Indium trifluoride - A Lewis acid catalyst for the addition of TMSCN to aldehydes in water

Article abstract of DOI:10.1055/s-1998-1676

Indium trifluoride promoted chemoselective additions of TMSCN to various aldehydes in water gave the respective cyanohydrins in good yields.

Full text of DOI:10.1055/s-1998-1676

April 1998
SYNLETT
369
Indium Trifluoride - A Lewis Acid Catalyst For The Addition Of TMSCN To Aldehydes In
Water
Teck-Peng Loh,* Kai-Chen Xu, Diana Sook-Chiang Ho and Keng-Yeow Sim
Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260
Fax no.: (65) 779 1691 E-mail: chmlohtp@nus.edu.sg
Received 8 January 1998
Abstract: Indium trifluoride promoted chemoselective additions of
TMSCN to various aldehydes in water gave the respective cyanohydrins
in good yields.
Cyanohydrins are versatile synthetic intermediates bearing two
functional groups which can be easily manipulated into a wide range of
other products such as α-hydroxy aldehydes, α-hydroxy ketones, β-
1
hydroxy amines and α-amino acid derivatives. Accordingly, much
attention has been focused on the development of new, versatile and
practical methods for the synthesis of cyanohydrins including most
2
recently the development of asymmetric version of this reaction.
Among the various methods, the most widely-used synthetic route to
cyanohydrins, discovered by Evans and co-workers involves the
addition of TMSCN, a safe alternative to the highly toxic gaseous HCN,
3
to an aldehyde in organic solvent catalyzed by a Lewis acid.
Nonetheless, efforts to carry out the corresponding reaction in water
poses an important challenge in the area of reaction design. This
communication describes our studies directed towards the development
of a Lewis acid catalyzed addition of TMSCN to aldehydes in water.
In the absence of any Lewis acid, no reaction was observed when
benzaldehyde was treated with TMSCN in water. This result omits the
possibility that TMSCN decomposes in water to generate HCN in-situ.
Similarly, even in the presence of KF or TBAF, we observed no desired
product even stirring the reaction overnight at ambient temperature.
4
However, when a stoichiometric amount of InCl , an established Lewis
3
acid for aqueous reaction was applied, the reaction proceeded with 60%
conversion. In search of a more efficient catalyst, we discovered that
presence of doped acetophenone or cyclopentanone, the cyanohydrins
derived from only benzaldehyde was obtained and unreacted ketones
were recovered (eqs. 1 and 2).
InF , a commercially available and water-stable Lewis acid is a highly
3
effective catalyst for this reaction. After much studies, we found that 30
5
mol% of InF is needed for complete conversion of the reactants.
3
After establishing that InF is the active catalyst involved, reactions
3
5
using various aldehydes were carried out. The results are summarized
in Table 1. In general the reactions were clean and the respective
cyanohydrins were obtained in high yields with total conversion of the
starting materials. Several characteristic features were observed for
these reactions. (1) In all cases, the reactions proceeded smoothly under
extremely mild conditions with both aromatic and aliphatic aldehydes as
well as α,β-unsaturated aldehydes to give the corresponding
Of mechanistic interest is the fact that the reaction of benzaldehyde with
TMSCN in the presence of TBAF (1 equivalent) or KF (1 equiv.) did
not give the desired products. These experiments exclude the possibility
that a fluoride catalyzation process is operative. C NMR studies also
indicated that an in-situ generation of HCN did not occur to afford the
cyanohydrins in high yields. (2) In the reaction of InF -promoted
3
trifluoroacetaldehyde ethyl hemiacetal with TMSCN in water, the
corresponding 1-trifluoromethylated cyanohydrin was obtained as the
product. The possible ethoxy substituted compound was not detected.
(3) Only 1,2-addition product was observed with acrolein.
13
respective cyanohydrins in such favourable yields. In conclusion, this
work demonstrates that the Lewis acid, InF is a highly efficient catalyst
3
for the addition of TMSCN to aldehydes to give cyanohydrins in water.
We next investigated the chemoselectivity of this reaction between
aldehydes and ketones. Interestingly, only aldehydes are preferentially
selected for cyano-addition which is similar to an analogous enzymatic
process. Thus under similar conditions, acetophenone, cyclopentanone,
3-pentanone, methyl vinyl ketone and 2-cyclopetenone did not undergo
reaction with TMSCN. The unreacted ketones can also be easily
recovered. When benzaldehyde was treated with TMSCN in the
Acknowledgement. This work was supported by the National
University of Singapore (Research Grant No RP 940633 and RP
930657).

370
LETTERS
SYNLETT
References
J. Org. Chem., 1993, 58, 1515. (g) Chakraborty, T. K.; Reddy, G.
V.; Hussain, K. A. Tetrahedron Lett., 1991, 32, 7597. (h) Reetz,
M. T.; Kesseler, K.; Jung, A. Angew. Chem. Int. Ed. Engl., 1985,
24, 989.
1.
(a) Matthews, B. R.; Gountzos, H.; Jackson, W. R.; Watson, K. G.
Tetrahedron Lett., 1989, 30, 5157. (b) Jackson, W. R.; Jacobs, H.
A.; Jayatilake, G. S.; Matthews, B. R.; Watson, K. G. Aust. J.
Chem., 1990, 43, 2045. (c) Jackson, W. R.; Jacobs, H. A.;
Matthews, B. R.; Jayatilake, G. S.; Watson, K. G. Tetrahedron
Lett., 1990, 31, 1447. (d) Ziegler, T.; Horsch, B.; Effenberger, F.
Synthesis, 1990, 575. (e) Effenberger, F.; Stelzer,U. Angew.
Chem. Int. Ed. Engl., 1991, 30, 873. (f) Zandbergen, P.; Brussee,
J.; Van der Gen, A.; Kruse, C. G. Tetrahedron Asy., 1992, 3, 769.
(g) Synthesis of pharmaceutical: Watson, K. G.; Fung, Y. M.;
Gredley, M.; Bird, G. J.; Watson, W. R.; Gountzos, H.; Matthews,
B. R. J. Chem. Soc. Chem. Commun., 1990, 1018. (h) For a recent
review: North, M. Synlett, 1993, 807 and references therein.
3.
4.
(a) Evans, D. A.; Hoffman, J. M.; Truesdale, L. K. J. Am. Chem.
Soc., 1973, 95, 5822. (b) Evans, D. A.; Carroll, G. L.; Truesdale,
L. K. J. Org. Chem., 1974, 39, 914.
For applications of InCl in aqueous media: (a) Loh, T.-P.; Pei, J.;
3
Cao, G.-Q. J. Chem. Soc. Chem. Commun., 1996, 1819. (b) Loh,
T.-P.; Pei, J.; Lin, M. J. Chem. Soc. Chem. Commun., 1996, 2315.
(c) Li, X.-R.; Loh, T.-P.Tetrahedron Asy., 1996, 7, 1535. (d) Loh,
T.-P.; Li, X.-R. J. Chem. Soc. Chem. Commun., 1996, 1929.
(e) Loh, T.-P.; Li, X.-R. Angew. Chem. Int. Ed. Engl.,1997, 36,
980.
2.
(a) Corey, E. J.; Wang, Z. Tetrahedron Lett., 1993, 34, 4001.
(b) Narasaka, K.; Yamada, T.; Minamikawa, H. Chem. Lett.,
1987, 2073. (c) Minamikawa, H.; Hayakawa, S.; Yamada, T.;
Iwasawa, N.; Narasaka, K. Bull. Chem. Soc. Jpn., 1988, 61, 4379.
(d) Tsuboyama, S. Bull. Chem. Soc. Jpn., 1962, 35, 1004. (e) Kim,
H. J.; Jackson, W. R. Tetrahedron Asy., 1992, 3, 1421. (f) Nitta,
H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am. Chem. Soc. 1992,
114, 7969. (f) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N.
5.
The general procedure for InF catalysed addition of TMSCN to
3
aldehyde is as follows: To a mixture of aldehyde (0.5 mmol, 1 eq.)
and InF (0.3 eq) in water (3 mL) was added TMSCN (2 eq.). The
3
reaction mixture was stirred vigorously overnight at room
temperature. After usual extraction workup, the respective
cyanohydrins were isolated. From our experience, vigorous
stirring is very important for these organic reactions in water.