source, modest chemical yield and enantioselectivity were observed
(Table 3, compound 4g).
Table 2 Effect of the solvent on the addition of TMSCN to PhCHO
catalysed by the complex formed between 1 and 2
In summary, we have demonstrated the effectiveness of the use
of a new chiral lanthanide complex as chiral Lewis acid in the
enantioselective addition of TMSCN to aldehydes. The present
methodology shows the first example that uses a europium
dithiocarbamate complex as a precursor for a lanthanide chiral
catalyst. Furthermore, the reaction was characterized by high
enantioselectivities in some cases, low catalyst loading (10 mol%),
reasonable tolerance to certain aldehydes and short reaction times.
Studies on the mechanism of this reaction as well as the synthesis
of other chiral ligands for further applications are currently in
progress.
Solvent
Timea/h
Yield (%)
Eeb (%)
CH3CN
CH2Cl2
THF
3.0
3.5
3.5
4.0
85
86
80
79
85
74
72.5
64,5c
PhCH3
Conditions: Catalyst 1 (10 mol%) and 2 (30 mol%), ratio 1 : 3,
PhCHO : TMSCN (1 : 1.3). The time for complete conversion of
a
b
PhCHO was determined by TLC. Determined by conversion to the
derived MTPA ester as monitored by 19F NMR spectroscopy. Not
a homogeneous mixture.
c
As can be seen in Table 1 using the ratio 1 : 2 has a substantial
influence on the enantioselectivity of the obtained product. The
optimum ratio was found to be 1 : 3 (Table 1, entry 3). This
stoichiometry dependence suggests that the formation of a
significant amount of 1 : 3 complex is required to maximize the
enantiomeric excess. In the absence of 1, no reaction was observed
and in the absence of the protected amino acid the reaction
proceeded over 5 h at room temperature to give the racemic
cyanohydrin in 75% isolated yield.
We gratefully acknowledge the financial support from CNPq,
CNPq/PROFIX (54045/01-4), IMMC-CNPq, FACEPE and
CAPES. The authors also thank Professors J. V. Comasseto
(USP, Sa˜o Paulo) and A. L. M. Porto (USP, Sa˜o Carlos).
Notes and references
{ Representative procedure: N-tosylated L-phenylalanine 2 (12.24 mg,
0.0384 mmol) was added to a solution of europium diethyldithiocarbamate
complex 1 (10 mg, 0.0128 mmol) in acetonitrile (3 mL) under argon at
room temperature. The mixture was then stirred for 10 min and the solvent
was removed under reduced pressure for withdrawal of dithiocarbamic acid
until a dry residue was obtained. The residue was redissolved in acetonitrile
(3 mL) and cooled to 0 uC. Benzaldehyde (13 mL, 0.128 mmol) was then
added followed by TMSCN (19 mL, 0.152 mmol) and the resulting solution
was stirred at room temperature for 3 h before quenching with 1 M HCl
(10 mL). The mixture was diluted with dichloromethane (15 mL) and the
organic phase was isolated, dried over anhydrous magnesium sulfate and
concentrated in vacuo. Purification by flash chromatography on silica gel
(30% EtOAc–n-hexane) to yield 14.5 mg (85%) of the desired compound.
Next, the influence of the solvent in the addition of TMSCN to
PhCHO was investigated. The results are shown in Table 2.
We found that the use of acetonitrile as a solvent at room
temperature brought about the best results. These conditions were
subsequently applied to all other substrates in this study. The
results are summarized on Table 3.
As shown in Table 3, the methodology gave the desired
cyanohydrins in good yields and in ee’s in all cases.
The electronic effects of the aldehyde were briefly studied. All
substituted aldehydes proved to have similar reactivities, except for
4-bromobenzaldehyde, giving the desired products in good yields
and high ee’s (Table 3, compounds 4a–f). Similar reactivities were
observed for both ortho- and para-substituted aldehydes (Table 3,
compounds 4c and 4d). When n-heptanal was used as the aldehyde
1 (a) R. J. H. Gregory, Chem. Rev., 1999, 99, 3649; (b) M. North,
Tetrahedron: Asymmetry, 2003, 14, 147.
2 (a) F. Effenberger, B. Ho¨rsch, F. Weingart, T. Ziegler and S. Ku¨hner,
Tetrahedron Lett., 1991, 32, 2605; (b) F. Effenberger and S. Heid,
Tetrahedron: Asymmetry, 1995, 6, 2945.
3 L. R. Krepski, K. M. Jensen, S. M. Heilmann and J. K. Rasmussen,
Synthesis, 1986, 301.
4 P. Zandbergen, J. Brussee, A. Vandergen and C. G. Kruse, Tetrahedron:
Asymmetry, 1992, 3, 769.
Table 3
5 (a) T. Ziegler, B. Ho¨rsch and F. Effenberger, Synthesis, 1990, 575; (b)
K. Tanaka, A. Mori and S. Inoue, J. Org. Chem., 1990, 55, 181; (c)
L. T. Kanerva, Acta Chem. Scand., 1996, 50, 234.
6 (a) H. Griengl, A. Hickel, D. V. Johnson, C. Kratky, M. Schmidt and
H. Schwab, Chem. Commun., 1997, 1933; (b) F. Effenberger, Chimia,
1999, 53, 3; (c) M. Schmidt and H. Griengl, Top. Curr. Chem., 1999,
200, 193; (d) G. Seoane, Curr. Org. Chem., 2000, 4, 283.
7 (a) J.-I. Oku and S. Inoue, J. Chem. Soc., Chem. Commun., 1981, 229;
(b) A. Mori, Y. Ikeda, K. Kinoshita and S. Inoue, Chem. Lett., 1989,
2119.
Compound R1
Timea/h Yield (%) Eeb (%) (confgn.)c
8 (a) C. Bolm, P. Muller and K. Harms, Acta Chem. Scand., 1996, 50,
305; (b) C. Bolm and P. Muller, Tetrahedron Lett., 1995, 36, 1625; (c)
W. Pan, X. Feng, L. Gong, W. Hu, Z. Li, A. Mi and Y. Jiang, Synlett,
1996, 337; (d) Y. Belokon, M. Flego, N. Ikonnikov, M. Moscalenko,
M. North, C. Orizu, V. Tararov and M. Tasinazzo, J. Chem. Soc.,
Perkin Trans. 1, 1997, 1293; (e) V. I. Tararov, D. E. Hibbs,
M. B. Hursthouse, N. S. Ikonnikov, K. M. A. Malik, M. North,
C. Orizu and Y. N. Belokon’, Chem. Commun., 1998, 387; (f)
S. Kobayashi, Y. Tsuchiya and T. Mukaiyama, Chem. Lett., 1991,
541; (g) I. Iovel, Y. Popelis, M. Fleisher and E. Lukevics, Tetrahedron:
Asymmetry, 1997, 8, 1279; (h) E. J. Corey and Z. Wang, Tetrahedron
Lett., 1993, 34, 4001.
4a
4b
4c
4d
4e
4f
C6H5
Naphthyl
4-NO2C6H4 1.0
2-NO2C6H4 1.0
4-EtOC6H4
4-BrC6H4
n-C6H13
3.0
3.0
85
87
93
90
89
45
60
85 (S)
85 (S)
99 (S)
99 (S)
89 (S)
44 (S)
30 (S)
3.5
12.0
7.0
4g
Conditions: Catalyst 1 (10 mol%) and 2 (30 mol%), PhCHO :
TMSCN (1 : 1.3). The time for complete conversion of RCHO was
a
b
determined by TLC. Determined by conversion of the obtained
cyanohydrin into the corresponding MTPA ester which was
9 (a) S.-K. Tian and L. Deng, J. Am. Chem. Soc., 2001, 123, 6195; (b)
S.-K. Tian, R. Hong and L. Deng, J. Am. Chem. Soc., 2003, 125, 9900;
(c) S.-K. Tian, Y. Chen, J. Hang, L. Tang, P. Mcdaid and L. Deng, Acc.
Chem. Res., 2004, 37, 621.
monitored by 19F NMR spectroscopy. Configuration assigned by
comparison to the literature values of optical rotations.
c
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