M. Omote et al. / Tetrahedron Letters 48 (2007) 2989–2991
2991
CH3MgBr (2.2 and 4.4 equiv to the aldehyde, respec-
tively) in toluene stirred for 30 min at room temperature
in advance. After stirring for 30 min at room tempera-
ture, the mixture was chilled to ꢀ78 °C and then a solu-
tion of the aldehyde in toluene was added slowly at
ꢀ78 °C. The reaction mixture was warmed up to
ꢀ30 °C over two hours. In most cases, the reaction com-
pleted within 12 h but every reaction was quenched after
stirring for 24 h. The enantioselectivity was highly af-
fected by the slight change of the reaction temperature
and reactivity of the aldehyde itself. For instance, in case
of aromatic aldehydes substituted with electron-with-
drawing groups, the initial temperature must be kept
at ꢀ78 °C to acquire the best enantioselectivity. In case
of alkylated aromatic aldehydes, the reaction gave the
products of more than 90% ee and in good yield (entries
1 and 2). Anisaldehyde gave 3d with 12% ee in 18%
yield. It is likely that this aldehyde was deactivated by
p-methoxy group, leading to the low yield. Further,
the oxygen atom of the methoxy group might concern
with low ee by its coordination. Extremely high enantio-
selective methylation was attained with aliphatic alde-
hydes. Chemical yields were fairly good, and 3e and 3f
were obtained in both 99% ee. The reaction of haloge-
nated benzaldehyde proceeded in good yields except
for ortho-fluorinated aldehyde 2j. ortho-Chlorinated
one 2i gave high chemical yield, but low ee probably
due to steric hindrance. Ester or ketone groups did not
disturb this reaction, and gave 3k and 3l in good yields
and ee’s.
In conclusion, titanoate complex of 1 prepared by
mixing 1 and Ti(OiPr)4 induced high enantioselective
methylation of aldehyde. In this reaction, (CH3)2Zn
prepared from ZnCl2 and CH3MgBr in a mixing ratio
of 1:2 was effective. This provided the same enantioselec-
tivity as pure (CH3)2Zn but in better chemical yield.
Namely, magnesium salts must have increased the reac-
tivity of 1 without disturbing the asymmetric inductivity.
This methylation was applicable to a variety of alde-
hydes. The detailed study of mechanism is now under
investigation.
References and notes
1. (a) Hope, E. G.; Stuart, A. M.; West, A. J. Green Chem.
2004, 6, 345–350; (b) Yin, Y.; Zhao, G.; Qian, Z.; Yin, W.
J. Fluorine Chem. 2003, 120, 117–120; (c) Cavazzini, M.;
Quici, S.; Pozzi, G. Tetrahedron 2002, 58, 3943–3949; (d)
Nakamura, Y.; Takeuchi, S.; Okumura, K.; Ohgo, Y.;
Curran, D. P. Tetrahedron 2002, 58, 3963–3969; (e) Tian,
Y.; Yang, Q. C.; Mak, T. C. W.; Chan, K. S. Tetrahedron
2002, 58, 3951–3961; (f) Tian, Y.; Chan, K. S. Tetrahedron
Lett. 2000, 41, 8813–8816; (g) Nakamura, Y.; Takeuchi, S.;
Ohgo, Y.; Curran, D. P. Tetrahedron Lett. 2000, 41, 57–
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2. (a) Zhu, D. W. Synthesis 1993, 953–954; (b) Meinert, H.;
Geister, U. J. Fluorine Chem. 1994, 68, 221–226; (c)
Chambers, R. D.; Sandford, G.; Shah, A. Synth. Commun.
1996, 26, 1861–1866; (d) Pozzi, G.; Montanari, F.; Rispens,
M. T. Synth. Commun. 1997, 27, 447–452; (e) Sandford, G.
Tetrahedron 2003, 59, 437–454.
3. (a) Omote, M.; Nishimura, Y.; Sato, K.; Ando, A.;
Kumadaki, I. Tetrahedron 2006, 62, 1886–1894; (b) Omote,
M.; Nishimura, Y.; Sato, K.; Ando, A.; Kumadaki, I. J.
Fluorine Chem. 2006, 127, 74–78; (c) Omote, M.; Nishi-
mura, Y.; Sato, K.; Ando, A.; Kumadaki, I. J. Fluorine
Chem. 2005, 126, 407–409; (d) Omote, M.; Nishimura, Y.;
Sato, K.; Ando, A.; Kumadaki, I. Tetrahedron Lett. 2005,
46, 319–322; (e) Omote, M.; Kominato, A.; Sugawara, M.;
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1991, 30, 99–101; (b) Schmidt, B.; Seebach, D. Angew.
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Tetrahedron: Asymmetry 2003, 14, 439–447; (b) Yus, M.;
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3003–3006; (d) Prieto, O.; Ramon, D.; Yus, M. Tetra-
hedron: Asymmetry 2000, 11, 1629–1644.
For the recovery of 1, fluorous phase separation tech-
nique was applied to this reaction. After the reaction
using aldehyde (0.25 mmol) and l (0.05 mmol), the reac-
tion mixture was quenched with 10% HCl (more than
5 mL), then hexane (3 mL) and perfluorohexane
(5 mL) were added. The resulting mixture was shaken
vigorously for the efficient extraction. After collection
of bottom phase, further 5 mL of perfluorohexane was
added for the next extraction. For the complete recovery
of 1, three times extraction in total were necessary.
Evaporation of the collected perfluorohexane phase
under vacuum gave 1 in 93% recovery and 98% purity.
From the upper organic phase, the product was
obtained by usual work-up. The use of the recovered
ligand without purification gave 1 in 86% yield with
92% ee. We have reported similar seven times recycled
use of 1 on the reaction of diethylzinc,3b and believe 1
can be used for this methylation repeatedly without loss
of any activity.
6. Bussche-Hunnefeld, J. L.; Seebach, D. Tetrahedron 1992,
¨
48, 5719–5730.