to facilitate nucleophilic attack of cyanide
from TMSCN, and this is achieved by using a suitable Lewis acid and
other additives.[6] Several of these already reported methods suffer from
drawbacks such as expensive catalyst systems, long reaction times, harsh
reaction conditions, low product yields and so on. Moreover, the use of
strong acids such as H2SO4 frequently leads to the formation of undesir-
able side products during aqueous workup, which in turn decrease the
yield of desired products. Therefore, there is still need to search for a
mild, inexpensive, and ecofriendly catalyst for the synthesis of a-amino
nitriles. We and others[7] have been using LiBr as a mild Lewis acid
in many chemical transformations, including Biginelli condensation,
Ehrlich–Sachs reaction, Friedel–Crafts reaction, and preparation of acy-
lals and xanthenes. In most of these reported reactions, LiBr is almost
neutral[8] and also does not form any corrosive or harsh by-products dur-
ing aqueous workup, unlike strong and expensive catalysts. Herein, we
report the catalytic use of mild Lewis acid LiBr in an one-pot coupling
of aldehydes, amines, and trimethylsilyl cyanide at room temperature
leading to a synthesis of a-amino nitriles (Scheme 1). In a typical case,
benzaldehyde (2 mmol), aniline (2 mmol), trimethylsilyl cyanide (2 mmol),
and LiBr (0.2 mmol, 10 mol%) were stirred in acetonitrile (15 mL) at
room temperature for 50 min to afford a-amino nitrile in 92% yield. Simi-
larly, other aldehydes and amines were reacted with trimethylsilyl cyanide
at room temperature using a catalytic amount of LiBr to obtain corre-
sponding a-amino nitriles in 75–92% yields.
A variety of aromatic, conjugated, and heterocyclic aldehydes have
been reacted with amines and TMSCN at room temperature to obtain
a-amino nitriles (Table 1). Secondary amines such as morpholine, piper-
idine, and pyrrolidine have also been employed along with aromatic
amines. The reaction completes within 50–85 min, and 10 mol% of cata-
lyst is enough to facilitate the reaction to completion. The use of a large
amount of catalyst did not improve the yields or reduce the reaction time.
When the reaction is conducted without the addition of LiBr, there was
no significant formation of a-amino nitriles even after several hours.

LiBr-Mediated Synthesis of a-Amino Nitriles
3657
Table 1. LiBr-mediated synthesis of a-amino nitriles
Compounda
Aldehyde
Amine
Time (min) Yield (%)b
3a
3b
3c
3d
3e
3f
Benzaldehyde
Aniline
Aniline
Benzyl amine
4-chloroaniline
4-Anisidine
50
55
55
50
65
70
55
60
80
85
75
70
80
85
92
90
86
84
89
92
82
80
83
78
76
84
79
75
4-Methylbenzaldehyde
4-Methylbenzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
4-Methylbenzaldehyde
4-Methoxybenzaldehyde Aniline
Cinnamaldehyde
Furfural
Benzaldehyde
Benzaldehyde
Cinnamaldehyde
Cinnamaldehyde
Benzyl amine
4-Chloroaniline
3g
3h
3i
Aniline
3j
Benzyl amine
Pyrrolidine
Morpholine
Piperidine
Morpholine
3k
3l
3m
3n
aThe products were characterized by comparison of their melting points and spectral (IR,
1H NMR) data with those of authentic samples.
bIsolated yields after recrystallization.
Further utility and superiority of the present protocol is demonstrated using
conjugated aldehydes, where no double bond migration 3ia is observed (4);
rather normal nitriles 3i, m, and n are obtained (Scheme 2). These results are
in contrast to previous reports where the double bond migrates to conjugate
with cyanide.[9] It is worth mentioning here that in conjugated systems, the
double bond migrates if nitriles are heated for a few minutes or allowed to
stand at room temperature in solution for a long time. We also did not
observe the formation of 1,4-addition products 3ib.[10]
In conclusion, the present protocol employing a catalytic amount of
LiBr is an efficient, mild, and one-pot strategy for the preparation of a-
amino nitriles. The time required is less, and products are obtained in excel-
lent yields. The present procedure is fairly general as a number of aromatic,
conjugated, and heterocyclic aldehydes are coupled with primary, second-
ary, and aromatic amines and trimethylsilyl cyanide at room temperature.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
Reagent-grade chemicals were purchased from a commercial source and
used without further purification. IR spectra were recorded in KBr discs
1
on a Perkin-Elmer 240 C analyzer. H NMR spectra were recorded on

3658
A. S. Suresh and J. S. Sandhu
Scheme 2.
Varian Gemini 300 (300-MHz) spectrometer using TMS as internal stan-
dard. The progress of the reaction was monitored by thin-layer chroma-
tography (TLC) using silica gel G (Merck).
General Procedure for Preparation of a-Amino Nitriles
To a stirred solution of aldehyde (2 mmol), amine (2 mmol), and trimethyl-
silyl cyanide (2 mmol) in acetonitrile (15 mL) at room temperature, anhyd-
rous LiBr (10 mol%) was added. The resulting solution was stirred for the
time indicated in Table 1. After completion of the reaction (TLC), the excess
of acetonitrile evaporated under reduced pressure. Residue was extracted
with diethyl ether (3 ꢀ 20 mL). The organic layer was washed with saturated
solution of NaHCO3 (2ꢀ 20ml) and brine, then dried over anhydrous
Na2SO4. Evaporation of solvent gave a crude product, which was purified
by recrystallization with benzene–pet. ether mixture to afford a-amino
nitriles.
Representative Spectral Data
2-(N-Anilino)-2-Phenylacetonitrile (3a)
1
Mp 72–73ꢁC IR (KBr): 3340, 2240 cmꢂ1. H NMR (300 MHz, CDCl3):
d ¼ 7.51 (m, 2H), 7.30 (t, 3H), 7.25 (t, J ¼ 7.9 Hz, 2H), 6.92 (t, J ¼ 7.6 Hz,

LiBr-Mediated Synthesis of a-Amino Nitriles
3659
Hz, 1H), 6.72 (d, J ¼ 7.9 Hz, 2H), 5.39 (s, 1H), 4.03 (br s, 1H). 13C NMR
(75 MHz, CDCl3): d ¼ 146.7, 136.5, 130.4, 129.9, 128.8, 128.2, 127.2,
122.7, 117.2, 51.2.
2-(N-Anilino)-2-(4-Methylphenyl)acetonitrile (3b)
1
IR (KBr): 3345, 2242 cmꢂ1. H NMR (300 MHz, CDCl3): d ¼ 7.53 (d,
J ¼ 8.0 Hz, 2H), 7.48 (d, J ¼ 8.0 Hz, 2H), 7.25–7.35 (m, 2H), 7.12 (t,
J ¼ 7.9 Hz, 1H), 6.92 (t, J ¼ 8.0 Hz, 2H), 5.45 (s, 1H) 4.02 (br s, 1H),
2.36 (s, 3H). 13C NMR (75 MHz, CDCl3): d ¼ 142.3, 137.7, 134.3,
129.8, 129.2, 128.4, 123.4, 120.3, 118.1, 112.2, 50.6.
2-Phenyl-2-(N-Pyrrolidino)acetonitrile (3k)
Colorless oil. IR (KBr): 2229 cmꢂ1 1H NMR (300 MHz, CDCl3):
.
d ¼ 7.54–7.42 (m, 2H), 7.40–7.29 (m, 3H), 4.48 (s, 1H), 2.72–2.60 (m,
4H), 1.90–1.69 (m, 4H). 13C NMR (75 MHz, CDCl3): d ¼ 135.6, 129.6,
129.1, 128.3, 117.8, 110.4, 60.3 52.3.
2-(N-Morpholino)-2-Phenylacetonitrile (3l)
Mp 68–70ꢁC IR (KBr): 2232 cmꢂ1 1H NMR (300 MHz, CDCl3):
.
d ¼ 7.48–7.29 (m, 5H), 4.78 (t, J ¼ 4.5 Hz, 4H), 2.57 (t, J ¼ 4.5 Hz, 4H).
13C NMR (75 MHz, CDCl3): d ¼ 133.2, 130.7, 129.5, 129.2, 128.5,
116.5, 72.2, 62.3 53.4.
ACKNOWLEDGMENT
The authors are thankful to the Council of Scientific and Industrial
Research, New Delhi, India, for financial assistance and to the Indian
National Science Academy for additional financial support for this
research project.
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