Effective activation of the chiral salen/Ti(OiPr)4 catalyst with achiral phenolic N-oxides as additives in the enantioselective cyanosilylation of ketones

Article abstract of DOI:10.1002/ejoc.200400411

The activation of chiral titanium(IV) complexes with phenolic N-oxides additives has been found to provide an alternative strategy for the asymmetric cyanosilylation of ketones. By using 10 mol % of chiral salen-titanium(IV) complex in combination with 1

Full text of DOI:10.1002/ejoc.200400411

FULL PAPER
Effective Activation of the Chiral Salen/Ti(OiPr)4 Catalyst with Achiral
Phenolic N-Oxides as Additives in the Enantioselective Cyanosilylation of
Ketones
Bin He,[a] Fu-Xue Chen,[a] Yan Li,[a] Xiaoming Feng,*[a,b] and Guolin Zhang[c]
Keywords: Asymmetric catalysis / N-Oxides / Cyanosilylation / Cyanohydrins
The activation of chiral titanium(IV) complexes with phenolic
N-oxides additives has been found to provide an alternative
strategy for the asymmetric cyanosilylation of ketones. By us-
ethers in 58−96% yields with 56−82% ee. Several factors
concerning the reactivity and enantioselectivity have been
discussed. A catalytic cycle based on experimental phenom-
ing 10 mol % of chiral salen−titanium(IV) complex in com- ena and studies has been proposed to explain the origin of
bination with 1 mol % achiral phenolic N-oxide as an addit-
ive, aromatic, aliphatic and heterocyclic ketones have been
converted into the corresponding cyanohydrin trimethylsilyl
this activation and the asymmetric induction.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
anosilylation of both aromatic and aliphatic ketones by
using a recyclable chiral peptide as ligand.[6]
In the mean time, a number of important observations
have been made recently regarding the effect of additives on
asymmetric catalytic reactions.[7] The addition of suitable
achiral additives and co-catalysts, which support the asym-
metric catalyst system, enhances the yield and, surprisingly,
in many cases also enhances the enantioselectivity very ef-
ficiently. Furthermore, chiral N-oxides have been exten-
sively used in asymmetric synthesis, for example, in the al-
lylation of aldehydes,[8] the addition of Et2Zn to alde-
hydes,[9] in the Strecker[10] and aldol reactions[11] and in the
reduction of ketones.[12] However, only a few achiral N-ox-
ides have been used as additives in asymmetric reactions.[13]
Looking back at our group’s research, we have found that
N-oxides play a key role in the activation of TMSCN in the
catalytic asymmetric cyanosilylation of ketones. Initially, we
developed a new catalytic system for the asymmetric cyano-
silylation of ketones that was based on bifunctional ti-
tanium complexes and chiral N-oxides.[14] Recently, we im-
proved this reaction by developing a catalytic double-acti-
vation method (CDAM) in which the salenϪTiIV complex
was used as the Lewis acid and an achiral N-oxide as the
Lewis base to activate the ketones and TMSCN, respec-
tively.[15] Subsequently, by introducing achiral N-oxides as
additives into the catalytic system, we developed an alterna-
tive activation strategy for the asymmetric cyanosilylation
of ketones based on a chiral salenϪTi(OiPr)4 catalyst with
a phenolic N-oxide as the additive.[16]
Optically pure cyanohydrins are important chiral build-
ing blocks for a wide variety of chiral products such as α-
hydroxy acids, α-hydroxy carbonyl compounds, α-hydroxy
amines, α-amino alcohols and α-amino acid derivatives.[1]
Therefore, the catalytic asymmetric addition of cyanide to
carbonyl compounds is currently being studied intensively.
Though there have been some advances in this field,[2] reac-
tions involving ketones remain a great challenge because of
their low reactivity and the difficulty in controlling facial
stereoselectivity in state-of-the-art asymmetric synthetic
methodologies. Much research has been carried out in an
effort to overcome these difficulties. Belokon et al. have re-
ported the Ti-catalyzed cyanosilylation of aromatic ketones
in which a C2-symmetric Schiff base was used as the chiral
ligand.[3] Shibashaki and co-workers have developed a novel
bifunctional catalyst in which a carbohydrate-derived bi-
functional ligand and Ti(OiPr)4 promote the asymmetric
addition of TMSCN to aromatic and aliphatic ketones.[4]
Deng and co-workers have outlined a method for the ad-
dition of cyanide to ketones using cyanoformate and cata-
lytic amounts of cinchona alkaloids.[5] Recently, Snapper
and co-workers reported a new approach to asymmetric cy-
[a]
Key Laboratory of Green Chemistry & Technology (Sichuan
University), Ministry of Education, College of Chemistry,
Sichuan University,
Chengdu 610064, China
Fax: (internat.) ϩ86-28-85418249
E-mail: xmfeng@scu.edu.cn
In this paper we describe the results of studies of the
relationship between catalyst efficiency and the structures
of the ligands and N-oxides, substrate generality and the
reaction mechanism.
[b]
State Key Laboratory of Applied Organic Chemistry,
Lanzhou 730000, China
[c]
Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu 610041, China
Eur. J. Org. Chem. 2004, 4657Ϫ4666
DOI: 10.1002/ejoc.200400411
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4657

B. He, F.-X. Chen, Y. Li, X. Feng, G. Zhang
FULL PAPER
Table 1. Asymmetric cyanosilylation of acetophenone catalyzed by
the 1mϪTi(OiPr)4 complex in the presence of achiral phenolic N-
oxides as additives
Results and Discussion
By contrast to the reactions involving aldehydes, the cy-
anosilylation of ketones remains a great challenge owing to
their low reactivity and greater steric hindrance. Based on
the understanding of the chiral inductive capabilities of
salenϪTiIV complexes in the asymmetric cyanosilylation of
aldehydes,[17] and of the NϪO dipolar activation of
TMSCN, an alternative activation strategy has been devel-
oped in which achiral phenolic N-oxides 3aϪl, 4 and 5 are
introduced as additives to the titanium complexes of ligands
1aϪm and 2 (Scheme 1). In this way, enhanced reactivity
and chiral inductivity were achieved in the enantioselective
addition of TMSCN to ketones.
Entry[a]
Additives
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
72
72
72
96
96
96
96
80
80
96
68
68
96
96
95
90
88
70
73
36
75
88
90
83
93
92
82
50
66
67
66
67
60
69
68
69
68
68
69
70
56
68
10
11
12
3j
3k
3l
4
5
Optimization of the Catalyst: To optimize the catalytic
reactivity and enantioselectivity of the reaction, phenolic N- 13
14
oxides 3aϪl, 4 and 5 were tested as additives to promote
cyanosilylation of acetophenone by using 1mϪTi(OiPr)4 as
[a]
All reactions were carried out at 0 °C under the following con-
ditions: 10 mol % 1mϪTi(OiPr)4 complex, 1 mol % N-oxide, 0.5 
acetophenone in CH2Cl2. [b] Isolated yield. [c] Determined by chiral
GC analysis on Chirasil DEX CB.
the catalyst. The results, shown in Table 1, illustrate that to
some extent the structure of the N-oxides affects the reactiv-
ity and enantioselectivity of the reaction.
In general, the N-oxides with electron-donating substitu-
ents on the aromatic ring were more active than those with
electron-withdrawing substituents (Table 1, Entries 1Ϫ3 had enantioselectivities of 66Ϫ67% ee (Table 1, Entries
and 8Ϫ12 vs. Entries 4, 6 and 7). In terms of the enantiose- 1Ϫ4) and the ortho-substituted N-oxides also had similar
lectivity, of the simplest N-oxides 3aϪl, N-oxide 3e with no enantioselectivities of 68Ϫ70% ee (Table 1, Entries 6Ϫ12).
substituents on the aromatic ring gave the lowest ee value The best result was obtained with 3l (ee ϭ 70%; Table 1,
(Table 1, Entry 5). The N-oxides with only para substituents Entry 12). Further efforts to improve the enantioselectivity
Scheme 1. Chiral Salen ligands and achiral phenolic N-oxides
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Eur. J. Org. Chem. 2004, 4657Ϫ4666

Enantioselective Cyanosilylation of Ketones
FULL PAPER
by modifying the structure of the N-oxides had no effect (Table 4, Entries 1Ϫ5). The best result was obtained when
(Table 1, Entries 13 and 14).
1 mol % of 3l was used (Table 4, Entry 4).
The effect of temperature is shown in Table 2. As the re-
action temperature was lowered from 0 to Ϫ20 °C, the en-
antioselectivity increased from 70% to 81% ee (Table 2, En-
tries 1 and 2). However, further decreases in the reaction
temperature led to a dramatic reduction in reactivity and a
remarkable drop in the enantioselectivity (Table 2, Entries
3 and 4).
Table 4. Effect of the amount of additive N-oxide 3l on the asym-
metric addition of TMSCN to acetophenone
Entry[a] Amount of N-oxide 3l [mol %] Yield [%][b] ee [%][c]
1
2
3
4
5
10
5
2.5
1
0.5
96
94
93
94
81
69
76
79
81
80
Table 2. Effect of temperature on the asymmetric addition of
TMSCN to acetophenone
[a]
All reactions were carried out at Ϫ20 °C under the following
Entry[a]
Temp. [°C]
Time [h]
Yield [%][b]
ee [%][c]
conditions: 10 mol % 1mϪTi(OiPr)4 complex, the indicated
[b]
[c]
amount of 3l, 0.5  acetophenone in CH2Cl2.
Isolated yield.
1
2
3
4
0
Ϫ20
Ϫ40
Ϫ78
68
96
168
168
92
94
23
12
70
81
72
70
Determined by chiral GC analysis on Chirasil DEX CB.
To assess the asymmetric catalytic ability of the ligands
1aϪm and 2, their complexes with Ti(OiPr)4 were used to
catalyze the enantioselective addition of TMSCN to aceto-
phenone. The results indicate that the substituents on the
salicylidene phenolic rings of the ligands play an important
role in determining the enantioselectivity of the reaction.
[a] All reactions were carried out at the indicated temperature under
the following conditions: 10 mol % 1mϪTi(OiPr)4 complex, 1
[b]
[c]
mol % 3l, 0.5  acetophenone in CH2Cl2. Isolated yield. De-
termined by chiral GC analysis on Chirasil DEX CB.
An increase in the catalyst loading had a slight effect on Both electron-withdrawing and electron-donating ligands as
the reactivity and enantioselectivity of the asymmetric cy- well as the unsubstituted ligand decreased the enantioselec-
anosilylation of acetophenone (Table 3, Entries 1Ϫ3). How- tivity considerably (Table 5, Entries 1Ϫ7). On the other
ever, when the catalyst loading was reduced to 5 mol % the hand, steric alkyl-substituted catalysts increased of the ee
yield dropped to 46% and the enantioselectivity also de- value (Table 5, Entries 8Ϫ11). However, the sterically most
creased to 71% ee (Table 3, Entry 4). Hence the optimal hindered substituent, adamantyl, did not show this steric
catalyst loading is 10 mol % (Table 3, Entry 3). Further benefit (Table 5, Entry 12). Ligand 1m was found to have
studies indicated that the concentration of acetophenone the highest enantioselective capability of the ligands tested
had a slight impact on the enantioselectivity, but a larger (Table 5, Entry 13). In addition, the structurally similar Ja-
effect on the yield (Table 3, Entries 3, 5 and 6). The best cobsen’s ligand 2 gave a lower enantioselectivity than ligand
result was obtained when the concentration of aceto- 1m (Table 5, Entry 14). In agreement with the work of Belo-
phenone was 0.5  (Table 3, Entry 3). Lowering the concen- kon et al.,[3] we used ligand (1S,2S)-2 and obtained (R)-7a.
tration of acetophenone to less than 0.5  led to a dramatic Hence we have shown that the chiral backbone of (1S,2S)-
drop in the reaction’s reactivity and a decrease in the en- 1,2-diphenylethane-1,2-diamine is superior to that of
antioselectivity (Table 3, Entry 6).
The effect of the amount of additive N-oxide 3l on the
(1S,2S)-cyclohexane-1,2-diamine in this catalytic system.
A series of 1mϪmetal complexes were screened for use as
asymmetric cyanosilylation of acetophenone was then catalysts in the asymmetric cyanosilylation of acetophenone
examined, and it was found that the amount had some ef- (Table 6, Entries 1Ϫ6). It was found that Ti(OiPr)4 was the
fect on the enantioselectivity. Decreasing the amount of 3l best choice (Table 6, Entry 4). We also examined the effect
from 10 to 0.5 mol % led to increases in enantioselectivity of solvent on this reaction (Table 7, Entries 1Ϫ6). Although
Table 3. Effects of catalyst loading and acetophenone concentration on the asymmetric addition of TMSCN to acetophenone
Entry[a]
Catalyst loading [mol %]
Acetophenone conc. [M]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
20
15
10
5
10
10
0.5
0.5
0.5
0.5
0.75
0.25
96
94
94
46
96
31
79
79
81
71
77
73
[a] All reactions were carried out at Ϫ20 °C under the following conditions: the indicated amount of 1mϪTi(OiPr)4 complex, corresponding
[b]
[c]
0.1 equiv. 3l compared to 1mϪTi(OiPr)4, the indicated concentration of acetophenone in CH2Cl2.
chiral GC analysis on Chirasil DEX CB.
Isolated yield. Determined by
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B. He, F.-X. Chen, Y. Li, X. Feng, G. Zhang
FULL PAPER
We also examined the influence of counter ions on the
enantioselectivity. The results, listed in Table 8, indicate that
the addition of counter ions led to a decrease in the enanti-
oselectivity. Notably, the addition of the phenolic ion led to
a sharp decrease in yield and a distinct drop in the enanti-
oselectivity (Table 8, Entry 5).
Table 5. Structural effect of the ligands 1aϪm and 2 on the asym-
metric addition of TMSCN to acetophenone in the presence of
achiral N-oxide 3l as additive
Entry[a]
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
2
42
78
51
74
73
65
71
54
56
63
70
27
94
90
53
50
28
55
18
35
47
48
32
73
75
12
81
70
Table 8. Effect of the counter ion on the enantioselectivity
Entry[a]
Counter ion
Yield [%][b]
ee [%][c]
1
2
3
4
5
Ϫ
94
67
88
90
19
81
66
79
77
67
MeOϪ
EtOϪ
iPrOϪ
PhOϪ
[a]
All reactions were carried out at Ϫ20 °C under the following
conditions: 10 mol % 1mϪTi(OiPr)4 complex, 1 mol % 3l, 0.5 
acetophenone in CH2Cl2, 96 hours. [b] Isolated yield. [c] Determined
by chiral GC analysis on Chirasil DEX CB.
[a]
All reactions were carried out at Ϫ20 °C under the following
conditions: 10 mol % indicated ligandϪTi(OiPr)4 complex, 1
[b]
[c]
mol % 3l, 0.5  acetophenone in CH2Cl2. Isolated yield. De-
termined by chiral GC analysis on Chirasil DEX CB.
Substrate Generality: Encouraged by the results obtained
with acetophenone, we investigated a number of other ke-
tones to probe their behavior under the optimized con-
ditions (Scheme 2). As shown in Table 9, major obser-
vations are in accord with those afforded by CDAM.[15a]
Most of the aromatic, α,β-unsaturated, α,β-saturated, het-
erocyclic and aliphatic ketones were converted into the cor-
responding cyanohydrin trimethylsilyl ethers in 58Ϫ95%
yields and with 56Ϫ82% ee. While the use of para-substi-
tuted acetophenone led to lower enantioselectivities and, in
general, lower yields than was the case with acetophenone,
the cyanohydrin derived from the meta-chloro-substituted
ketone had a similar enantioselectivity and yield to that
from acetophenone (Table 9, Entries 1Ϫ6). Curiously, the
electron-deficient 4-nitroacetophenone was converted into
the corresponding product with a higher chemical yield and
enantioselectivity in the absence of 3l than in its presence
(Table 9, Entry 7). β-Acetonaphthone afforded a lower ee
value than acetophenone (Table 9, Entry 8). Steric cyclic
ketones such as α-tetralone and 1-indanone afforded the
corresponding products with similar enantioselectivities
(Table 9, Entries 9 and 10). Interestingly, the product de-
rived from the α,β-saturated ketone has a higher ee value
than that derived from the α,β-unsaturated one (Table 9,
Entries 11 and 12) in contrast with Snapper and co-work-
ers’ report,[6] but in agreement with Shibasaki and co-work-
ers’ results.[4] However, the heterocyclic and aliphatic ke-
tones gave the corresponding products with relatively low
chemical yields and ee values (Table 9, Entries 13 and 14).
Mechanistic Studies and Suggestion: To identify a reason-
able mechanism, we carried out control experiments with
acetophenone as the standard substrate under the optimal
conditions. As shown in Table 10, neither Ti(OiPr)4 nor N-
oxide 3l alone was effective enough to promote the addition
of TMSCN to acetophenone (Table 10, Entries 1 and 2). In
addition, it was shown that no background reaction oc-
curred in the presence of the non-coordinated Ti(OiPr)4
a similar ee value was obtained when the reaction was car-
ried out in THF, the reactivity was clearly inferior to that
in CH2Cl2 (Table 7, Entry 3). Therefore, the optimal solvent
is CH2Cl2 (Table 7, Entry 6).
Table 6. Effect of different 1mϪmetal complexes on the asymmetric
addition of TMSCN to acetophenone
Entry[a]
Metal
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
Al(OiPr)4
La(OiPr)4
Zr(OiPr)4
Ti(OiPr)4
Ti(OiPr)2Cl2
TiCl4
53
64
40
94
Ϫ
16
1.2
0.4
81
Ϫ
Ϫ
Ϫ
[a]
All reactions were carried out at Ϫ20 °C under the following
conditions: 10 mol % 1mϪindicated metal complex, 1 mol % 3l, 0.5
[b]
[c]
 acetophenone in CH2Cl2.
Isolated yield.
Determined by
chiral GC analysis on Chirasil DEX CB.
Table 7. Effect of solvent on the asymmetric addition of TMSCN
to acetophenone
Entry[a]
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
toluene
Et2O
THF
CH3CN
CHCl3
CH2Cl2
53
trace
12
86
84
69
65
79
44
70
81
94
[a]
All reactions were carried out at Ϫ20 °C under the following
conditions: 10 mol % 1mϪTi(OiPr)4 complex, 1 mol % 3l, 0.5 
[b]
[c]
acetophenone in the indicated solvent.
Isolated yield. Deter-
mined by chiral GC analysis on Chirasil DEX CB.
4660
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Enantioselective Cyanosilylation of Ketones
FULL PAPER
Table 9. Asymmetric cyanosilylation of ketones catalyzed by 1mϪTi(OiPr)4 in the presence of 3l
Entry[a]
Ketone 6
Yield [%][b]
ee [%][c]
Config.[d]
1
2
3
4
5
Acetophenone (6a)
94
70
87
95
93
90
81
75
77
75
82
77
R
4Ј-Methoxyacetophenone (6b)
4Ј-Methylacetophenone (6c)
4Ј-Chloroacetophenone (6d)
3Ј-Chloroacetophenone (6e)
4Ј-Fluoroacetophenone (6f)
4Ј-Nitroacetophenone (6g)
β-Acetonaphthone (6h)
α-Tetralone (6i)
6
7[e]
8
23(93)[f]
90
15(65)[f]
72
9
75
96
93
95
58
71
77
10
11
12
13
14
1-Indanone (6j)
trans-4-Phenyl-3-buten-2-one (6k)
Benzylacetone (6l)
2-Acetylthiophene (6m)
2-Heptanone (6n)
79
56[g]
77
59
69
R
[a] Reaction conditions: 10 mol % 1mϪTi(OiPr)4 complex, 1 mol % 3l (unless otherwise indicated), 0.5  ketone in CH2Cl2, Ϫ20 °C, 96 h.
[b]
[c]
[d]
Isolated yield. Determined by chiral GC analysis on Chirasil DEX CB (unless otherwise indicated). Determined by comparison
with the reported values of the optical rotation (see ref.[4a]). The yield and ee are given in parentheses for the reaction conducted in
the absence of 3l. Determined by HPLC on Chiralcel AD-H. Determined by HPLC on Chiralcel OD.
[e]
[f]
[g]
Based on the above observations, we proposed the pre-
liminary catalytic cycle shown in Scheme 3. We considered
that different complexes were formed that exhibited differ-
ent reactivities when Ti(OiPr)4, salen and phenolic N-oxide
were mixed directly. Among these different complexes, com-
plex 8, a bifunctional catalyst, was expected to form. Com-
plex 8 then interacted with acetophenone to form complex
9. Thus, a combination of complex 9 and TMSCN would
generate the key intermediate 10 that contains both the acti-
vated ketone and the activated TMSCN. Intramolecular
transfer of cyanide within intermediate 10 and subsequent
intramolecular trimethylsilylation would give the O-TMS
cyanohydrin product and complex 8. In the study of the
effect of counter ions on the reaction, it was found that
the presence of the phenolic ion made the formation of the
effective catalyst 8 more difficult, leading to a sharp de-
crease in the yield and a distinct reduction of the enantiose-
lectivity (Table 8, Entry 5). The catalytic cycle presented
here also correctly predicts the sense of asymmetric induc-
tion; acetophenone is coordinated to the catalyst so as to
minimize the interactions between the acetophenone and
the phenyl group of the ligand, which results in an orien-
tation in which the Si face of the acetophenone is exposed
to intramolecular attack by the cyanide of the activated
TMSCN to produce the R enantiomer of the O-TMS cy-
anohydrin.
Scheme 2. Asymmetric cyanosilylation of ketones
and N-oxide 3l (Table 10, Entry 3). While 10 mol % of
1mϪTi(OiPr)4 catalyzed this reaction to give a yield of 31%
and 72% ee, the use of 1 mol % N-oxide 3l as an additive
in this catalytic system led to an increase in both the reactiv-
ity and enantioselectivity of this reaction (up to 94% yield
and 81% ee; Table 10, Entries 4 and 5). Hence we have
shown that the use of achiral phenolic N-oxide 3l as an
additive provides an effective activation strategy for the chi-
ral salen/Ti(OiPr)4 catalyst in the asymmetric cyanosilyl-
ation of ketones.
Table 10. Control experiments for the investigation of catalytic
mechanism
Entry[a]
Lewis acid
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
Ti(OiPr)4
Ϫ
Ti(OiPr)4
1mϪTi(OiPr)4
1mϪTi(OiPr)4
Ϫ
3l
3l
Ϫ
3l
0
0
0
31
94
Ϫ
Ϫ
Ϫ
72
81
Conclusions
In summary, by introducing achiral phenolic N-oxides as
additives into the asymmetric cyanosilylation of ketones, we
achieved results comparable to those afforded by
CDAM.[15a] Under the optimized conditions, most aro-
matic, α,β-unsaturated, α,β-saturated, heterocyclic and ali-
phatic ketones were converted into the corresponding cy-
[a]
All reactions were carried out at Ϫ20 °C under the following
conditions: 10 mol % 1mϪTi(OiPr)4 complex and/or 1 mol % 3l,
[b]
[c]
0.5  acetophenone in CH2Cl2, 96 h.
mined by chiral GC analysis on Chirasil DEX CB.
Isolated yield.
Deter-
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B. He, F.-X. Chen, Y. Li, X. Feng, G. Zhang
FULL PAPER
Scheme 3. Proposed catalytic cycle
authentic racemates. Optical rotations were recorded with a
PerkinϪElmer Polarimeter-341. HRMS was recorded on
BRUKER-APEX-2. All ketones, TMSCN and substituted salicylal
were purchased from Acros, Aldrich and Fluka, and used directly
without further purification. Solvents were purified by the usual
methods. CH2Cl2 was distilled over CaH2. CHCl3 was passed
through a column of basic alumina. Other solvents were dried
with Na.
anohydrin trimethylsilyl ethers in 58Ϫ95% yields and with
56Ϫ82% ee. As a result of control experiments a mechanism
for the catalytic cycle has been proposed for the asymmetric
cyanosilylation of ketones and the probable effective cata-
lyst has been suggested. Moreover, the use of additives sim-
plified the procedure and provides a method for the effec-
tive screening of efficient catalyst systems.
Preparation of Achiral Phenolic N-Oxides: The synthesis of phe-
nolic N-oxides 3aϪl, 4 and 5 were carried out according to the
methods reported in the literature.[18]
Experimental Section
General Remarks: 1H NMR spectra were recorded with a Varian
General Procedure: Formaldehyde and dimethylamine (or diethyl-
Unity INOVA 400 (400 MHz) or with a Bruker (300 MHz) spec- amine) were added to a solution of the various phenols in EtOH.
trometer. Chemical shifts are reported in ppm relative to tetrameth- The solution was then refluxed and the reaction monitored by
ylsilane with the solvent resonance as the internal standard TLC. After completion, the reaction mixture was concentrated un-
(CDCl3, δ ϭ 7.26). Data are reported as follows: Chemical shift,
multiplicity (s ϭ singlet, d ϭ doublet, t ϭ triplet, m ϭ multiplet),
coupling constants (Hz), integration. 13C NMR spectroscopic data
were collected with a Varian Unity INOVA 400 (100 MHz) or with
a Bruker (75 MHz) spectrometer with complete proton decoupling.
Chemical shifts are reported in ppm relative to tetramethylsilane
with the solvent resonance as internal standard (CDCl3, δ ϭ 77.0
ppm). Elemental analyses were performed on a Carlo-1160 appar-
atus. Enantiomeric ratios were determined by chiral GC analysis
on a Varian Chirasil DEX CB instrument or by chiral HPLC analy-
sis on a Daicel Chiralcel OD/OJ apparatus in comparison with
der reduced pressure to remove the surplus formaldehyde and the
resulting mixture was extracted with CH2Cl2. The extract was
washed with brine and dried with anhydrous sodium sulfate; the
solvents were evaporated under reduced pressure to give a residue,
which was purified by silica gel column chromatography to give the
corresponding Mannich-type product. Next, mCPBA was added at
Ϫ78 °C to a solution of the Mannich-type product and anhydrous
K2CO3 in CH2Cl2. The resulting mixture was stirred at the same
temperature and the reaction monitored by TLC. After completion,
the mixture was allowed to warm slowly to room temperature and
filtered, and the solvents were evaporated under reduced pressure.
4662
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4657Ϫ4666

Enantioselective Cyanosilylation of Ketones
FULL PAPER
Purification of the residue by silica gel column chromatography
afforded the corresponding N-oxides 3aϪl, 4 and 5.
N,N-Dimethyl-(3-tert-butyl-2-hydroxybenzyl)amine N-Oxide (3l):
1
M.p. 95Ϫ97 °C. H NMR (400 MHz, CDCl3): δ ϭ 1.43 (s, 9 H),
3.24 (s, 6 H), 4.49 (s, 2 H), 6.72Ϫ7.33 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 30.94, 36.33, 59.45, 74.99, 118.85, 119.64,
130.27, 131.73, 140.76, 161.13 ppm.
N,N-Dimethyl-(2-hydroxy-5-methoxybenzyl)amine N-Oxide (3a):
M.p. 130Ϫ132 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 3.24 (s, 6 H),
3.77 (s, 3 H), 4.46 (s, 2 H), 6.58Ϫ6.93 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 56.15, 58.42, 73.58, 117.25, 117.82, 118.05,
119.60, 152.00, 154.35 ppm.
4-tert-Butyl-2,6-bis[(dimethylamino)methyl]phenol Di-N-oxide (4):
1
M.p. 70Ϫ72 °C. H NMR (400 MHz, CDCl3): δ ϭ 1.30 (s, 9 H),
3.21 (s, 12 H), 4.51 (s, 4 H), 7.30 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 31.70, 34.09, 58.17, 72.09, 118.62, 132.79,
140.89, 158.18 ppm.
N,N-Dimethyl-(2-hydroxy-5-methylbenzyl)amine N-Oxide (3b):
M.p. 100Ϫ101 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 2.26 (s, 3 H),
3.24 (s, 6 H), 4.46 (s, 2 H), 6.80Ϫ7.11 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 20.43, 58.29, 73.77, 117.28, 118.77, 127.43,
132.75, 132.74, 158.16 ppm.
(3-tert-Butyl-2-hydroxybenzyl)-N,N-diethylamine N-Oxide (5): M.p.
107Ϫ109 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 1.37 (m, 6 H), 1.43
(s, 9 H), 3.30 (m, 4 H), 4.40 (s, 2 H), 6.70Ϫ7.31 (m, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 9.06, 29.72, 35.13, 59.44, 68.79,
117.27, 117.88, 128.71, 130.28, 139.39, 160.20 ppm.
N,N-Dimethyl-(5-tert-butyl-2-hydroxybenzyl)amine N-Oxide (3c):
M.p. 123Ϫ125 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 1.29 (s, 9 H),
3.25 (s, 6 H), 4.51 (s, 2 H), 6.94Ϫ7.34 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 31.78, 34.06, 38.29, 74.26, 116.73, 118.54,
128.95, 129.24, 141.17, 158.07 ppm.
Preparation of Salen Ligands:
Salen ligands 1aϪm and 2 were prepared according to the methods
N,N-Dimethyl-(2-hydroxy-5-nitrobenzyl)amine N-Oxide (3d): M.p.
reported in the literature.[19]
1
176Ϫ178 °C. H NMR (400 MHz, CDCl3): δ ϭ 3.34 (s, 6 H), 4.61
(s, 2 H), 6.94Ϫ8.20 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
(1S,2S)-N,NЈ-Bis[(5-methoxy-2-hydroxyphenyl)methylene]-1,2-di-
1
δ
ϭ 58.06, 73.45, 116.94, 119.75, 128.73, 128.99, 137.92,
phenylethylenediamine (1a): M.p. 89Ϫ91 °C. H NMR (400 MHz,
169.83 ppm.
CDCl3): δ ϭ 3.70 (s, 6 H), 4.71 (s, 2 H), 6.64 (s, 2 H), 6.89 (m, 4
H), 7.16Ϫ7.21 (m, 10 H), 8.26 (s, 2 H), 12.82 (s, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ ϭ 55.8, 80.3, 114.9, 117.6, 118.1,
119.8, 127.6, 127.8, 128.4, 139.3, 152.0, 155.1, 165.9 ppm.
N,N-Dimethyl-(2-hydroxybenzyl)amine N-Oxide (3e): M.p. 97Ϫ99
1
°C. H NMR (400 MHz, CDCl3): δ ϭ 3.25 (s, 6 H), 4.51 (s, 2 H),
6.77Ϫ7.32 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 58.26,
73.78, 117.60, 118.36, 119.06, 132.19, 132.53, 160.69 ppm.
(1S,2S)-N,NЈ-Bis[(5-methyl-2-hydroxyphenyl)methylene]-1,2-di-
phenylethylenediamine (1b): M.p. 55Ϫ56 °C. H NMR (400 MHz,
CDCl3): δ ϭ 2.21 (s, 6 H), 4.69 (s, 2 H), 6.86 (m, 2 H), 6.92 (m, 2
H), 7.06Ϫ7.09 (m, 2 H), 7.16Ϫ7.21 (m, 10 H), 8.26 (s, 2 H), 13.07
(s, 2 H) ppm. HRMS (ESI): calcd. for C30H28N2O2: 449.2224;
found 449.2222 [M ϩ H]ϩ.
1
N,N-Dimethyl-(3,5-dichloro-2-hydroxybenzyl)amine N-Oxide (3f):
M.p. 148Ϫ149 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 3.29 (s, 6 H),
4.49 (s, 2 H), 6.91Ϫ7.40 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 59.36, 74.14, 120.55, 122.40, 125.96, 131.45, 133.17,
158.25 ppm.
(1S,2S)-N,NЈ-Bis[(5-chloro-2-hydroxyphenyl)methylene]-1,2-di-
phenylethylenediamine (1c): M.p. 86Ϫ88 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 4.75 (s, 2 H), 6.92 (d, J ϭ 8.8 Hz, 2 H), 7.10 (d, J ϭ
2.8 Hz, 2 H), 7.16Ϫ7.25 (m, 12 H), 8.18 (s, 2 H), 13.26 (s, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 80.0, 118.6, 119.2, 123.4,
127.7, 127.9, 128.6, 130.7, 132.6, 138.8, 159.5, 165.1 ppm.
N,N-Dimethyl-(3,5-difluoro-2-hydroxybenzyl)amine N-Oxide (3g):
M.p. 155Ϫ156 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 3.28 (s, 6 H),
4.52 (s, 2 H), 6.58Ϫ6.92 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 58.33, 72.83, 106.93, 113.02, 119.06, 146.51, 152.60,
154.20 ppm.
N,N-Dimethyl-(3,5-di-tert-butyl-2-hydroxybenzyl)amine N-Oxide
(3h): M.p. 145Ϫ150 °C. H NMR (400 MHz, CDCl3): δ ϭ 1.29 (s,
9 H), 1.44 (s, 9 H), 3.24 (s, 6 H), 4.48 (s, 2 H), 6.84Ϫ7.36 (m, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 31.05, 33.07, 35.50, 36.54,
59.43, 75.34, 118.79, 127.51, 128.05, 139.79, 141.23, 158.46 ppm.
(1S,2S)-N,NЈ-Bis[(5-bromo-2-hydroxyphenyl)methylene]-1,2-di-
phenylethylenediamine (1d): M.p. 156Ϫ158 °C. 1H NMR
(400 MHz, CDCl3): δ ϭ 4.75 (s, 2 H), 6.87 (d, J ϭ 8.8 Hz, 2 H),
7.16Ϫ7.26 (m, 12 H), 7.34Ϫ7.37 (m, 2 H), 8.18 (s, 2 H), 13.29 (s,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 80.0, 110.3, 119.0,
119.8, 127.7, 127.9, 128.6, 133.7, 135.4, 138.8, 160.0, 165.0 ppm.
1
N,N-Dimethyl-(2-hydroxy-3-methoxybenzyl)amine N-Oxide (3i):
M.p. 123Ϫ125 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 3.24 (s, 6 H),
3.88 (s, 3 H), 4.52 (s, 2 H), 6.61Ϫ6.91 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 56.09, 58.19, 73.55, 113.71, 117.79, 117.80,
124.09, 150.58, 150.93 ppm.
(1S,2S)-N,NЈ-Bis[(2-hydroxy-5-nitrophenyl)methylene]-1,2-diphenyl-
ethylenediamine (1e): M.p. 150Ϫ152 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 4.89 (s, 2 H), 7.07 (m, 2 H), 7.20Ϫ7.30 (m, 12 H),
8.13Ϫ8.21 (m, 2 H), 8.31 (s, 2 H), 14.39 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 79.3, 117.3, 118.3, 127.6, 128.0, 128.3,
128.4, 128.9, 137.9, 138.0, 165.1, 166.8 ppm.
N,N-Dimethyl-(2-hydroxy-3-methylbenzyl)amine N-Oxide (3j): M.p.
1
98Ϫ99 °C. H NMR (400 MHz, CDCl3): δ ϭ 2.28 (s, 3 H), 3.24 (s,
6 H), 4.49 (s, 2 H), 6.69Ϫ7.18 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 16.66, 58.26, 73.75, 116.90, 117.97, 127.97, 130.11,
133.06, 158.90 ppm.
(1S,2S)-N,NЈ-Bis[(3,5-dichloro-2-hydroxyphenyl)methylene]-1,2-di-
phenylethylenediamine (1f): M.p. 109Ϫ110 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 4.76 (s, 2 H), 7.09 (d, J ϭ 2.4 Hz, 2 H), 7.12Ϫ7.15
(m, 4 H), 7.20Ϫ7.23 (m, 6 H), 7.38 (d, J ϭ 2.8 Hz, 2 H), 8.27 (s, 2
H), 14.07 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 80.0,
119.4, 122.5, 123.4, 127.7, 128.1, 128.7, 129.5, 132.6, 138.0, 155.6,
N,N-Dimethyl-(2-hydroxy-3-phenylbenzyl)amine N-Oxide (3k):
M.p. 144Ϫ146 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 3.29 (s, 6 H),
4.56 (s, 2 H), 6.86Ϫ7.66 (m, 8 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 58.18, 73.77, 118.23, 118.41, 126.96, 128.19, 129.67, 164.6 ppm. HRMS (ESI): calcd. for C28H20Cl4N2O2: 557.0352;
131.48, 131.93, 133.13, 139.07, 158.35 ppm.
found 557.0356 [M ϩ H]ϩ.
Eur. J. Org. Chem. 2004, 4657Ϫ4666
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4663

B. He, F.-X. Chen, Y. Li, X. Feng, G. Zhang
FULL PAPER
(1S,2S)-N,NЈ-Bis[(2-hydroxyphenyl)methylene]-1,2-diphenyl-
Preparation of Optically Active Trimethylsilyl Cyanohydrin Ethers.
General Procedure: Ti(OiPr)4 (1  solution in toluene, 50 µL,
ethylenediamine (1g): M.p. 155Ϫ156 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 4.73 (s, 2 H), 6.81 (td, J ϭ 8.4, J ϭ 2.0 Hz, 2 H), 6.95 0.05 mmol) was added to a solution of 1m (32.2 mg, 0.05 mmol)
(d, J ϭ 8.4 Hz, 2 H), 7.11Ϫ7.28 (m, 14 H), 8.29 (s, 2 H), 13.32 (s, and N-oxide 3l (1.1 mg, 0.005 mmol) in CH2Cl2 (1 mL) at room
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 80.2, 116.9, 118.5, temperature, and the mixture was stirred at 35 °C for 1 h under N2.
118.7, 127.6, 127.8, 128.3, 131.7, 132.5, 139.3, 160.9, 166.1 ppm.
The ketone (0.5 mmol) was added to this solution at Ϫ20 °C, fol-
lowed by the addition of TMSCN (137 µL, 1 mmol). After 96 h,
the solution was concentrated and the residue was purified by silica
gel column chromatography to give the corresponding cyanohydrin
trimethylsilyl ethers.
(1S,2S)-N,NЈ-Bis[(2-hydroxy-3-methylphenyl)methylene]-1,2-di-
1
phenylethylenediamine (1h): M.p. 52Ϫ54 °C. H NMR (400 MHz,
CDCl3): δ ϭ 2.29 (s, 6 H), 4.74 (s, 2 H), 6.73 (m, 2 H), 7.03 (m, 2
H), 7.15Ϫ7.27 (m, 12 H), 8.35 (s, 2 H), 13.53 (s, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ ϭ 15.71, 80.61, 118.08, 118.49, 125.95,
127.78, 128.12, 128.57, 129.69, 133.80, 139.71, 159.38, 166.53 ppm.
HRMS (ESI): calcd. for C30H28N2O2: 449.2224; found 449.2232
[M ϩ H]ϩ.
2-Phenyl-2-(trimethylsilyloxy)propanenitrile (7a): The title com-
pound 7a (100.3 mg, 94%) was obtained as a colorless oil. [α]2D0
ϭ
ϩ16.7 (c ϭ 0.85 in CHCl3, 81% ee) {ref.[4a] [α]2D4 ϭ ϩ21.9 (c ϭ 1.18
1
in CHCl3, 93% ee)}. H NMR (300 MHz, CDCl3): δ ϭ 0.19 (s, 9
H), 1.87 (s, 3 H), 7.38Ϫ7.58 (m, 5 H) ppm. GC [Varian, CP-Chirasil
DEX CB (0.25 mm ϫ 25 m), column temperature: 110 °C (iso-
thermal), injection temperature: 200 °C, detector temperature: 250
°C, inlet pressure: 5.516 ϫ 104 Pa]: tr[minor, (S)] ϭ 20.27 min,
tr[major, (R)] ϭ 20.87 min.
(1S,2S)-N,NЈ-Bis[(2-hydroxy-3-phenylphenyl)methylene]-1,2-di-
phenylethylenediamine (1i): M.p. 94Ϫ96 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 4.72 (s, 2 H), 6.91 (m, 2 H), 7.15Ϫ7.21 (m, 12 H),
7.36Ϫ7.39 (m, 4 H), 7.47 (m, 4 H), 7.61 (d, J ϭ 7.08, 4 H), 8.44
(s, 2 H), 13.83 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
80.72, 118.99, 127.37, 127.86, 128.13, 128.38, 128.60, 129.56,
129.86, 131.52, 133.81, 137.93, 139.40, 158.39, 166.53 ppm.
2-(4-Methoxyphenyl)-2-(trimethylsilyloxy)propanenitrile (7b): The
title compound 7b (87.2 mg, 70%) was obtained as a colorless oil.
[α]2D0 ϭ ϩ18.1 (c ϭ 1.67 in CHCl3, 75% ee) {ref.[6] [α]2D0 ϭ ϩ22.6
(1S,2S)-N,NЈ-Bis[(3-tert-butyl-2-hydroxyphenyl)methylene]-1,2-di-
phenylethylenediamine (1j): M.p. 109Ϫ110 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 1.43 (s, 18 H), 4.74 (s, 2 H), 6.72 (m, 2 H), 7.00 (m,
2 H), 7.19Ϫ7.27 (m, 12 H), 8.37 (s, 2 H), 13.79 (s, 2 H) ppm. 13C
NMR (100 MHz, CDCl3), δ ϭ 29.53, 35.00, 80.37, 118.05, 118.76,
127.74, 128.22, 128.54, 129.81, 130.30, 137.35, 139.74, 160.46,
167.07 ppm. HRMS (ESI): calcd. for C36H40N2O2: 533.3163; found
533.3155 [M ϩ H]ϩ.
1
(c ϭ 1.09 in CHCl3, 91% ee)}. H NMR (400 MHz, CDCl3): δ ϭ
0.19 (s, 9 H), 1.87 (s, 3 H), 3.85 (s, 3 H), 6.93 (m, 2 H), 7.49 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 33.41, 55.33, 71.28,
113.89, 121.81, 126.06, 134.04, 159.80 ppm. GC [Varian, CP-Chira-
sil DEX CB (0.25 mm ϫ 25 m), column temperature: 105 °C (iso-
thermal), injection temperature: 200 °C, detector temperature: 250
°C, inlet pressure: 5.516 ϫ 104 Pa]: tr(minor) ϭ 118.13 min,
tr(major) ϭ 120.27 min.
(1S,2S)-N,NЈ-Bis[(3-tert-butyl-5-methyl-2-hydroxyphenyl)-meth-
1
ylene]-1,2-diphenylethylenediamine (1k): M.p. 69Ϫ71 °C. H NMR
2-(4-Methylphenyl)-2-(trimethylsilyloxy)propanenitrile (7c): The
title compound 7c (101.8 mg, 87%) was obtained as a colorless oil.
[α]2D0 ϭ ϩ19.8 (c ϭ 1.91 in CHCl3, 77% ee) {ref.[4a] [α]2D5 ϭ ϩ21.3
(400 MHz, CDCl3): δ ϭ 1.41 (s, 18 H), 2.18 (s, 6 H), 4.68 (s, 2 H).
6.77 (d, J ϭ 1.6 Hz, 2 H), 7.05 (d, J ϭ 1.6 Hz, 2 H), 7.17Ϫ7.21 (m,
10 H), 8.30 (s, 2 H), 13.50 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 20.6, 29.3, 34.7, 80.2, 118.2, 126.5, 127.4, 128.0, 128.3,
130.0, 130.6, 136.7, 140.0, 157.9, 166.9 ppm.
1
(c ϭ 1.28 in CHCl3, 90% ee)}. H NMR (400 MHz, CDCl3): δ ϭ
0.16 (s, 9 H), 1.84 (s, 3 H), 2.36 (s, 3 H), 7.21 (m, 2 H), 7.43 (m, 2
H) ppm. C13H19NOSi: C 66.90, H 8.21, N 6.00; found C 66.78, H
8.03, N 6.39. GC [Varian, CP-Chirasil DEX CB (0.25 mm ϫ 25
m), column temperature: 100 °C (isothermal), injection tempera-
ture: 200 °C, detector temperature: 250 °C, inlet pressure: 5.516 ϫ
104 Pa]: tr(minor) ϭ 55.33 min, tr(major) ϭ 56.27 min.
(1S,2S)-N,NЈ-Bis[(3-adamantyl-5-tert-butyl-2-hydroxyphenyl)-
1
methylene]-1,2-diphenylethylenediamine (1l): M.p. 190Ϫ192 °C. H
NMR (400 MHz, CDCl3): δ ϭ 1.22 (s, 18 H), 1.57 (s, 4 H), 1.84
(m, 10 H), 2.08Ϫ2.16 (m, 16 H), 4.72 (s, 2 H), 6.97 (s, 2 H), 7.18
(m, 10 H), 7.26 (d, J ϭ 1.2 Hz, 2 H), 8.40 (s, 2 H), 13.52 (s, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 29.1, 31.4, 34.1, 37.2, 40.2,
80.1, 117.9, 126.3, 127.1, 127.3, 128.0, 128.2, 136.6, 139.8, 140.0,
158.2, 167.4 ppm. HRMS (ESI): calcd. for C56H68N2O2: 801.5354;
found 801.5374 [M ϩ H]ϩ.
2-(4-Chlorophenyl)-2-(trimethylsilyloxy)propanenitrile (7d): The title
compound 7d (120.6 mg, 95%) was obtained as a colorless oil. [α]
20 ϭ ϩ17.2 (c ϭ 2.18 in CHCl3, 75% ee) {ref.[4a] [α]2D5 ϭ ϩ29.5 (c ϭ
D
1
1.04 in CHCl3, 92% ee)}. H NMR (400 MHz, CDCl3): δ ϭ 0.19
(s, 9 H), 1.83 (s, 3 H), 7.38 (m, 2 H), 7.48 (m, 2 H) ppm.
C12ClH16NOSi: C 56.79, H 6.35, N 5.52; found C 56.82, H 6.41, N
5.93. GC [Varian, CP-Chirasil DEX CB (0.25 mm ϫ 25 m), column
temperature: 105 °C (isothermal), injection temperature: 200 °C,
detector temperature: 250 °C, inlet pressure: 5.516 ϫ 104 Pa]:
tr(minor) ϭ 73.73 min, tr(major) ϭ 76.67 min.
(1S,2S)-N,NЈ-Bis[(3,5-di-tert-butyl-2-hydroxyphenyl)methylene]-1,2-
diphenylethylenediamine (1m): M.p. 195Ϫ197 °C. 1H NMR
(400 MHz, CDCl3): δ ϭ 1.22 (d, J ϭ 1.6 Hz, 18 H), 1.42 (d, J ϭ
2.0 Hz, 18 H), 4.73 (d, J ϭ 1.6 Hz, 2 H), 6.98 (m, 2 H), 7.16Ϫ7.20
(m, 10 H), 7.31 (d, J ϭ 2.4 Hz, 2 H), 8.40 (d, J ϭ 1.2 Hz, 2 H),
13.60 (d, J ϭ 2.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 29.4, 31.4, 34.0, 35.0, 80.1, 117.8, 126.3, 127.1, 127.4, 128.0,
128.2, 136.3, 139.8, 140.0, 157.9, 167.2 ppm.
2-(3-Chlorophenyl)-2-(trimethylsilyloxy)propanenitrile (7e): The title
compound 7e (118.0 mg, 93%) was obtained as a colorless oil.
[α]2D0 ϭ ϩ19.1 (c ϭ 1.11 in CHCl3, 82% ee) {ref.[14d] [α]2D6 ϭ ϩ7.1
1
(1S,2S)-N,NЈ-Bis[(3,5-di-tert-butyl-2-hydroxyphenyl)methylene]-1,2-
cyclohexanediamine (2): M.p. 206Ϫ207 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 1.23 (s, 18 H), 1.41 (s, 18 H), 1.48 (m, 2 H), 1.72Ϫ1.96
(m, 6 H), 3.30Ϫ3.33 (m, 2 H), 6.98 (d, J ϭ 2.4 Hz, 2 H), 7.30 (d,
(c ϭ 0.34 in CHCl3, 33% ee)}. H NMR (300 MHz, CDCl3): δ ϭ
0.22 (s, 9 H), 1.86 (s, 3 H), 7.34Ϫ7.55 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 1.0, 33.4, 70.9, 121.0, 122.7, 124.8, 128.8,
129.9, 134.6, 144.0 ppm. C12ClH16NOSi (421.0): C 56.79, H 6.35,
J ϭ 2.0 Hz, 2 H), 8.30 (s, 2 H), 13.72 (s, 2 H) ppm. 13C NMR N 5.52; found C 56.61, H 6.39, N 5.90. GC [Varian, CP-Chirasil
(100 MHz, CDCl3): δ ϭ 24.3, 29.4, 31.4, 33.3, 34.0, 34.9, 72.4,
117.8, 126.0, 126.7, 136.3, 139.8, 158.0, 165.8 ppm.
DEX CB (0.25 mm ϫ 25 m), column temperature: 105 °C (iso-
thermal), injection temperature: 200 °C, detector temperature: 250
4664
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4657Ϫ4666

Enantioselective Cyanosilylation of Ketones
°C, inlet pressure: 5.516 ϫ 104 Pa]: tr(minor) ϭ 56.13 min, 2-Methyl-4-phenyl-2-(trimethylsilyloxy)butanenitrile (7l): The title
FULL PAPER
tr(major) ϭ 57.07 min.
compound 7l (117.8 mg, 95%) was obtained as a colorless oil. [α]
20
ϭ ϩ10.0 (c ϭ 2.26 in CH2Cl2, 77% ee) {ref.[4a] [α]2D5 ϭ ϩ13.3
D
2-(4-Fluorophenyl)-2-(trimethylsilyloxy)propanenitrile (7f): The title
compound 7f (106.8 mg, 90%) was obtained as a colorless oil. [α]
1
(c ϭ 1.15 in CHCl3, 81% ee)}. H NMR (300 MHz, CDCl3): δ ϭ
0.29 (s, 9 H), 1.65 (s, 3 H), 2.02Ϫ2.08 (m, 2 H), 2.80Ϫ2.91 (m, 2
H), 7.22Ϫ7.33 (m, 5 H) ppm. GC [Varian, CP-Chirasil DEX CB
(0.25 mm ϫ 25 m), column temperature: 135 °C (isothermal), injec-
tion temperature: 200 °C, detector temperature: 250 °C, inlet press-
ure: 5.516 ϫ 104 Pa]: tr(major) ϭ 28.33 min, tr(minor) ϭ 28.87 min.
ϭ ϩ15.9 (c ϭ 2.01 in CHCl3, 77% ee) {ref.[15a] [α]2D2 ϭ Ϫ18.6
20
D
1
(c ϭ 1.47 in CHCl3, 83% ee)}. H NMR (400 MHz, CDCl3): δ ϭ
0.18 (s, 9 H), 1.84 (s, 3 H), 7.08 (m, 2 H), 7.52 (m, 2 H) ppm. 13C
2
NMR (100 MHz, CDCl3): δ ϭ 1.0, 33.5, 71.0, 115.6 (d, JCCF
ϭ
21.9 Hz), 121.4, 126.5 (d, 3JCCCF ϭ 8.5 Hz), 138.0, 162.2 (d, 1JC,F ϭ
246.4 Hz) ppm. GC [Varian, CP-Chirasil DEX CB (0.25 mm ϫ 25
m), column temperature: 115 °C (isothermal), injection tempera-
ture: 200 °C, detector temperature: 250 °C, inlet pressure: 5.516 ϫ
104 Pa]: tr(minor) ϭ 17.13 min, tr(major) ϭ 17.70 min.
2-(2-Thienyl)-2-(trimethylsilyloxy)propanenitrile (7m): The title
compound 7m (66.0 mg, 58%) was obtained as a colorless oil.
[α]2D0 ϭ ϩ47.2 (c ϭ 0.41 in CH2Cl2, 59% ee) {ref.[4a] [α] 2D4 ϭ ϩ13.3
(c ϭ 1.15 CHCl3, 81% ee)}. 1H NMR (300 MHz, CDCl3): δ ϭ 0.20
(s, 9 H), 2.00 (s, 3 H), 7.00 (m), 7.21Ϫ7.34 (m) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 0.78, 33.40, 68.24, 120.82, 124.70, 125.97,
126.61, 146.27 ppm. C10H15NOSSi (225.4): C 53.29, H 6.71, N
6.21; found C 53.48, H 6.94, N 6.43. GC [Varian, CP-Chirasil DEX
CB (0.25 mm ϫ 25 m), column temperature: 80 °C (isothermal),
injection temperature: 200 °C, detector temperature: 250 °C, inlet
pressure: 5.516 ϫ 104 Pa]: tr(minor) ϭ 20.20 min, tr(major) ϭ
20.87 min.
2-(4-Nitrophenyl)-2-(trimethylsilyloxy)propanenitrile (7g): The title
compound 7g (122.9 mg, 93%) was obtained as white crystals. [α]
22
ϭ ϩ1.5 (c ϭ 1.15 in CH2Cl2, 65% ee) {ref.[6] [α]2D0 ϭ ϩ16.2 (c ϭ
D
1
1.67 in CHCl3, 88% ee)}. H NMR (300 MHz, CDCl3), δ ϭ 0.26
(s, 9 H), 1.89 (s, 3 H), 7.75 (d, J ϭ 9.0 Hz, 2 H), 8.30 (d, J ϭ
9.0 Hz, 2 H, aromatic H) ppm. HPLC (Chiralcel AD-H, iPrOH/n-
hexane, 1:99, flow: 1.0 mL·minϪ1): tr(minor)
tr(major) ϭ 6.78 min.
ϭ 5.68 min,
2-Methyl-2-(trimethylsilyloxy)heptanenitrile (7n): The title com-
pound 7n (75.9 mg, 71%) was obtained as a colorless oil. [α]2D0
ϭ
2-Naphthyl-2-(trimethylsilyloxy)propanenitrile (7h): The title com-
pound 7h (121.3 mg, 90%) was obtained as white crystals. [α]2D0
ϭ
ϩ9.1 (c ϭ 1.05 in CH2Cl2, 69% ee) {ref.[4a] [α]2D4 ϭ ϩ1.8 (c ϭ 2.63
ϩ10.3 (c ϭ 2.45 in CH2Cl2, 72% ee) {ref.[4a] [α]2D5 ϭ ϩ15.6 (c ϭ 1.9
1
CHCl3, 76% ee)}. H NMR (300 MHz, CDCl3), δ ϭ 0.25 (s, 9 H),
1
in CHCl3, 95% ee)}. H NMR (300 MHz, CDCl3): δ ϭ 0.22 (s, 9
0.92 (t, J ϭ 6.9 Hz, 3 H), 1.34 (m, 4 H), 1.42 (m, 1 H), 1.50 (m, 2
H), 1.58 (s, 3 H), 1.70 (m, 2 H) ppm. GC [Varian, CP-Chirasil DEX
CB (0.25 mm ϫ 25 m), column temperature: 80 °C (isothermal),
injection temperature: 200 °C, detector temperature: 250 °C, inlet
pressure: 5.516 ϫ 104 Pa]: tr[major, (R)] ϭ 36.40 min, tr[minor,
(S)] ϭ 38.33 min.
H), 1.97 (s, 3 H), 7.54Ϫ7.66 (m, 3 H), 7.90Ϫ7.93 (m, 3 H), 8.07 (d,
J ϭ 1.8 Hz, 1 H) ppm. HPLC (Chiralcel OJ, iPrOH/n-hexane, 1:99,
flow: 1.0 mL·minϪ1): tr(minor) ϭ 7.48 min, tr(major) ϭ 8.29 min.
1-(Trimethylsilyloxy)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
(7i): The title compound 7i (102.5 mg, 75%) was obtained as a
colorless oil. [α]2D0 ϭ ϩ11.9 (c ϭ 1.97 in CH2Cl2, 77% ee). 1H NMR
(300 MHz, CDCl3): δ ϭ 0.24 (s, 9 H), 2.06 (m, 2 H), 2.23 (m, 1 H),
2.35 (m, 1 H), 2.85 (m, 2 H), 7.13 (m, 1 H), 7.29 (m, 2 H), 7.67
(m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 1.3, 18.6, 28.2,
37.6, 69.8, 122.0, 126.6, 127.9, 129.0, 129.2, 135.6, 136.0 ppm.
C14H19NOSi (245.4): C 68.52, H 7.80, N 5.71; found C 68.30, H
7.70, N 6.11. GC [Varian, CP-Chirasil DEX CB (0.25 mm ϫ 25
m), column temperature: 120 °C (isothermal), injection tempera-
ture: 200 °C, detector temperature: 250 °C, inlet pressure: 5.516 ϫ
104 Pa]: tr(major) ϭ 73.87 min, tr(minor) ϭ 75.20 min.
Acknowledgments
We thank the National Natural Science Foundation of China (No.
20225206, 20390050 and 20372050) and the Ministry of Education,
P. R. China (No. 01144, 104209 and others) for financial support.
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Eur. J. Org. Chem. 2004, 4657Ϫ4666