One-pot three-component synthesis of α-amino nitriles catalyzed by 2,4,6-trichloro-1,3,5-triazine (cyanuric acid)

Article abstract of DOI:10.1002/hlca.200790119

A simple and efficient method has been developed for the synthesis of α-amino nitriles from aldehydes, amines and trimethylsilyl cyanide (Me₃SiCN) in the presence of a catalytic amount of cyanuric acid at room temperature.

Full text of DOI:10.1002/hlca.200790119

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Helvetica Chimica Acta – Vol. 90 (2007)
One-Pot Three-Component Synthesis of a-Amino Nitriles Catalyzed by
2,4,6-Trichloro-1,3,5-triazine (Cyanuric Acid)1)
by Biswanath Das*, Rathod Aravind Kumar, and Ponnaboina Thirupathi
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
A simple and efficient method has been developed for the synthesis of a-amino nitriles from
aldehydes, amines and trimethylsilyl cyanide (Me3SiCN) in the presence of a catalytic amount of
cyanuric acid at room temperature.
Introduction. – a-Amino nitriles are important intermediates in the preparation of
amino acids [1] and various nitrogen heterocycles [2] such as imidazoles and
thiadiazoles. They are generally prepared by nucleophilic addition of the cyanide
anion (CNÀ) to imines (Strecker-type reaction). Several modifications of the Strecker
reaction have been reported with a variety of cyanating agents such as HCN [3], KCN
[4], Et2AlCN [5], (EtO)2P(O)CN [6], Bu3SnCN [7], or Me3SiCN [8]. Trimethylsilyl
cyanide (Me3SiCN) is an especially safe and effective source of CNÀ for nucleophilic
addition reactions of imines. However, many of the methods applying this cyanating
agent involve the use of expensive catalysts, and require extended reaction times and
harsh reaction conditions.
In continuation of our work [9] on the development of useful synthetic method-
ologies, we report herein a facile synthesis of a-amino nitriles 1 by treatment of an
aldehyde 2 and an amine 3 with Me3SiCN at room temperature in the presence of a
catalytic amount of 2,4,6-trichloro-1,3,5-triazine (TCT; Scheme 1). TCT, which is
better known as ꢀcyanuric chlorideꢁ, has been used in various organic transformations
due to its excellent catalytic activity [10], and because it is a safe and inexpensive
reagent.
Scheme 1
Results and Discussion. – We have tested TCT for the first time in the preparation
of a-amino nitriles from various aldehydes and amines. The results of our studies are
summarized in the Table for 20 different pairs of substrates. Initially, we studied the
1
)
Part 138 in the series ꢀStudies on Novel Synthetic Methodologiesꢁ; IICT Communication No. 070516.
ꢂ 2007Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
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Table. Cyanuric Acid Catalyzed Synthesis of a-Amino Nitriles. For details, see Scheme 1 and Exper. Part.
The structures of the products were settled by 1H-NMR and MS, and confirmed by elemental analyses.
Series
Aldehyde (2)
Amine (3)
Product (1)
Time
[min]
Isolated
yield [%]
a
35
96
b
c
45
50
88
89
d
45
92
e
f
7
5
5
87
7
85
g
h
60
35
89
93
i
40
92
85
j
60
7
k
0
80

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Helvetica Chimica Acta – Vol. 90 (2007)
Table (cont.)
Series
Aldehyde (2)
Amine (3)
Product (1)
Time
[min]
Isolated
yield [%]
l
40
93
m
n
45
91
45
50
92
90
o
p
q
65
45
87
94
r
60
89
87
s
t
65
7
0
86
Strecker-type reaction of benzaldehyde (2a) and aniline (3a) (Table) in the presence of
Me3SiCN and a catalytic amount of TCT at room temperature, which afforded the
corresponding a-amino nitrile 1a in high yield (96%). Among various solvent systems,
including CHCl3, CH2Cl2, MeCN, THF, EtOH, and Et2O, the conversion proceeded
best in MeCN.
A variety of other aldehydes, including aromatic, aliphatic, as well as a,b-
unsaturated ones, were treated with different primary or secondary amines in the

Helvetica Chimica Acta – Vol. 90 (2007)
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presence of TCT in MeCN. In all cases, high yields (80 – 94%) of the desired products 1
were obtained, typically within 1 h or less (Table). Aromatic aldehydes with both
electron-donating and -withdrawing groups underwent the condensation very smooth-
ly. Aliphatic and unsaturated aldehydes also afforded the corresponding products
(1j,k,s,t) in good yields. However, ketones did not yield any product under these
reaction conditions. For a,b-unsaturated aldehydes (2j,k), the reaction was highly
regioselective, the conjugated C¼C bond basically being unaffected.
TCT is known to react with ꢀincipientꢁ moisture to form HCl along with 2,4,6-
trihydroxy-1,3,5-trazine, which can activate [9a] the imine system through H-bonding
and facilitate cyanation (Scheme 2). The above conversion, thus, completely failed
under perfectly anhydrous conditions. Also, with dilute HCl, instead of TCT, only the
corresponding imines (rather than the a-amino nitriles) were isolated. Further, in the
absence of TCT as catalyst, only very low yields (7– 12%) of the a-amino nitriles were
obtained (data not shown).
Scheme 2
In conclusion, we have developed a simple, mild, efficient, and fast protocol for the
TCT-catalyzed synthesis of a-amino nitriles in high yields through one-pot three-
component coupling of aldehydes, amines, and Me3SiCN.
We wish to thank CSIR and UGC (New Delhi, India) for financial assistance.
Experimental Part
General. 1H-NMR Chemical shifts d and coupling constants Jare provided in ppm (rel. to Me4Si) and
in Hz, resp. Mass-spectrometric data are given as m/z values. MeCN as solvent was purchased from
Aldrich (purity 99%) and used as received. Trimethylsilyl cyanide (Me3SiCN) and 2,4,6-trichloro-1,3,5-
triazine (cyanuric acid) were obtained from Aldrich (purity 99%) and used without further purification.
General Procedure for the Synthesis of a-Amino Nitriles. To a mixture of an aldehyde 2 (1 mmol), an
amine 3 (1 mmol), and Me3SiCN (1.2 mmol) in MeCN (5 ml), TCT (10 mol-%) was added. The mixture
was stirred at r.t., and the reaction was monitored by TLC. After completion of the reaction, the solvent
was evaporated, and H2O (5 ml) was added. The mixture was extracted with AcOEt (3 ꢀ 5 ml), and the
org. layer was concentrated. The residue was purified by column chromatography (SiO2; AcOEt/hexane
5 :95) to afford the corresponding pure a-amino nitrile 1 (see Table). The anal. data of some
representatives are given below.
(3-Hydroxyphenyl)(phenylamino)acetonitrile (1m). 1H-NMR (200 MHz, CDCl3): 7.35 – 7.16 (m,
3 H); 7.02 (br. s, 2 H); 6.92 – 6.81 (m, 2 H); 6.80 (dd, J ¼ 8.0, 2.0, 2 H); 6.30 (br. s, 1 H); 5.31 (d, J ¼ 8.0,

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Helvetica Chimica Acta – Vol. 90 (2007)
1 H); 4.03 (d, J ¼ 8.0, 1 H). FAB-MS: 225 ([M þ 1]þ). Anal. calc. for C14H12N2O: C 75.00, H 5.35, N
12.50; found: C 75.06, H5.37, N 12.56.
(4-Hydroxy-3-methoxyphenyl)(phenylamino)acetonitrile (1n). 1H-NMR (200 MHz, CDCl3): 7.22 (t,
J ¼ 8.0, 2 H); 7.09 (d, J ¼ 2.0, 1 H); 7.07 (dd, J ¼ 8.0, 2.0, 1 H); 6.88 – 6.82 (m, 2 H); 6.71 (dd, J ¼ 8.0, 2.0,
2 H); 5.64 (br. s, 1 H); 5.25 (d, J ¼ 8.0, 1 H); 3.98 (d, J ¼ 8.0, 1 H); 3.92 (s, 3 H). FAB-MS: 254 ([M þ
1]þ). Anal. calc. for C15H14N2O2: C 70.86, H 5.51, N 11.02; found: C 70.90, H 5.55, N 11.13.
Naphthalen-2-yl(phenylamino)acetonitrile (1q). 1H-NMR (200 MHz, CDCl3): 8.12 (d, J ¼ 2.0, 1 H);
7.96 – 7.82 (m, 3 H); 7.66 – 7.50 (m, 3 H), 7.34 – 7.21 (m, 2 H); 6.92 – 6.3 (m, 3 H); 5.53 (d, J ¼ 8.0, 1 H);
4.02 (d, J ¼ 8.0, 1 H). FAB-MS: 259 ([M þ 1]þ). Anal. calc. for C18H14N2: C 83.72, H 5.42, N 10.85; found:
C 83.78, H 5.48, N 11.00.
1
(3,4-Dimethoxyphenyl)(phenylamino)acetonitrile (1r). H-NMR (200 MHz, CDCl3): 7.39 – 7.22 (m,
2 H); 7.14 (dd, J ¼ 8.0, 2.0, 1 H); 7.03 (dd, J ¼ 2.0, 1 H); 6.91 6.83 (m, 2 H); 6.7 2 (dd, J ¼ 8.0, 2.0, 2 H);
5.31 (d, J ¼ 8.0, 1 H); 3.96 (d, J ¼ 8.0, 1 H); 3.90 (s, 6 H). FAB-MS: 258 ([M þ 1]þ). Anal. calc. for
C16H16N2O2: C 74.41, H 6.20, N 10.85; found: C 74.50, H 6.31, N 11.02.
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Received February 12, 2007