Bismuth trichloride catalyzed synthesis of α-aminonitriles

Article abstract of DOI:10.1016/j.tetlet.2004.08.071

A simple and efficient one-pot method has been developed for the synthesis of α-aminonitriles from aldehydes, amines, and trimethylsilyl cyanide in the presence of a catalytic amount of bismuth trichloride.

Full text of DOI:10.1016/j.tetlet.2004.08.071

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7407–7408
Bismuth trichloride catalyzed synthesis of a-aminonitriles
*
Surya K. De and Richard A. Gibbs
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue Cancer Center,
Purdue University, West Lafayette, IN 47907, USA
Received 20 July 2004; revised 11 August 2004; accepted 13 August 2004
Abstract—A simple and efficient one-pot method has been developed for the synthesis of a-aminonitriles from aldehydes, amines,
and trimethylsilyl cyanide in the presence of a catalytic amount of bismuth trichloride.
Ó 2004 Elsevier Ltd. All rights reserved.
The addition of cyanide to imines (the Strecker reac-
1
tion) provides one of the most efficient methods for
strates. This method does not require any additives to
promote the reaction. The results have been summarized
in Table 1, which clearly indicates the scope and gener-
ality of this method with respect to various amines and
aldehydes including aromatic, aliphatic, and hetero-
cyclic (Scheme 1).
the synthesis of a-aminonitriles. a-Aminonitriles are
important intermediates for the synthesis of amino
2
acids and various nitrogen containing heterocycles such
3
as thiadiazoles and imidazoles. The classical Strecker
reaction is generally carried out with alkaline cyanides
in aqueous solution. Among various cyanide ion
In conclusion, we have demonstrated a very simple, effi-
cient, and practical method for the synthesis of a-amino-
nitriles through a one-pot three component coupling of
aldehydes, amines, and trimethylsilyl cyanide using a
catalytic amount of bismuth(III) chloride. The major
advantage of this method is that it is truly a one-pot
4
sources, trimethylsilyl cyanide is a safer and easily hand-
led reagent compared to hydrogen cyanide, sodium
cyanide, or potassium cyanide.
Recently, there has been considerable interest growing
in the use of bismuth(III) halides as potential Lewis
5
acids in various organic reactions because they are inex-
Table 1. BiCl
silyl cyanide
3
catalyzed synthesis of a-amino nitriles with trimethyl-
pensive, relatively non-toxic, fairly insensitive to small
amounts of water, and environmentally benign reagents.
In this communication, we wish to report a simple and
efficient method for the synthesis of a-aminonitriles in
the presence of a catalytic amount of bismuth(III) chlo-
ride in acetonitrile at room temperature.
a
Entry Aldehyde
Amine
Time Yield
(h)
(%)
1
2
Benzaldehyde
Aniline
Benzyl amine
10
8
84
91
4-Chloro-
benzaldehyde
Hexanal
3
4
5
Benzyl amine
Aniline
Benzyl amine
9
8
6
83
81
90
The reaction of benzaldehyde and benzyl amine with
TMSCN in the presence of a catalytic amount of BiCl3
afforded the corresponding 2-(N-benzylamino)-2-phenyl-
Pentanal
4-Methoxy-
benzaldehyde
Furfural
6
,7
6
7
Benzyl amine
Benzyl amine
6
6
82
84
acetonitrile in 85% yield. The reaction is successful
using both primary and secondary amines with a variety
of aldehydes but not ketones. Moreover, acid sensitive
aldehyde such as furfuraldehyde afforded with high
yield. The reaction conditions are mild enough to per-
form the reactions in the presence of acid sensitive sub-
Thiophene
-carboxaldehyde
2
8
9
Benzaldehyde
4-Methoxy-
Morpholine
Pyrrolidine
7
6
89
86
benzaldehyde
Benzaldehyde
Benzaldehyde
1
1
0
1
Furfurylamine
3-Methoxybenzyl
amine
5
5
89
90
a
1
*
Corresponding author. Tel.: +1 765 743 9702; fax: +1 765 494
414; e-mail: skd125@pharmacy.purdue.edu
Yields refer to pure isolated products, characterized by H NMR and
MS.
1
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.071

7408
S. K. De, R. A. Gibbs / Tetrahedron Letters 45 (2004) 7407–7408
NHR
1
4. (a) Mai, K.; Patil, G. Tetrahedron Lett. 1984, 125, 4583; (b)
Harusawa, S.; Hamada, Y.; Shiori, T. Tetrahedron Lett.
1979, 20, 4663; (c) Iyer, M. S.; Gigstad, M.; Namdev, N.
D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910; (d)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
120, 5315; (e) Takamura, M.; Hamashima, Y.; Usuda, H.;
Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. Engl.
2000, 39, 1650; (f) Kobayashi, S.; Busujima, T.; Nagayama,
S. J. Chem. Soc., Chem. Commun. 1998, 981.
BiCl3
R-CHO + R -NH + TMSCN
1
2
CH CN, rt
3
R
CN
Scheme 1.
procedure that does not require a separate step to pre-
pare an imine for subsequent use. The significant fea-
tures of this method include (a) operational simplicity,
5
. Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron
002, 58, 8373.
. Typical procedure: a mixture of benzaldehyde (106mg,
mmol), benzyl amine (110mg, 1mmol), and trimethylsilyl
cyanide (148mg, 1.5mmol) in acetonitrile (2mL) in the
presence of BiCl (32mg, 0.1mmol) was stirred at room
2
(
b) inexpensive reagents, (c) no need for any additive
6
to promote the reaction, (d) high yields of products,
and (e) the use of relatively non-toxic reagents and
solvents.
1
3
temperature. After completion of the reaction (TLC), the
reaction mixture was partitioned between 100mL of ether
and 50mL of water. The organic layer was washed with
Acknowledgements
4
brine (50mL), dried (MgSO ), and concentrated. The
Authors are thankful to reviewers for valuable
suggestions.
residue was chromatographed over silica gel (15% ethyl
acetate in hexane) to give a pure product.
. Selected spectral data: 2-(N-benzylamino)-2-phenylaceto-
7
1
References and notes
nitrile: H NMR (300MHz, CDCl ): d 1.85 (br s, NH), 3.96
3
(AB, q, J = 13.5Hz, 2H), 4.72 (s, 1H), 6.77 (d, J = 8Hz,
1H), 7.16 (t, J = 7.8Hz, 1H), 7.22–7.43 (m, 6H), 7.48–7.52
1
2
. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
. Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ.
Chem. Rev. 1989, 58, 148.
+
(m, 2H); MS m/z 223 (M + H) ; 2-(N-morpholino)-
1
2-phenylacetonitrile:
2.56–2.64 (m, 4H), 4.75–4.83 (m, 4H), 7.35–7.56 (m,
3
H NMR (300MHz, CDCl ): d
3
. (a) Weinstock, L. M.; Davis, P.; Handelsman, B.; Tull, R.
J. Org. Chem. 1967, 32, 2823; (b) Matier, W. L.; Owens, D.
A.; Comer, W. T.; Deitchman, D.; Ferguson, H. C.;
Seidehamel, R. J.; Young, J. R. J. Med. Chem. 1973, 16,
1
5H); 2-(N-benzylamino)-2-furfurylacetonitrile: H NMR
3
(300MHz, CDCl ): d 1.94 (br s, NH), 3.94 (AB, q,
J = 13.1Hz, 2H), 4.73 (s, 1H), 6.31 (m, 1H), 7.17–7.49 (m,
7H), MS m/z 213 (M + H) .
+
901.