Supramolecular catalysis of Strecker reaction in water under neutral conditions in the presence of β-cyclodextrin

Article abstract of DOI:10.1021/jo052510n

An environmentally benign and highly efficient procedure for the nucleophilic addition of trimethylsilyl cyanide to imines (Strecker reaction) has been developed under biomimetic conditions in water in the presence of β-cyclodextrin to afford α-aminonitriles in quantitative yields. The use of cyclodextrin precludes the use of either acid or base, and the catalyst can be recycled a number of times without loss in activity.

Full text of DOI:10.1021/jo052510n

ever, trimethylsilyl cyanide is a safe and easy to handle reagent
and more effective cyanide ion source for the nucleophilic
addition reactions under mild conditions as compared to
hydrogen, sodium, or potassium cyanides.
Supramolecular Catalysis of Strecker Reaction in
Water under Neutral Conditions in the Presence
of â-Cyclodextrin†
Although nucleophilic addition reaction to imines is a great
source for the synthesis of a variety of amines,6 the activation
of the CdN bond, which is generally poor in reactivity, is
necessary to obtain satisfactory efficiencies. Such activation can
be classified as either post- or preactivation. In the case of
postactivation, the CdN bond is not substituted with an
activating group, and therefore, a Bronsted or Lewis acid or a
metallic species is essential to effectively activate the formation
of iminium cations or the equivalent species.7 On the other hand,
in the case of preactivation, the CdN bond is substituted with
an activating group, such as carbonyl, sulfonyl, sulfinyl,
phosphoryl, or silyl, to facilitate the addition reaction.8
K. Surendra, N. Srilakshmi Krishnaveni, A. Mahesh, and
K. Rama Rao*
Organic Chemistry DiVision-I, Indian Institute of Chemical
Technology, Hyderabad-500 007, India
drkrrao@yahoo.com
ReceiVed December 6, 2005
Recently, one-pot procedures have also been developed for
the synthesis of R-aminonitriles from aldehydes, amines, and
trimethylsilyl cyanide or tributyltin cyanide using different Lewis
acids such as lithium perchlorate, polymeric scandium triflamide,
vanadyl triflate, NiCl2, BiCl3, zinc halides, RuCl3, ytterbium
triflate, and montmorillonite, etc.9 However, most of these
methods involve the use of strong acidic conditions, expensive
reagents, extended reaction times, harsh conditions, and tedious
workup leading to the generation of a large amount of toxic
waste. Furthermore, many of these protocols are limited to
aldehydes only and are not applicable to ketones.
There is also a recent report of carrying out these reactions
in ionic liquids,10 water-containing DMF,4d and Sc(OTf)3 in
water.11 These ionic liquids have been shown to have serious
drawbacks, especially imidazoliums with PF6 and BF4 anions
that are as toxic as benzene on certain aquatic ecosystems and
also liberate hazardous HF during recycling.12 Apart from this,
the high cost13 and disposability of these solvents also limit their
utility. Moreover, these reactions were unsuccessful in water
An environmentally benign and highly efficient procedure
for the nucleophilic addition of trimethylsilyl cyanide to
imines (Strecker reaction) has been developed under biomi-
metic conditions in water in the presence of â-cyclodextrin
to afford R-aminonitriles in quantitative yields. The use of
cyclodextrin precludes the use of either acid or base, and
the catalyst can be recycled a number of times without loss
in activity.
The Strecker reaction is one of the most efficient and
straightforward methods for the synthesis of R-aminonitriles,1
which are very useful precursors for the synthesis of R-amino
acids and various nitrogen-containing heterocycles such as
thiadiazoles, imidazoles, etc.2 R-Amino acids are also of great
biological and economical importance due to their significance
in chemistry and biology and as useful chiral building blocks.3
The classical Strecker reaction is generally carried out by the
nucleophilic addition of cynide ion to the imines using different
Lewis acid or base catalysts.4 Subsequently, several modifica-
tions of the Strecker reaction have been reported using a variety
of cyanating agents such as R-trimethylsiloxynitriles or dieth-
ylphosphorocyanidate under various reaction conditions.5 How-
(5) (a) Mai, K.; Patil, G. Tetrahedron Lett. 1984, 25, 4583. (b) Harusawa,
S.; Hamada, Y.; Shioiri, T.; Tetrahedron Lett. 1979, 20, 4663.
(6) (a) Kobayashi, S.; Ishitani, H.; Chem. ReV. 1999, 99, 1069. (b) Bloch,
R. Chem. ReV. 1998, 98, 1407.
(7) For recent examples of imines with postactivation, see: (a) Yanada,
R.; Okaniwa, M.; Kaieda, A.; Ibuka, T.; Takemoto, Y. J. Org. Chem. 2001,
66, 1283. (b) Yamamoto, Y.; Maruyama, K.; Komatsu, T.; Ito, W. J. Am.
Chem. Soc., 1986, 108, 7786.
(8) For recent examples of imines with preactivation, see: (a) Yraguchi,
D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (b) Soeta, T.; Nagai,
K.; Fujihara, H.; Kuriyama, M. Tomioka, K. J. Org. Chem. 2003, 68, 9723.
(c) Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125, 14133. (d) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55,
8883. (f) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 5634. (g) Uyehara, T.; Suzuki, I.; Yamamoto,
Y. Tetrahedron Lett. 1989, 32, 4275.
† IICT communication no. 060116.
(1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
(2) Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ. Chem. ReV.
1989, 58, 148.
(9) (a) Heydari, A.; Fatemi, P.; Alizadesh, 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) Mulzer, J.; Meier,
A.; Buschmann, J.; Luger, P. Synthesis 1996, 123. (g) De, S. K. Synth.
Commun. 2005, 35, 653. (h) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett
1997, 115. (i) Yadav, J. S.; Reddy, B. V. S.; Eswaraiah, B.; Srinivas, B.
Tetrahedron 2004, 60, 1767.
(10) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Srinivas, M.;
Vishnumurthy, P. New. J. Chem. 2003, 27, 462.
(11) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Commun. 1998,
981.
(3) (a) Weinstock, L. M.; Davis, P.; Handelsman, B.; Tull, R. J. Org.
Chem. 1967, 32, 2823. (b) Matier, 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. (c) Williams, R. M. Synthesis of Optically ActiVe
R-Amino Acids; Pergamon: Oxford, 1989. (d) Synthesis of R-amino acids:
O’Donnell, M. J., Ed. Tetrahedron Symposia in Print. Tetrahedron 1988,
44, 5253. (e) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(4) (a) Groger, H. Chem. ReV. 2003, 103, 2795. (b) Prasad, B. A. B.;
Bisai, A.; Singh, V. K. Tetrahedron Lett. 2004, 45, 9565. (c) Fossey, J. S.;
Richards, C. J. Tetrahedron Lett. 2003, 44, 8773. (d) Takahashi, E.;
Fujisawa, H.; Yanai, T.; Mukaiyama, T. Chem. Lett. 2005, 34, 318.
(12) Maginn, E. J. www.nd.edu/∼ed/IL_toxicology.htm.
10.1021/jo052510n CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/23/2006
2532
J. Org. Chem. 2006, 71, 2532-2534

TABLE 1. â-Cyclodextrin-Catalyzed Strecher Synthesis of
r-Amino Nitriles in Water
SCHEME 1
yielda
(%)
entry
R
R1
R2
time (h)
alone. To the best of our knowledge, efficient carbon-carbon
bond formation via nucleophilic attack of cynide anion to the
imines without pre- or postactivation has yet to be reported in
water without using any acid or base catalyst.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
C6H5
C6H5
C6H5
C6H5
C6H5
H
C6H5
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
98b
98
96
95
92
98
98
96
94
94
96
94
95
90
90
92
95
90
94
94
92
90
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-F-C6H4
2-CH3-C6H4
2-OCH3-C6H4
C6H5-CH2
C6H5
4-F-C6H4
C6H5
Ts
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-F-C6H4
C6H5
C6H5
4-Br-C6H4
4-Cl-C6H4
With green chemistry becoming a central issue in both
academic and industrial research in the 21st century,14 the
development of environmentally benign and clean synthetic
procedures has become the goal of present day organic synthesis.
Thus, there is a need for developing nucleophilic addition of
cyanide anion to the imines (Strecker reaction) in water with a
recyclable catalyst and without the use of any harmful organic
solvents because water is a safe, economical, and environmen-
tally benign solvent.15 To achieve these ideal conditions, the
best choice appeared to be through supramolecular catalysis
involving cyclodextrins with water as a solvent.
Cyclodextrins (CDs) are cyclic oligosaccharides possessing
hydrophobic cavities, which bind substrates selectively and
catalyze chemical reactions with high selectivity. They catalyze
reactions by supramolecular catalysis involving reversible
formation of host-guest complexes by noncovalent bonding
as seen in enzymes. Complexation depends on the size, shape,
and hydrophobicity of the guest molecule. Thus, mimicking of
biochemical selectivity, which is due to orientation of the
substrate by complex formation positioning only certain regions
for favorable attack, will be superior to chemical selectivity,
which involves random attack due to intrinsic reactivity of the
substrate at different regions. Our earlier expertise in the field
of biomimetic modeling of organic chemical reactions involving
cyclodextrins16 prompted us to attempt the Strecker reaction of
various aldimines and ketoimines under biomimetic conditions
using cyclodextrins with water as solvent at room temperature
(Scheme 1).
4-Me-C6H4
4-Me-C6H4
2,4,6-tri-Me-C6H2
4-MeO-C6H4
2,4-di-MeO-C6H3
4-allyloxy-C6H4
4-NO2-C6H4
C6H5-CHdCH
1-naphthyl
2-naphthyl
C10H20
C6H5
CH3 C6H5
CH3 C6H5
CH3 C6H5
CH3 C6H5
4-Me-C6H4
2-naphthyl
C6H10
a Isolated yields. b Catalyst was recovered and resued for five consecutive
runs in this reaction without change in the yield and purity.
FIGURE 1. â-CD catalysis of the Strecher reaction.
the known compounds.9 Moreover, these reactions are clean with
nearly quantitative yields as compared to conventional methods,
with shorter reaction times, higher selectivities, and recyclable
catalyst. All of the reactions do take place with R-CD; however,
â-CD was chosen as the catalyst since it is inexpensive and
easily accessible. Though asymmetric induction was seen to
some extent in these reactions, the ee’s observed are not
encouraging (<10%). However, when these reactions are carried
out in the presence of sugars such as glucose and sucrose, the
yields are only to the extent of 30% even after 12 h. These
experiments indicate the substantial role of cyclodextrin. Thus,
cyclodextrin may be forming a reversible complex with the
imine, thus facilitating the reaction with the cyanide ion in its
microenvironment.
The catalytic activity of cyclodextrins for this Strecker
reaction is established by the fact that no reaction was observed
in the absence of cyclodextrin. The mechanism of Strecker
reaction was postulated as follows: hydrogen bonding of CD
hydroxyl with the nitrogen of the imine increases the electro-
philicity of the imine carbon, thus activating it for attack by
the cyanide ion (Figure 1).
This is the first practically feasible Strecker reaction of various
aldimines and ketoimines with trimethylsilyl cyanide in water.
The reaction proceeds efficiently at room temperature without
the need of any acid or base catalyst. The reaction goes to
completion in a short time (1-2 h) (Table 1). This methodology
is compatible with various substituted aldimines and ketoimines
such as chloro, bromo, fluoro, methyl, methoxy, allyloxy, nitro,
and double bonds under mild reaction conditions. No byproduct
formation was observed. All of the products were characterized
1
by mass, H NMR, and IR spectroscopy and compared with
(13) Ionic Liquids cost 60-400 USD/50 g as opposed to â-CD, which
costs 105 USD/100 g.
(14) (a) Anastas, P. T.; Warner, J. C. Green Chemistry, Theory and
Practice; Oxford University Press: Oxford, 1998. (b) Handbook of Green
Chemistry & Technology; Clark, J., Macquarrie, D., Eds.; Blackwell:
Cambridge, MA, 2002. (c) Eissen, M.; Metzger, J. O.; Schmidt, E.;
Schneidewind, U. Angew. Chem., Int. Ed. 2002, 41, 414.
(15) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
and Professional: London, 1998. (b) Li, C,-J.; Chan, T.-H. Organic
Reactions in Aqueous Media; John Wiley & Sons: New York, 1997.
(16) (a) Krishnaveni, N. S.; Surendra, K.; Rao, K. R. Chem. Commun.
2005, 669. (b) Krishnaveni, N. S.; Surendra, K.; Rao, K. R. AdV. Synth.
Catal. 2004, 346, 346. (c) Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.;
Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68, 9119.
These CD-mediated water solvent reactions are very useful
both from economical and environmental points of view.
J. Org. Chem, Vol. 71, No. 6, 2006 2533

â-Cyclodextrin, apart from being nontoxic is also considered
as metabolically safe.17 In contrast to the existing methods using
many acidic catalysts, this methodology is very simple, high
yielding, and environmentally friendly. Significant improve-
ments offered by this procedure are (i) faster reaction times,
(ii) operationally simple and mild conditions (room temperature),
(iii) excellent yields, (iv) cost efficiency providing recyclability
of the catalyst, and (v) green aspect avoiding hazardous organic
solvents and toxic and expensive reagents. Further potential
applications of this reaction are under study.
followed by trimethylsilyl cyanide (1 mmol) and the mixture
stirred at room temperature until the reaction was complete
(Table 1). The organic material was extracted with ethyl acetate,
dried, and concentrated under reduced pressure, and the resulting
product, though seen as single compound by TLC, was further
purified by passing over a column of silica gel. After extraction
with ethyl acetate, the aqueous phase was lyophilized to get
the CD.
Acknowledgment. K.S., N.S.K., and A.M. thank CSIR, New
Delhi, India, for the award of a research fellowship.
Experimental Section
Supporting Information Available: General information and
experimental data for the compounds described in this work.
This material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure. To â-CD (0.1 mmol) dissolved in water
(10 mL) was added imine (1 mmol) in methanol (1 mL)
(17) Uekama, K.; Hirayama, F.; Irie, T. Chem. ReV. 1998, 98, 2045.
JO052510N
2534 J. Org. Chem., Vol. 71, No. 6, 2006