Water-mediated strecker reaction: An efficient and environmentally friendly approach for the synthesis of α-aminonitriles via a three-component condensation

Article abstract of DOI:10.1080/00397910903457381

The synthesis of α-aminonitriles by a direct three component Strecker reaction has been achieved in water, which is found to be an inexpensive, non-toxic and eco-friendly reaction medium for the nucleophilic addition. This protocol is effective to a wide variety of substrates with different functional groups and does not require the use any other catalyst. Copyright Taylor & Francis Group, LLC.

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Water-Mediated Strecker Reaction:
An Efficient and Environmentally
Friendly Approach for the Synthesis of
α-Aminonitriles via a Three-Component
Condensation
Samikannu Ramesh a , Kulanthaivel Sivakumar a , Chiradeep Panja a ,
Pirama Nayagam Arunachalam a & Appaswami Lalitha a
a Department of Chemistry , Periyar University , Salem, India
Published online: 05 Nov 2010.
To cite this article: Samikannu Ramesh , Kulanthaivel Sivakumar , Chiradeep Panja , Pirama Nayagam
Arunachalam & Appaswami Lalitha (2010) Water-Mediated Strecker Reaction: An Efficient and
Environmentally Friendly Approach for the Synthesis of α-Aminonitriles via a Three-Component
Condensation, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:23, 3544-3551, DOI: 10.1080/00397910903457381
To link to this article: http://dx.doi.org/10.1080/00397910903457381
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Synthetic Communications1, 40: 3544–3551, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457381
WATER-MEDIATED STRECKER REACTION: AN
EFFICIENT AND ENVIRONMENTALLY FRIENDLY
APPROACH FOR THE SYNTHESIS OF
a-AMINONITRILES VIA A THREE-COMPONENT
CONDENSATION
Samikannu Ramesh, Kulanthaivel Sivakumar,
Chiradeep Panja, Pirama Nayagam Arunachalam, and
Appaswami Lalitha
Department of Chemistry, Periyar University, Salem, India
The synthesis of a-aminonitriles by a direct three component Strecker reaction has been
achieved in water, which is found to be an inexpensive, non-toxic and eco-friendly reaction
medium for the nucleophilic addition. This protocol is effective to a wide variety of
substrates with different functional groups and does not require the use any other catalyst.
Keywords: a-Aminonitriles; Strecker reaction; three-component reaction; TMSCN; water
INTRODUCTION
The conventional synthetic procedures invariably use organic solvents as
reaction media to provide a homogeneous phase that allows molecular interactions to
occur effectively, bringing the reaction to completion. But the organic solvents used
are generally harmful, difficult to dispose of, and also lacking in the ability to bring
the reactions to total completion. Among the alternative reaction media, reactions that
can be performed in pure water are particularly valuable,[1] also for the added economi-
cal benefit. In recent decades, water has raised considerable attention in synthetic com-
munity and proved to be a promising solvent in organic synthesis due to its economic,
environmentally friendly and polar nature. Synthesis of a-aminonitriles through the
modified Strecker reaction employing trimethylsilyl cyanide (TMSCN) is highly signifi-
cant, in the view of formation of new C-C bond and also the a-aminonitriles serve as
precursors for a variety of important nitrogen containing organic compounds. There-
fore, if the Strecker reaction can be developed to operate in water, it will be of practical
value and will contribute to the area of green chemistry.
The development of methods that avoid the use of organic solvents and=or
metal-based catalysts is a fundamental strategy in this field. More recent methods
employed for Strecker reaction involve the use of strong Lewis acids, such as lithium
Received August 11, 2009.
Address correspondence to Appaswami Lalitha, Department of Chemistry, Periyar University,
Salem 636011, India. E-mail: lalitha2531@yahoo.co.in
3544

WATER-MEDIATED STRECKER REACTION
3545
perchlorate,[2] polymeric scandium triflamide,[3] vanadyl triflate,[4] nickel(II) chlori-
de,[5a] ruthenium(III) chloride,[5b] praseodymium triflate,[5c] ytterbium triflate,[6]
bismuth(III) chloride,[7a] Montmorillonite KSF,[7b] iodine,[8] H14[NaP5W30O110],[9]
and InI3.[11] However, many of these reported methods involve the use
[10]
H2SO4
of expensive reagents, toxic organic solvents, tedious workup procedures, and longer
reaction times. Therefore, it is still desirable to develop an efficient and simple
method for the Strecker reaction under less extreme conditions. Strecker reactions
were reported in solvent systems like DMF-H2O,[12] polyethylene glycol-H2O[13] as
well as b-cyclodextrin in water.[14] Apart from these, a-aminonitriles are synthesized
from N,N-dialkyl hydrazones in pure water.[15]
RESULTS AND DISCUSSION
In this article,we describe an efficient and environmentally friendly method for
the synthesis of a-aminonitriles in pure water via a three-component condensation of
aldehyde, amine and trimethylsilyl cyanide (TMSCN) under pressure without any
added catalyst.
Due to the ever-mounting environmental concern in the field of chemistry, it is
advisable to use environmental friendlier green catalyst. The search for an effective
green catalyst suitable for the direct Strecker reaction of aldehydes led us to the
present investigation. In the present work, a series of a-aminonitriles were synthe-
sized using different aldehydes, amines and TMSCN in the presence of water as sol-
vent. As shown in Table 1, all aldehydes could react effectively with aniline and
TMSCN in water mediated reaction to afford the corresponding products with excel-
lent yields up to 95%. It is noteworthy to mention that these reactions are working
well in water medium without using any catalyst in a 10 mL crimp-sealed thick
walled glass tube equipped with a pressure sensor and magnetic stirrer. This system
also worked moderately with benzyl amine instead of aniline to generate the corre-
sponding products with good yields of 68%, 70%, 64%, and 72% (entries 8, 9, 10, 11,
and 20). However, if the reaction time was prolonged to above 10 hrs, moderate to
good yields of the desired products could be obtained.
CONCLUSION
In summary, the reactions are efficient affording exclusively a-aminonitriles in
high. This method is equally effective with aldehydes bearing electron-withdrawing=
donating substituents in the aromatic ring. This methodology is compatible with
various substituted aldehydes such as chloro, bromo, fluoro, methyl, methoxy, nitro,
and double bonds under mild reaction conditions. No by-product formation was
Scheme 1. Synthesis of a-aminonitriles using water-mediated Strecker synthesis.

3546
S. RAMESH ET AL.
Table 1. Water-mediated Strecker reactions of various aldehydes and amines
Entry
1
Aldehydes
Amine
Producta
Time (h)
Yieldb (%)
4
95[16]
2
3
8
95[22]
12
70[17]
4
4
70[17]
5
6
7
4
8
71[23]
65[18]
76[16]
12
8
12
68[15]
9
12
12
70[9]
10
64[17]
11
12
72[17]
(Continued )

WATER-MEDIATED STRECKER REACTION
3547
Table 1. Continued
Entry
12
Aldehydes
Amine
Producta
Time (h)
Yieldb (%)
12
87[17]
13
14
12
12
86[20]
74[19]
15
16
17
12
12
12
72[21]
92[19]
91[18]
18
12
63[17]
19
20
12
12
60[16]
83[16]
(Continued )

3548
S. RAMESH ET AL.
Table 1. Continued
Entry
Aldehydes
Amine
Producta
Time (h)
Yieldb (%)
21
22
12
92x
13
94x
23
24
6
95x
12
90x
xNovel compounds (entry 21–24) are characterized by IR,1H NMR,13C and LC-mass spectral analysis.
aProducts (entry 1–20) are known and compared with authentic samples [refs. 8, 9, 16–24].
bIsolated yields.
observed. Moreover, these reactions are clean with nearly quantitative yields as
compared to conventional methods, with shorter reaction times, higher selectivity,
and more eco-friendly.
EXPERIMENTAL
Chemicals are commercial products and were used without further purification.
The products were characterized by comparison of their physical data with those of
known samples or by comparison of their Infrared (IR), 1H NMR, and liquid
chromatography (LC)-mass spectra (MS) data.
General Experimental Procedure
Aldehyde (2.2 mmol), amine (2 mmol), TMSCN (2 mmol), and water (20)
volume were taken in a sealed pressure tube) and the reaction mixture was stirred
at the temperature of 95 ꢀC for 4–13 hrs as indicated (Table 1). Completion of the
reaction was monitored by TLC. After completion of the reaction, the mixture
was cooled to room temperature, then extracted with ethyl acetate (3 ꢁ 5 mL). The
combined organic layers were washed with water and brine, dried over Na2SO4,
and filtered, and the solvent evaporated, to obtain the crude product. The residue

WATER-MEDIATED STRECKER REACTION
3549
was purified by flash column chromatography (silica gel 230–400 mesh) with
petroleum ether and ethyl acetate, as eluent to afford the pure compounds. All the
known and novel compounds were characterized by NMR and MS analysis.
Spectral Data of All Novel Compounds
Anilino(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)acetonitrile (Entry 21). White
1
solid, mp – 112.7–114.7ꢀC, H NMR (400 MHz, CDCl3) d 2.04 (s, 6H), 3.95–3.96
(d, J ¼ 6.8 Hz, 1NH), 5.23–5.25 (d, J ¼ 7.2 Hz, 1H), 6.18 (s, 1H), 6.80–6.82 (d, 2H,
J ¼ 8.40, Hz, 2H), 6.86–6.90 (t, 1H), 7.20–7.22 (d, 2H, J ¼ 7.2 Hz, 2H), 7.26–7.27
(d, J ¼ 4.4, Hz, 2H), 7.29–7.31 (d, J ¼ 8.00 Hz, 2H), 7.45–7.52 (m, 3H) ppm; 13C
NMR (100 MHz, CDCl3) d ¼ 10.86, 12.74, 43.59, 76.72, 77.04, 77.36, 105.38,
112.43, 113.80, 119.24, 119.60, 126.75, 128.23, 128.34, 129.21, 129.35, 129.50,
138.13, 145.24 ppm; IR (KBr, cmꢂ1): t 3349, 1600; MS: m=z ¼ 301.38 (Mþ).
Anal. calcd. for C20H19N3: C, 79.70; H, 6.35; N, 13.94. Found: C79.73; H, 6.31,
N, 13.97.
Anilino(3-methyl-2-thienyl)acetonitrile (Entry 22). Red color oil. 1H
NMR (400 MHz, CDCl3) d ¼ 2.32 (s, 3H), 4.14–4.16 (d, J ¼ 8.8, Hz, NH),
5.52–5.54 (d, J ¼ 7.2, Hz, 2H), 6.70–6.74 (d, 2H), 6.85–6.95 (d, 2H), 7.38–7.41 (q,
3H, J ¼ 6.7 Hz), 5H) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 13.95, 44.32, 114.29,
114.58, 117.61, 120.53, 120.74, 125.06, 129.10, 129.28, 129.36, 129.55, 129.60,
130.99, 136.38, 136.82, 137.91, 144.18, 144.45 ppm; IR (KBr, cmꢂ1): t 3364, 1600;
MS: m=z ¼ 228.31 (Mþ) .
Anal calcd. for C13H12N2S:C, 68.39; H, 5.30; N, 12.27. Found: C, 68.36; H,
5.32, N, 12.24.
Anilino(4-bromo-2-fluorophenyl)acetonitrile (Entry 23). White solid. mp,
71.8–73.1ꢀC; 1H NMR (400 MHz, CDCl3) d ¼ 4.07 (br, NH), 5.57 (s, 1H), 6.76–6.78
(d, J ¼ 7.6, Hz, 2H), 6.90–6.94 (t, 1H), 7.26–7.29 (t, 1H), 7.35–7.41 (m, 2H,
J ¼ 6.7 Hz), 7.49–7.53 (t, 1H) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 44.49, 44.52,
77.36, 114.51, 117.14, 120.00, 120.24, 128.44, 128.48, 129.66, 129.95, 129.98,
144.13, 158.59, 161.12 ppm; IR (KBr, cmꢂ1): t 3394, 1603; MS: m=z ¼ 305.14 (Mþ).
Anal. calcd. for C14H10BrFN2: C, 55.11; H, 3.30; N, 9.18. Found: C, 55.15; H,
3.34, N, 9.16.
Anilino[5-chloro-2-(trifluoromethyl)phenyl]acetonitrile (Entry 24). Brown
colour pasty mass. 1H NMR (400 MHz, CDCl3): d 5.69 (s, 1H), 6.73–6.74 (d, J ¼ 5.2,
Hz, 2H), 6.91–6.95 (t, 1H), 7.25–7.29 (q, 2H), 7.54–7.56 (d, J ¼ 9.6, Hz 1H),
7.71–7.34 (d, 1H), 7.94–7.95 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 46.69,
46.72, 114.41, 117.38, 120.96, 122.08, 124.81, 126.51, 126.82, 128.50, 128.56,
128.61, 128.67, 129.56, 129.67, 130.14, 134.65, 139.70, 144.01 ppm; IR (KBr,
cmꢂ1): t 3338, 1599; MS: m=z ¼ 310.70 (Mþ).
Anal. calcd. for C15H10ClF3 N2: C, 63.84; H, 9.87; N, 3.92. Found: C, 63.87; H,
9.90, N, 3.94.

3550
S. RAMESH ET AL.
REFERENCES
1. Organic reactions in water, for reviews, see: (a) Herrerias, C. I.; Yao, X. Q.; Li, Z. P.; Li,
C. J. Reactions of C-H Bonts in water. Chem. Rev. 2007, 107, 2546–2562; (b) Li, C. J.;
Chen, L. Water: The solvent for organic chemists. Chem. Soc. Rev. 2006, 35, 68–86; (c)
Dallinger, D.; Kappe, C. O. Microwave assisted synthesis in water as solvent. Chem.
Rev. 2004, 107(6), 2563–2591.
2. Heydari, A.; Fatemi, P.; Alizadeh, A. A. Lithium perchlorate=diethylether catalyzed
aminocyanation of aldehydes. Tetrahedron Lett. 1998, 39, 3049–3050.
3. Kobayashi, S.; Nagayama, S.; Busujima, T. Polymer scandium-catalyzed three-
component reactions leading to diverse amino ketone, amino ester, and a-aminonitrile
derivatives. Tetrahedron Lett. 1996, 37, 9221–9224.
4. De, S. K.; Gibbs, R. A. Vanadyl triflate as an efficient and recyclable catalyst for
trimethylsilyl cyanide addition to carbonyl compounds. J. Mol. Catal. A: Chem. 2005,
232, 123–125.
5. (a) De, S. K. Nickel(II) chloride catalyzed one-pot synthesis of a-aminonitriles. J. Mol.
Catal. A: Chem. 2005, 225, 169–171; (b) De, S. K. RuCl3 catalyzed one-pot synthesis of
a-aminonitriles. Synth. Commun. 2005, 35, 653–656; (c) De, S. K. Praseodymium
trifluoromethylsulfonate as an efficient and recyclable catalyst for the synthesis of
a-aminonitriles. Synth. Commun. 2005, 35, 961–966.
6. (a) Kobayashi, S.; Ishitani, H.; Ueno, M. Facile synthesis of a-aminonitriles using
lanthanide triflate as a Lewis acid catalyst. Synlett 1997, 115–116; (b) Sakurai, R.; Suzuki,
S.; Hashimoto, J.; Baba, M.; Itoh, O.; Uchida, A.; Hattori, T.; Miyano, S.; Yamaura, M.
Epimerization of diastereomeric a-amino nitriles to single stereoisomers in the solid state.
Org. Lett. 2004, 6, 2241–2244.
7. (a) De, S. K.; Gibbs, R. A. Bismuth trichloride catalyzed synthesis of a-aminonitriles.
Tetrahedron Lett. 2004, 45, 7407–7408; (b) Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah,
B.; Srinivas, M. Montmorillonite KSF clay catalyzed one-pot synthesis of a-aminonitriles.
Tetrahedron 2004, 60, 1767–1771.
8. Royer, L.; De, S. K.; Gibbs, R. A. 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. Tetrahedron Lett. 2005, 46, 4595–4597.
9. Oskooie, H. A.; Heravi, M. M.; Bakhtiari, K.; Zadsirjan, V.; Bamoharram, F. F.
H14[NaP5W30O110] as an efficient catalyst for the one-pot synthesis of a-aminonitriles.
Synlett 2006, 1768–1770.
10. Oskooie, H. A.; Heravi, M. M.; Sadnia, A.; Jannati, F.; Behbahani, F. K. The multicom-
ponent Strecker reaction using trimethylsilyl cyanide was performed at room temperature
and a-aminonitriles were prepared in excellent yields in the presence of a catalytic amount
of H2SO4 adsorbed on silica gel. Synth. Commun. 2007, 37, 2543–2548.
11. Shen, Z.; Ji, S.; Loh, T. P. Indium(III) iodide-mediated Strecker reaction in water: An
efficient and environmentally friendly approach for the synthesis of a-aminonitrile via a
three component condensation. Tetrahedron 2008, 64, 8159–8163.
12. Blackmond, D. G.; Armstrong, A.; Coombe, V.; Well, A. Water in organocatalytic pro-
cesses: Debunking the myths. Angew. Chem. Int. Ed. 2007, 46, 3798–3800.
13. (a) Takahashi, E.; Fujisawa, H.; Yanai, T.; Mukaiyama, T. Lewis base-catalyzed
Strecker-type reaction between trimethylsilyl cyanide and N-tosylimines in water-
containing DMF. Chem. Lett. 2005, 34, 318–319; (b) Kumar, M. A.; Babu, M. F. S.;
Srinivasulu, K.; Kiran Y. B.; Reddy, C. S. Polyethylene glycol in water: A simple and
environment friendly media for Strecker reaction. J. Mol. Catal. A: Chem. 2007, 265,
268–271.

WATER-MEDIATED STRECKER REACTION
3551
14. Surandra, K.; Krishnaveni, N. S.; Mahesh, A.; Rao, K. R. Supramolecular catalysis of
Strecker reaction in water under neutral conditions in the presence of b-cyclodextrin.
J. Org. Chem. 2006, 71, 2532–2534.
15. Opez, E. M. L.; Herrera, R. P.; Fernandez, R.; Lassaletta, J. M. Uncatalyzed Strecker
type reaction of N,N0 dialkylhydrazones in pure water. Eur. J. Org. Chem. 2008, 20,
3457–3460.
16. Anjoy, M.; Sung, S. K.; Santhosh, T. K. Rhodium(III) iodide hydrate catalyzed three-
component coupling reaction: Synthesis of a-aminonitriles from aldehydes, amines and
trimethylsilyl cyanide. Tetrahedron 2008, 64, 5509–5514.
17. Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Singh, S.; Suresh, E.; Jasra, R.
V. Fe(Cp)2PF6 catalyzed efficient Strecker reactions of ketones and aldehydes under
solvent-free conditions. Tetrahedron Lett. 2008, 49, 640–644.
18. Das, B.; Kumar, R. A.; Thirupathi, P. One-pot three-component synthesis of
a-aminonitriles catalyzed by 2,4,6-trichloro-1,3, triazine (cyanuric acid). Helv. Chim. Acta
2007, 90(6), 1043–1243.
19. Ishitani, H.; Komiyama, S.; Kobayashi, S. Catalytic, enantioselective synthesis of
a-aminonitriles with a novel zirconium catalyst. Angew. Chem. Int. Ed. 1998, 22, 3186–
3188.
20. Osamu, O.; Makoto, F. Heterogeneous catalysis of a coordination network: Cyanosilyla-
tion of imines catalyzed by a Cd(II)-(4,4-bipyridine) square grid complex. Chem. Commun.
2004, 14, 1586–1587.
21. Nasser, A.; Hassen.; Bayer, E.; Jochims, J. C. Synthesis of optically active a-amino nitriles
by asymmetric transformation of the second kind of O-dimroth. J. Chem. Soc., Perkin
Trans. 1 1998, 22, 3747–3758.
22. Mai, G.; Patil, G. A fast N-substituted a-aminonitrile synthesis. Synth. Commun. 1985, 15,
157–164.
23. Martinez, R.; Ramon, D. J.; Yus, M. Catalyst-free multicomponent Strecker reaction in
acetonitrile. Tetrahedron Lett. 2005, 46, 8471–8474.
24. Weinhardt, K.; Colin, C.; Dvorak, B. C.; Marx, M.; John, P.; Roszkowski, P.; Schuler,
M.; Stefan, H.; Unger, P. J.; Wanger.; Wallach, M. B. Synthesis and central nervous sys-
tem properties of 2-[(alkoxycarbonyl)amino]-4(5)-phenyl-2-imidazolines. J. Med. Chem.
1984, 27(5), 616–627.