K2PdCl4 catalyzed efficient multicomponent synthesis of α-aminonitriles in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2010.03.059

An efficient, mild and environmentally friendly method has been developed for the Strecker reaction to synthesize α-aminonitriles in the presence of K₂PdCl₄ as a catalyst. The three-component one-pot condensation of an aldehyde, amine and trimethylsilyl cyanide proceeded smoothly in water to afford the corresponding product in high yield with short reaction times. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2010.03.059

Tetrahedron Letters 51 (2010) 2748–2750
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
K2PdCl4 catalyzed efficient multicomponent synthesis of
in aqueous media
a-aminonitriles
Bikash Karmakar a, Julie Banerji b,
*
a Gobardanga Hindu College, Department of Chemistry, Khantura, North 24, Parganas 743 273, India
b Centre of Advances Studies on Natural products including Organic Synthesis, Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, mild and environmentally friendly method has been developed for the Strecker reaction to
Received 15 January 2010
Revised 11 March 2010
Accepted 16 March 2010
Available online 19 March 2010
synthesize
a-aminonitriles in the presence of K2PdCl4 as a catalyst. The three-component one-pot con-
densation of an aldehyde, amine and trimethylsilyl cyanide proceeded smoothly in water to afford the
corresponding product in high yield with short reaction times.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
Strecker synthesis
Multicomponent reaction
Water chemistry
K2PdCl4
1. Introduction
source.11 Many of the catalysts used as a promoter in this reaction
are either moisture sensitive or take longer reaction time, involve te-
In recent times organic reactions in aqueous media have re-
ceived high priority in view of green methodology.1 The use of
water is also preferred due to its abundance, being economical
and also due to its highly polar nature. Sometimes it shows higher
reactivity and selectivity compared to other conventional organic
solvents due to its strong hydrogen bonding ability.2 The use of
water in multicomponent organic reactions is also of great interest.
The Strecker reaction3 is one of the most important multicompo-
nent reactions in organic chemistry for the one-pot synthesis of
dious work-up and generate toxic byproducts.12 In continuation of
our studies in developing simple methodologies following green
protocol,13 we report herein the use of K2PdCl4 for one-pot three-
component condensation of amine, aldehyde and trimethylsilyl
cyanide in water for the expeditious synthesis of
a-aminonitriles
(Scheme 1). The synthetic use of K2PdCl4 in multicomponent organic
reactions has not been very common. This has prompted us to apply
this catalyst in the Strecker synthesis. The reactions were observed
to be completed within several minutes with high yield of
a-aminonitriles. They serve as efficient precursors for the synthesis
a-aminonitriles.
of natural and unnatural a-amino acids and different nitrogen con-
taining heterocycles.4 They are also very effective intermediates for
the preparation of different diamines, amides and pharmaceuti-
a-amino acids have gained immense importance due
to their significant biological activities.
2. Results and discussion
cals.5 The
A very simple methodology has been followed in our protocol.
In this synthesis, a mixture of aryl aldehyde, aryl or aliphatic amine
and TMSCN was stirred in water in the presence of K2PdCl4. The
progress of the reaction was checked by TLC and after work-up
The Strecker reaction provides an important method for the
synthesis of these
a-amino acids and their analogues. One of the
popular methods involves the nucleophilic addition of cyanide an-
ions to imines.3 A number of cyanating agents have been utilized
in this process, viz., alkaline cyanides,6 Et2AlCN,7 Bu3SnCN,8 (EtO)2-
POCN9 andacetonecyanohydrin.10 However, mostof themare found
to be hazardous and special caution has to be taken during their use.
It has been observed that the use of Me3SiCN could overcome all
those problems as it is safe to handle and is an effective cyanide
the corresponding
yields. The reaction between benzaldehyde, aniline and TMSCN
a-aminonitriles were obtained in excellent
R'
O
R
N
H
K2PdCl4
Water, RT
+
R''
+
N
Me3SiCN
R'
R
H
R''
CN
* Corresponding author. Tel.: +91 33 2350 8386; fax: +91 33 2351 9755.
E-mail address: juliebanerji47@gmail.com (J. Banerji).
Scheme 1. Strecker synthesis of
a-aminonitriles.
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.059

B. Karmakar, J. Banerji / Tetrahedron Letters 51 (2010) 2748–2750
2749
Table 1
Standardization of the catalytic conditions in Strecker reactiona
Table 3
One-pot synthesis of a
-aminonitriles with various aromatic aldehydes in watera
Yieldb (%)
Ar
CN
Entry
K2PdCl4 (mol %)
Time (h)
+
+
ArCHO
PhNH2
TMSCN
1
2
3
4
5
0
5
10
20
30
12
8
0.5
15 min
15 min
<5
84
95
97
98
NHPh
3a-n
1a-n
2a
Entry
1
Aldehyde
Product
Time (h)
Yieldb (%)
a
Reaction condition: 1.0 mmol benzaldehyde, 1.0 mmol aniline, 1.3 mmol TMSCN,
room temperature stirring in water.
CHO
3a
3b
0.2
0.5
95
b
Isolated yield.
CHO
was chosen as a probe to evaluate the catalytic activity of K2PdCl4
(Table 1). An increase in the quantity of the catalyst up to 30 mol %
not only increased the yield but also reduced the reaction time.
Considerably, our studies clearly indicate that even 10 mol % of
K2PdCl4 was sufficient to catalyze the reaction efficiently to pro-
duce high yield (95%) within very short reaction time. Therefore,
the catalyst loading was optimized to 10 mol % for further reac-
tions. It seems noteworthy to mention that the reaction was not
successful in the absence of the catalyst. A screening of the sol-
vents was also carried out under similar reaction conditions. Sol-
vents such as dichloromethane, toluene, THF, acetonitrile,
ethanol and water were used to study the reaction. The results
have been summarized in Table 2. The yields of the reactions in
ethanol and acetonitrile were comparable to that in water but in
an aqueous medium the reaction was much faster. This could be
due to the high polarizability and amphoteric nature of water.14
2
3
92
86
O2N
CHO
3c
0.5
NO2
CHO
4
5
6
3d
3e
3f
0.5
1.0
0.7
91
88
89
Cl
CHO
Me
MeO
CHO
On establishing optimum conditions, a series of a-aminonitriles
CHO
were synthesized by using different aldehydes and amines using
TMSCN in the presence of K2PdCl4 in water in order to prove the
scope and generality of our method.16 Most of the aldehydes re-
acted efficiently with aniline and TMSCN in water in the presence
of the catalyst to furnish the corresponding product in good to
excellent yield (73–95%). The results are summarized in Table 3.
A variety of substituted aromatic aldehydes were used and all of
them furnished good results. Acid sensitive heterocycles like furfu-
ral and pyridine-2-carboxaldehyde and unsaturated aldehyde like
cinnamaldehyde also produced excellent yields without affecting
any other functionality.
7
8
9
3g
3h
3i
1.0
1.0
1.5
86
83
75
OMe
HO
CHO
CHO
HO
OMe
Encouraged by the above-mentioned results we continued our
exploration of the Strecker synthesis by treating various amines
with benzaldehyde and TMSCN under similar reaction conditions.
Different aromatic and aliphatic amines were used in the reaction
and they underwent efficient coupling with benzaldehyde and
TMSCN as shown in Table 4. We observed that the reaction rates
were comparable for both aromatic and aliphatic amines. Cyclic
amines like pyrrolidine and piperidine also produced high yields
in short time.
The protocol devised by us did not require any other additives
to promote the reaction. The reactions were carried out at ambient
condition in open atmosphere. K2PdCl4 acts as efficient Lewis acid
to furnish the formation of imines by condensation of aldehyde
CHO
10
11
3j
0.7
0.5
89
90
MeO
MeO
OMe
CHO
3k
MeO
OMe
CHO
12
13
3l
0.5
1.0
96
88
O
N
3m
CHO
CHO
Table 2
a
14
3n
1.0
80
Screening of solvents using 10 mol % K2PdCl4
Entry
Solvent
Time (h)
Yieldb (%)
a
Reaction condition: 1.0 mmol aldehyde, 1.0 mmol aniline, 1.3 mmol TMSCN,
10 mol % K2PdCl4, room temperature stirring.
1
2
3
4
5
6
Dichloromethane
Toluene
THF
Acetonitrile
Ethanol
Water
8
12
8
2
2
68
52
47
88
91
95
b
Isolated yield.
0.5
and amine. The activated imine reacts with TMSCN to generate
the desired product. No silylated cyanohydrins were observed to
be formed. So, this methodology could be regarded as one of the
better methods for Strecker reaction in a single step.
a
Reaction condition: 1.0 mmol benzaldehyde, 1.0 mmol aniline, 1.3 mmol TMSCN,
room temperature stirring.
b
Isolated yield.

2750
B. Karmakar, J. Banerji / Tetrahedron Letters 51 (2010) 2748–2750
Table 4
One-pot synthesis of
4. Weinstock, L. M.; Davis, P.; Handelsman, B.; Tull, R. J. Org. Chem. 1967, 32, 2823;
a
-aminonitriles with various amines in watera
Mantier, W. L.; Owens, D. A.; Comer, W. T.; Deitchman, D.; Ferguson, H. C.;
Seidehamel, R. J.; Young, J. R. J. Med. Chem. 1973, 16, 901.
5. Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359. and references cited
therein.
Ph
CN
PhCHO
+
RNH2
TMSCN
+
NHR
4a-i
6. Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
7. Nakamura, S.; Sato, N.; Sugimoto, M.; Toru, T. Tetrahedron: Asymmetry 2004, 15,
1513.
1a
2a-i
8. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 762.
Entry
1
Amines
Product
Time (h)
Yieldb (%)
9. Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1979, 20, 4663.
10. Paraskar, A. S.; Sudalai, A. Tetrahedron Lett. 2006, 47, 5759.
11. Shaabani, A.; Maleki, A. Appl. Catal. A: Gen. 2007, 331, 149.
12. (a) Heydari, A.; Fatemi, P.; Alizadeh, A.-A. Tetrahedron Lett. 1998, 39, 3049; (b)
Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron Lett. 1996, 37, 9221; (c)
De, S. K.; Gibbs, R. A. J. Mol. Catal. A: Chem. 2005, 232, 123; (d) De, S. K. J. Mol.
Catal. A: Chem. 2005, 225, 169; (e) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2004,
45, 7407; (f) De, S. K. Synth. Commun. 2005, 35, 653; (g) Kobayashi, S.; Ishitani,
H.; Ueno, M. Synlett 1997, 115; (h) Sakurai, R.; Suzuki, S.; Hashimoto, J.; Baba,
M.; Itoh, O.; Uchida, A.; Hattori, T.; Miyano, S.; Yamaura, M. Org. Lett. 2004, 6,
2241; (i) Majhi, A.; Kim, S. S.; Kadam, S. T. Tetrahedron 2008, 64, 5509.
13. (a) Karmakar, B.; Nayak, A.; Chowdhury, B.; Banerji, J. Arkivoc 2009, XII, 209; (b)
Postole, G.; Chowdhury, B.; Karmakar, B.; Pinki, K.; Banerji, J.; Auroux, A. J.
Catal. 2010, 269, 110; (c) Karmakar, B.; Chowdhury, B.; Banerji, J. Catal.
Commun. 2010, 11, 601.
14. (a) Harrerias, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546; (b)
Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563; (c) Babu, G.; Perumal, P.
T. Aldrichim. Acta 2000, 33, 16.
15. (a) Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron 2008, 64, 8159; (b) Karimi, B.; Safari,
A. A. J. Orgmet. Chem. 2008, 693, 2967; (c) Shaabani, A.; Maleki, A.; Soudi, M. R.;
Mofakham, H. Catal. Commun. 2009, 10, 945; (d) Kumar, M. A.; Babu, M. F. S.;
Srinivasulu, K.; Kiran, Y. B.; Reddy, C. S. J. Mol. Catal. A: Chem. 2007, 265, 268.
NH2
4a
4b
0.5
0.5
95
84
NH2
Me
2
3
4
5
NH2
NH2
NH2
4c
4d
4e
0.5
1.0
1.0
89
90
88
Me
Cl
Br
NH2
16. Representative experimental procedure:
A mixture of aldehyde (1.0 mmol),
6
7
4f
1.2
1.0
80
85
amine (1.0 mmol), and trimethylsilylcyanide (1.3 mmol) was stirred at room
temperature in water (5 mL) in the presence of 10 mol % of K2PdCl4 for certain
period as indicated in Tables 3 and 4. After completion of the reaction as
indicated by TLC (after elusion the silica gel precoated aluminium plates were
visualized under UV light and dipping into ethanolic-ninhydrin solution and
charring), the reaction mixture was extracted with ethyl acetate (3 Â 10 mL).
The extract was concentrated under reduced pressure and purified by column
chromatography using 60–120 mesh silica gel with ethyl acetate/hexane as
eluant. However, in some cases solid product appeared in the reaction flask
which were filtered and crystallized from hot ethanol to get the pure products.
The isolated compounds were characterized by mp, IR, 1H NMR, 13C NMR and
elemental analysis (C, H and N) and the data of known compounds were found
to be identical with the literature.15 The spectral data of some representative
new products are provided below.
4g
N
H
8
9
4h
4i
1.0
88
78
N
H
NH2
0.75
a
Reaction condition: 1.0 mmol benzaldehyde, 1.0 mmol amine, 1.3 mmol
TMSCN, 10 mol % K2PdCl4, room temperature stirring.
2-(N-Anilino)-2-(4-hydroxyphenyl)acetonitrile (3h): Yield 152 mg; grey solid,
b
Isolated yield.
mp 120–122 °C; IR (KBr): 3341, 3022, 2232, 1602, 1271, 1156, 751 cmÀ1 1H
;
NMR (CDCl3, 300 MHz): d 4.58 (br s, 1H), 5.28 (s, 1H), 6.70–6.85 (m, 5H), 7.17
(t, J = 7.0 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 9.74 (br s, 1H); 13C NMR (CDCl3,
75.5 MHz): d 49.19, 113.69, 115.85, 118.54, 119.21, 124.36, 128.25, 129.03,
144.9, 157.99. Anal. Calcd for C14H12N2O: C, 75.0; H, 5.36; N, 12.5. Found: C,
75.11; H, 5.41; N, 12.38.
3. Conclusion
2-(N-Anilino)-2-(4-hydroxy-3-methoxyphenyl)acetonitrile (3i): Yield 125 mg;
yellow solid, mp 106–108 °C; IR (KBr): 3377, 3021, 2237, 1604, 1509, 1253,
In summary, we have developed an efficient and clean protocol
employing catalytic amount of K2PdCl4 for the one-pot synthesis of
1208, 1028, 758, 691 cmÀ1 1H NMR (CDCl3, 300 MHz): d 3.93 (br s, 1H), 3.93 (s,
;
a-aminonitriles. The reaction is completed within a very short time
3H), 5.35 (s, 1H), 5.76 (br s, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.88–6.98 (m, 3H), 7.06
(d, J = 2.0 Hz, 1H), 7.3 (d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 75.5 MHz): d 50.08,
56.11, 109.6, 114.13, 114.9, 118.37, 120.26, 120.49, 125.69, 144.72, 146.67,
147.05. Anal. Calcd for C15H14N2O2: C, 70.87; H, 5.51; N, 11.02. Found: C, 70.84;
H, 5.56; N, 11.0.
with excellent yields of the product. This methodology does not in-
volve the use of hazardous chemicals and it is carried out in an
aqueous medium satisfying the green chemistry criteria.
2-(N-Anilino)-2-(3,4-dimethoxyphenyl)acetonitrile (3j): Yield 144 mg; pale
yellow solid, mp 134–136 °C; IR (KBr): 3337, 2933, 2230, 1601, 1512, 1287,
Acknowledgements
1239, 1141, 1024, 761 cmÀ1 1H NMR (CDCl3, 300 MHz): d 3.83 (s, 3H), 3.84 (s,
;
3H), 3.9 (s, 1H), 5.31 (s, 1H), 6.72 (d, J = 8.5 Hz, 2H), 6.83 (t, J = 8.7 Hz, 2H), 6.99
(d, J = 2.1 Hz, 1H), 7.1 (d, J = 9.3 Hz, 1H), 7.2 (t, J = 7.0 Hz, 2H); 13C NMR (CDCl3,
75.5 MHz): d 50.05, 56.0, 56.02, 110.22, 111.37, 114.27, 118.28, 119.73, 120.37,
126.17, 129.54, 144.57, 149.6, 149.95. Anal. Calcd for C16H16N2O2: C, 71.64; H,
5.97; N, 10.45. Found: C, 71.60; H, 5.99; N, 10.41.
The authors are thankful to UGC, New Delhi, for providing
financial assistance. B.K. thanks Mr. A. Nayak for his support and
Central Instrumentation Division, Calcutta University, for technical
help.
2-(N-Anilino)-2-(3,4,5-trimethoxyphenyl)acetonitrile (3k): Yield 137 mg; pale
yellow solid, mp 130–132 °C; IR (KBr): 3350, 2974, 2942, 2220, 1599, 1505,
1238, 1129, 1001, 760, 701 cmÀ1 1H NMR (CDCl3, 300 MHz): d 3.7 (s, 3H), 3.72
;
References and notes
(s, 3H), 3.73 (s, 3H), 3.9 (s, 1H), 5.21 (s, 1H), 6.64 (d, J = 9.7 Hz, 2H), 6.66 (s, 2H),
6.76 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 75.5 MHz): d
50.05, 56.28, 60.86, 104.35, 112.3, 117.17, 120.38, 129.31, 129.57, 139.31,
144.64, 153.8. Anal. Calcd for C17H18N2O3: C, 68.46; H, 6.04; N, 9.40. Found: C,
68.51; H, 6.01; N, 9.44.
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