Highly enantioselective cyanosilylation of aldehydes catalyzed by novel β-amino alcohol-titanium complexes

Article abstract of DOI:10.1021/jo0488356

The β-amino alcohol 1b-Ti(Oi-Pr)₄ complex has been shown to catalyze the enantioselective cyanosilylation of aldehydes efficiently. In the presence of 5 mol % of 1b-Ti(Oi-Pr)₄ complex catalyst, the aromatic, conjugated, heteroaromatic, and aliphatic aldehydes were converted to their corresponding trimethylsilyl ethers of cyanohydrins in 90-99% yields with up to 94% ee under mild conditions.

Full text of DOI:10.1021/jo0488356

Highly Enantioselective Cyanosilylation of Aldehydes Catalyzed
by Novel â-Amino Alcohol-Titanium Complexes
Yan Li,† Bin He,† Bo Qin,† Xiaoming Feng,*,† and Guolin Zhang‡
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064, China
xmfeng@scu.edu.cn
Received July 9, 2004
The â-amino alcohol 1b-Ti(Oi-Pr)4 complex has been shown to catalyze the enantioselective
cyanosilylation of aldehydes efficiently. In the presence of 5 mol % of 1b-Ti(Oi-Pr)4 complex catalyst,
the aromatic, conjugated, heteroaromatic, and aliphatic aldehydes were converted to their
corresponding trimethylsilyl ethers of cyanohydrins in 90-99% yields with up to 94% ee under
mild conditions.
The synthesis of optically active cyanohydrins, a type
of versatile reagent in organic synthesis and good precur-
sors to some important insecticides and medicines, via
asymmetric cyanosilylation of aldehydes catalyzed by
metal complexes with chiral auxiliary ligands constitutes
an area of increasing interest.1 A number of synthetic
methods have been reported employing enzymes,2 syn-
thetic peptides,3 and chiral metal complexes. Of chiral
metal complexes reported so far, titanium-based Lewis
acids have attracted the most interest, and the chiral
ligands used include sulfoximines,4 o-hydroxyarylphos-
phine oxide,5 BINOLs,6 TADDOL,7 and others.8 Among
those catalysts reported, the Ti(Oi-Pr)4-Schiff base
system first reported by Oguni and co-workers received
special attention.9 Extensive studies on these systems by
employing a variety of Schiff bases derived from different
chiral amino alcohols or diamine compounds revealed
that the enantioselective cyanosilylation of aldehydes is
highly dependent on the type of Schiff base used.10 In
the meantime, chiral amino alcohol ligands have also
been extensively employed in asymmetric syntheses,
including the enantioselective cyanosilylation of alde-
hydes.11 A family of novel â-amino alcohol ligands can
be easily achieved from these Schiff bases, which have
been successfully used in asymmetric Strecker reac-
tions.12 Due to the similar mechanistic aspects of cy-
anosilylation of imines and aldehydes, the asymmetric
cyanosilylation of aldehydes catalyzed by chiral â-amino
alcohol-Ti(Oi-Pr)4 complexes was investigated. Herein,
we wish to report a full description of the synthesis of
chiral â-amino alcohol ligands derived from some Schiff
bases and the results obtained for the asymmetric
cyanosilylation of aldehydes catalyzed by chiral â-amino
alcohol-Ti(IV) complexes.
* Address correspondence to this author. Fax: +86(28) 85418249.
† College of Chemistry, Sichuan University, China.
‡ Chengdu Institute of Biology, Chinese Academy of Sciences, China.
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Rev. 1999, 99, 3649-3682. (d) North, M. Tetrahedron: Asymmetry 2003,
14, 147-176.
Results and Discussion
The synthetic strategy described in the literature
provides a tremendous pool of various â-amino alcohols
via variation of chiral amine R1 and R2 groups (Scheme
1).12, 13
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10.1021/jo0488356 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/14/2004
7910
J. Org. Chem. 2004, 69, 7910-7913

Cyanosilylation of Aldehydes
TABLE 1. Asymmetric Cyanosilylation of Benzaldehyde
Catalyzed by Lewis Acidsa
SCHEME 1. Chiral Ligands Employed for
Asymmetric Induction
catalyst
loading time yieldb eec
absolute
(%) configuration
entry Lewis acid (mol %)
(h)
(%)
1
2
3
4
AlEt3
10
10
10
10
42
42
42
23
65
44
99
94
11
19
10
85
R
R
R
S
AlEt2Cl
Al(Oi-Pr)3
Ti(Oi-Pr)4
a Reaction was carried out with 1b-Lewis acid (1:1) at -20 °C,
concentration of benzaldehyde ) 0.2 M in CH2Cl2. b Isolated yield
of the corresponding cyanohydrin trimethylsilyl ether. c Deter-
mined by HPLC on a Chiralcel OD column, after being converted
to the corresponding acetate. The absolute configuration was S
by comparison of the reported optical rotation.
Under the same conditions, we examined the steric
effect and the electronic effect based on the different
structures of ligand 1 and other amino alcohol ligands 2
derived from different chiral resources (Table 2). The
results indicated that the enantioselectivity was influ-
enced by the structures of the ligands. The reaction
catalyzed by the titanium(IV) complex of 1b (R1 ) Me,
R2 ) H) gave higher enantioselectivity (85% ee) (entry
2, Table 2). More or less bulky substitutes all led to less
enantioselectivity (entries 1-3, Table 2). Bulky R1, such
as tert-butyl or adamantanyl, is highly detrimental for
both the enantioselectivity and the reactivity (entry 2 vs
entries 3 and 10, Table 2), which is caused by the baffling
interaction between R1 and the O-iPr group in the
transition state (Figure 1). Then, the study of the
electronic effects of substituents on ligands (1d-g)
showed that neither electron-donating nor electron-
withdrawing groups on the para position of the OH group
could increase the enantiomeric excess (entries 4-7,
Table 2). So there was no surprise that the ligands (1h-
j) gave the worse results concerning both the yield and
enantioselectivity (entries 8-10, Table 2). Ligands 2a-c
with only one stereocenter exhibited an inferior ability
of chiral induction compared to 1b with two stereocenters
in this catalytic system (entries 11-13 vs entry 2, Table
2). Therefore, the correct assembly of the substituents
and backbone of (1R,2S)-1,2-diphenylaminoethanol in the
ligands is a key point for high reactivity and enantiose-
lectivity of the asymmetric cyanosilylation of aldehydes.
The study of metal complexes of 1b showed that 1b-
Ti(Oi-Pr)4 was the best catalyst for the cyanosilylation
of benzaldehyde, which gave 85% ee in 10 mol % of
catalyst in CH2Cl2. When 1.0 equiv of 1b was used per
titanium, the highest enantioselectivity was obtained. We
were pleased to find that the 1b-Ti(Oi-Pr)4 (ratio of 1:1)
complex was quite effective for the enantioselectivity and
reactivity of cyanosilylation of benzaldehyde. The condi-
tions of the asymmetric cyanosilylation of benzaldehyde
in the presence of 1b-Ti(Oi-Pr)4 complexes were opti-
mized (entries 14-21, Table 2). A preliminary solvent
study showed that the best result was obtained in CH2-
Cl2 (entry 2, Table 2). Although the similar enantiose-
lectivity also could be found in THF, the yield was
With these new â-amino alcohol ligands in hand, we
took the first trial that complexes of different metals with
1b were used to catalyze the cyanosilylation of benzal-
dehyde at -20 °C with 2 equiv of trimethylsilyl cyanide
(TMSCN) with respect to benzaldehyde as the model
reaction. The results are summarized in Table 1. Ti(O-
iPr)4 gave more promising enantioselectivity than other
Lewis acids (Table 1, entry 4). Ti(O-iPr)4 was thus chosen
to assess the following ligands.
(10) (a) Jiang, Y.; Zhou, X.; Hu, W.; Wu, L.; Mi, A. Tetrahedron:
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1617-1619. (i) Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 2702-
2704. (j) Tararov, V. I.; Hibbs, D. E.; Hursthouse, M. B.; Ikonnikov, N.
S.; Malik, K. M. A.; North, M.; Orizu, C.; Belokon’, Y. N. Chem.
Commun. 1998, 387-388. (k) Belokon, Y. N.; Caveda-Cepas, S.; Green,
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G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968-3973. (l)
Belokon, Y. N.; Green, B.; Ikonnikov, N. S.; Larichev, V. S.; Lokshin,
B. V.; Moscalenko, M. A.; North, M.; Orizu, C.; Peregudov, A. S.;
Timofeeva, G. I. Eur. J. Org. Chem. 2000, 2655-2661. (m) Belokon,
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244-245. (n) Belokon, Y. N.; Carta P.; Gutnov, A. V.; Maleev, V. I.;
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(o) Reference deleted in proof. (p) Holmes, I. P.; Kagan, H. B.
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J. Org. Chem, Vol. 69, No. 23, 2004 7911

Li et al.
TABLE 2. Asymmetric Cyanosilylation of Benzaldehyde Catalyzed by Different Amino Alcohol Ligands and Titanium
Complexes under Various Conditionsa
concn of
benzaldehyde
(mol/L)
tem.
(°C)
yield of
ee of
absolute
configuration
entry
ligand
solvent
5ab (%)
5ac (%)
1
2
1a
1b
1c
1d
1e
1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Et2O
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.5
1.0
0.5
0.5
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
0
99
76
85
3
69
68
61
66
4
S
S
R
S
S
S
S
R
94
3
23
4
88
5
26
6
47
7
1g
1h
1i
62
8
28
9
N.D.d
N.D.d
98
10
11
12
13
14
15
16
17
18
19
20
21
1j
2a
2b
2c
1b
1b
1b
1b
1b
1b
1b
1b
12
10
6
S
R
R
S
S
S
S
S
S
S
S
99
96
95
72
77
83
64
92
81
90
87
76
THF
28
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
83
99
99
98
-40
64
a Reaction was carried out with 10 mol % ligand (1 or 2)-Ti(Oi-Pr)4 (1:1). b Isolated yield of the corresponding cyanohydrin trimethylsilyl
ether. c Determined by HPLC on a Chiralcel OD column, after conversion to the corresponding acetate. d N.D. ) not detected.
TABLE 3. Effect of Varying the Amount of Catalyst
1b/Ti(IV) on the Enantiomeric Excess of 5aa
catalyst
loading (mol %)
time
(h)
yield of
ee of
entry
5ab (%)
5ac (%)
1
2
3
4
20
10
5
20
22
20
44
94
99
98
33
88
92
94
80
FIGURE 1. Effect of R1 and Oi-Pr group in the transition
state.
1
a Reaction was carried out with 1b-Ti(Oi-Pr)4 (1:1) in CH2Cl2
at -20 °C; concentration of benzaldehyde ) 0.2 M. b Isolated yield
of the corresponding cyanohydrin trimethylsilyl ether. c Deter-
mined by HPLC on a Chiralcel OD column, after conversion to
the corresponding acetate. The absolute configuration was S by
comparison of the reported optical rotation.
obviously inferior to that in CH2Cl2 (entry 16 vs entry 2,
Table 2). Further studies indicated that the concentration
of benzaldehyde had an important effect on the enantio-
selectivity. When the concentration of benzaldehyde was
0.5 M, the enantioselectivity increased to 92% ee (entry
18, Table 2). Further increasing the concentration to 1.0
M led to a lower ee value (entry 19, Table 2). The
temperature effect was also obvious. Higher or lower
temperature than -20 °C disadvantaged this reaction
(entries 18, 20, and 21, Table 2).
To obtain the optimal reaction conditions, the effect of
the amount of catalyst on the enantioselectivity and yield
of cyanosilylation of benzaldehyde was studied. The
catalyst loading also dramatically influenced the enan-
tioselectivity and yield. When the amount of catalyst was
5 mol % and the concentration of benzaldehyde was 0.5
M, the optimal enantioselectivity (94% ee) and yield
(98%) were obtained (entry 3, Table 3). Extensive screen-
ing showed the optimized catalytic system as 5 mol % of
1b-Ti(Oi-Pr)4, 0.5 M aldehydes, and 2 equiv of TMSCN,
at -20 °C.
Encouraged by the result obtained for the benzal-
dehyde, in the presence of 5 mol % of 1b-Ti(Oi-Pr)4
complex, the asymmetric cyanosilylation of aromatic,
conjugated, heteroaromatic, and aliphatic aldehydes
proceeded smoothly as well under the optimized reaction
conditions to provide corresponding O-TMS ethers of
cyanohydrins in high yields with moderate to excellent
enantioselectivities (Table 4). Aldehydes with substitu-
ents on the aromatic ring gave similar ee values with
benzaldehyde (entries 1-9, Table 4). However, 2-chlo-
robenzaldehyde only gave 76% ee, probably because of
the steric hindrance of the chlorine atom on the ortho
position (entry 7, Table 4). Besides, 4-cyanobenzaldehyde
7912 J. Org. Chem., Vol. 69, No. 23, 2004

Cyanosilylation of Aldehydes
TABLE 4. Asymmetric Cyanosilylation of Aldehydes
Catalyzed by the 1b/Ti(IV) Complexa
time
(h)
yieldb
(%)
eec
(%)
entry
aldehydes
1
2
benzaldehyde (4a)
22
15
16
14
16
14
15
20
15
20
16
20
16
14
16
16
14
16
99
90
99
98
99
94
99
98
98
93
99
98
98
96
99
99
98
99
94
4-methylbenzaldehyde (4b)
3-methylbenzaldehyde (4c)
4-methoxybenzaldehyde (4d)
3-methoxybenzaldehyde (4e)
4-fluorobenzaldehyde (4f)
2-chlorobenzaldehyde (4g)
3-chlorobenzaldehyde (4h)
4-chlorobenzaldehyde (4i)
4-cyanobenzaldehyde (4j)
1-naphthaldehyde (4k)
2-naphthaldehyde (4l)
93d
88d
93
3
4
5
90d
92d
76d
90d
87d
80
6
FIGURE 2. Proposed working model for asymmetric cyanosi-
lylation of benzaldehyde.
7
8
9
10
11
12
13
14
15
16
17
18
bond, and there remains only one isopropoxy on titanium
instead of two. In this transition state, the Re face of the
carbonyl of benzaldehyde is much more accessible to a
nucleophile than the Si face since the latter is strongly
shielded by the nearby phenyl subunit (Model A, Figure
2). On the other hand, benzaldehyde could not bond Ti-
(IV) by the other aspect of CdO, which is caused by the
large steric hindrance between two phenyl subunits
(Model B, Figure 2). The nucleophile of CN will attack
the highly polarized CdO of benzaldehyde at the carbon
atom from a less stereohindered direction (Re) to give the
product in the (S)-configuration.
In conclusion, the asymmetric cyanosilylation of alde-
hydes has been achieved by the catalysis of 5 mol % of
chiral â-amino alcohol-Ti(Oi-Pr)4 complex giving corre-
sponding O-TMS ethers of cyanohydrins in high yields
(up to 99%) with moderate to excellent enantioselectivi-
ties (up to 94% ee) under the mild reaction conditions.
The results described show that it is feasible for the 1b-
Ti(Oi-Pr)4 complex to efficiently catalyze the cyanosily-
lation of aldehydes with high ee. Further efforts should
be directed to provide a basis for optimization of the
chiral â-amino alcohol structure to enhance both the
enantioselectivity and the catalytic ability.
82
75
2-furaldehyde (4m)
89d
82d
82d
57d
72d
60d
(E)-cinnamaldehyde (4n)
(E)-crotonaldehyde (4o)
n-hexaldehyde (4p)
2-phenylacetaldehyde (4q)
2-methylpropionaldehyde (4r)
a All reactions were carried out with 5 mol % of 1b-Ti(Oi-Pr)4
(1:1), 2 equiv of TMSCN, at 0.5 M in CH2Cl2 at -20 °C. b Isolated
yield of the corresponding cyanohydrin trimethylsilyl ether. c De-
termined by HPLC on a Chiralcel OD column, after conversion to
the corresponding acetate. The absolute configuration was S by
comparison of the reported optical rotation. d Determined by GC
analysis on Chirasil DEX CB.
with a strong electron-withdrawing substituent (CN) also
gave a lower ee value (80%) than benzaldehyde (entry
10, Table 4). This is in agreement with Oguni’s report.9
1-Naphthaldehyde afforded a higher ee value than
2-naphthaldehyde (entries 11 and 12, Table 4). The
reaction of a heteroaromatic aldehyde such as 2-fural-
dehyde took place in high yield with 89% ee (entry 13,
Table 4). R,â-Unsaturated aldehydes gave the same
enantioselectivity (entries 14 and 15, Table 4). Aliphatic
aldehydes can give moderate enantioselectivities from
57% to 72% ee (entries 16-18, Table 3).
As to the reaction pathway, because of the similar
structure of 1b and the Schiff base that Oguni reported,
we consider that 1b was still a tridentate ligand coordi-
nated with Ti(Oi-Pr)4. The only difference is that the
CdN double bond of the ligand was converted to the C-N
single bond. Therefore, this transformation makes the
molecule of 1b more flexible. On the basis of the observed
absolute configuration of the O-TMS ethers of cyanohy-
drins and Oguni’s transition-state model,9a we proposed
a possible asymmetric induction pathway, which is shown
in Figure 2. We suggested that the difference in the chiral
induction effects comes from the formation of the N-Ti
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 20225206, 20390050,
and 20372050), Sichuan University, and the Ministry
of Education, P. R. China (Nos. 01144, 104209, and
others) for financial support.
Supporting Information Available: Experimental pro-
cedure for the asymmetric cyanosilylation of aldehydes, and
the characterization of ligands and products, including 1H and
13C NMR, HRMS data, HPLC and GC conditions, etc. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0488356
J. Org. Chem, Vol. 69, No. 23, 2004 7913