One-pot three-component synthesis of α-amino nitriles catalyzed by nano powder TiO2 P 25

Article abstract of DOI:10.1016/j.cclet.2010.12.003

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:10.1016/j.cclet.2010.12.003

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 555–558
www.elsevier.com/locate/cclet
One-pot three-component synthesis of a-amino nitriles
catalyzed by nano powder TiO2 P 25
b
b
Seyed Meysam Baghbanian a, , Maryam Farhang , Robabeh Baharfar
*
a Chemistry Department, Islamic Azad University, Rasht Branch, Pole-taleshan, PO Box 41325-3516, Rasht, Iran
b Department of Chemistry, Mazandaran University, Babolsar 47415, Iran
Received 2 September 2010
Available online 3 March 2011
Abstract
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.
# 2010 Seyed Meysam Baghbanian. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Nano powder TiO2 P 25; a-Amino nitriles; One-pot three-component synthesis; Strecker reaction; Trimethylsilyl cyanide
The Strecker reaction is one of the most efficient and straightforward methods for the synthesis of a-aminonitriles.
a-Aminonitriles are especially potent representatives of bifunctional compounds. Importance of amino moiety for
drug design is hard to overestimate due to a set of intrinsic properties, i.e. ability to act as hydrogen bond donor and
acceptor or to be involved into electrostatic interactions (after protonation), diversity of chemical modification
pathways (acylation, alkylation, reductive alkylation reactions), predictable chemical reactivity and reliability of
chemical transformations allowing their use in combinatorial synthesis. Recently, modified method using one-pot
procedure via a three-component condensation of aldehyde, amine and trimethylsilyl cyanide catalyzed by Lewis
acids in conventional organic solvents has been described [1]. However, many of these reported methods involved the
use of expensive, moisture sensitive, non-recyclable regents, and required extended reaction times and harsh
conditions. Therefore, it is still desirable to improve an efficient and practical method for the Strecker reaction. In
order to avoid partially this inconvenience, diethylaluminium cyanide, acetone cyanohydrin, TMSCN, etc. have been
introduced as cyanide sources in the Strecker reaction [2]. Considering the importance of the Strecker reaction for
providing various chiral amino acid precursors in both laboratory and industrial scale, it is highly desirable to develop
heterogeneous catalysts. However, there are only few reports that are published on Strecker reaction by using
heterogeneous catalysts [3]. Catalytic applications of titanium dioxide have been studied for decades regarding the
elimination of environmental pollutants and, more recently, for photocatalytic processes concerning the degradation of
pollutants in air, water and soil [4]. Degussa TiO2 (P 25) is a well known and widely investigated catalyst and
photocatalyst. Acid–base and redox properties are one of the most important types of surface chemical properties that
in Table 1 properties of TiO2 P 25 summarized.
* Corresponding author.
E-mail address: m.baghbanian@iaurasht.ac.ir (S.M. Baghbanian).
1001-8417/$ – see front matter # 2010 Seyed Meysam Baghbanian. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.003

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S.M. Baghbanian et al. / Chinese Chemical Letters 22 (2011) 555–558
Table 1
Properties of TiO2 P 25.
Degussa TiO2 P25 (powder)
Unit
m2/g
Properties
50 Æ 15
3.5–4.5
21
A/R (80/20)a
Specific surface area (BET)
pH in 4% dispersion
Average primary particle size
Phase
nm
a
A: anatase; R: rutile. Mass ratios of A/R were listed in the parenthesis.
As part of our current studies on the development of new catalysts [5], herein, we report an efficient and
environmentally friendly method for the synthesis of a-aminonitriles catalyzed by Nano TiO2 P 25 in acetonitrile at
room temperature (Scheme 1).
1. Results and discussion
Benzaldehyde, aniline and TMSCN were selected as the model reaction to examine catalytic activity of nano TiO2 P
25 at ambient temperature. To indicated the need of TiO2 P 25 for this condensation. We observed that the model reaction
did not proceed in the absence of TiO2even after 12 h (Table 2, entry 1). When using catalytic amount of 10 mol% TiO2 P
25, the reaction gave a-aminonitriles with 70% yield in 10 min in CH3CN (Table 2, entry 3), and further lowering the
catalyst loading up to 5 mol% led to lower yield of 55% in 10 min (Table 2, entry 2). In the presence of 20 mol% catalyst
the reaction affords the corresponding 2-phenyl-2-(phenylamino)acetonitrile in 98% yield within 10 min (Table 2, entry
4), and TiO2 P 25 (25 mol%) also gives 98% yield in 10 min (Table 2, entry 5). The solvents examined were
dichloromethane, tetrahydrofuran, and acetonitrile, among whichacetonitrile is shown to be the best (Table 2).
Accordingly, 20 mol% TiO2 P 25 catalyst loading in CH3CN is considered optimal for the synthesis of a-aminonitriles.
To word, we prepared a range of a-aminonitriles under the optimized conditions (Table 3). Both aromatic and aliphatic
aldehydes as well as a,b-unsaturatedonesanddifferentamineswerecoupledwithTMSCNunder thesereactionconditions.
The reactions are clean and highly selective affordingexclusivelya-aminonitriles in high yields in a short reaction time. The
reaction of benzaldehyde with aniline and benzyl amine is completed within 10 min with 98 and 93% yield, respectively
(Table 3, entries1and2). Therewith,thereactionofbenzaldehydewithdiethyl-amineiscompletedwithin10 minwith96%
yield (Table 3, entries 3). Similar reaction of p-methoxy, m-phenoxy-benzaldehydeorp-tolualdehydewith aniline produces
the corresponding products in excellent yield of 93, 89 and 98% in 10, 12 and 14 min, respectively (Table 3, entries 4–6).
This method is equally effective with electron-withdrawing 4-chlorobenzaldehyde, 4-fluorobenzaldehyde and
2-cyanoaniline (Table 3, entries 7–10). It should be noted that the reaction of 4-nitrobenzaldehyde and benzyl amine
gavenodesired product. This illustrates that strongly electron-withdrawing substituent such as p-nitro may not product in
[()TD$FIG]
CN
O
Nano TiO2 P 25 (20 mol%)
CH3CN, r.t.
R'
R' NH2
TMSCN
R
N
R
H
H
Scheme 1. Strecker reaction in CH3CN.
Table 2
Three-component synthesis of a-aminonitriles under various conditionsa.
Entry
Catalyst (mol%)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
No catalyst
12 h
0
5
10 min
10 min
10 min
10 min
15 min
25 min
55
10
20
25
20
20
70
98
98
86c
90d
a
TiO2 P 25 was added to a mixture of 1 mmol of benzaldehyde, 1 mmol of aniline, and 1.2 mmol of TMSCN.
b
c
d
Isolated yield.
In the presence of CHCl3.
In the presence of THF.

S.M. Baghbanian et al. / Chinese Chemical Letters 22 (2011) 555–558
557
Table 3
Preparation of various a-amino nitriles in the presence of nano TiO2 P 25 in CH3CN at room temperaturea.
Entry
Aldehyde/ketone
Amine
Time (min)
Yield (%)b
1
2
C6H5CHO
C6H5-NH2
10
10
10
14
10
12
10
10
14
10
1 h
8
98 [1f]
93 [6]
C6H5CHO
C6H4CH2-NH2
(CH3CH2)2NH
C6H5-NH2
3
C6H5CHO
96 [7]
4
4-Me-C6H4CHO
4-MeO-C6H4CHO
3-PhO-C6H4CHO
4-Cl-C6H4CHO
4-F-C6H4CHO
4-Cl-C6H4CHO
4-Cl-C6H4CHO
4-Nitro-C6H4CHO
Ph
98 [8]
5
C6H5-NH2
93 [8]
6
C6H5-NH2
89 [1i]
97 [1i]
95 [9]
7
C6H5-NH2
8
C6H5-NH2
9
(CH3CH2)2NH
C6H11NH2
98 [10]
91 [11]
N. R. [11]
97 [1f]
10
11
12
C6H5CH2-NH2
C6H5-NH2
[TD$LINE]
CHO
Ph
13
14
C6H5-NH2
C6H5-NH2
12
12
90 [11]
99 [1f]
[TD$LINE]
CHO
O
H
[TD$LINE]
O
15
16
17
18
2-Thienyl-CHO
i-C4H9-CHO
C6H5-NH2
C6H5-NH2
C6H5-NH2
C6H5-NH2
20
25
25
1 h
92 [8]
80 [12]
78 [1j]
85 [13]
i-C9H17-CHO
[TD$LINE]
O
19
20
C6H5-NH2
C6H5-NH2
1 h
1 h
88 [13]
98 [14]
[TD$LINE]
O
O
H
[TD$LINE]
a
Reaction conditions: aldehyde (1 mmol), aniline (1 mmol), TMSCN (1.2 mmol), TiO2 P 25 (20 mol%), room temperature, acetonitrile.
The spectral data (1H, 13C NMR) of known compounds were found to be identical with those reported in the literature [1–13].
b
Strecker reaction (Table 3, entry 11). Furthermore, the reaction conditions are mild enough to perform these reactions
with acid sensitive aldehydes such as cinnamaldehyde, 2-furaldehyde and 2-thiophene-2-carbaldehyde which form the
corresponding aminocyano compounds in good yield (Table 3, entry 12, 14 and 15). This may indicate that the catalytic
system selectively activates the carbonyl function and keeps the furan or 2-thienyl ring and double bond of
cinnamaldehyde intact. While, the reaction of hydrocinnamaldehydepentanal and decanal gives the corresponding
products in 90%, 80% and 78% yield, respectively (Table 3, entries 16 and 17). The reaction of cyclohexanone and
cyclopentanone with aniline produces the corresponding products in 85 and 88% yield in ‘longer’ reaction time (1 h),
respectively (Table 3, entries 18 and 19). Moreover, the reaction cyclohexanecarbaldehyde with aniline give the
corresponding product in 98% yield in 1 h (Table 3, entry 20). This indicates that aliphatic aldehydes lower yield with
‘longer’reaction time (1 h). Moreover, we continued our exploration of the synthesis a-aminonitriles by treating various
amineswithaldehydesandTMSCNundersimilarreactionconditions. Differentaromaticandaliphaticamineswere used
in the reaction and they underwent efficient coupling with benzaldehyde and TMSCN as shown in Table 3. The recycling
of catalyst was achieved through filtration followed by washing with acetonitrile and the recycled catalyst obtained thus
was sufficient for its reuse. For example, the reaction of benzaldehyde, aniline, and trimethylsilyl cyanide gave the
corresponding a-aminonitriles (Table 3, entry 1) in 98%, 97%, and 95% yields over three cycles.
To conclude, we have shown that the nano TiO2 P 25 is a highly active, reusable catalyst for the synthesis of a-amino
nitriles. General procedure for the preparation of a-aminonitriles: A mixture of amine (1 mmol), aldehyde (1 mmol),
trimethylsilylcyanide (1.2 mmol) and nano TiO2 P 25 (20 mol%) in CH3CN (1 mL) was stirred at ambient temperature for
an appropriate time (Table 2). After completion of the reaction as indicated by TLC, the nano TiO2 P 25 was filtered and
washed with acetonitrile (2Â 10 mL). The crude product was purified by recrystallization from diethyl ether (solid
products) or by chromatography using silica gel and mixtures of hexane/ethyl acetate of increasing polarity. The physical
data (mp, IR, NMR) of known compounds were found to be identical with those reported in the literature [1f,j, 6–14]. The
isolated yields were in good agreement with those obtained by GC analysis [1–13]. Spectroscopic data for a selected
example; (Table 2, entry 1) [1f]: Solid, mp 75–76 8C, IR (KBr): n 3349, 3016, 2965, 2276, 1643, 1565. 1H NMR (CDCl3): d
4.15 (d, 1H, J = 8.1 Hz), 5.43 (d, 1H, J = 8.1 Hz), 6.65(d, 2H, J = 8.0 Hz), 6.86 (t, 1H, J = 7.8 Hz), 7.45(t, 2H, J = 7.8 Hz),

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S.M. Baghbanian et al. / Chinese Chemical Letters 22 (2011) 555–558
7.45–7.58 (m, 3H), 7.50–7.68 (m, 2H). 13C NMR (CDCl3): d 50.5, 112.5, 119.9, 123.7, 126.9, 129.9, 130.0, 130.2, 135.5,
147.5. EIMS: m/z: 208 M+, 180, 116, 91, 77, 51. Anal. Calcd. forC14H12N2 (208.26): C, 80.74;H, 5.81;N, 13.45. Found: C,
80.53; H, 5.74; N, 13.89%.
Acknowledgments
The authors are also grateful to Degussa for the supply of the TiO2 P 25 colloids.
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