Iodine as a novel and efficient reagent for the synthesis of α-aminonitriles by a three-component condensation of carbonyl compounds, amines, and trimethylsilyl cyanide

Article abstract of DOI:10.1016/j.tetlet.2005.05.005

A straightforward and general method has been developed for the synthesis of α-aminonitriles by simply combining aldehydes or ketones, amines, and trimethylsilyl cyanides in the presence of a catalytic amount of molecular iodine at room temperature.

Full text of DOI:10.1016/j.tetlet.2005.05.005

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4595–4597
Iodine as a novel and efficient reagent for the synthesis of
a-aminonitriles by a three-component condensation of
carbonyl compounds, amines, and trimethylsilyl cyanide
Laurel Royer, 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 3 March 2005; revised 2 May 2005; accepted 3 May 2005
Available online 23 May 2005
Abstract—A straightforward and general method has been developed for the synthesis of a-aminonitriles by simply combining alde-
hydes or ketones, amines, and trimethylsilyl cyanides in the presence of a catalytic amount of molecular iodine at room temperature.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
there are no examples of the use of molecular iodine
as catalyst for the synthesis of a-aminonitriles.
a-Aminonitriles are important intermediates in the prep-
aration of many amino acids1 and various nitrogen
containing heterocycles such as imidazoles and thiadiaz-
oles.2,3 They are usually synthesized by the nucleophilic
addition of a cyanide anion to imines. Numerous meth-
ods describing the preparation of a-aminonitriles have
been reported4–12 in the literature. However, most of
these methods involve the use of expensive reagents,
lengthy reaction times, and tedious work-up procedure.
Furthermore, many of these protocols are limited to
aldehydes only and are not applicable to acyclic ketones.
Most recently, we reported BiCl3 as a catalyst13 for the
Strecker amino acid synthesis reaction, but this proce-
dure did not work with ketones. Therefore, there is a
need of an efficient and inexpensive catalyst for the syn-
thesis of a-aminonitriles.
2. Results and discussion
The treatment of benzaldehyde and benzyl amine with
TMSCN in the presence of a catalytic amount of iodine
afforded 2-(N-benzylamino)-1-phenylacetonitrile in 94%
yield. In the same manner, a variety of aldehydes were
coupled with a wide range of amines and trimethylsilyl
cyanide in a one-pot operation in the presence of a cat-
alytic amount of iodine at room temperature to give the
corresponding a-aminonitriles in good to excellent
yields (Scheme 1). Both aromatic and aliphatic alde-
hydes afforded excellent yields, whereas ketones gave
moderate yields. On the other hand, all types of primary
and secondary amines are readily coupled to give the
desired product in good yields. Due to steric hindrance
(or a combination of steric hindrance and electronic
factors), benzophenone did not give the desired product
in good yield. However, acid sensitive aldehydes such as
furfuraldehyde gave the aminocyano compound in high
yield. This method does not require any other additives
to promote the reaction. No undesired side product
In continuation of our work to develop new organic
transformations,14 we report herein that iodine, which
acts as a mild Lewis acid, might be a useful and inexpen-
sive catalyst for the synthesis of a-aminonitriles.
Although, iodine has been extensively used as a mild
catalyst for a plethora of organic transformations,15
NHR1
I2
CH3CN, rt
R-CHO
Keywords: Aldehydes; Ketones; Amines; Trimethylsilyl cyanide;
a-Aminonitriles; Iodine.
Corresponding author. Fax: +1 765 494 1414; e-mail: skd125@
pharmacy.purdue.edu
R1-NH2 + TMSCN
+
R
CN
*
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.005

4596
L. Royer et al. / Tetrahedron Letters 46 (2005) 4595–4597
Table 1. Iodine-catalyzed synthesis of a-amino nitriles with trimethylsilyl cyanide
Entry
Aldehyde/ketone
Amine
Time (h)
Yielda (%)
1
Benzaldehyde
Aniline
Aniline
1
1
2
2
1
1
1
2
2
2
2
3
3
2
8
6
8
94
90
88
79
91
84
86
78
81
86
88
87
84
89
68
76
72
2
4-Chlorobenzaldehyde
Isobutyraldehyde
Decylaldehyde
3
Benzyl amine
Aniline
4
5
3-Methoxybenzaldehyde
Furfural
Benzyl amine
Benzyl amine
Benzyl amine
Morpholine
6
7
Thiophene 2-carboxaldehyde
Benzaldehyde
Butyraldehyde
8
9
Pyrrolidine
10
11
12
13
14
15
16
17
Benzaldehyde
Benzaldehyde
Benzaldehyde
Furfurylamine
3-Methoxybenzyl amine
Butylamine
2,4-Dimethoxybenzaldehyde
4-Methylbenzaldehyde
Acetophenone
3,4,5-Trimethoxyaniline
Aniline
3,4,5-Trimethoxyaniline
Benzyl amine
Butylamine
Cyclohexanone
Cyclohexanone
a Yields refer to pure isolated products and were characterized by spectral data.
(such as cyanohydrin trimethyl silyl ether, an adduct
between the aldehyde and trimethylsilyl cyanide) was
observed because of the rapid formation of the imine
intermediate. The results shown in Table 1 clearly indi-
cate the scope and generality of the reaction with respect
to various carbonyl compounds and amines.
O
CH3
CN
I2 (cat)
+TMSCN
H
R
1
3
Ph
N
H
R
+
CH3CN, rt
CH3
4
(S, S)
In comparison with other catalysts such as Sc(OTf)3,
InCl3, BiCl3, Pr(OTf)3, Lu(OTf)3, and RuCl3 employed
for the aminocyanation of acetophenone, molecular
iodine shows more catalytic reactivity than the others
in terms of the amount of catalyst required, reaction
times, and yields of the product (Table 2).
+
Ph
NH2
CH3
CN
2
Ph
N
H
R
To evaluate the possibility of 1,3-asymmetric induction,
we extended this procedure to the preparation of opti-
cally active a-aminonitriles derived from (S)-(À)a-meth-
ylbenzylamine and aldehydes. The reaction with both
aryl and alkyl aldehydes in every case produced
mixtures of diastereoisomers, with one diastereoisomer
predominating. The relative stereochemistry of the
products was determined by 1H NMR spectroscopy
using the literature methods.16 For instance, the
1H NMR of the crude a-(1-methylbenzyl)amino valero-
nitrile (R = iso-propyl, Scheme 2) showed two doublets,
one at 2.92 ppm (J = 6.5 Hz) and the other at 3.32 ppm
(J = 6.5 Hz) in a ratio of 71:29. Each doublet is derived
from the proton attached to the carbon bearing the
nitrile. According to the literature16 hypothesis, nucleo-
philic attack on the imine should take place antiperpen-
dicular to the a-phenyl group. In all cases, in this
5
(S, R)
R
4:5
Yield (%)
i-propyl
71:29
68:32
81:19
91
87
tert-butyl
Phenyl
4-MeO-phenyl 84:16
92
84
Scheme 2.
reaction S-a-methylbenzylamine and R-a-methylbenzyl-
amine gave similar enantiomeric excesses but opposite
chiralities.
3. Conclusion
Table 2. Comparison of the effect of catalysts in the aminocyanation
of acetophenone with 3,4,5-trimethylaniline and trimethylsilyl cyanide
We have demonstrated a very simple, efficient, and
practical method for the synthesis of a-aminonitriles
through a one-pot three component coupling of car-
bonyl compounds, amines, and trimethylsilyl cyanide
using a catalytic amount of molecular iodine. High dia-
stereoselection can be obtained in the synthesis of a-
aminonitriles using R or Sa-methylbenzylamine. The
major advantage of this method is that it is truly a
one-pot procedure that does not require a separate step
to prepare an imine for subsequent use. The important
Catalyst
Catalyst load (mol%)
Time (h)
Yield (%)
Sc(OTf)3
InCl3
20
20
20
20
20
20
10
12
10
12
12
12
12
8
15
12
5
Pr(OTf)3
RuCl3
BiCl3
5
8
Lu(OTf)3
I2
6
68

L. Royer et al. / Tetrahedron Letters 46 (2005) 4595–4597
4597
features of this method include (a) operational simplic-
References and notes
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Supplementary data
Representative experimental procedures in details and
spectral data of all compounds. The supplementary data
are available online with the paper at doi:10.1016/
j.tetlet.2005.05.005.