rather than the stereochemistry of the cyanoformate that is
primarily responsible for determining the configuration of the
products. Since the (R,R)-enantiomer of catalyst 1 has been shown
to always induce the formation of the (S)-enantiomer of a
cyanohydrin for a wide range of substrates and cyanide sources,
the major diastereomer of compounds 4–5a,b is assumed to have
the (S)-configuration at the newly created stereocentre. In both
cases, a significantly higher diastereomeric ratio was observed
using the combination of catalyst 1 and cyanoformate 3 than was
obtained from catalyst 1 and cyanoformate 2. Thus, the
combination of 1 and 3 is a matched pair whilst 1 and 2 constitute
a mismatched pair. The diastereomeric excesses obtained for the
matched cases were almost identical to the enantiomeric excesses
obtained using ethyl cyanoformate under the same conditions
(cf. Table 1, entry 5 and the last entry in Table 2). Control
experiments demonstrated that in the absence of potassium
cyanide and/or catalyst 1, no reaction occurred between benzalde-
hyde and cyanoformates 2/3, even at room temperature.
Table 5 Potassium cyanide/18-crown-6 induced synthesis of cyano-
hydrin ethyl carbonates
R
Conversion (%)
ee (%)b
Previous ee (%)
95
Ph
100
100
100
100
100
100
100
100
100a
100
100
100a
98
91
97
99
100
97
90
93
100
90
93
91
89
81
78
71
2-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-ClC6H4
4-ClC6H4
PhCHLCH
MeCHLCH
EtCHLCH
MeCHLC(Me)
CH3(CH2)7
Cy
94
98
99
97
94
95
84
79
76
b
100
100
Me3C
a
Reaction required 48 hours to go to completion. ee values were
determined by chiral GC and are accurate to ¡ 4%.
All of the above reactions employing solid potassium cyanide as
a cocatalyst for reactions conducted in dichloromethane were
carried out under heterogeneous reaction conditions. We felt that
if the reaction could be made homogeneous then it might be
possible to further reduce the amount of catalyst 1 and/or decrease
the reaction time. However, an initial reaction carried out at room
temperature using tetrabutylammonium cyanide (5 mol%) in place
of potassium cyanide along with catalyst 1 (2 mol%) and ethyl
cyanoformate (1.2 equivalents) was not encouraging since
although the reaction had gone to completion after 24 hours,
mandelonitrile ethyl carbonate was obtained with just 4% ee.
The 1 : 1 complex 6 formed from potassium cyanide and 18-
crown-6 is also known to be soluble in dichloromethane13,14 and
this reagent did allow the synthesis of cyanohydrin ethyl
carbonates under homogeneous conditions. Thus, in the presence
of just 1 mol% of complex 6 and 1.5 mol% of catalyst 1, a wide
range of aldehydes were converted into the corresponding
cyanohydrin ethyl carbonates3,9,15 in 24 hours at 240 uC as
shown in Table 5. The results in Table 5 indicate that the
enantioselectivities obtained using the potassium cyanide/18-
crown-6 system are comparable with those obtained using
5 mol% of catalyst 1 or 2 mol% of catalyst 1 and 10 mol% of
potassium cyanide.
service at Daresbury and mass spectrometry service at the
University of Wales, Swansea is gratefully acknowledged.
Notes and references
1 For a review of the development and applications of catalyst 1 see:
T. R. J. Achard, L. A. Clutterbuck and M. North, Synlett, 2005, 1828.
2 Y. N. Belokon, S. Caveda-Cepas, B. Green, N. S. Ikonnikov,
V. N. Khrustalev, V. S. Larichev, M. A. Mosckalenko, M. North,
C. Orizu, V. I. Taravov, M. Tasinazzo, G. I. Timofeeva and
L. V. Yashkina, J. Am. Chem. Soc., 1999, 121, 3968.
3 Y. N. Belokon, J. Blacker, L. A. Clutterbuck and M. North, Org. Lett.,
2003, 23, 4505; Y. N. Belokon, J. Blacker, P. Carta, L. A. Clutterbuck
and M. North, Tetrahedron, 2004, 60, 10433.
4 S. Lundgren, E. Wingstrand, M. Penhoat and C. Moberg, J. Am. Chem.
Soc., 2005, 127, 11592.
5 Y. N. Belokon, P. Carta, A. V. Gutnov, V. Maleev, M. A. Moskalenko,
L. V. Yashkina, N. S. Ikonnikov, N. V. Voskoboev, V. N. Khrustalev
and M. North, Helv. Chim. Acta, 2002, 85, 3301.
6 For recent reviews of asymmetric cyanohydrin synthesis see: M. North,
Tetrahedron: Asymmetry, 2003, 14, 147; J.-M. Brunel and I. P. Holmes,
Angew. Chem., Int. Ed., 2004, 43, 2752.
7 Catalyst 1 is being commercialised by Avecia under the trademark
CACHy2: A. J. Blacker and M. North, Chem. Ind., 2005, 12, 22.
8 For other catalysts for the asymmetric synthesis of cyanohydrin
carbonates see: S. K. Tian and L. Deng, J. Am. Chem. Soc., 2001,
123, 6195; J. Tian, N. Yamagiwa, S. Matsunaga and M. Shibasaki,
Angew. Chem., Int. Ed., 2002, 41, 3636; J. Casas, A. Baeza,
J. M. Sansano, C. Na´jera and J. M. Saa´, Tetrahedron: Asymmetry,
2003, 14, 197.
9 D. R. Deardorff, C. M. Taniguchi, S. A. Tafti, H. Y. Kim, S. Y. Choi,
K. J. Downey and T. V. Nguyen, J. Org. Chem., 2001, 66, 7191;
D. R. Deardorff, C. M. Taniguchi, A. C. Nelson, A. P. Pace, A. J. Kim,
A. K. Pace, R. A. Jones, S. A. Tafti, C. Nguyen, C. O’Connor, J. Tang
and J. Chen, Tetrahedron: Asymmetry, 2005, 16, 1655.
Reactions carried out using less than 1.5 mol% of catalyst 1, less
than 1 mol% of complex 6, or at temperatures below 240 uC failed
to produce any mandelonitrile ethyl carbonate. Use of 3 mol% of
complex 6 in combination with catalyst 1 (1.0 mol%) did give
mandelonitrile ethyl carbonate, but with just 17% ee, presumably
due to a facile uncatalysed reaction in the presence of higher
concentrations of soluble cyanide.
In conclusion, we have shown that by use of potassium cyanide
(either alone under heterogeneous conditions, or complexed to 18-
crown-6 under homogeneous conditions) as a cocatalyst, the
synthetic utility of the asymmetric addition of cyanoformates to
aldehydes catalyzed by complex 1 can be increased. We have also
demonstrated the first cases of diastereoselective cyanohydrin
synthesis using chiral cyanoformates and shown that the stereo-
chemistry of these reactions is principally controlled by catalyst 1
rather than the cyanoformate.
10 M. North, Comprehensive Organic Functional Group Transformations,
ed. A. R. Katritzky, O. Meth-Cohn, C. W. Rees and G. Pattenden,
Pergamon, Oxford, UK, 1st edn, 1995, vol. 3, ch. 18.
11 M. Scholl, C.-K. Lim and G. C. Fu, J. Org. Chem., 1995, 60, 6229.
12 L. A. Carpino, J. Am. Chem. Soc., 1960, 82, 2725; H. G. Thomas and
H. D. Greyn, Synthesis, 1990, 129.
13 T. Livinghouse, Org. Synth., 1981, 60, 126.
14 For the use of potassium cyanide/18-crown-6 in related chemistry of acyl
silanes see: X. Linghu, D. A. Nicewicz and J. S. Johnson, Org. Lett.,
2002, 4, 2957.
15 J. S. Buck, J. Am. Chem. Soc., 1933, 55, 2593; N. Thasana,
V. Prachyawarakorn, S. Tontoolarug and S. Ruchirawat, Tetrahedron
Lett., 2003, 44, 1019.
The authors thank the EU (Descartes prize research fund) for
financial support. Access to the EPSRC’s chemical database
This journal is ß The Royal Society of Chemistry 2006
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