K. Iwanami et al. / Tetrahedron Letters 46 (2005) 5881–5883
5883
OH
OCO2Me
CN
NCCO2Me (1.2 equiv.)
CHO
+
Ph
Ph
CN
Ph
DMSO−water (5:1)
rt, 7 h
72%
23%
Scheme 2. Cyanation performed in the presence of water.
1973, 49, 4929; (c) Kobayashi, S.; Tsuchiya, Y.; Mukai-
yama, T. Chem. Lett. 1991, 537; (d) Kobayashi, S.;
Tsuchiya, Y.; Mukaiyama, T. Chem. Lett. 1991, 541; (e)
Golinski, M.; Brock, C. P.; Watt, D. S. J. Org. Chem.
1993, 58, 159; (f) Yang, Y.; Wang, D. Synlett 1997, 1379;
(g) Saravanan, P.; Anand, R. V.; Singh, V. K. Tetrahedron
Lett. 1998, 39, 3823; (h) Bandini, M.; Cozzi, P. G.;
Melchiorre, P.; Umani-Ronchi, A. Tetrahedron Lett. 2001,
42, 3041; (i) Azizi, V.; Saidi, M. R. Phosphorus Sulfur
Silicon Relat. Elem. 2003, 178, 2111; (j) Tian, S.-K.; Hong,
R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900; (k) Zhou,
H.; Chen, F.-X.; Qin, B.; Feng, X.; Zhang, G. Synlett
2004, 1077.
OCO2Me
CN
NCCO2Me (1.2 equiv.)
CHO
Ph
Ph
MS 4A (10 mg)
DMSO (0.5 equiv.)
hexane, rt, 3 h
83%
Scheme 3. Cyanation using 0.5 equiv of DMSO.
DMSO. In contrast, when the reaction was performed
without a dehydrating agent, an alkoxide 4 would be
hydrolyzed to form a free cyanohydrin (Table 1, Runs
1 and 9). When the reaction was performed in
DMSO–water (5:1), the corresponding free cyanohydrin
was produced in 72% yield (Scheme 2). In addition, to
clarify the regeneration of DMSO, we examined the
reaction of 3-phenylpropionaldehyde with methyl
cyanoformate in the presence of 0.5 equiv of DMSO in
hexane. And the expected product was obtained in
83% yield, as shown in Scheme 3.
3. Cyanohydrin esters: Hoffmann, H. M. R.; Ismail, Z. M.;
Hollweg, R.; Zein, A. R. Bull. Chem. Soc. Jpn. 1990, 63,
1807.
4. Cyanohydrin alkyl ether from acetal: Mukaiyama, T.;
Soga, T.; Takenoshita, H. Chem. Lett. 1989, 997.
5. Iwanami, K.; Oriyama, T. Chem. Lett. 2004, 33, 1324.
6. (a) Okimoto, M.; Chiba, T. Synthesis 1996, 1188; (b)
Poirier, D.; Berthiaume, D.; Boivin, R. P. Synlett 1999,
1423; (c) Deardorff, D. R.; Taniguchi, C. M.; Tafti, S. A.;
Kim, H. Y.; Choi, S. Y.; Downey, K. J.; Nguyen, T. V.
J. Org. Chem. 2001, 66, 7191.
In conclusion, we have developed an efficient and conve-
nient method for the synthesis of cyanohydrin carbonate
starting from a variety of aldehydes in DMSO. This
reaction has the following synthetic advantages: (1) in
contrast to the known cyanation of aldehydes using
cyanoformate, the present procedure needs neither a
base nor a metal catalyst, (2) various carbonate types
of a protecting group for the hydroxyl function are
obtained by using the corresponding cyanoformate, (3)
the atom economy is extremely high as almost all of
the reagent is consumed, (4) extremely mild reaction
conditions, and (5) experimental convenience. Further
investigations to broaden the scope and synthetic appli-
cations of this efficient and convenient cyanation are
under way in our laboratory.
7. Scholl, M.; Lim, C.-K.; Fu, G. C. J. Org. Chem. 1995, 60,
6229.
8. (a) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123,
6195; (b) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shiba-
saki, M. Angew. Chem., Int. Ed. 2002, 41, 3636; (c) Casas,
´
´
J.; Baeza, A.; Sansano, J. M.; Najera, C.; Saa, J. M.
Tetrahedron: Asymmetry 2003, 14, 197.
9. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New
York, 1999, p 179.
10. Watahiki, T.; Matsuzaki, M.; Oriyama, T. Green Chem.
2003, 5, 82.
11. Watahiki, T.; Ohba, S.; Oriyama, T. Org. Lett. 2003, 5,
2679.
12. Typical procedure: To a solution of 3-phenylpropional-
dehyde (40.3 mg, 0.30 mmol) in DMSO (2.0 mL) was
added methyl cyanoformate (29 lL, 0.36 mmol) in the
presence of MS 4A (120 mg) under argon atmosphere. The
reaction mixture was stirred for 1 h at room temperature
and quenched with a phosphate buffer (pH 7). The organic
materials were extracted with Et2O and dried over
anhydrous magnesium sulfate. 2-Methoxycarboxy-4-
phenylbutanenitrile (63.4 mg, 96%) was isolated by thin-
layer chromatography on silica gel.
References and notes
1. (a) Gregory, R. J. H. Chem. Rev. 1999, 3649; (b) Brunel,
J.-M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752;
(c) Chen, F.-X.; Feng, X. Synlett 2005, 892.
2. Cyanohydrin silyl ethers: (a) Evans, D. A.; Truesdale, L.
K.; Carroll, G. L. J. Chem. Soc., Chem. Commun. 1973,
55; (b) Evans, D. A.; Truesdale, L. K. Tetrahedron Lett.
13. Childs, M. E.; Weber, W. P. J. Org. Chem. 1976, 41,
3486.