Trimethylsilyl cyanide addition to aldimines and its application in the synthesis of (S)-phenylglycine methyl ester

Article abstract of DOI:10.1016/j.tetlet.2004.11.015

The addition of TMSCN to a variety of arylaldimines (Strecker reaction) in the presence of LiClO₄ or BF₃?Et₂O in acetonitrile has been studied. The reaction provided the addition products in very high yields. The method has been successfully utilized for the synthesis of (S)-phenylglycine methyl ester.

Full text of DOI:10.1016/j.tetlet.2004.11.015

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9565–9567
Trimethylsilyl cyanide addition to aldimines and its application
in the synthesis of (S)-phenylglycine methyl ester
B. A. Bhanu Prasad, Alakesh Bisai and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 16 September 2004; revised 27 October 2004; accepted 2 November 2004
Abstract—The addition of TMSCN to a variety of arylaldimines (Strecker reaction) in the presence of LiClO4 or BF3ÆEt2O in aceto-
nitrile has been studied. The reaction provided the addition products in very high yields. The method has been successfully utilized
for the synthesis of (S)-phenylglycine methyl ester.
Ó 2004 Elsevier Ltd. All rights reserved.
a-Amino acids are of great biological and economical
importance due to their significance in chemistry and
biology.1 Substantial progress has been made towards
the development of efficient methods for the preparation
of these compounds.2 The asymmetric Strecker reaction
is one of the most important methods for the synthesis
of enantiomerically pure a-amino acids.3 A variety of
chiral catalysts has been developed to achieve high
asymmetric induction for addition of cyanide (usually
as TMSCN) to imines.4 Since simple imines are not very
stable, N-benzyl and N-allyl imines or hydrazones have
been used as substrates. However, N-tosyl imines have
not been used as substrates for addition of TMSCN.
The diastereoselective Strecker synthesis involving the
addition of cyanide to chiral imines obtained from alde-
hydes and chiral auxiliaries such as a-methylbenzylam-
ine,5 (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane,6
1-amino-tetra-O-pivaloyl-b-D-galactopyranose,7 a-phen-
ylglycinol,8 sulfinimines9 and (S)-1-amino-2-methoxy-
methylindoline (SAMI)10 have already been investi-
gated. In all these cases, removal of the chiral
auxiliaries needed harsh conditions. However, the use
of (S)-(4-methoxyphenyl)ethylamine derived aldimines
could have a significant role in the diastereoselective
Strecker synthesis where the chiral auxiliary can be eas-
ily removed using ceric ammonium nitrate (CAN) or
DDQ under mild conditions. To the best of our know-
ledge this has not been reported in the literature. In this
letter, we report that the addition of TMSCN to N-
tosylaldimines is catalyzed by LiClO4 or BF3ÆEt2O.
We further report that (S)-1-(4-methoxyphenyl)ethyl-
amine is an excellent chiral auxiliary for asymmetric
Strecker synthesis.
N-Tosyl phenylaldimine was treated with TMSCN
(1.1mmol) in the presence of 10mol% of LiClO4 or
BF3ÆOEt2 in acetonitrile (5mL) at room temperature.
After completion of the reaction (checked by TLC),
aqueous NaHCO3 solution (1mL) was added. Work-
up and purification over silica gel gave the correspond-
ing a-aminonitrile in high yield (Table 1, entry 1). In
order to evaluate the scope and limitations of this
method, the reaction was extended to a wide variety of
N-tosyl arylaldimines, N-benzyl imines and N-aryl
imines. In all cases, the yields were excellent (Table 1).
The N-tosyl aldimines were synthesized by condensation
of aldehydes and p-toluenesulfonamide in the presence of
a cata- lytic amount of BF3ÆEt2O. In the case of the
imine derived from phenylhydrazine and benzaldehyde,
the addition of TMSCN did not take place.
The utility of the above reaction was demonstrated by
synthesizing a chiral a-amino acid. Chiral imine 1 was
prepared by condensation of (S)-(+)-1-(4-methoxyphen-
yl)ethylamine and benzaldehyde in the presence of anhy-
drous Na2SO4 in MeOH at room temperature for 24h.
Treatment of 1 with TMSCN at room temperature in
the presence of either BF3ÆEt2O or LiClO4 provided a
mixture of diastereomers 2 (major; Rf 0.46 in 10%
EtOAc in petroleum ether) and 3 (minor; Rf 0.40 in
10% EtOAc in petroleum ether) in a ratio of 4:1 and
Keywords: Imines; TMSCN addition; a-Amino acid.
*
Corresponding author. Tel.: +91 512 2597291; fax: +91 512
2597436; e-mail: vinodks@iitk.ac.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.015

9566
B. A. Bhanu Prasad et al. / Tetrahedron Letters 45 (2004) 9565–9567
a
Table 1. Strecker reaction of a variety of aldimines in the presence of LiClO4 or BF3ÆOEt2
NHR
CN
CH3CN, rt
R
LiClO4 or BF3.Et2O
+
TMSCN +
Ar
N
Ar
Entry
Product
BF3ÆEt2O
Time
Yieldb
LiClO4
Entry
Product
BF3ÆEt2O
Time
Yieldb
(h)
LiClO4
Time
(h)
Yieldb
(%)
Time
(h)
Yieldb
(%)
(h)
(%)
(%)
NHTs
CN
NHTs
1
2
8
92
6
6
92
9
4
4
96
2
97
97
Ph
CN
OCH3
NHTs
CN
NHTs
CN
8
8
6
6
6
90
90
85
93
94
9210
96
94
96
4
4
3
MeO
NHTs
CN
OMe NHTs
CN
MeO
3
4
5
6
6
5
5
5
91
86
94
96
11
12
13
14
8
4
95
96
NHTs
CN
NHTs
CN
O
O
Br
NHTs
CN
NHCH2Ph
CN
1298
11
2
10
99
Ph
F
NHTs
CN
F
HN
97
10
97
Ph
CN
F
Cl
NHTs
CN
F
NHPh
CN
7
8
5
5
96
94
5
4
96
94
15
16
4
96
2
4
96
Ph
NHTs
CN
OMe
HN
Ph
1282 1294
F
CN
Cl
a In all cases 10mol% of Lewis acid was used.
b Isolated yields after column chromatography.
in 97% yield (Scheme 1). Since these diastereomers
showed good separation on TLC, they could be sepa-
rated over silica gel by column chromatography. The
major (S,S)-diastereomer 2 was treated with DDQ in
DCM–phosphate buffer or CAN in CH3CN–H2O (4:1)
to remove the chiral auxiliary. Thus, chiral aminonitrile
4 was obtained in 91% yield. This was treated with acidic
methanol to provide (S)-phenylglycine methyl ester as
its HCl salt in 88% yield and with >99% enantiopurity
(Scheme 1).11
In summary, we have developed an efficient method for
the TMSCN addition to aldimines in the presence of
either BF3ÆEt2O or LiClO4. We have further shown the

B. A. Bhanu Prasad et al. / Tetrahedron Letters 45 (2004) 9565–9567
9567
HN
HN
N
LiClO4
+
CH3CN, rt
97%
+
OMe
TMSCN
or
+
CN
OMe
CN
OMe
H
BF3.Et2O
2 (major)
3
1
Ratio = 4 : 1
DDQ, CH2Cl2-Phosphate buffer
(10:1), 5 h, 90%
or
CAN, CH3CN:H2O (4:1), 4 h, rt,
91%
NH2.HCl
NH2
CN
HCl-MeOH
88%
COOMe
[α]D 118 (c 1, H2O)
4
62% (overall yield
starting from 1)
>99 % optical purity
Scheme 1. Synthesis of (S)-phenylglycine methyl ester via the diastereoselective addition of TMSCN to chiral imine 1.
J. Org. Chem. 1999, 64, 120–125; (f) Ma, D.; King, K. Org.
Lett. 2000, 2, 2515–2517.
application of the method in the synthesis of (S)-phenyl-
glycine methyl ester in an efficient manner with high
enantiopurity in an overall yield of 62%.
4. (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
1998, 120, 4901–4902; (b) Vallee, Y.; Chavant, P. Y.;
Byrne, J. J.; Chavarot, M. Tetrahedron: Asymmetry 2001,
12, 1147–1150; (c) Vachal, P.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 10012–10014; (d) Keith, J. M.;
Jacobsen, E. N. Org. Lett. 2004, 6, 153–155.
5. (a) Harada, K.; Okawara, T. J. Org. Chem. 1973, 38, 707–
710; (b) Ojima, I.; Inaba, S. Chem. Lett. 1975, 737–740; (c)
Inaba, T.; Fujita, M.; Ogura, K. J. Org. Chem. 1991, 56,
1274–1279.
Acknowledgements
V.K.S. thanks the Department of Science and Technol-
ogy, India for a research grant. A.B. thanks CSIR, New
Delhi for a junior research fellowship.
6. (a) Weinges, K.; Brune, G.; Droste, H. Liebigs Ann. Chem.
1980, 212–218; (b) Weinges, K.; Brachmann, H.; Stah-
necker, P.; Rodewald, H.; Nixdorf, M.; Irngartinger, H.
Liebigs Ann. Chem. 1985, 566–578.
7. (a) Kunz, H.; Sager, W. Angew. Chem., Int. Ed. 1987, 26,
557–559; (b) Kunz, H.; Sager, W.; Pfrengle, W.; Schan-
zenbach, D. Tetrahedron Lett. 1988, 29, 4397–4400; (c)
Kunz, H.; Pfrengle, W. J. Am. Chem. Soc. 1988, 110, 651–
652.
References and notes
1. (a) Williams, R. M. Synthesis of Optically Active a-Amino
Acids; Pergamon: Oxford, 1989; (b) For a series of papers
on synthesis of a-amino acid, see: Tetrahedron Symposia in
print; OꢀDonnell, M. J., Ed., Tetrahedron 1988, 44, 5253–
5614; (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539–
1650.
2. (a) Harada, K. Nature 1963, 200, 1201; (b) Harada, K.;
Fox, S. W. Naturwissenschaften 1964, 51, 106; (c) Patel, M.
S.; Worsley, M. Can. J. Chem. 1970, 48, 1881–1884; (d)
Weinges, K.; Gries, K.; Stemmle, B.; Schrank, W. Chem.
Ber. 1977, 110, 2098–2113.
3. (a) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai,
M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650–
1652; (b) Fondekar, K. P.; Corey, E. J. Org. Lett. 1999, 1,
157–160; (c) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.;
Lipton, M. J. J. Am. Chem. Soc. 1996, 118, 4910–4911; (d)
Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2000, 39, 1279–1281; (e) Ma, D.; Tian, H.; Zou, G.
8. (a) Chakraborty, T. K.; Reddy, G. V.; Hussain, K. A.
Tetrahedron Lett. 1991, 32, 7597–7600; (b) Chakraborty,
T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51,
9179–9190.
9. (a) Davis, F. A.; Reddy, R. E.; Portonovo, P. S.
Tetrahedron Lett. 1994, 35, 9351–9354; (b) Davis, F. A.;
Portonovo, P. S.; Reddy, R. E.; Chiu, Y. J. Org. Chem.
1996, 61, 440–441.
10. Choi, J. Y.; Kim, Y. H. Tetrahedron Lett. 1996, 37, 7795–
7796.
11. Aldrich Handbook of Fine Chemicals and Laboratory
Equipment; India 2003–2004; p 1452.