Enantioselective silylcyanation of aldehydes and ketones by a titanium catalyst prepared from a partially hydrolyzed titanium alkoxide and a Schiff base ligand

Article abstract of DOI:10.1002/adsc.200900207

In the presence of small amount (0.2-1.0 mol%) of a titanium complex catalyst prepared from a partially hydrolyzed titanium alkoxide and an optically active tridentate Schiff base ligand, the enantioselective silylcyanation of aldehydes and ketones procee

Full text of DOI:10.1002/adsc.200900207

COMMUNICATIONS
DOI: 10.1002/adsc.200900207
Enantioselective Silylcyanation of Aldehydes and Ketones by a
Titanium Catalyst Prepared from a Partially Hydrolyzed Titanium
Alkoxide and a Schiff Base Ligand
Kazuhiko Yoshinagaa,* and Takushi Nagataa
a
Mitsui Chemicals Asia Pacific Technical Centre, Mitsui Chemicals Asia Pacific, Ltd., 1 Pesek Road, Jurong Island,
Singapore 62783, Singapore
Fax : (+65)-6515-4308; e-mail: Kazuhiko.Yoshinaga@mitsui-chem.co.jp
Received: March 31, 2009; Published online: June 24, 2009
Dedicated to the late Ms. Haruna Teraoka.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900207.
Abstract: In the presence of small amount (0.2–1.0
mol%) of a titanium complex catalyst prepared
from a partially hydrolyzed titanium alkoxide and
an optically active tridentate Schiff base ligand, the
enantioselective silylcyanation of aldehydes and ke-
tones proceeded in a short reaction time at room
temperature to afford the corresponding optically
active cyanohydrin derivatives in excellent chemical
yield with high enantiomeric excess (86–97% ee).
The results indicate that partially hydrolyzed titani-
um alkoxides are a promising titanium source for
the preparation of efficient catalysts for asymmetric
synthesis.
tion.[4] However, the enantioselective silylcyanation of
a broad range of substrates including aliphatic alde-
hydes and ketones with low catalyst loading under
mild reaction conditions is still a challenge. Herein,
we would like to describe a simple and practical
method for the enantioselective silylcyanation of alde-
hydes and ketones using a novel titanium catalyst pre-
pared from a partially hydrolyzed titanium alkoxide
as a Lewis acidic metal compound and an optically
active tridentate Schiff base ligand. The titanium cata-
lyst afforded the corresponding cyanohydrin deriva-
tives in excellent chemical yield with high enantio-
meric excess at room temperature.
The novel titanium catalyst (S)-3 was prepared
from pre-catalyst 2, TiACTHUNGTERNU(NG O-n-Bu)4 hydrolyzed with 1.0
Keywords: asymmetric catalysis; cyanohydrins;
Schiff bases; titanium; water
equivalent of water, and chiral Schiff base (S)-1
(Scheme 1). In the presence of 0.2 mol% of the cata-
lyst (S)-3, the reaction of heptanal with trimethylsilyl
cyanide (TMSCN) rapidly proceeded to afford the de-
sired optically active cyanohydrin trimethylsilyl ether
The enantioselective silylcyanation of carbonyl com- quantitatively with 87% ee in 1 hour at room temper-
pounds is one of the most useful carbon-carbon bond- ature (Table 1, entry 5). In contrast, a combined use
forming reactions in organic synthesis for producing of Ti
optically active cyanohydrin derivatives. This is be-
cause these compounds can be converted to a variety
of chiral building blocks such as optically active a-hy-
droxy carboxylic acids and a-amino alcohols.[1] After
the pioneering work by Hayashi and Oguni on the
catalytic enantioselective silylcyanation of aldehydes
using an optically active Schiff base ligand with
ACHTUNGTRNEUN(NG O-n-Bu)4 and the ligand (S)-1 under strictly an-
TiACHTUNGTRENNUNG a
(O-i-Pr)4 as a Lewis acidic metal compound,[2]
wide variety of chiral molecular catalysts have been
developed.[3] Additionally, because of the importance
of the enantioselective construction of quaternary ste-
reocenters, the catalytic asymmetric silylcyanation of
Scheme 1. Preparation of catalyst 3 from pre-catalyst 2, a
partially hydrolyzed titanium alkoxide, and optically active
prochiral ketones has attracted considerable atten- tridentate Schiff base ligand (S)-1.
Adv. Synth. Catal. 2009, 351, 1495 – 1498
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1495

Kazuhiko Yoshinaga and Takushi Nagata
COMMUNICATIONS
the ligand was less effective.[6] The structure of pre-
catalyst 2 is unclear at the present, however, we
assume it to be composed of a titanium oxo-alkoxide,
Table 1. Asymmetric silylcyanation of heptanal catalyzed by
titanium catalyst (S)-3.[a]
[7,8]
À À
an oligomer including a Ti O Ti structure,
gener-
ated from the hydrolysis of titanium alkoxides.[9] The
oligomeric structure may be maintained in catalyst
(S)-3 since a positive non-linear effect (NLE) be-
tween enantiomeric excesses (ees) of the ligand and
ees of the product was observed for the reaction of
heptanal with TMSCN in the presence of catalyst (S)-
3.[10,11]
Entry
Titanium
alkoxide
H2O/Ti
[mol/mol]
Conv.[b]
[%]
ee[c]
[%]
N
1
2
3
4
5
6
7
8
Ti
Ti
Ti
Ti
Ti
Ti
Ti
Ti
Ti
Ti
Ti
Ti
N
–
43
70
<5
28
85
85
87
87
86
83
<5
87
0.5
0.75
0.85
1.0
1.1
1.2
1.3
1.5
1.0
1.0
1.0
Recently, several effective catalysts containing a
metal-O-metal structure have been reported for enan-
tioselective silylcyanation.[3e,s,4a,c,d] In previous reports,
multi-metallic activation systems, in which both CN
and C=O are activated by two metal centers simulta-
neously, have been proposed to explain the high per-
formance of the catalysts. We assume that cyanation
using our catalyst system would proceed via a similar
multi-metallic activation pathway.[12]
>99
>99
>99
>99
99
70
10
>99
>99
<5
9
10
11
12
88
<5
The novel catalyst for the enantioselective silylcya-
nation was successfully applied to various aldehydes
(Table 2). The silylcyanation of benzaldehyde pro-
ceeded quantitatively with 89% ee (entry 1). Substi-
tuted benzaldehydes were also transformed into the
corresponding cyanohydrin silyl ethers in good yield
[a]
The reactions were performed with TMSCN (1.5 equiv.)
in the presence of (S)-3 prepared from (S)-1 (0.2 mol%)
and Ti(OR)4 (0.2 mol%) under a nitrogen atmosphere.
Determined by GC analysis.
Determined by GC analysis. The absolute configuration
was determined as (S) by comparison of the sign of opti-
cal rotation with literature data. See the Supporting In-
formation.
[b]
[c]
Table 2. Enantioselective silylcyanation of aldehydes and ke-
tones catalyzed by catalyst (S)-3.[a]
hydrous conditions gave a racemic product for the re-
action with low efficiency (Table 1, entry 1). We inves-
tigated the effect of water for the preparation of the
pre-catalyst 2 on the asymmetric silylcyanation of
heptanal as a model substrate with TMSCN (Table 1,
entries 2–9). It should be noted that the ratio of water
to titanium is crucial to achieve high enantioselectivi-
ty and efficiency. The results clearly show the suitable
ratio of water to titanium is approximately one.[5]
Other titanium alkoxides as a titanium source were
Entry R1
R2 Catalyst Time Yield[b] ee[c]
A
[%]
[%]
1[d]
2
3
Ph
H
H
H
H
H
H
H
0.5
0.5
0.5
1.0
0.2
0.2
0.2
2
2
2
2
>99
91
91
89 (S)
89 (S)
92[f]
4-MeO-C6H4
2-F-C6H4
4-CF3-C6H4
n-C6H13
Et2CH
c-C6H11
Ph
c-C6H11
4
86
89[f]
5[d]
6[d]
7
0.33 97
2
1
24
24
86 (S)
97 (S)
97 (S)
88 (S)
90[f]
examined in place of Ti
ACHTUNGTRENNUNG
99
89
96
97
tries 10–12). Ti(OEt)4 and Ti
A
ACHTUNGTRENNUNG
be also efficient titanium sources. The performance of
the catalysts prepared from these titanium alkoxides
8[d,e]
9[e]
Me 0.4
Me 0.2
were comparable to those prepared from Ti
Bu)4. However, a combined use of (S)-1 and a hydro-
lyzed product from Ti(O-i-Pr)4 showed poor catalytic
performance under the same reaction conditions be-
ACHTUNGTNER(NUNG O-n-
[a]
Unless noted otherwise, the reactions were performed
T
with TMSCN (1.5 equiv.) in the presence of (S)-3 [(S)-1/
TiACTHNUTRGEN(NUG O-n-Bu)4 =1, H2O/Ti=0.75] under a nitrogen atmos-
phere.
Isolated yield.
cause hydrolysis of Ti
white precipitate.
ACHTUNGRTEN(NUNG O-i-Pr)4 afforded an insoluble
[b]
[c]
Determined by GC analysis. The absolute configurations
were determined by comparison of the sign of optical ro-
tation with literature data. See the Supporting Informa-
tion.
H2O/Ti=1.1.
(S)-1 (0.2 mol%), Ti
Bu)4 =0.5].
Pre-catalyst 2, partially hydrolyzed titanium alkox-
ide, is a key component for the preparation of an effi-
cient catalytic system for the enantioselective silylcya-
nation. Water should be added to the titanium alkox-
ide before addition of the ligand (S)-1 in order to
achieve high selectivity and efficiency. The addition of
[d]
[e]
ACHUTNGTREN(NUG O-n-Bu)4 (0.4 mol%) [(S)-1/TiACHTUNGTRENNUNG(O-n-
[f]
water to the combined mixture of Ti
N
The absolute configurations were not determined.
1496
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1495 – 1498

Enantioselective Silylcyanation of Aldehydes and Ketones by a Titanium Catalyst
COMMUNICATIONS
hedron: Asymmetry 2003, 14, 147–176; c) J. M. Brunel,
I. P. Holmes, Angew. Chem. 2004, 116, 2810–2837;
Angew. Chem. Int. Ed. 2004, 43, 2752–2778; d) N. H.
Khan, R. I. Kureshy, S. H. R. Abdi, S. Agrawal, R. V.
Jasra, Coord. Chem. Rev. 2008, 252, 593–623; e) M.
North, D. L. Usanov, C. Young, Chem. Rev. 2008, 108
5146–5226.
with good enantiomeric excess (entries 2–4). The sub-
stituent on the benzene ring did not exert a significant
influence on the enantioselectivity of the reaction. In
the case of aliphatic aldehydes, the corresponding cya-
nohydrin silyl ethers were obtained in high yield with
high enantioselectivities. The reaction of heptanal was
completed in 20 min in the presence of 0.2 mol% of
catalyst (S)-3 to give the desired product with 86% ee
(entry 5). Excellent results were obtained for secon-
dary aldehydes such as 2-ethylbutyraldehyde and cy-
clohexanecarbaldehyde (entries 6 and 7).
The catalyst system was also effective for the silyl-
cyanation of aromatic and aliphatic ketones; aceto-
phenone and cyclohexylmethylketone afforded the
corresponding cyanated products in 24 h with 88% ee
and 90% ee, respectively (entries 8 and 9). The cata-
lyst system was applicable for the highly enantioselec-
tive silylcyanation of a wide range of carbonyl com-
pounds.
In summary, we have demonstrated that partially
hydrolyzed titanium alkoxides are a promising titani-
um source for the preparation of an efficient catalyst
for asymmetric synthesis. The reaction in the presence
of catalyst (S)-3 proceeded smoothly to afford prod-
ucts with high enantioselectivity with high efficiency
at room temperature. A detailed study of the titanium
catalyst structure and the scope and limitations of the
substrates is now underway.
[2] a) M. Hayashi, Y. Miyamoto, T. Inoue, N. Oguni, J.
Chem. Soc. Chem. Commun. 1991, 1752–1753; b) M.
Hayashi, Y. Miyamoto, T. Inoue, N. Oguni, J. Org.
Chem. 1993, 58, 1515–1522; c) M. Hayashi, T. Inoue,
Y. Miyamoto, N. Oguni, Tetrahedron 1994, 50, 4385–
4398.
[3] a) A. Abiko, G. q. Wang, J. Org. Chem. 1996, 61, 2264–
2265; b) W. B. Yang, J. M. Fang, J. Org. Chem. 1998,
63, 1356–1359; c) C. D. Hwang, D. R. Hwang, B. J.
Uang, J. Org. Chem. 1998, 63, 6762–6763; d) Y. Hama-
shima, D. Sawada, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 1999, 121, 2641–2642; e) Y. N. Belokon, S.
Caveda-Cepas, B. Green, N. S. Ikonnikov, V. N. Khrus-
talev, V. S. Larichev, M. A. Moscalenko, M. North, C.
Orizu, V. I. Tararov, M. Tasinazzo, G. I. Timofeeva,
L. V. Yashkina, J. Am. Chem. Soc. 1999, 121, 3968–
3973; f) L. Z. Flores-Lopez, M. Parra-Hake, R. Soma-
nathan, P. J. Walsh, Organometallics 2000, 19, 2153–
2160; g) Y. N. Belokon, M. North, T. Parsons, Org. Lett.
2000, 2, 1617–1619; h) J. S. You, H. M. Gau, M. C. K.
Choi, Chem. Commun. 2000, 1963–1964; i) I. P.
Holmes, H. B. Kagan, Tetrahedron Lett. 2000, 41, 7453–
7460; j) I. P. Holmes, H. B. Kagan, Tetrahedron Lett.
2000, 41, 7457–7460; k) S. Liang, X. R. Bu, J. Org.
Chem. 2002, 67, 2702–2704; l) J. Casas, C. Najera, J. M.
Sansano, J. M. Saa, Org. Lett. 2002, 4, 2589–2592;
m) 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, M. North, Helv.
Chim. Acta 2002, 85, 3301–3312; n) S. Lundgren, S.
Lutsenko, C. Jonsson, C. Moberg, Org. Lett. 2003, 5,
3663–3665; o) Y. Li, B. He, B. Qin, X. Feng, G. Zhang,
J. Org. Chem. 2004, 69, 7910–7913; p) D. H. Ryu, E. J.
Corey, J. Am. Chem. Soc. 2004, 126, 8106–8107;
q) H. C. Aspinall, J. F. Bickley, N. Greeves, P. M. Smith,
Organometallics 2005, 24, 3458–3467; r) M. Hatano, T.
Ikeno, T. Miyamoto, K. Ishihara, J. Am. Chem. Soc.
2005, 127, 10776–10777; s) Y. N. Belokon, V. I. Maleev,
M. North, D. L. Usanov, Chem. Commun. 2006, 4614–
4616; t) B. Zeng, X. Zhou, X. Liu, X. Feng, Tetrahe-
dron 2007, 63, 5129–5136; u) F. Yang, Siping Wei, C.
Chen, P. Xi, L. Yang, J. Lan, H. Gau, J. You, Chem.
Eur. J. 2008, 14, 2223–2231; v) Z. Zeng, G. Zhao, Z.
Zhou, C. Tang, Eur. J. Org. Chem. 2008, 1615–1618;
w) N. Kurono, K. Arai, M. Uemura, T. Ohkuma,
Angew. Chem. 2008, 120, 6745–6748; Angew. Chem.
Int. Ed. 2008, 47, 6643–6646.
Experimental Section
Typical Experimental Procedure
An optically active Schiff-base ligand (S)-1 was synthesized
according to the reported method.[2b] Ti
ACHTNUTRGNE(NUG O-n-Bu)4 was hy-
drolyzed with wet dichloromethane containing 1.0 equiv. of
water per titanium at room temperature. A solution of cata-
lyst (S)-3 was prepared from a solution of ligand (S)-1 and
the partially hydrolyzed titanium n-butoxide [the molar
ratio of ligand (S)-1/Ti=1/1]. Asymmetric silylcyanation
was carried out using 0.2–1.0 mol% of the catalyst (S)-3 and
TMSCN (1.5 equiv. to substrates) in anhydrous dichlorome-
thane at 208C.
Acknowledgements
We would like to thank Prof. Tohru Yamada of Keio Univer-
sity for helpful discussions. We are also grateful to Mr. Satoru
Miyazoe, Mr. Masanori Iwazumi, and Dr. Terunori Fujita.
[4] a) Y. N. Belokon, B. Green, N. S. Ikonnikov, M. North,
V. I. Tararov, Tetrahedron Lett. 1999, 40, 8147–8150;
b) Y. Hamashima, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2000, 122, 7412–7413; c) Y. N. Belokon, B.
Green, N. S. Ikonnikov, M. North, T. Parsonsa, V. I.
Tararov, Tetrahedron 2001, 57, 771–779; d) K. Yabu, S.
Masumoto, S. Yamasaki, Y. Hamashima, M. Kanai, W.
Du, D. P. Curran, M. Shibasaki, J. Am. Chem. Soc.
References
[1] For recent reviews on enantioselective synthesis of cya-
nohydrins and their derivatives, see: a) R. J. H. Grego-
ry, Chem. Rev. 1999, 99, 3649–3682; b) M. North, Tetra-
Adv. Synth. Catal. 2009, 351, 1495 – 1498
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1497

Kazuhiko Yoshinaga and Takushi Nagata
COMMUNICATIONS
2001, 123, 9908–9909; e) H. Deng, M. P. Isler, M. L.
Snapper, A. H. Hoveyda, Angew. Chem. 2002, 114,
1051–1054; Angew. Chem. Int. Ed. 2002, 41, 1009–
1012; f) F. Chen, X. Feng, B. Qin, G. Zhang, Y. Jiang,
Org. Lett. 2003, 5, 949–952; g) F.-X. Chen, H. Zhou, X.
Liu, B. Qin, X. Feng, G. Zhang, Y. Jiang, Chem. Eur. J.
2004, 10, 4790–4797; h) Y. Shen, X. Feng, Y. Li, G.
Zhang, Y. Jiang, Eur. J. Org. Chem. 2004, 129–137;
i) B. He, F. X. Chen, Yan Li, X. Feng, G. Zhang, Eur. J.
Org. Chem. 2004, 4657–4666; j) D. H. Ryu, E. J. Corey,
J. Am. Chem. Soc. 2005, 127, 5384–5487; k) D. E.
Fuerst, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127,
8964–8965; l) X. Liu, B. Qin, X. Zhou, B. He, X. Feng,
J. Am. Chem. Soc. 2005, 127, 12224–12225; m) S. J.
Zuend, E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129,
15872–15883.
b) H. Hanawa, D. Uraguchi, S. Konishi, T. Hashimoto,
K. Maruoka, Chem. Eur. J. 2003, 9, 4405–4413; c) T.
Kano, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc.
2005, 127, 11926–11927; d) T. Kano, T. Hashimoto, K.
Maruoka, J. Am. Chem. Soc. 2006, 128, 2174–2175;
e) T. Hashimoto, M. Omote, T. Kano, K. Maruoka,
Org. Lett. 2007, 9, 4805–4808; f) B. Schetter, B.
Ziemer, G. Schnakenburg, R. Mahrwald, J. Org. Chem.
2008, 73, 813–819.
[9] a) V. W. Day, T. A. Eberspacher, W. G. Klemperer,
C. W. Park, F. S. Rosenberg, J. Am. Chem. Soc. 1991,
113, 8190–8192; b) R. Schmid, A. Mosset, J. Galy, J.
Chem. Soc. Dalton Trans. 1991, 1999–2005; c) V. W.
Day, T. A. Eberspacher, W. G. Klemperer, C. W. Park,
J. Am. Chem. Soc. 1993, 115, 8469–8470; d) C. F.
Capana, Y. Chen, V. W. Day, W. G. Klempere, R. A.
Sparks, J. Chem. Soc. Dalton Trans. 1996, 691–702;
e) D. C. Bradley, R. C. Mehrotra, I. P. Rothwell, A.
Singh, Alkoxo and Aryloxo Derivatives of Metals, Aca-
demic Press, New York, 2001.
[10] See the Supporting Information for details.
[11] For recent reviews of NLE see: a) C. Girard, H. B.
Kagan, Angew. Chem. 1998, 110, 3088–3127; Angew.
Chem. Int. Ed. 1998, 37, 2922–2959; b) D. G. Black-
mond, Acc. Chem. Res. 2000, 33, 402–411; c) H. B.
Kagan, Adv. Synth. Catal. 2001, 343, 227; d) H. B.
Kagan, Synlett 2001, 888–899.
[5] In some cases, a small amount of water was an effective
additive for asymmetric reactions using Lewis acid cat-
alysts. For representative examples, see: a) M. Terada,
Y. Matsumoto, Y. Nakamura, K. Mikami, Chem.
Commun. 1997, 281–282; b) M. Terada, Y. Matsumoto,
Y. Nakamura, K. Mikami, Inorg. Chim. Acta 1999, 296,
267–272; c) S. Ribe, P. Wipf, Chem. Commun. 2001,
299–307; d) Y. Yamashita, H. Ishitani, H. Shimizu, S.
Kobayashi, J. Am. Chem. Soc. 2002, 124, 3292–3302;
e) Y. Yamashita, S. Saito, H. Ishitani, S. Kobayashi, J.
Am. Chem. Soc. 2003, 125, 3793–3798; f) N. Yamagiwa,
J. Tian, S. Matsunaga, M Shibasaki, J. Am. Chem. Soc.
2005, 127, 3413–3422.
[12] A monomeric catalyst prepared from TiACTHNURTGNENG(U O-i-Pr)4 and
(S)-1 under strictly anhydrous conditions has been re-
ported by Hayashi and Oguni. The asymmetric induc-
tion of our catalyst was opposite to that of the mono-
meric catalyst; the reaction of benzaldehyde with
TMSCN in the presence of catalyst (S)-3 prepared
from (S)-1 gave (S)-product selectively in our system,
meanwhile Hayashiꢁs method afforded (R)-product
from the same ligand (S)-1, see ref.[2b,2c]
[6] An almost racemic product (<5% ee) was obtained
with low conversion.
[7] Belokon et al. reported asymmetric cyanation in the
presence of a bimetallic titanium complex including a
[3e,3m,3s,4a,4c]
À À
Ti O Ti structure, see refs.
À
[8] For other examples of chiral catalysts a including Ti
À
O Ti structure, see: a) H. Hanawa, T. Hashimoto, K.
Maruoka, J. Am. Chem. Soc. 2003, 125, 1708–1709;
1498
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1495 – 1498