Zr(HSO4)4 catalyzed one-pot strecker synthesis of α-amino nitriles from aldehydes and ketones under solvent-free conditions

Article abstract of DOI:10.1007/BF03246031

A mild and efficient method has been developed for the preparation of α-amino nitriles from the condensation of aldehydes and ketones with aniline and TMSCN in the presence of a catalytic amount of Zr(HSO ₄)₄ under solvent-free conditions at room temperature.

Full text of DOI:10.1007/BF03246031

J. Iran. Chem. Soc., Vol. 7, No. 2, June 2010, pp. 447-454.
JOUIRrNaAnLiaOnF THE
Chemical Society
Zr(HSO4)4 Catalyzed One-Pot Strecker Synthesis of ꢀ-Amino Nitriles from Aldehydes
and Ketones under Solvent-Free Conditions
A.R. Hajipoura,b,*, Y. Ghayebb and N. Sheikhanb
aDept. of Pharmacology, University of Wisconsin, Medical School, 1300 University Avenue, Madison, 53706-1532,
WI, USA
bPharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, IR
Iran
(Received 16 May 2009, Accepted 26 July 2009)
A mild and efficient method has been developed for the preparation of ꢀ-amino nitriles from the condensation of aldehydes
and ketones with aniline and TMSCN in the presence of a catalytic amount of Zr(HSO4)4 under solvent-free conditions at room
temperature.
Keywords: Strecker, ꢀ-Amino nitriles, Zr(HSO4)4, Solid acid
INTRODUCTION
significance because of their widespread use in chemistry and
biology. For example, they are the key precursors for the
synthesis of proteins and have several applications as the
chiral building blocks in the pharmaceutical industry [4].
Generally, ꢀ-amino nitriles are prepared by the nucleophilic
addition of cyanide ion to the imines (in situ generated from
condensation of aldehydes with amines) in the presence of
Lewis acid or Lewis base catalysts. Many cyanide sources
such as HCN [5], KCN [6], Bu3SnCN [7], Et2AlCN [8],
(Et2O)P(O)CN [9] and TMSCN [10] have been used for
Strecker reaction. Among the aforementioned reagents,
TMSCN is the safer and more efficient cyanide anion source
[11].
Many Lewis acid catalysts including NiCl2 [12], Cu(OTf)2
[13], RuCl3 [14], iodine [15], La(NO3)3.6H2O or GdCl3.6H2O
[16], InCl3 [17], RhI3.H2O [18] and Fe(CP)2PF6 [19] have
recently been employed for the preparation of ꢀ-amino nitriles
from aldehydes, amines and trimethylsilylcyanide or
tributyltin cyanide. Solid catalysts such as montmorillonite
KSF [20], silica-supported heteropoly acids [21], Guanidine
One-pot multi-component condensation reactions are
important and attractive due to the formation of multi-bonds in
one pot, high atom economy, mild and simplified conditions
and environmentally benign friendliness. Strecker reaction as
the first multicomponent reaction (MCR), which was
discovered in 1850, represented one of the most important
reactions, especially from the life science viewpoint [1]. In
this reaction three components including a carbonyl compound
(generally an aldehyde), an amine and either alkaline metal
cyanide or hydrogen cyanide couple together and produce ꢀ-
amino nitriles. The Strecker reaction is one of the most
straightforward and efficient methods for the synthesis of ꢀ-
amino nitriles as one of the very useful synthones for the
preparation of ꢀ-amino acides [2] and heterocyclic compounds
such as imidazoles and other biologically important molecules
[3]. ꢀ-Amino acids have the great biological and economical
*Corresponding author. E-mail: haji@cc.iut.ac.ir

Hajipour et al.
CN
R2
R1
R2
Zr(HSO4)4 ( 2-6 mol% )
TMSCN, neat, RT
Ph-NH2
O
NHPh
+
R1
R1 = Aryl and Alkyl, R2 = Alkyl and H
Scheme 1
hydrochloride [22] and cellulose sulfuric acid [23] have been
used for the synthesis of ꢀ-amino nitriles from aldehydes. The
synthesis of ꢀ-amino nitriles from ketones has been reported
under different conditions [24-26].
General Procedure for the Preparation of ꢀ-Amino
Nitriles
A mixture of carbonyl compound (1 mmol), aniline or other
amines (1 mmol), trimethylsilylcyanide (1.2 mmol) and
zirconium hydrogen sulfate (0.02-0.04 mmol for aldehydes
and 0.06 mmol for ketones) was stirred at room temperature.
The completion of the reaction was monitored with TLC
(ethyl acetate/cyclohexane, 1/3), then water (10 ml) was added
and the reaction mixture was extracted by ethyl acetate (10 ꢀ 3
ml), washed with brine and dried over anhydrous MgSO4.
Solvent evaporated under reduced pressure and the product
was purified by column chromatography using silica gel to
Recently, the solvent-free reactions have attracted great
interest due to the pollution reducing, low cost and convenient
and straightforward work-up. In continuation of our efforts to
develop new methods in organic synthesis [27-29], we found
out that zirconium hydrogen sulfate has many advantages over
sulfuric acid alone. This reagent is safe and environmentally
benign and presents fewer disposal problems. Lately, the use
of Zr(HSO4)4 as an efficient catalyst for the preparation of
acylals, regeneration of carbonyl compounds by cleavage of
C=N bonds and acetylation or formylation of primary,
secondary and tertiary alcohols has been published [30-33].
Herein, we wish to report an efficient method for one-pot
three-component synthesis of ꢀ-amino nitriles from various
carbonyl compounds, aniline and TMSCN in the presence of
catalytic amount of Zr(HSO4)4 under solvent-free conditions at
room temperature (Scheme 1).
1
afford the pure product. The spectral (IR, H NMR and 13C
NMR) data and the elemental analyses of the products are
given below. Spectral data were compared with the literature
data. Entries 6, 14 and 17 are new compounds.
2-Anilino-2-phenyl acetonitrile (entry 1): IR (KBr): 3337,
2237 cm-1; 1H NMR (CDCl3, 400 MHz) ꢁ 3.84 (d, 1H, J = 8.0
Hz), 5.25 (d, 1H, J = 8.4 Hz), 6.60 (d, 2H, J = 8.0 Hz), 6.72 (t,
1H, J = 8.0 Hz), 7.04-7.11 (m, 2H), 7.27-7.31 (m, 3H), 7.41-
7.43 (m, 2H).
EXPERIMENTAL
2-Anilino-2-(4-methoxy phenyl) acetonitrile (entry 2): IR
1
(KBr): 3328, 2227 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 3.65
General
(s, 3H), 3.78 (bs, 1H), 5.15 (d, 1H, J = 6.4 Hz), 6.59 (d, 2H,
J = 8.0 Hz), 6.69-6.79 (m, 3H), 7.09 (d, 2H, J = 8.0 Hz), 7.32
(d, 2H, J = 8.0 Hz).
All reagents were purchased from Merck and Aldrich and
used without further purification. All yields refer to isolated
products after purification. Zr(HSO4)4 was synthesised
according to the reported procedure [31]. Products were
2-Anilino-2-(2-chloro phenyl) acetonitrile (entry 3): IR
1
(KBr): 3338, 2241 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 3.83
characterized by spectroscopy data (IR, H NMR, 13C NMR
(d, 1H, J = 7.6 Hz), 5.54 (d, 1H, J = 8.0 Hz), 6.60 (d, 2H, J =
8.0 Hz), 6.72 (t, 1H, J = 7.6 Hz), 7.09 (t, 2H, J = 8.0 Hz), 7.20-
7.22 (m, 2H), 7.29-7.31 (m, 1H), 7.55-7.58 (m, 1H).
1
1
spectra) and elemental analyses and melting points. H NMR
(400, 500 MHz) and 13C NMR (125 MHz) spectra were run in
CDCl3 solution relative to TMS (0.00 ppm). IR spectra were
recorded on a Shimadzu 435 IR spectrophotometer and
performed using KBr pellets. All melting points were taken on
a Gallenkamp melting apparatus and were uncorrected.
2-Anilino-2-(4-methyl phenyl) acetonitrile (entry 4): IR
1
(KBr): 3309, 2243 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 2.21
(s, 3H) 3.83 (bs, 1H), 5.20 (s, 1H), 6.59 (d, 2H, J = 8.0 Hz),
6.71 (t, 1H, J = 7.2 Hz), 7.07-7.11 (m, 4H), 7.29 (d, 2H, J =
448

Zr(HSO4)4 Catalyzed One-Pot Strecker Synthesis of ꢀ-Amino Nitriles
7.6 Hz).
8.0 Hz), 6.73 (t, 1H, J = 7.2 Hz), 7.09 (t, 2H, J = 8.8 Hz).
2-Anilino-2-(4-chloro phenyl) acetonitrile (entry 5): IR
2-Anilino-2-phenyl propanenitrile (entry 13): IR (KBr):
1
1
(KBr): 3301, 2246 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 3.84
3386, 2226 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 1.76 (s, 3H)
(bs, 1H), 5.24 (d, 1H, J = 6.0 Hz), 6.56 (d, 2H, J = 7.8 Hz),
6.73 (t, 1H, J = 7.2 Hz), 7.09 (t, 2H, J = 8.0 Hz), 7.25 (d, 2H,
J = 8.8 Hz), 7.37 (d, 2H, J = 8.4 Hz).
4.10 (s, 1H), 6.35 (d, 2H, J = 8.0 Hz), 6.61 (t, 1H, J = 8.0 Hz),
6.93 (t, 2H, J = 8.0 Hz), 7.16-7.23 (m, 3H), 7.44 (d, 2H, J =
7.2 Hz).
2-Anilin-2-(2,6-dichloro phenyl) acetonitrile (entry 6): IR
2-Anilino-2-(3-methoxy phenyl) propanenitrile (entry 14):
1
1
(KBr): 3407, 2245 cm-1; H NMR (CDCl3, 500 MHz) ꢁ 4.53
IR (KBr): 3384, 2230 cm-1; H NMR (CDCl3, 500 MHz) ꢁ
(d, 1H, J = 10.0 Hz), 6.09 (d, 1H, J = 10.4 Hz), 6.66 (d, 2H,
J = 8.0 Hz), 6.72 (t, 1H, J = 7.2 Hz), 7.07-7.14 (m, 3H), 7.21
(d, 2H, J = 7.6 Hz); 13C NMR (CDCl3, 125 MHz): ꢁ 46.21,
115.32, 116.94, 121.28, 129.99, 130.08, 130.46, 131.61,
135.55, 144.45; Anal. Calcd. for C14H10N2Cl2: C, 60.67; H,
3.64; N, 10.11; Found: C, 60.10; H, 3.80; N, 10.20.
1.99 (s, 3H) 3.85 (s, 3H), 4.30 (bs, 1H), 6.61 (d, 2H, J = 8.0
Hz), 6.86 (t, 1H, J = 7.3 Hz), 6.93 (dd, 1H, J = 2.6, 8.0 Hz),
7.17 (t, 2H, J = 8.0 Hz), 7.21 (t, 1H, J = 2.0 Hz), 7.27 (d, 1H,
J = 7.8 Hz), 7.37 (t, 1H, J = 7.9 Hz); 13C NMR (CDCl3, 125
MHz): ꢁ 33.74, 55.77, 57.53, 111.16, 114.29, 116.21, 117.55,
120.47, 121.05, 129.44, 130.77, 142.08, 143.90, 160.73; Anal.
Calcd. for C16H13N2O: C, 77.09; H, 5.26; N, 11.24; Found: C,
77.30; H, 5.40; N, 10.90.
2-Anilino-2-(3-methoxy phenyl) acetonitrile (entry 7): IR
1
(KBr): 3354, 2225 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 3.65
(s, 3H), 3.86 (bs, 1H), 5.21 (s, 1H), 6.59 (d, 2H, J = 8.0 Hz),
6.72 (t, 1H, J = 7.6 Hz), 6.76 (dd, 1H, J = 2.0, 8.2 Hz), 6.93 (s,
1H), 6.98 (d, 1H, J = 7.6 Hz), 7.09 (t, 2H, J = 8.0 Hz), 7.19 (t,
1H, J = 8.0 Hz).
1-Anilino-1-cycloheptane carbonitrile (entry 15): IR (KBr):
3365, 2238 cm-1; 1H NMR (CDCl3, 500 MHz) ꢁ 1.65-1.70 (m,
2H), 1.72-1.81 (m, 6H), 2.00-2.05 (m, 2H), 2.33-2.38 (m, 2H),
3.69 (bs, 1H), 6.92-6.95 (m, 3H), 7.29 (t, 2H, J = 8.2 Hz).
1-Anilino-1-cyclopentane carbonitrile (entry 16): IR (KBr):
3368, 2235 cm-1; 1H NMR (CDCl3, 500 MHz) ꢁ 1.89-1.97 (m,
4H), 2.16-2.21 (m, 2H), 2.41-2.46 (m, 2H), 3.90 (bs, 1H), 6.87
(d, 2H, J = 7.8 Hz), 6.92 (t, 1H, J = 7.4 Hz), 7.28-7.31 (m,
3H).
2-Anilino-2-(4-cyano phenyl) acetonitrile (entry 8): IR
1
(KBr): 3354, 2237 cm-1; H NMR (CDCl3, 500 MHz) ꢁ 4.19
(bs, 1H), 5.58 (s, 1H), 6.80 (d, 2H, J = 7.8 Hz), 6.99 (t, 1H, J =
7.4 Hz), 7.33 (t, 2H, J = 7.6 Hz), 7.81 (s, 4H).
2-Anilino-2-[4-(1-Anilino-1-cyano)-methyl]
phenyl
1
acetonitrile (entry 9): IR (KBr): 3330, 2238 cm-1; H NMR
(CDCl3, 500 MHz) ꢁ 2.22 (s, 1H), 5.54 (s, 1H), 6.83 (d, 2H,
J = 7.7 Hz), 6.98 (t, 1H, J = 7.5 Hz), 7.34 (t, 2H, J = 8.0 Hz),
7.77 (s, 2H).
5-Methoxy-1-anilino-1,2,3,4-tetrahydronaphthalene-1-
1
carbonitrile (entry 17): IR (KBr): 3395, 2227 cm-1; H NMR
(CDCl3, 500 MHz) ꢁ 1.59 (bs, 1H), 1.91-1.93 (m, 2H), 2.19-
2.21 (m, 1H), 2.66-2.67 (m, 1H), 2.74-2.77 (m, 1H), 2.86-2.90
(m, 1H), 6.91-6.97 (m, 4H), 7.29 (t, 2H, J = 7.7 Hz), 7.34 (t,
1H, J = 8.0 Hz), 7.43 (d, 1H, J = 7.8 Hz); 13C NMR (CDCl3,
125 MHz): ꢁ17.34, 22.87, 31.75, 55.47, 55.98, 110.62, 117.20,
120.70, 120.89, 122.38, 126.51, 127.98, 129.74, 135.85,
143.91, 157.64; Anal. Calcd. for C18H18N2O: C, 77.67; H,
6.52; N, 10.06; Found: C, 77.50; H, 6.80; N, 9.80.
(E)-2-Anilino-4-phenyl 3-butenenitrile (entry 10): IR
1
(KBr): 3351, 2224 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 3.92
(d, 1H, J = 9.6 Hz), 5.08-5.11 (m, 1H), 6.31 (dd, 1H, J = 4.8,
15.8 Hz ), 6.80 (d, 1H, J = 8.0 Hz), 6.93 (t, 1H, J = 8.0 Hz),
7.08 (d, 1H, J = 16.0 Hz), 7.30-7.47 (m, 7H).
2-Anilino-2-furfuryl acetonitrile (entry 11): IR (KBr):
3375, 2242 cm-1; 1H NMR (CDCl3, 500 MHz) ꢁ 4.21 (bs, 1H),
5.55 (d, 1H, J = 6.7 Hz), 6.48 (t, 1H, J = 2.6 Hz), 6.64 (d, 1H,
J = 3.4 Hz), 6.84 (d, 2H, J = 7.8 Hz), 6.97 (t, 1H, J = 7.4 Hz),
7.33 (t, 2H, J = 7.8 Hz), 7.54 (d, 1H, J = 1.0 Hz).
RESULTS AND DISSCUTION
In order to obtain the best reaction conditions, the reaction
of benzaldehyde (1 mmol), aniline (1 mmol) and TMSCN (1.2
mmol) was examined in the presence of 4 mol% of Zr(HSO4)4
as catalyst in acetonitrile at room temperature. When the
reaction mixture was stirred at room temperature for 6 h, some
2-Anilino-2-(5-methyl furfuryl) acetonitrile (entry 12): IR
1
(KBr): 3330, 2241 cm-1; H NMR (CDCl3, 400 MHz) ꢁ 2.14
(s, 3H) 3.95 (d, 1H, J = 8.0 Hz), 5.23 (d, 1H, J = 8.4 Hz), 5.81
(d, 1H, J = 2.0 Hz), 6.27 (d, 1H, J = 2.8 Hz), 6.58 (d, 2H, J =
449

Hajipour et al.
Table 1. Effect of Different Amounts of the Catalyst on the
Synthesis of 2-Anilino-2-phenyl Acetonitrilea
catalyst and undesired products were observed (entry 5, Table
1).
In order to show the catalytic activity of Zr(HSO4)4 in
comparison to the other catalysts, we have compared the
results of the synthesis of 2-anilino-2-phenyl acetonitrile from
benzaldehyde, aniline and TMSCN at room temperature. The
results are presented in (Table 2).
Entry
1
1
2
2
5
3
4
5
4
5
Mol% catalyst
Time (min)b
10
10
15
30c
10
aBezaldehyde (1 mmol), aniline (1 mmol), TMSCN (1.2
mmol) and Zr(HSO4)4 (1-15 mol%) under solvent-free
conditions at room temprature. bThe time of completion of
the reaction based on TLC. cThe reaction did not complete
and undesired product was observed.
We employed 2-4 mol% of the catalyst for one-pot
synthesis of ꢀ-amino nitriles from aldehydes under solvent-
free conditions at room temperature (entries 1-13, Table 3).
Aromatic, aliphatic and heterocyclic aldehydes under the
optimum conditions coupled with aniline and TMSCN to
produce the corresponding ꢀ-amino nitriles in high to
excellent yields. The mildness of the reaction conditions
permits furfural, 5-methyl furfural and cinnamaldehyde to
undergo reactions successfully to produce ꢀ-amino nitriles in
high yields and short reaction times without formation of any
polymerization products (entries 10-12, Table 3). The reaction
times for 2-chloro benzaldehyde and 2,6-dichloro
benzaldehyde were longer than the others (entries 3 and 6,
Table 3), which may be due to the steric hindrance effect. It
should be noted that electron-withdrawing substituents such as
-CN, or -Cl, decreased the Strecker reaction yields (entry 8,
Table 3).
undesired products were observed. Therefore, we tried to
trigger this reaction under solvent-free conditions and found
that the reaction took place in 5 min. Optimized amounts of
the catalyst were provided using several molar amounts of
Zr(HSO4)4 under solvent-free conditions (Table 1). As it is
shown in Table 1, no improvement was observed for the
reaction rate by increasing the amount of the catalyst from 2 to
4 mol% (entries 2-3, Table 1). Both the lesser (1 mol %) and
the higher (10 mol%) amounts of the catalyst worked with
longer reaction times (entries 1 and 4, Table 1). The reaction
did not complete even after 30 min and using 15 mol% of the
To the best of our knowledge, only few studies on Strecker
Table 2. Effect of Different Catalysts for Synthesis of ꢀ-Amino Nitriles from Benzaldehyde (1 mmol), Aniline (1
mmol) and TMSCN at Room Temperature and Different Solvents or Solvent-Free Conditions
Entry Catalyst (mol%)
TMSCN (mmol)
Solvent
Time
Yield (%)
Ref.
1
2
3
4
5
6
7
8
Cu(OTf)2 (2)
GuHCl (3)
PW/SiO2 (7)
PW/SiO2 (7)
TMSCN (1)
TMSCN (1.1)
TMSCN (1.5)
KCN (1.5)
CH3CN
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
CH3CN
-
CH3CN
-
6 h
1 h
5 min
30 min
45 min
1 h
1 h
6 h
10 min
20 min
17.5 h
5 min
89
94
98
95
97
96
94
75
97
94
92
92
[13]
[22]
[21]
[21]
[23]
[16]
[16]
[17]
[18]
[19]
[34]
-
Cellulose sulfuric acid (0.05 g) TMSCN (1.2)
La(NO3).6H2O (10)
GdCl3.6H2O (10)
InCl3 (30)
RhI3.H2O (2)
Fe(CP)2PF6 (5)
Catalyst-free
TMSCN (1.2)
TMSCN (1.2)
KCN (1.5)
TMSCN (1.2)
TMSCN (1.3)
TMSCN (1.03)
TMSCN (1.2)
9
10
11
12
Zr(HSO4)4 (2)
450

Zr(HSO4)4 Catalyzed One-Pot Strecker Synthesis of ꢀ-Amino Nitriles
Table 3. Strecker Synthesis of ꢀ-Amino Nitriles from Various Aldehydes and Ketones Catalyzed by Zr(HSO
)
4 4
under Solvent-Free Conditions at Room Temperature
Entry
Substrate
Product
Time
(min)
Yield
(%)a,b
M.P.
CN
NHPh
H
1
2
3
4
Benzaldehyde
5
92
85
80
90
82-84
94-97
63-66
72-74
4-Methoxy benzaldehyde
2-Chloro benzaldehyde
4-Methyl benaldehyde
10
30
10b
5
6
4-Chloro benzaldehyde
10
60
85
86
104-106
73-76
Cl CN
NHPh
H
2,6-Dichloro benzaldehyde
Cl
7
8
9
3-Methoxy benzaldehyde
4-Cyano benzaldehyde
Terephthaldialdehyde
15
15c
10c
91
70
83
56-58
118-121
157-160
10
11
Cinnamaldehyde
Fufural
15
5
85
90
104-106
66-69
12
5-Methyl furfural
5
83
108-110
451

Hajipour et al.
Table 3. Continued
13
14
15
16
17
Acetophenone
10
15
20
20
20
80
75
90
93
84
133-136
120-123
83-86
3'-Methoxy acetophenone
Cycloheptanone
Cyclopentanone
51-54
PhHN CN
5-Methoxy-1-tetralone
99-102
OMe
CN
N
H
Cl
Br
18
19
Benzaldehyded
Benzaldehydef
10
10
85
88
69-72
94-96
CN
N
H
aIsolated yields. bThe products were characterized from their spectral (IR, 1H NMR) and compared with authentic
samples. c4 mol% catalyst. d4-chloro aniline was used. f4-Bromo aniline was used.
reaction with ketones have been reported in the literatures
[19,24-26]. In this study, we examined the condensation of
ketones with aniline and TMSCN in the presence of 6 mol%
of Zr(HSO4)4 under solvent-free conditions at room
temperature (entries 13-17, Table 3). The reactions proceeded
in longer times in comparison to aldehydes, to produce the
corresponding ꢀ-amino nitriles from ketones.
Furthermore, the reactions of benzaldehyde with other
aromatic amines such as 4-chloro aniline and 4-bromo aniline
in the presence of TMSCN as cyanating agent and Zr(HSO4)4
as catalyst were investigated. As it is displayed in Table 3
(entries 18-19), the corresponding ꢀ-amino nitriles were
produced in high yields and short reaction times. Also, the
reactions of benzaldehyde with TMSCN and aliphatic amines
such as benzyl amine, homoveratryl amine and butyl amine in
the presence of Zr(HSO4)4 as catalyst were examined under
solvent-free conditions and room temperature. The yields of
the corresponding ꢀ-amino nitriles after 3 h were low and the
undesired products were observed. This may be due to the
higher basicity of the aliphatic amines.
To measure the selectivity of this method, we started some
competitive reactions for the preparation of ꢀ-amino nitriles
from aldehydes in the presence of ketones using zirconium
hydrogen sulfate as catalyst under solvent-free conditions. As
shown in Scheme 2, the aldehydes in the presence of ketones
were selectively converted to the corresponding ꢀ-amino
nitriles and the starting ketones were recovered intact.
CONCLUSIONS
In conclusion, we have developed a facile, convenient and
solvent-free method for the one-pot Strecker synthesis of ꢀ-
452

Zr(HSO4)4 Catalyzed One-Pot Strecker Synthesis of ꢀ-Amino Nitriles
CH3
NC
NHPh
NC
NHPh
CHO
COCH3
Zr(HSO4)4 (2 mol%)
Ph-NH2
+
+
+
TMSCN (1.2 mmol)
neat, RT, 10 min
R'
R'
(1 mmol )
R
R
(1 mmol)
(1 mmol)
R = H
92%
R' = H, 3-MeO 0%
R' = H, 3-MeO 0%
R = 4-OMe, 4-Cl 85%
Scheme 2
amino nitriles from the coupling of various aldehydes and
ketones with aniline and trimethylsilyl cyanide using
zirconium hydrogen sulfate as an efficient catalyst. Making
use of inexpensive and relatively non-toxic catalyst, high
catalytic efficiency, short reaction times, straightforward
work-up and environmentally benign procedure are among the
advantages of the method in question. Moreover, this method
is highly selective for the preparation of ꢀ-amino nitriles from
aldehydes in the presence of ketones. Therefore, this
procedure is general and can be used for coupling of various
aliphatic, aromatic, benzylic and cyclic aldehydes and ketones.
R.J. Seidehamel, J.R. Young, J. Med. Chem. 16 (1973)
901; c) R.O. Duthaler, Tetrahedron 50 (1994) 1539.
a) D. Enders, J.P. Shilvock, Chem. Soc. Rev. 29 (2000)
359; b) J. March, Advanced Organic Chemistry, 4th ed.,
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We gratefully acknowledge the funding support received
for this project from the Isfahan University of Technology
(IUT), IR Iran (A. R. H.) and Grants GM 033138, MH
065503, NS 033650 (A. E. R.) from the National Institute of
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