LETTER
Molecular Iodine-Catalyzed Imine Activation
1327
We also investigated the iodine catalyst in a Strecker-type
reaction of imine and cyanide for the production of a-ami-
no nitriles. This reaction, followed by hydrolysis of the ni-
trile to a carboxylic acid, is one of the more widely used
synthetic routes to a-amino acids.1b When trimethylsilyl
cyanide was used as a nucleophile instead of silyl enol
ether under the same reaction conditions as used for b-
amino ketone synthesis (aldehyde and aniline), the corre-
sponding a-amino nitriles were obtained in excellent
yields (Table 3). Similar to b-amino ketone synthesis, no
reaction took place with aliphatic amines or aldehydes
(entry 5–8).
Acknowledgment
We gratefully acknowledge financial support from The Skaggs
Institute for Chemical Biology and The Scripps Research Institute,
and Jason Moss for critical reading of the manuscript.
References
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H. Chem. Rev. 2003, 103, 2795. (c) Kobayashi, S.; Ishitani,
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(2) (a) Weinreb, S. M. Comprehensive Organic Synthesis, Vol.
5; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
401. (b) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic: San Diego,
1987, Chap. 2. (c) Boger, D. L.; Weinreb, S. M. Hetero
Diels–Alder Methodology in Organic Synthesis; Academic:
San Diego, 1987, Chap. 9.
Table 3 Iodine-Catalyzed Three-Component a-Amino Nitrile
Synthesis7,a
R2
I2 (2 mol%)
NH
R1-CHO
R2-NH2
+
+
TMSCN
(3) (a) Ojima, I.; Inaba, S.-I.; Yoshida, K. Tetrahedron Lett.
1977, 18, 3643. (b) Veenstra, S. J.; Schmid, P. Tetrahedron
Lett. 1997, 38, 997.
MeOH
r.t.
R1
CN
(4) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L.
Chem. Rev. 2002, 102, 2227.
Entry
R1
Ph
R2
Time (min) Yield (%)b
1
2
3
4
5
6
7
8
Ph
90
90
97
97
97
98
0
(5) (a) Bhosale, R. S.; Bhosale, S. V.; Bhosale, S. V.; Wang, T.;
Zubaidha, P. K. Tetrahedron Lett. 2004, 45, 7187.
(b) Phukan, P. J. Org. Chem. 2004, 69, 4005. (c) Yadav, J.
S.; Reddy, B. V. S.; Rao, K. V.; Raj, K. S.; Rao, P. P.;
Prasada, A. R.; Gunasekar, D. Tetrahedron Lett. 2004, 45,
6505. (d) Bandgar, B. P.; Bettigeri, S. V.; Joshi, N. S. Synth.
Commun. 2004, 34, 1447. (e) Phukan, P. Synth. Commun.
2004, 34, 1065. (f) Karimi, B.; Golshani, B. Synthesis 2002,
784. (g) He, Z.; Gao, G.; Hand, E. S.; Kispert, L. D.; Strand,
A.; Liaaen-Jensen, S. J. Phys. Chem. A 2002, 106, 2520.
(h) Xu, X.; Zhang, Y. Synth. Commun. 2002, 32, 2643.
(i) Basu, M. K.; Samajdar, S.; Becker, F. F.; Banik, B. K.
Synlett 2002, 319. (j) Yadav, J. S.; Reddy, B. V. S.; Rao, C.
V.; Rao, K. V. J. Chem. Soc., Perkin Trans. 1 2002, 1401.
(k) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
Tetrahedron Lett. 2002, 43, 879. (l) Yadav, J. S.; Chand, P.
K.; Anjaneyulu, S. Tetrahedron Lett. 2002, 43, 3783.
(m) Periana, R. A.; Mirinov, O.; Taube, D. J.; Gamble, S.
Chem. Commun. 2002, 20, 2376. (n) Firouzabadi, H.;
Iranpoor, N.; Sobhani, S. Tetrahedron Lett. 2002, 43, 3653.
(6) Lee, B. S.; Mahajan, S.; Janda, K. D. Tetrahedron Lett.
2005, 46, 807.
1-Naphthyl
Ph
4-Methoxy-Ph
4-Cyano-Ph
Ph
Ph
30
Ph
60
Bn
n-Bu
Ph
180
180
180
180
Ph
0
Cyclohexyl
Cyclohexyl
0
Bn
0
a All reactions were carried out using aldehyde (1.0 mmol), aniline
(1.1 mmol) and trimethylsilyl cyanide (1.2 mmol).
b Isolated yield.
In conclusion, catalytic amounts of iodine were shown to
effectively activate imine compounds to undergo Man-
nich and Strecker-type reactions under neutral conditions.
Reactants and amine products did not interfere with the
catalytic activity of iodine. We note that the reaction se-
quence has limitations as it only functions with aromatic
aldehydes and amines. The use of iodine as a catalyst in
these reactions is preferred to rare earth metal catalysts
and typical Lewis acids, because iodine is not only inex-
pensive but also less sensitive to moisture.
(7) Typical Procedure for b-Amino Ketone and a-Amino
Nitrile Synthesis.
To a MeOH solution (10 mL) was added aldehyde (1.0
mmol), aniline (1.1 mmol) and nucleophile (1.2 mmol, silyl
enol ether for b-amino ketone or trimethylsilyl cyanide for a-
amino nitrile). Upon completion of the reaction (monitored
by TLC), aq Na2SO3 (1 mL) and H2O (100 mL) were added.
The organic compounds were extracted with EtOAc (3 × 20
mL) from the aqueous solution and the combined extract was
dried over Na2SO4. The solvent was evaporated under
reduced pressure. The residue was purified by flash
chromatography on silica gel to afford pure product,
characterized by 1H NMR, 13C NMR and mass spectrometry.
Since iodine provides an easy method for imine activa-
tion, we expect that the use of catalytic molecular iodine
can be extended to other reactions requiring imine activa-
tion.
Synlett 2005, No. 8, 1325–1327 © Thieme Stuttgart · New York